Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][CH2:6][SH:7].Cl[C:9]1[CH:14]=[CH:13][N+:12]([O-:15])=[C:11]([CH3:16])[C:10]=1[CH3:17]>CN1CCCC1=O>[CH3:16][C:11]1[C:10]([CH3:17])=[C:9]([S:7][CH2:6][CH2:5][CH2:4][OH:3])[CH:14]=[CH:13][N+:12]=1[O-:15]
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Reactant: OCCCS
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1c(SCCCO)cc[n+]([O-])c1C
Reaction time: 0.25 h

Procedure:
6 g (60% strength) NaH are added in portions to 50 ml of dry N-methylpyrrolidone (NMP), the mixture is stirred for 15 min., 9.5 g (0.11 mol) of 3-hydroxypropyl mercaptan are metered in in the course of 20 min. and the mixture is again stirred for 30 min. until evolution of gas has ended. A solution of 14.4 g (0.1 mol) of 4-chloro-2,3-dimethylpyridine-N-oxide in 100 ml of NMP is then added dropwise in the course of 20 min., and the reaction mixture is stirred for 1 h at room temperature, then for 1 h at 70° C. and after that for a further 1 h at 100° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[C:4]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[C:6](Cl)[N:5]=1)[CH3:2].[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>O>[CH2:1]([N:3]([CH2:17][CH3:18])[C:4]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[C:6]([N:23]2[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]2)[N:5]=1)[CH3:2]
Reactant: CCN(CC)c1nc(Cl)cc(N2CCNCC2)n1
Reactant: CN1CCNCC1
Solvent: O
Product: CCN(CC)c1nc(N2CCNCC2)cc(N2CCN(C)CC2)n1

Procedure:
2-Diethylamino-4,6-dichloropyrimidine (10 g) is reacted with piperazine (14.5 g) in ethanol (200 ml) at reflux for 2 hr. The mixture is concentrated and the product isolated by silica gel chromatography giving 2-diethylamino-4-piperazine-6-chloropyrimidine. The 2-diethylamino-4-piperazino-6-chloropyrimidine (8 g) and N-methylpiperazine (8 g) is heated neat at 70° for 16 hr. Then water (2.5 ml) is added and the mixture is heated at 100° for 50 hr. The mixture is chromatographed on silica gel, the appropriate fractions are pooled and concentrated to give the title compound, NMR (CDCl3) 1.15, 2.80, 2.85, 2.90, 3.30, 3.70 and 4.95 δ.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:9][CH3:10])[CH2:4][CH2:5][N+:6]([O-])=O.[C:11](OC)(=[O:15])/[CH:12]=[CH:13]/[CH3:14]>>[O:9]1[CH2:10][CH2:1][O:2][CH:3]1[CH2:4][C@@H:5]1[NH:6][C:11](=[O:15])[CH2:12][C@H:13]1[CH3:14]
Reactant: COC(CC[N+](=O)[O-])OC
Reactant: C/C=C/C(=O)OC
Product: C[C@@H]1CC(=O)N[C@H]1CC1OCCO1

Procedure:
Example 300 A) cis and trans-5-[(1,3-dioxolan-2-yl)methyl]-4-(methyl)pyrrolidin-2-one was prepared in the manner described (R. Ohrlein, W. Schwab, R. Ehrler, V. Jager, Synthesis 1986, 535-538) starting with 1,1-dimethoxy-3-nitropropane and methyl crotonate.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31](/[C:44](=[CH:48]\[CH:49]2[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]2)/[C:45](O)=[O:46])[CH:32]=[CH:33][C:34]=1[N:35]1[C:39]([C:40]([F:43])([F:42])[F:41])=[N:38][N:37]=[N:36]1.[NH2:55][C:56]1[S:57][CH:58]=[CH:59][N:60]=1>C(Cl)Cl>[Cl:28][C:29]1[CH:30]=[C:31](/[C:44](=[CH:48]\[CH:49]2[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]2)/[C:45]([NH:55][C:56]2[S:57][CH:58]=[CH:59][N:60]=2)=[O:46])[CH:32]=[CH:33][C:34]=1[N:35]1[C:39]([C:40]([F:43])([F:42])[F:41])=[N:38][N:37]=[N:36]1
Reactant: Nc1nccs1
Reactant: O=C(O)/C(=C/C1CCCCC1)c1ccc(-n2nnnc2C(F)(F)F)c(Cl)c1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1nccs1)/C(=C/C1CCCCC1)c1ccc(-n2nnnc2C(F)(F)F)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 11.5 %

Procedure:
A solution of triphenylphosphine (772 mg, 2.96 mmol) in methylene chloride (10 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (526 mg, 2.96 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with a solution of (E)-2-[3-chloro-4-(5-trifluoromethyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-acrylic acid (594 mg, 1.48 mmol) in methylene chloride (5 mL). The reaction mixture was then stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 1.5 h. The reaction mixture was then treated with 2-aminothiazole (444 mg, 4.44 mmol), and the resulting suspension was stirred for 2 d at 25° C. The reaction mixture was concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (70 mL) and a 1N aqueous hydrochloric acid solution (50 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×50 mL). The combined organic extracts were successively washed with a 1N aqueous hydrochloric acid solution (1×100 mL), a saturated aqueous sodium bicarbonate solution (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 5/1 to 3/2 hexanes/ethyl acetate) afforded (E)-2-[3-chloro-4-(5-trifluoromethyl-tetrazol-1-yl)-phenyl] -3-cyclohexyl-N-thiazol-2-yl-acrylamide (82 mg, 11%) as an amorphous solid: EI-HRMS m/e calcd for C20H18ClF3N6OS (M+) 482.0903, found 482.0906.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[Cl:18][CH:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20](Cl)=[O:21]>C1COCC1>[Cl:18][CH:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20]([NH:8][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1)=[O:21]
Reactant: Cc1cccc(N)n1
Reactant: O=C(Cl)C(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)C(Cl)c2ccccc2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 124.4 %

Procedure:
To an ice-cooled solution of 6-methylpyridin-2-amine [CAS 1824-81-3] (5.22 g, 44.08 mmol) in 350 mL anhydrous THF was added diisopropylethylamine (15.36 mL, 88.16 mmol). Chloro(phenyl)acetyl chloride [CAS 2912-62-1] (10.0 g, 52.9 mmol) was added dropwise and the resulting mixture was stirred for 1 h while cooling was maintained. The mixture was partitioned between ethyl acetate and water and the organic phase was washed with brine. The organic phase was filtered through a Whatman filter and the volatile components were removed by the use of a rotary evaporator to give title compound (14.3 g) in ˜80% purity (LC-MS). The crude material was forwarded directly to the next step.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]2[C:11]([CH2:12][CH2:13][CH2:14]O)=[CH:10][N:9]=[CH:8]2)=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O>>[Br:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]2[C:11]([CH2:12][CH2:13][CH2:14][Cl:20])=[CH:10][N:9]=[CH:8]2)=[CH:4][CH:3]=1
Reactant: OCCCc1cncn1Cc1ccc(Br)cc1
Reactant: O=S(Cl)Cl
Product: ClCCCc1cncn1Cc1ccc(Br)cc1

Procedure:
1-p-Bromobenzyl-5-(3-hydroxypropyl)-1H-imidazole is treated with thionyl chloride analogous to the method described in example (1c) to give the title compound (b).
Reaction SMILES: [CH:1]12[CH:9]([CH2:10][C:11](Cl)=[O:12])[CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][CH2:2]2.[NH2:14][N:15]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[C:16]1[CH:26]([CH3:28])[CH3:27]>>[CH:1]12[CH:9]([CH2:10][C:11]([NH:14][N:15]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=[C:16]3[CH:26]([CH3:28])[CH3:27])=[O:12])[CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][CH2:2]2
Reactant: CC(C)c1nc2ccccc2c(=O)n1N
Reactant: O=C(Cl)CC1C2CCCC1CCC2
Product: CC(C)c1nc2ccccc2c(=O)n1NC(=O)CC1C2CCCC1CCC2

Procedure:
The product from Example 56D and 3-amino-2-isopropylquinazolin-4(3H)-one (Aldrich) were processed using the method described in Example 42C to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.20 (d, J=6.7 Hz, 3 H) 1.24 (d, J=6.7 Hz, 3 H) 1.43-1.59 (m, 4 H) 1.65-1.95 (m, 10 H) 1.97-2.08 (m, 1 H) 2.51-2.56 (m, 2 H) 3.02-3.14 (m, 1 H) 7.53 (t, J=6.9 Hz, 1 H) 7.67 (d, J=8.3 Hz, 1 H) 7.79-7.89 (m, 1 H) 8.11 (dd, J=7.9, 1.5 Hz, 1 H) 10.94 (s, 1 H); MS (ESI+) m/z 368 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8](=[O:13])OC(=O)[NH:11][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:14]([NH2:17])([CH3:16])[CH3:15]>>[NH2:11][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[C:7]=1[C:8]([NH:17][CH:14]([CH3:16])[CH3:15])=[O:13]
Reactant: O=c1[nH]c2cccc(F)c2c(=O)o1
Reactant: CC(C)N
Product: CC(C)NC(=O)c1c(N)cccc1F

Procedure:
2-Amino-6-fluoro-N-(1-methylethyl)benzamide was prepared from 5-fluoro-2H-3,1-benzoxazine-2,4(1H)-dione and isopropyl amine following a procedure substantially as described for the preparation of Intermediate 25. MS: (M+H)+=197.
Reaction SMILES: [C:1]1([N:7]2[C:11]([NH:12][C:13](=[O:21])OC3C=CC=CC=3)=[CH:10][C:9]([C:22]3([C:25]([F:28])([F:27])[F:26])[CH2:24][CH2:23]3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][C:40]=1[O:41][CH3:42])[N:37]=[CH:36][N:35]=[C:34]2[O:43][C:44]1[CH:45]=[C:46]([CH:48]=[CH:49][CH:50]=1)[NH2:47]>>[CH3:29][O:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][C:40]=1[O:41][CH3:42])[N:37]=[CH:36][N:35]=[C:34]2[O:43][C:44]1[CH:45]=[C:46]([NH:47][C:13]([NH:12][C:11]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[C:9]([C:22]3([C:25]([F:26])([F:28])[F:27])[CH2:24][CH2:23]3)[CH:10]=2)=[O:21])[CH:48]=[CH:49][CH:50]=1
Reactant: O=C(Nc1cc(C2(C(F)(F)F)CC2)nn1-c1ccccc1)Oc1ccccc1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C5(C(F)(F)F)CC5)nn4-c4ccccc4)c3)c2cc1OC
Yield: 71 %

Procedure:
The title compound was prepared from phenyl 1-phenyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-ylcarbamate described in Example 137A (129 mg, 0.33 mmol) and 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline described in Example 113A (100 mg, 0.33 mmol) using the procedure described in Example 115C. The crude product was purified by column chromatography (25-100% EtOAc/hexanes) to give 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(1-phenyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-yl)urea (139 mg, 0.24 mmol, 71%). 1H NMR (300 MHz, DMSO-d6) δ 9.28 (s, 1H), 8.61 (s, 1H), 8.55 (s, 1H), 7.63-7.51 (m, 6H), 7.48 (d, 1H), 7.39 (s, 1H), 7.37 (t, 1H), 7.17 (d, 1H), 6.93 (d, 1H), 6.55 (s, 1H), 4.00 (s, 3H), 3.98 (s, 3H), 1.31 (d, 4H); LC-MS (ESI) m/z 591 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3=[CH:12][CH:13]=[CH:14][N:9]3[CH2:8][C:7](=[O:15])[C:6]=2[CH:16]=1.[BH4-].[Na+]>O1CCCC1.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3=[CH:12][CH:13]=[CH:14][N:9]3[CH2:8][CH:7]([OH:15])[C:6]=2[CH:16]=1
Reactant: O=C1Cn2cccc2Sc2ccc(F)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: OC1Cn2cccc2Sc2ccc(F)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
To a solution of 9c (0.037 g 0.16 mmol) in dry tetrahydrofuran (0.5 ml) and dry methanol (0.7 ml), cooled to 0° C. under argon atmosphere, was added in portions sodium borohydride (0.09 g, 0.16 mmol). After stirring for 1 hour at 0° C. the reaction was quenched with a saturated solution of ammonium chloride (1 ml), the solvent was removed and the mixture was extracted with ethyl acetate (3×2 ml). The organic layers were dried and evaporated, the crude product was chromatographed (30% petroleum ether 40-60° in dichloromethane) to give 24c 0.036 g (96% yield). 1H NMR (CDCl3) δ7.40-7.33 (m, 1H); 7.24-7.18 (m, 1H); 6.93-6.84 (m, 2H); 6.33-6.31 (m, 1H); 6.11-6.08 (m, 1H); 5.12-5.04 (m, 1H); 4.91-4.83 (dd, 1H, J=14.22, 2.25 Hz); 4.34-4.24 (dd, 1H, J=14.02, 6.51 Hz); 2.09-2.04 (d, 1H, J=9.83 Hz).
Reaction SMILES: [CH3:1][NH:2]C([C@H]1CC[C@H](C2N3C=CN=C(N)C3=C(C3C=CC=C(OCC4C=CC=CC=4)C=3)N=2)CC1)=O.[NH2:35][C:36]1[C:37]2[N:38]([C:42]([CH:61]3[CH2:66][CH2:65][CH:64]([C:67](O)=[O:68])[CH2:63][CH2:62]3)=[N:43][C:44]=2[C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([O:51][CH2:52][C:53]3[C:58]([F:59])=[CH:57][CH:56]=[CH:55][C:54]=3[F:60])[CH:46]=2)[CH:39]=[CH:40][N:41]=1>>[CH3:1][NH:2][C:67]([CH:64]1[CH2:63][CH2:62][CH:61]([C:42]2[N:38]3[CH:39]=[CH:40][N:41]=[C:36]([NH2:35])[C:37]3=[C:44]([C:45]3[CH:50]=[CH:49][CH:48]=[C:47]([O:51][CH2:52][C:53]4[C:58]([F:59])=[CH:57][CH:56]=[CH:55][C:54]=4[F:60])[CH:46]=3)[N:43]=2)[CH2:66][CH2:65]1)=[O:68]
Reactant: Nc1nccn2c(C3CCC(C(=O)O)CC3)nc(-c3cccc(OCc4c(F)cccc4F)c3)c12
Reactant: CNC(=O)[C@H]1CC[C@H](c2nc(-c3cccc(OCc4ccccc4)c3)c3c(N)nccn32)CC1
Product: CNC(=O)C1CCC(c2nc(-c3cccc(OCc4c(F)cccc4F)c3)c3c(N)nccn23)CC1

Procedure:
The amide coupling procedures applied to the synthesis of (trans-4-[8-Amino-1-(3-benzyloxy-phenyl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic acid methylamide was applied to 4-{8-Amino-1-[3-(2,6-difluoro-benzyloxy)-phenyl]-imidazo[1,5-a]pyrazin-3-yl}-cyclohexanecarboxylic acid to afford the title compound; MS (ES+): m/z 492.12 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:26])=[C:12]3[CH:18]=[C:17]([CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:35](Br)[CH:36]1[O:40][CH2:39][CH2:38][CH2:37]1.O>CN(C=O)C>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:26])[C:12]3[CH:18]=[C:17]([CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)[S:16][C:13]=3[N:14]([CH2:35][CH:36]3[CH2:37][CH2:38][CH2:39][O:40]3)[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(CN3CCOCC3)cc2c1O
Reactant: BrCC1CCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1ccc(Cl)cc1)c1cn(CC2CCCO2)c2sc(CN3CCOCC3)cc2c1=O
Temperature: 60 °C
Reaction time: 18 h
Yield: 3 %

Procedure:
N-(4-Chlorobenzyl)-4-hydroxy-2-(4-morpholinylmethyl)thieno[2,3-b]pyridine-5-carboxamide (418 mg) from Example No. 41 and potassium carbonate (152 mg) are suspended in DMF (10 mL) and to the mixture is added tetrahydrofurfurylbromide (125 μL). The reaction mixture is heated to 60° C. for 4 h and then allowed to stand at room temperature for 18 h. The reaction mixture is poured into water (25 mL) and extracted with EtOAc (3×25 mL). The organic layer is dried (Na2SO4) and concentrated. The resulting crude solid is purified by recrystallization from ethanol to afford 15 mg (3%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[N:8]([CH2:17]O)[N:7]=1)[CH3:2].P(Br)(Br)[Br:21]>CCOCC>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[N:8]([CH2:17][Br:21])[N:7]=1)[CH3:2]
Reactant: BrP(Br)Br
Reactant: CCOC(=O)Cc1nn(CO)c(=O)c2ccccc12
Solvent: CCOCC
Product: CCOC(=O)Cc1nn(CBr)c(=O)c2ccccc12
Yield: 60.4 %

Procedure:
A solution of ethyl-3-hydroxymethyl-4-oxo-3-H-phthalazin-1-ylacetate (13.1 g), phosphorous tribromide (13.5 g) and anhydrous ether (250 ml) was stirred overnight at room temperature. It was then poured onto water (200 ml). The organic layer was collected, washed again with water (3×100 ml) and then dried over anhydrous sodium sulfate. The dried organic extract was evaporated to dryness and the resulting crude solid was purified by chromatography on silica gel, eluting with 95% CH2Cl2 -5% ethyl acetate (percents by volume) to obtain the title compound (yield: 9.8 g; m.p. 96° C.).
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:23][O:24][C:25]1[CH:35]=[CH:34][CH:33]=[CH:32][C:26]=1[O:27][CH2:28][CH2:29][CH2:30]Cl.[C:36]([OH:43])(=[O:42])/[CH:37]=[CH:38]/[C:39]([OH:41])=[O:40]>C(#N)C.C(O)C>[C:36]([OH:43])(=[O:42])/[CH:37]=[CH:38]/[C:39]([OH:41])=[O:40].[CH3:23][O:24][C:25]1[CH:35]=[CH:34][CH:33]=[CH:32][C:26]=1[O:27][CH2:28][CH2:29][CH2:30][C:15]1[C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=[CH:2][CH:16]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: COc1ccccc1OCCCCl
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCO
Product: COc1ccccc1OCCCc1cccc2onc(C3CCNCC3)c12
Temperature: 90 °C

Procedure:
A stirred mixture of 6-fluoro-(4-piperidinyl)-1,2-benzisoxazole (2.45 g; 11.1 mmol), K2CO3 (2.0 g), and 3-(2-methoxyphenoxy)propyl chloride (3.5 g, 17.4 mmol) in acetonitrile (40 ml) was heated at 90° C. for 4 hours. At the end of the reaction, the solvent was removed, and the solids were dissolved into dichloromethane (100 ml). The solution was washed with water and brine, then dried over MgSO4. The crude material from the solution was combined with 1.2 g of crude material prepared in the same fashion (using 0.5 g of starting material). The combined material was purified by flash chromatography on a silica gel column (49 g, eluted with 0.5% diethylamine: 1% methanol:98.5% dichloromethane, 1 L). The fractions containing the pure product were pooled and concentrated down to a light oil (3.68 g). This oil was treated with fumaric acid (1.14 g, 9.8 mmol) in ethanol (13 ml). The 6fluoro-3-[1-[3-(2-methoxyphenoxy)propyl[-4piperidinyl]-1,2-benzisoxazole fumarate crystals obtained weighed 4.01 g (60%), m.p.=169-170° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[O:13]1[C:18]2[CH:19]=[CH:20][C:21]([CH:23]=O)=[CH:22][C:17]=2[O:16][CH2:15][CH2:14]1.C(O)(C(F)(F)F)=O>>[O:13]1[C:18]2[CH:19]=[CH:20][C:21]([CH:23]3[C:5]4[NH:6][C:7]5[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=5)[C:4]=4[CH2:3][CH2:2][NH:1]3)=[CH:22][C:17]=2[O:16][CH2:15][CH2:14]1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: O=Cc1ccc2c(c1)OCCO2
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2c3c([nH]c2c1)C(c1ccc2c(c1)OCCO2)NCC3
Yield: 75 %

Procedure:
This product was prepared using the same procedure as for Intermediate 1 with tryptamine (4.92 g, 30.7 mmol), 2,3-dihydrobenzo[1,4]dioxin-6-carboxaldehyde (5.05 g, 1.0 equiv.) and TFA (5.0 mL, 2 equiv.) to give the title compound (7.05 g, 75%) as white crystals after recrystallization from iPr2O. MP: 144° C.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([O:12][C:13]([CH3:22])([CH2:15][CH2:16][CH2:17][CH:18]([CH3:21])[CH:19]=[CH2:20])[CH3:14])(=[O:11])[CH3:10].[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[C:33](Cl)=[O:34]>C1COCC1>[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[C:33](=[O:34])[CH2:10][C:9]([O:12][C:13]([CH3:22])([CH2:15][CH2:16][CH2:17][CH:18]([CH3:21])[CH:19]=[CH2:20])[CH3:14])=[O:11]
Reactant: C=CC(C)CCCC(C)(C)OC(C)=O
Reactant: O=C(Cl)c1ccc2ccccc2c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC(C)CCCC(C)(C)OC(=O)CC(=O)c1ccc2ccccc2c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Lithium diisopropylamide in the amount of (100.0 mL of a 2.0 M solution, 0.201 mol) is placed into a 500 mL three-necked round-bottomed flask fitted with a magnetic stirrer, internal thermometer, argon inlet, and addition ftnnel. The flask is cooled to −78° C. 2,6-Dimethyl-7-octen-2-yl acetate in the amount of (18.75 g, 0.095 mol) is dissolved in THF (5 mL) and the resulting solution added to the flask over 45 min. Once addition is complete, the mixture is stirred for an additional 15 min before being treated with a solution of 2-naphthoyl chloride in the amount of (17.00 g, 0.089 mol) dissolved in THF (25 mL) over 30 min. The mixture is warmed to −20° C. and stirred at that temperature for 18 h. After warming to 0° C., the mixture is quenched with 20% HCl (55 mL). The mixture is poured into a separatory funnel containing ether (150 mL) and water (250 mL). The aqueous layer is extracted with ether (150 mL). The combined organic layers are washed with saturated NaHCO3 solution (2×100 mL), water (2×150 mL) and brine (150 mL), dried over MgSO4 and filtered. The solvent is removed by rotary evaporation to give an orange/red oil. The oil is purified by column chromatography (elution with 2% ethyl acetate dissolved in petrolewn ether) to give an oil. Purity of the product is determined by thin layer chromatography and the structure confirmed by 1H and 13C NMR.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH:13]=O)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].ClCCCl.Cl.[CH3:20][O:21][C:22](=[O:25])[CH2:23][NH2:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[C:4]([Si:1]([CH3:2])([CH3:3])[O:8][CH2:9][C:10]1([CH2:13][NH:24][CH2:23][C:22]([O:21][CH3:20])=[O:25])[CH2:11][CH2:12]1)([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)OCC1(C=O)CC1
Reactant: COC(=O)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)CNCC1(CO[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopropanecarbaldehyde (5.0 g, 0.023 mol) in anhydrous 1,2-dichloroethane (113 mL, 1.44 mol) was added glycine methyl ester, hydrochloride (2.92 g, 0.0232 mol), TEA (6.53 mL, 0.0466 mol), and sodium triacetoxyborohydride (10.4 g, 0.0467 mol). The resulting mixture was stirred at RT for 1 h. LC/MS data indicated that the reductive amination was complete to afford methyl ({[1-({[tert-butyl-(dimethyl)silyl]oxy}methyl)cyclopropyl]methyl}amino)acetate. LC-MS: 288.2 (M+1H)+. To the crude reaction mixture was added benzaldehyde (2.8 mL, 0.028 mol), followed by a second aliquot of sodium triacetoxyborohydride (6 g). After stirring at RT for 2 h, the reaction was quenched by the addition of saturated aqueous NaHCO3. The organic layer was separated and washed with brine, then dried (MgSO4), and concentrated in vacuo. The crude product (9.1 g) was purified by Combiflash chromatography (120 g silica gel column, 0-15% EtOAc/hexanes 20 min), to afford the desired product as an oil (4.6 g). LC/MS: 378.2 (M+1H)+.
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]=[C:10]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[O:11][C:7]=2[C:6](F)=[C:5]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)[C:4]=1[CH3:23])#[N:2].C(N(CC)CC)C.[CH3:31][NH:32][C@H:33]1[CH2:37][CH2:36][NH:35][CH2:34]1>CS(C)=O>[C:1]([C:3]1[C:8]2[N:9]=[C:10]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[O:11][C:7]=2[C:6]([N:35]2[CH2:36][CH2:37][C@H:33]([NH:32][CH3:31])[CH2:34]2)=[C:5]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)[C:4]=1[CH3:23])#[N:2]
Reactant: CN[C@H]1CCNC1
Reactant: Cc1c(-c2cccs2)c(F)c2oc(C(=O)N(C)C)nc2c1C#N
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN[C@H]1CCN(c2c(-c3cccs3)c(C)c(C#N)c3nc(C(=O)N(C)C)oc23)C1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 59.3 %

Procedure:
4-Cyano-7-fluoro-N,N,5-trimethyl-6-(thiophen-2-yl)-1,3-benzoxazole-2-carboxamide (I-308) (160 mg, 0.49 mmol) was dissolved in dimethyl sulfoxide (8.7 ml), and at room temperature, triethylamine (81 μl, 0.58 mmol) was added. The solution was gradually heated from room temperature up to 150° C., and a solution of (3S)-3-(methylamino)pyrrolidine (62 μl, 0.58 mmol) dissolved in dimethyl sulfoxide (1 ml) was added all at a time. After stirred at the same temperature for 50 minutes, this was cooled to room temperature. The solvent was evaporated away under reduced pressure, and the resulting residue was fractionated with chloroform and saturated brine. The aqueous layer was further fractionated twice with chloroform. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was roughly purified by preparative TLC (eluent, chloroform:7 N ammonia/methanol solution=95:5, v/v), and the roughly-purified product was again purified by preparative TLC (eluent, chloroform:methanol=9:1, v/v) to obtain the entitled compound (119 mg, 60%) as a yellow amorphous substance.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[N:14]([CH2:17][CH2:18][CH:19]([OH:24])[C:20]([F:23])([F:22])[F:21])=[N+:15]=[N-:16].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[N:14]([CH2:17][CH2:18][CH:19]([C:20]([F:21])([F:23])[F:22])[O:24][C:2]1[N:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])=[N+:15]=[N-:16]
Reactant: N#Cc1ccc(C(F)(F)F)nc1Cl
Reactant: [N-]=[N+]=NCCC(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(C(F)(F)F)nc1OC(CCN=[N+]=[N-])C(F)(F)F
Reaction time: 20 h
Yield: 91.3 %

Procedure:
A mixture of 2-chloro-6-(trifluoromethyl)nicotinonitrile (0.675 g, 3.27 mmol) and 4-azido-1,1,1-trifluoro-2-butanol (0.552 g, 3.26 mmol) in DMF (8.5 mL) was treated with caesium carbonate (2.18 g, 6.69 mmol) at ambient temperature. After 20 h, the mixture was diluted with water and extracted with diethyl ether. The combined organic extracts were washed (water, brine), dried, and-evaporated to give the product as a brown oil (1.01 g, 90%).