Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)[N:10]2[C:14]3[C:15]4[C:20]([CH2:21][C:13]=3[C:12]([C:30]3[S:34][C:33]([CH:35]=[O:36])=[CH:32][CH:31]=3)=[N:11]2)=[CH:19][C:18]([CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)=[CH:17][CH:16]=4)=[CH:5][CH:4]=1.[BH4-].[Na+]>CO.O1CCCC1>[CH3:44][O:43][C:40]1[CH:41]=[CH:42][C:37]([CH:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]2[C:14]3[C:15]4[C:20]([CH2:21][C:13]=3[C:12]([C:30]3[S:34][C:33]([CH2:35][OH:36])=[CH:32][CH:31]=3)=[N:11]2)=[CH:19][C:18]([CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)=[CH:17][CH:16]=4)=[CH:38][CH:39]=1
Reactant: COc1ccc(C(c2ccc(OC)cc2)n2nc(-c3ccc(C=O)s3)c3c2-c2ccc(CN4CCN(C)CC4)cc2C3)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(C(c2ccc(OC)cc2)n2nc(-c3ccc(CO)s3)c3c2-c2ccc(CN4CCN(C)CC4)cc2C3)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of Example 331 (8.5 g, 14.1 mmol) in methanol (150 mL) and tetrahydrofuran (80 mL) was added sodium borohydride (530 mg, 14.1 mmol) at about 0° C. The mixture was stirred for about 3 hours while being allowed to warm to room temperature and was then concentrated under vacuum. The residue was diluted with water, extracted with ethyl acetate and the combined organic extracts were dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel using dichloromethane/methanol (10:1) as eluent to provide the desired product. MS (ESI): m/z 607 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH2:5])[CH3:2].Cl[CH2:13][CH:14]1[O:20][CH2:19][CH2:18][CH2:17][CH2:16][O:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:15]1[CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH:14]1[CH2:13][NH:5][C:4]1[C:6]([CH2:10][CH3:11])=[CH:7][CH:8]=[CH:9][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1cccc(CC)c1N
Reactant: ClCC1OCCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cccc(CC)c1NCC1OCCCCO1

Procedure:
2,6-Diethylaniline (75 grams), 2-chloromethyl- 1,3-dioxepane (15 grams), potassium carbonate (34 grams) and dimethylformamide (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 18 hours. After this time the mixture is filtered and distilled to yield the desired product N-(1,3-dioxepan-2-ylmethyl)-2,6 -diethylaniline.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[N:9][CH:10]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[C:30](=O)([O:36]N1C(=O)CCC1=O)[O:31][CH2:32][CH:33]1[CH2:35][CH2:34]1>ClCCl.[NH4+].[Cl-]>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][N:20]([C:30]([O:31][CH2:32][CH:33]3[CH2:35][CH2:34]3)=[O:36])[CH2:19][CH2:18]2)=[N:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(OCC[C@@H]2C[C@@H]2C2CCNCC2)nc1
Reactant: O=C(OCC1CC1)ON1C(=O)CCC1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(OCC[C@@H]2C[C@@H]2C2CCN(C(=O)OCC3CC3)CC2)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 5-(methylsulfonyl)-2-(2-((1S,2R)-2-(piperidin-4-yl)cyclopropyl)ethoxy)pyridine (Step A, Example 11; 0.30 g, 0.93 mmol) in dichloromethane (4.6 mL) under a nitrogen atmosphere was added triethylamine (0.36 mL, 2.6 mmol) and cyclopropylmethyl 2,5-dioxopyrrolidin-1-yl carbonate (0.35 g, 1.67 mmol). The resulting solution was stirred for 18 h at ambient temperature. The solution was diluted with saturated NH4Cl(aq.) (10 mL). The resulting layers were separated and the aqueous phase extracted with dichloromethane (2×30 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification of the obtained residue by CombiFlash chromatography (12 g silica gel, 0 to 25% EtOAc in heptane) provided the title compound as an off white semi-solid: 1H NMR (500 MHz, CDCl3) δ 8.72 (d, J=2.0 Hz, 1 h), 8.03 (m, 1H), 6.84 (d, J=8.5 Hz, 1H), 4.49 (m, 2H), 4.15 (m, 2H), 3.90 (d, J=7.0 Hz, 2H), 3.07 (s, 3H), 2.80-2.68 (m, 2H), 2.10 (m, 1H), 1.75 (m, 2H) 1.52 (m, 1H), 1.37-1.29 (m, 2H), 1.13 (m, 1H), 1.01-0.87 (m, 2H), 0.70-0.53 (m, 4H), 0.27 (m, 2H), −0.11 (q, J=5.0 Hz, 1H); MS (ESI) m/z 423 [M+H]+.
Reaction SMILES: O[CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.C(Br)(Br)(Br)[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1CCCCC1>C(Cl)Cl>[Br:17][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](CO)C1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCCCC1
Product: CC(C)(C)OC(=O)N1CCC[C@H](CBr)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
To a solution of 1,1-dimethylethyl (3S)-3-(hydroxymethyl)-1-piperidinecarboxylate (30.0 g, 139 mmol) and carbon tetrabromide (72.0 g, 217 mmol) in methylene chloride (150 mL) was added dropwise a solution of triphenyl phosphine (42.4 g, 162 mmol) in methylene chloride (150 mL). An ice-bath was used to maintain an internal temperature between 20 and 25° C. during the addition. After stirring the mixture at ambient temperature for 1 h, cyclohexane (500 mL) was added. Approximately one-half of the solvent was removed under reduced pressure. The remaining solution was cooled in an ice bath and the resulting precipitate was removed by filtration. The filtrate was concentrated under reduced pressure and the residue subjected to flash chromatography (0% to 25% ethyl acetate/hexanes, silica gel) to give 35.1 g (91% yield) of the desired product as a solid. MS (ES+) m/z 278 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:18]([OH:20])=O)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)[N:3]=1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH3:27][N:24]1[CH2:23][CH2:22][N:21]([C:4]2[CH:5]=[C:6]([N:8]3[CH2:17][CH2:16][C:15]4[C:10](=[CH:11][C:12]([C:18]([N:28]5[CH2:32][CH2:31][CH2:30][CH2:29]5)=[O:20])=[CH:13][CH:14]=4)[CH2:9]3)[N:7]=[C:2]([NH2:1])[N:3]=2)[CH2:26][CH2:25]1
Reactant: CN1CCN(c2cc(N3CCc4ccc(C(=O)O)cc4C3)nc(N)n2)CC1
Reactant: C1CCNC1
Product: CN1CCN(c2cc(N3CCc4ccc(C(=O)N5CCCC5)cc4C3)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 18 starting from 2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid and pyrrolidine (Aldrich Cat. No. P73803). LCMS (M+H)+: m/z=422.2.
Reaction SMILES: P(Br)(Br)[Br:2].[F:5][C:6]([F:25])([F:24])[O:7][C:8]1[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][C:19]([CH2:22]O)=[CH:18][CH:17]=2)=[CH:10][CH:9]=1>C(Cl)Cl>[Br:2][CH2:22][C:19]1[CH:20]=[CH:21][C:16](/[CH:15]=[CH:14]/[C:11]2[CH:12]=[CH:13][C:8]([O:7][C:6]([F:25])([F:24])[F:5])=[CH:9][CH:10]=2)=[CH:17][CH:18]=1
Reactant: OCc1ccc(/C=C/c2ccc(OC(F)(F)F)cc2)cc1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: FC(F)(F)Oc1ccc(/C=C/c2ccc(CBr)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.3 %

Procedure:
PBr3 (56 μL, 0.60 mmol) was added to a solution of alcohol 127 (0.177 g, 0.601 mmol) in anhydrous CH2Cl2 (10 mL) at 0° C. The mixture was stirred at room temperature for 1 h, and then cooled to 0° C., quenched with ice, and extracted with CH2Cl2. The organic fraction was dried, and evaporated, and then column chromatography of the residue, eluting with CH2Cl2, gave 1-{(E)-2-[4-(bromomethyl)phenyl]ethenyl}-4-(trifluoromethoxy)benzene (128) (0.125 g, 58%) as a white solid: mp 100-102° C.; 1H NMR (CDCl3) δ 7.52 (d, J=8.6 Hz, 2H), 7.48 (d, J=8.3 Hz, 2H), 7.39 (d, J=8.3 Hz, 2H), 7.20 (br d, J=8.1 Hz, 2H), 7.10 (d, J=16.3 Hz, 1H), 7.05 (d, J=16.3 Hz, 1H), 4.51 (s, 2H). APCI MS m/z 277 [M+H−HBr]+.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][C:12](=[O:14])[N:11]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][C:9]2=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].[O:31]=[C:32]1[CH2:35][N:34]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:33]1>C1COCC1>[O:14]=[C:12]1[N:11]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:9](=[O:22])[N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:13]1[C:32]1([OH:31])[CH2:33][N:34]([C:36]([O:38][C:39]([CH3:41])([CH3:40])[CH3:42])=[O:37])[CH2:35]1
Reactant: O=C1CN(Cc2ccccc2)C(=O)CN1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(O)(C2C(=O)N(Cc3ccccc3)CC(=O)N2Cc2ccccc2)C1
Temperature: -78 °C
Reaction time: 0.38 h
Yield: 49.6 %

Procedure:
To a solution of commercially available 1,4-bis(phenylmethyl)piperazine-2,5-dione (2.0 g, 6.8 mmol) in dry THF (50 mL) at −78° C. was added lithium diisopropylamide (2.0 M solution in heptane/THF/ethylbenzene, 3.4 mL, 6.8 mmol). The resulting reddish brown suspension was stirred for 23 min at −78° C., and then a solution of 1,1-dimethylethyl 3-oxoazetidine-1-carboxylate (770 mg, 4.5 mmol) in THF (10 mL) was added over 30 min by syringe pump. The mixture became a bright yellow solution as it was allowed to warm to room temperature over 3 hours. The mixture was quenched with saturated aqueous ammonium chloride. Water was added to dissolve precipitated salts, and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography (60% ethyl acetate:40% hexanes) to provide 1,1-dimethylethyl 3-[3,6-dioxo-1,4-bis(phenylmethyl)piperazin-2-yl]-3-hydroxyazetidine-1-carboxylate as a colorless foam (1.04 g, 2.23 mmol, 50% yield). 1H NMR. (400 MHz, CDCl3): 7.39-7.29 (m, 7H), 7.23-7.19 (m, 3H), 5.34 (d, 1H), 4.82 (d, 1H), 4.58 (d, 1H), 4.37 (d, 1H), 4.37 (d, 1H), 4.22 (d, 1H), 4.15 (s, 1H), 4.08 (d, 1H), 3.97 (d, 1H), 3.75 (d, 1H), 3.74 (d, 1H), 3.67 (d, 1H), 3.64 (br s, 1H), 1.43 (s, 9H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:9]=[C:10]([NH:18][C:19](=[O:27])OC3C=CC=CC=3)[CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=2)[CH2:3][CH2:2]1.[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[N:36]=[CH:35][N:34]=[C:33]2[S:42][C:43]1[CH:44]=[C:45]([CH:47]=[CH:48][CH:49]=1)[NH2:46].C(N(C(C)C)CC)(C)C>CN(C1C=CN=CC=1)C>[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[N:36]=[CH:35][N:34]=[C:33]2[S:42][C:43]1[CH:44]=[C:45]([NH:46][C:19]([NH:18][C:10]2[CH:11]=[C:12]([C:14]([F:15])([F:17])[F:16])[CH:13]=[C:8]([CH2:7][N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[CH:9]=2)=[O:27])[CH:47]=[CH:48][CH:49]=1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: O=C(Nc1cc(CN2CCOCC2)cc(C(F)(F)F)c1)Oc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(CN5CCOCC5)cc(C(F)(F)F)c4)c3)c2cc1OC

Procedure:
The procedure described in Example 138B was used to react phenyl 3-(morpholinomethyl)-5-(trifluoromethyl)phenylcarbamate described in example 151A (140 mg, 0.37 mmol) with 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (77 mg, 0.25 mmol). To this solution was added diisopropylethyl amine (64 μL, 0.37 mmol) and DMAP (3.0 mg, 0.03 mmol). The reaction was concentrated to dryness and triturated with methanol to give 47 mg. 1H NMR (300 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.98 (s, 1H), 8.70 (s, 1H), 7.88 (d, 2H), 7.55 (m, 2H), 7.44 (m, 1H), 7.35 (s, 2H), 7.25 (m, 2H), 4.00 (s, 6H), 3.58 (s, 4H), 3.34 (s, 2H), 2.39 (s, 4H). LCMS (ESI) m/z 600 (M+H)
Reaction SMILES: [NH2:1][C:2](=[S:16])[C:3]1[CH:4]=[C:5]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])[S:6][C:7]=1[CH2:8][CH3:9].[C:17]([C:19]1C=C(C(OC(C)C)=O)SC=1CC)#N>>[CH2:8]([C:7]1([CH2:17][CH3:19])[S:6][CH:5]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])[CH:4]=[C:3]1[C:2]([NH2:1])=[S:16])[CH3:9]
Reactant: CCc1sc(C(=O)OC(C)C)cc1C(N)=S
Reactant: CCc1sc(C(=O)OC(C)C)cc1C#N
Product: CCC1(CC)SC(C(=O)OC(C)C)C=C1C(N)=S
Yield: 74 %

Procedure:
Isopropyl 4-(aminothioxomethyl)-5-ethylthiophene-2-carboxylate: A stirred solution of 1.7 g (7.6 mmol) of isopropyl 4-cyano-5-ethylthiophene-2-carboxylate was treated as in Example 139, step (c) to give isopropyl 5-ethyl-4-(aminothioxomethyl)-5-ethylthiophene-2-carboxylate (1.45 g, 74%) as a yellow solid. 1H-NMR (DMSO-d6; 300 MHz) δ 9.93 (br s, 1H), 9.39 (br s, 1H), 8.04 (s, 1H), 5.08 (septet, 1H, J=6.2 Hz), 3.08 (q, 2H, J=7.5 Hz), 1.29 (d, 6H, J=6.2 Hz), 1.24 (t, 3H, J=7.5 Hz).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][N+:10]([O-])=[CH:11]2)=[CH:6][CH:5]=1.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:11]1[C:12]2[C:7](=[CH:6][CH:5]=[C:4]([O:3][CH3:2])[CH:13]=2)[CH:8]=[CH:9][N:10]=1
Reactant: COc1ccc2cc[n+]([O-])cc2c1
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Product: COc1ccc2ccnc(Cl)c2c1
Temperature: 90 °C

Procedure:
7-Methoxy-isoquinoline-N-oxide hydrochloride (38.2 g) was added in portions to phosphoryl chloride (275 mL) and the mixture heated at 90° C. for 6 h. Excess of phosphoryl chloride was removed in vacuo. The remaining white solid was washed with water, filtered and dried in vacuo.
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[C:9]([NH2:12])[CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:15][CH:16]=[CH:17][C:18](Cl)=O)C>C(Cl)Cl.[OH-].[Na+]>[NH:12]1[C:9]2[C:10](=[CH:11][C:6]3[CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:7]=3[CH:8]=2)[CH:18]=[CH:17][C:16]1=[O:15]
Reactant: CCOC=CC(=O)Cl
Reactant: Nc1ccc2c(c1)NCCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=c1ccc2cc3c(cc2[nH]1)NCCCC3
Temperature: 50 °C

Procedure:
A solution of 2,3,4,5-tetrahydro-1H-1-benzazapin-8-amine (0.6 g, 3.4 mmol) and 3-ethoxyacryloyl chloride (0.45 g, 3.4 mmol) in CH2Cl2 (50 mL) and 3N NaOH (10 mL) was stirred for 1 h at ambient temperature. The reaction was partitioned between CH2Cl2 and water. The organic layer was concentrated and the remaining brown oil was dissolved in 70% aq. H2SO4 (20 mL) and heated gently (50° C.) for 2 h. The reaction was cooled and neutralized with aq. NH4OH and partitioned between water and EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The residue was dissolved in DMF (1 mL) and purified on a GILSON automated system affixed with a YMC COMBIFLASH 50 mm×20 mm reverse phase column eluted 5–95% CH3CN in water at 30 mL/min over 10.5 min to provide pure desired product. HRMS m/z (M+1) calcd 215.1179; found 215.1186.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:32]=1)[O:7][CH2:8][C:9]1[CH:19]=[C:18]([CH2:20][C:21]3[C:26](=O)[NH:25][C:24]([CH3:28])=[N:23][C:22]=3[CH2:29][CH2:30][CH3:31])[CH:17]=[CH:16][C:10]=1/[C:11]/2=[C:12](/[CH3:15])\[C:13]#[N:14].P(Cl)(Cl)([Cl:35])=O>>[Cl:35][C:26]1[C:21]([CH2:20][C:18]2[CH:17]=[CH:16][C:10]3/[C:11](=[C:12](/[CH3:15])\[C:13]#[N:14])/[C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:32][C:6]=4[O:7][CH2:8][C:9]=3[CH:19]=2)=[C:22]([CH2:29][CH2:30][CH3:31])[N:23]=[C:24]([CH3:28])[N:25]=1
Reactant: CCCc1nc(C)[nH]c(=O)c1Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Reactant: O=P(Cl)(Cl)Cl
Product: CCCc1nc(C)nc(Cl)c1Cc1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Temperature: 100 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
[step 3] (E)-2-{3-fluoro-8-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]dibenzo[b,e]oxepin-11(6H)-ylidene}propanenitrile (960 mg, 2.23 mmol) obtained in step 2 was dissolved in phosphorus oxychloride (2.5 mL, 26.8 mmol), and the mixture was stirred at 100° C. for 2 hr. The mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1 v/v) to give (E)-2-{8-[(4-chloro-2-methyl-6-propylpyrimidin-5-yl)methyl]-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene}propanenitrile (970 mg, 97%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2].[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:10]2[CH:15]=[N:14][CH:13]=[N:12][CH:11]=2)[CH2:21][C:20]2[CH:23]=[CH:24][C:17]([F:16])=[CH:18][CH:19]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(Nc2cncnc2)cc1
Reactant: Fc1ccc(CBr)cc1
Product: N#Cc1ccc(N(Cc2ccc(F)cc2)c2cncnc2)cc1

Procedure:
Starting compounds: 5-[(4-cyanophenyl)amino]pyrimidine and 4-fluorobenzyl bromide
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]([F:15])([F:14])[F:13])=[C:6]([CH2:8][C:9]([OH:11])=O)[CH:7]=1.CN1CCOCC1.ON1C2C=CC=CC=2N=N1.[NH2:33][C:34]1[CH:35]=[C:36]([C:40]([C:42]2[C:50]3[CH:49]=[N:48][CH:47]=[N:46][C:45]=3[N:44]([CH3:51])[CH:43]=2)=[O:41])[CH:37]=[N:38][CH:39]=1>Cl.CN(C)CCCN=C=NCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]([F:15])([F:14])[F:13])=[C:6]([CH2:8][C:9]([NH:33][C:34]2[CH:39]=[N:38][CH:37]=[C:36]([C:40]([C:42]3[C:50]4[CH:49]=[N:48][CH:47]=[N:46][C:45]=4[N:44]([CH3:51])[CH:43]=3)=[O:41])[CH:35]=2)=[O:11])[CH:7]=1
Reactant: O=C(O)Cc1cc(F)ccc1C(F)(F)F
Reactant: Cn1cc(C(=O)c2cncc(N)c2)c2cncnc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: Cn1cc(C(=O)c2cncc(NC(=O)Cc3cc(F)ccc3C(F)(F)F)c2)c2cncnc21
Temperature: 50 °C
Reaction time: 2 h

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide HCl (150 μL, 0.5M in DMF) was added to 5-fluoro-2-(trifluoromethyl)phenylacetic acid (90 μmol), N-methylmorpholine (25 μL, 150 μmol), 1-hydroxybenzotriazole (15 μmol, 0.05M in DMF) and (5-aminopyridin-3-yl)(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Preparation 110, 75 μmol, 0.25 M in DMF). The mixture was stirred at 50° C. for 2 hours and then evaporated in vacuo and purified by prep-HPLC (method 4) to afford the title compound.
Reaction SMILES: [C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25][CH2:26]OS(C4C=CC(C)=CC=4)(=O)=O)[CH:21]=3)[NH:16][N:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH:38]1([NH2:41])[CH2:40][CH2:39]1>C1COCC1>[CH:38]1([NH:41][CH2:26][CH2:25][CH2:24][O:23][C:20]2[CH:21]=[C:22]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[C:14]3[S:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)(=[O:12])=[O:13])[CH2:40][CH2:39]1
Reactant: Cc1ccc(S(=O)(=O)OCCCOc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)cc1
Reactant: NC1CC1
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2ccc(OCCCNC3CC3)cc12
Temperature: 25 °C

Procedure:
A solution of toluene-4-sulfonic acid 3-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-propyl ester (0.080 mg, 0.15 mmol) and cyclopropylamine (0.45-0.75 mmol) in THF (10 mL) was stirred at 90° C. for about 2 hours in a sealed tube. After cooling to ambient temperature the reaction mixture was solvent evaporated. It was dissolved in ethyl acetate and washed twice with aqueous sodium bicarbonate. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified twice by flash chromatography using 0.75% ammonium hydroxide/7.5% methanol in chloroform and 0.5% ammonium hydroxide/5.0% methanol in chloroform to give cyclopropyl-{3-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-propyl}-amine as a clear yellow film (51.0 mg, 80.7%). This compound was dissolved in methanol, and ethereal hydrochloride was added. Concentrating and drying in vacuo for 24 hours at 83° C. gave the hydrochloride as a yellow foam (48.9 mg, 71.2%); Mass Spectrum (+EI, [M+H]+) m/z 422. 1HNMR (500 MHz, DMSO-d6): δ14.15 (s, 1H), 9.01 (s, 2H), 8.74-8.76 (m, 1H), 8.51-8.53 (m, 1H), 8.27 (d, 1H, J=8.29 Hz), 8.02-8.05 (m, 1H), 7.71-7.75 (m, 1H), 7.51-7.65 (m, 3H), 7.29 (d, 1H, J=2.19 Hz), 7.08-7.11 (m, 1H), 4.11 (t, 2H, J=6.10 Hz), 3.11-3.20 (br, s, 2H), 2.65-2.75 (m, 1H), 2.08-2.15 (m, 2H), 0.83-0.87 (m, 2H), 0.70-0.77 ppm (m, 2H). Elemental Analysis for C23H23N3O3S.1.00 mol HCl.0.70 mol H2O: Calcd: C, 58.70; H, 5.44; N, 8.93; Found: C, 58.70; H, 5.09; N, 8.68.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:23][C:24]([O:26]CC)=O.O.[NH2:30][NH2:31]>C(O)C>[O:1]=[C:2]1[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:23][C:24]([NH:30][NH2:31])=[O:26]
Reactant: NN
Reactant: CCOC(=O)CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21
Solvent: CCO
Solvent: O
Product: NNC(=O)CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21
Temperature: 25 °C
Yield: 84.3 %

Procedure:
To a solution of ethyl (2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)acetate (0.35 g, 0.92 mmol) in ethanol (10 mL) was added hydrazine hydrate (0.15 mL, 1.84 mmol) and the solution was heated at reflux for 16 h. Upon being allowed to cool to ambient temperature a solid precipitate formed. The solid was filtered and washed with ethanol (2 mL) to afford 2-(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)acetohydrazide (0.285 g, 84%) as a colorless solid: MS (ES+) m/z 367.9 (M+1).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[CH2:11]([N:13]([CH2:16][C:17]1[S:21][C:20]2=[N:22][C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:24][N:19]2[N:18]=1)[CH2:14][CH3:15])[CH3:12].[OH-].[Na+]>O>[CH2:11]([N:13]([CH2:16][C:17]1[S:21][C:20]2=[N:22][C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:24]([CH:8]=[O:9])[N:19]2[N:18]=1)[CH2:14][CH3:15])[CH3:12]
Reactant: CN(C)C=O
Reactant: CCN(CC)Cc1nn2cc(-c3ccccc3)nc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCN(CC)Cc1nn2c(C=O)c(-c3ccccc3)nc2s1
Temperature: 100 °C

Procedure:
2.3 ml (0.025 mol) of phosphorus oxychloride are added dropwise to 20 ml of dimethylformamide at 0°-5° C. 5.7 g (0.02 mol) of 2-diethylaminomethyl-6-phenyl-imidazo-[2,1-b]-1,3,4-thiadiazole are then added and the mixture is warmed at 100° C. for 2 hours. After cooling, 50 ml of water are added and the mixture is neutralised with 20% strength sodium hydroxide solution and extracted with ether.
Reaction SMILES: [H-].[Na+].[CH2:3]([CH2:13][NH2:14])[CH2:4][C:5]([NH2:12])([C:9]([OH:11])=[O:10])[CH:6]([F:8])[F:7].O.[ClH:16]>C1COCC1>[OH2:10].[ClH:16].[F:7][CH:6]([F:8])[C@@:5]([C:9]([OH:11])=[O:10])([CH2:4][CH2:3][CH2:13][NH2:14])[NH2:12]
Reactant: NCCCC(N)(C(=O)O)C(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: NCCC[C@](N)(C(=O)O)C(F)F
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Into a dry 100 ml three necked RB flask equipped with a stirrer, gas inlet and outlet arrangement methyl-2,5-di[1-(3,4-chlorophenyl)methylidene amino]pentanoate (2.0 g) and sodium hydride (0.21 g) in dry THF (20 ml) were added. The resulting suspension was stirred at 50° C. under a nitrogen atmosphere for 2 hrs. The reaction mixture was then cooled to 5° C. and the nitrogen inlet was replaced with chlorodifluoromethane gas tube. The gas was passed for about 45 mts. The reaction was stirred at RT and allowed to stand overnight. The reaction mixture was worked up by quenching with water and the pH was adjusted to 2 with aqueous HCl. The reaction mixture was extracted with MDC twice. The water layer was concentrated and taken up in methanol and chilled. The crystallized inorganic material was removed. The filtrate was concentrated and the residue taken up in 6N HCl and hydrolyzed. The resulting aqueous layer was evaporated. The crude product was dissolved in ethanol, chilled again to remove any inorganic material and further purified by water-acetone to give a product with a melting point (mp) 223-225° C. with spectral data such as NMR matching with material obtained in Example 8.