Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[S:16])[NH:11][CH2:12][C:13](N)=[O:14])[CH:5]=[CH:6][C:7]=1[CH3:8].[CH2:17](I)[CH3:18]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[CH2:12][N:11]=[C:10]2[S:16][CH2:17][CH3:18])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(NC(=S)NCC(N)=O)cc1Cl
Reactant: CCI
Solvent: CCO
Product: CCSC1=NCC(=O)N1c1ccc(C)c(Cl)c1
Yield: 80.6 %

Procedure:
A mixture of 2-[3-(3-chloro-4-methylphenyl)-thioureido]-acetamide (10.0 g), ethyl iodide (17.5 g), and ethanol (200 mL) was heated at reflux for 2.5 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate (500 mL) and water (500 mL). The organic phase was washed with water (2×300 mL). The organic phase was extracted with 2N HCl (2×500 mL). The acid extract was neutralized with solid sodium bicarbonate and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous Na2SO4 then evaporated to dryness. The residue was stirred in diethyl ether and filtered to give the title compound (8.4 g) as a white solid, m.p. 133°-135° C. Anal. Calcd. for. C12H13Cl N2O S: C, 53.63; H, 4.88; N,10.42. Found: C, 53.66; H, 4.78; N, 10.39. Mass spectrum (EI, M.+) m/z 268/270. 1H-NMR (DMSO-d6 ; 400 MHz) δ7.47 (d, 1 H), 7.43 (d, 1 H), 7.20 (dd, 1 H), 4.29 (s, 2 H), 3.07 (q, 2 H), 2.36 (s, 3 H), and 1.28 ppm (t, 3 H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C(N([CH2:21][CH3:22])CC)C>ClCCl>[CH2:12]([O:11][C:9]([NH:1][CH2:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:10])[C:22]1[CH:21]=[CH:8][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CCN
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CCNC(=O)OCc1ccccc1
Yield: 177.5 %

Procedure:
A mixture of Example 535B (560 mg, 2.62 mmol), benzyloxycarbonylsuccinimide ester (0.783 g, 3.93 mmol, and triethylamine (0.55 mL, 3.93 mmol) in 10 mL of dichloromethane was stirred overnight, concentrated, treated with ethyl acetate, washed with brine, 10% potassium hydrogen sulfate (3×), and brine (3×), dried (MgSO4), filtered, concentrated, and purified by silica gel column chromatography, eluting with 20% ethyl acetate in n-hexane to provide 0.81 g of the desired product. MS (ESI(+)) m/e 347 (M+H)+; 1H NMR (300 MHz, CDCl3) δ 7.28-7.39 (m, 5H), 7.23 (br, 1H), 5.00 (s, 2H), 3.62-3.74 (m, 1H), 3.19-3.29 (m, 2H), 2.92-3.05 (m, 2H), 1.73-1.91 (m, 5H), 1.54-1.62 (m, 1H), 1.38 (s, 9H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:14](Br)[CH:15]=[CH2:16]>C(O)C>[CH2:16]([N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1)[CH:15]=[CH2:14]
Reactant: C=CCBr
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C=CCN1CCC(O)CC1
Temperature: 25 °C
Yield: 50.9 %

Procedure:
Into a mixture of 4-hydroxypiperidine (75 g, 0.74 mol) and potassium carbonate (104 g, 0.75 mol) in ethanol (250 ml) is added allyl bromide (65 ml, 0.74 mol) in four equal portions over a three-hour period. After the addition is complete, the reaction mixture is stirred at ambient temperature until the disappearance of the reactants, as determined by TLC analysis (approximately six hours). The insoluble solids formed are then removed by filtration and the filtrate is concentrated in vacuo. The residue is purified by flash chromatography on silica gel with a mixture of 25% (vol.) methanol in ethyl acetate as the solvent to give 53.2 g (51% yield) of the title compound as a yellow oil.
Reaction SMILES: [CH:1]1([NH:7][C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[C:16]([CH3:19])[CH:15]=[C:14]([OH:20])[CH:13]=3)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[Cs+].[Cs+].[Br:27][CH2:28][CH2:29]Br>C(#N)C.O>[Br:27][CH2:28][CH2:29][O:20][C:14]1[CH:13]=[C:12]2[C:17]([CH:18]=[C:10]([C:8]([NH:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[O:9])[NH:11]2)=[C:16]([CH3:19])[CH:15]=1
Reactant: Cc1cc(O)cc2[nH]c(C(=O)NC3CCCCC3)cc12
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: Cc1cc(OCCBr)cc2[nH]c(C(=O)NC3CCCCC3)cc12
Temperature: 0 °C
Reaction time: 16 h
Yield: 20.5 %

Procedure:
To a stirred solution of N-cyclohexyl-6-hydroxy-4-methyl-1H-indole-2-carboxamide (I-9A-b: 0.7 g, 2.57 mmol) in acetonitrile (20 mL) was added Cs2CO3 (1.67 g, 5.14 mmol) cooled to 0° C. followed by 1,2-dibromoethane (1.1 mL, 12.86 mmol) dropwise. The reaction mixture was stirred at room temperature for 16 h, diluted with water (20 mL) and extracted with ethyl acetate (2×100 mL). The combined ethyl acetate layers were washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by column chromatography over silica gel (100-200 mesh) using a solvent gradient of 50% ethyl acetate in petroleum ether as eluent to afford 200 mg (21%) of 6-(2-bromoethoxy)-N-cyclohexyl-4-methyl-1H-indole-2-carboxamide (I-9A-c) as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:4]=2[S:5][C:6]=1[C:7](=[O:9])[CH3:8].N[C:16]1[C:17]2[CH:27]=[CH:26][CH:25]=[CH:24][C:18]=2SC=1C(=O)C>>[C:7]([C:6]1[S:5][C:4]2[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:3]=2[C:2]=1[NH2:1])(=[O:9])/[CH:8]=[CH:16]/[C:17]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:18]=1
Reactant: CC(=O)c1sc2ccccc2c1N
Reactant: CC(=O)c1sc2cc(F)ccc2c1N
Product: Nc1c(C(=O)/C=C/c2ccccc2)sc2cc(F)ccc12

Procedure:
The procedure was similar to step S3C, while the starting material was 17B in stead of 3B.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:3]=1[CH:4]([OH:21])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][C:6]=1[O:19][CH3:20].[CH:27](=O)[C:28]([CH3:31])([CH3:30])[CH3:29].C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[CH2:12]([O:11][C:8]1[CH:9]=[CH:10][C:5]([CH:4]([OH:21])[C:3]2[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:2]=2[NH:1][CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[C:6]([O:19][CH3:20])[CH:7]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1cc(OCc2ccccc2)ccc1C(O)c1cc(Cl)ccc1N
Reactant: CC(C)(C)C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cc(OCc2ccccc2)ccc1C(O)c1cc(Cl)ccc1NCC(C)(C)C
Reaction time: 0.5 h

Procedure:
A mixture of 2-amino-α-(4-benzyloxy-2-methoxyphenyl)-5-chlorobenzyl alcohol (9.5 g), pivalaldehyde (3.35 ml), acetic acid (1.85 g) and ethanol (200 ml) was stirred for 30 min. To the mixture was added sodium cyanoborohydride (2.33 g) and the mixture was stirred for 24 h. After the mixture was concentrated in vacuo, the residue was diluted with water (200 ml) and extracted with ethyl acetate (200 ml). The extract was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to give α-(4-benzyloxy-2-methoxyphenyl)-2-neopentylamino-5-chlorobenzyl alcohol (10.0 g) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.Br[C:15]1[C:23]2[C:18](=[CH:19][C:20]([S:24]([N:27](CC3C=CC(OC)=CC=3OC)[C:28]3[S:32][N:31]=[CH:30][N:29]=3)(=[O:26])=[O:25])=[CH:21][CH:22]=2)[N:17]([CH3:44])[CH:16]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[C:23]3[C:18](=[CH:19][C:20]([S:24]([NH:27][C:28]4[S:32][N:31]=[CH:30][N:29]=4)(=[O:25])=[O:26])=[CH:21][CH:22]=3)[N:17]([CH3:44])[CH:16]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(OC)cc(B(O)O)c1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Br)cn(C)c3c2)c(OC)c1
Product: COc1cc(OC)cc(-c2cn(C)c3cc(S(=O)(=O)Nc4ncns4)ccc23)c1

Procedure:
The title compound was prepared in an analogous manner to that described in Example 28 using (3,5-dimethoxyphenyl)boronic acid and 3-bromo-N-(2,4-dimethoxybenzyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide, and the desired product, 3-(3,5-dimethoxyphenyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide, was isolated as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 3.78-3.88 (m, 9 H) 6.39 (t, J=2.23 Hz, 1 H) 6.77 (d, J=2.29 Hz, 2 H) 7.52 (dd, J=8.42, 1.55 Hz, 1 H) 7.75-7.89 (m, 4 H). m/z (ESI) 430.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[C@@H:11]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[C@H:10]([O:35][CH2:36][C@H:37]2[CH2:41][O:40][C:39]([CH3:43])([CH3:42])[O:38]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:45][CH2:46][CH2:47][O:48][CH2:49][C:50]1[CH:55]=[C:54]([F:56])[CH:53]=[CH:52][C:51]=1[O:57][CH3:58]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[C@@H:11]([C:28]2[CH:29]=[CH:30][C:31]([O:34][CH2:45][CH2:46][CH2:47][O:48][CH2:49][C:50]3[CH:55]=[C:54]([F:56])[CH:53]=[CH:52][C:51]=3[O:57][CH3:58])=[CH:32][CH:33]=2)[C@H:10]([O:35][CH2:36][C@H:37]2[CH2:41][O:40][C:39]([CH3:43])([CH3:42])[O:38]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(F)cc1COCCCCl
Reactant: COc1cc(CO[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H](OC[C@H]3COC(C)(C)O3)[C@@H]2c2ccc(O)cc2)cc2ccccc12
Product: COc1ccc(F)cc1COCCCOc1ccc([C@@H]2[C@@H](OCc3cc(OC)c4ccccc4c3)CN(C(=O)OC(C)(C)C)C[C@H]2OC[C@H]2COC(C)(C)O2)cc1

Procedure:
In analogy to the procedure described in example 1 (e) the (3S,4R,5R)-3-[(4S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-4-(4-hydroxy-phenyl)-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester was treated with the 2-(3-chloro-propoxymethyl)-4-fluoro-1-methoxy-benzene [example 11 (α)] to yield the (3S,4R,5R)-3-[(4S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-4-[4-[3-(5-fluoro-2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester as light yellow oil; MS: 790 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([NH:11][O:12][CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]([N:30]=[C:31]=[S:32])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([N:11]([C:31](=[S:32])[NH:30][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:12][CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2CONC2(c2ccccc2)C1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC2CON(C(=S)NC(=O)c3ccccc3)C2(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
To a mixture of tert-butyl-6a-phenyl-3,3a,4,6-tetrahydro-1H-pyrrolo[3,4-c]isoxazole-5-carboxylate (1.5 g, 5.2 mmol) in tetrahydrofuran (34 mL) is added benzoyl isothiocyanate (0.84 g, 5.17 mmol). The reaction is stirred for 1 hour at room temperature, concentrated under reduced pressure, and triturated with hexane/ethyl acetate (1:1) to give title compound (1.84 g). The collected solute is purified by silica gel flash chromatography, eluting with hexane/ethyl acetate (1:0) to hexane/ethyl acetate (0:1) to give the title compound, which is combined with the triturated material (2.12 g, 90%). ES/MS (m/e): 454 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][N:18]([CH2:20][CH2:21][CH2:22][OH:23])[CH:19]=2)=[CH:11][C:3]=1[C:4]([N:6](CC)[CH2:7]C)=[O:5].NC1C(C(NC)=O)=C([Cl:35])C(Br)=CC=1>>[NH2:1][C:2]1[C:3]([C:4]([NH:6][CH3:7])=[O:5])=[C:11]([Cl:35])[C:12]([C:15]2[CH:16]=[N:17][N:18]([CH2:20][CH2:21][CH2:22][OH:23])[CH:19]=2)=[CH:13][CH:14]=1
Reactant: CCN(CC)C(=O)c1cc(-c2cnn(CCCO)c2)ccc1N
Reactant: CNC(=O)c1c(N)ccc(Br)c1Cl
Product: CNC(=O)c1c(N)ccc(-c2cnn(CCCO)c2)c1Cl
Yield: 33 %

Procedure:
Prepared analogously to Compound 3C replacing compound 3D with 6-amino-3-bromo-2-chloro-N-methylbenzamide (Compound 28D, 700 mg, 2.66 mmol) and to afford 274 mg of the title compound (33%). 1H NMR (400 MHz, CD3OD) δ=7.87 (s, 1H), 7.68 (s, 1H), 7.25 (d, J=8.6 Hz, 1H), 6.73 (d, J=8.6 Hz, 1H), 4.27 (t, J=7.0 Hz, 2H), 3.55 (t, J=6.2 Hz, 2H), 2.92 (s, 3H), 2.06 (quin, J=6.5 Hz, 2H). MS (ESI): m/z=309.10 [M+H]+. UPLC: tR=0.81 min (UPLC-TOF: polar—3 min).
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][CH:12]([C:15]([N:17]2[CH2:38][CH2:37][C:20]3([NH:24]/[C:23](=[N:25]/[C:26]([C:28]4[C:33]([NH2:34])=[N:32][C:31]([NH2:35])=[C:30]([Cl:36])[N:29]=4)=[O:27])/[NH:22][CH2:21]3)[CH2:19][CH2:18]2)=[O:16])[CH2:11][CH2:10]1)=O)(C)(C)C>O1CCOCC1>[ClH:36].[NH:9]1[CH2:10][CH2:11][CH:12]([C:15]([N:17]2[CH2:18][CH2:19][C:20]3([NH:24]/[C:23](=[N:25]/[C:26]([C:28]4[C:33]([NH2:34])=[N:32][C:31]([NH2:35])=[C:30]([Cl:36])[N:29]=4)=[O:27])/[NH:22][CH2:21]3)[CH2:37][CH2:38]2)=[O:16])[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCC3(CC2)CN/C(=N\C(=O)c2nc(Cl)c(N)nc2N)N3)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1nc(N)c(C(=O)/N=C2\NCC3(CCN(C(=O)C4CCNCC4)CC3)N2)nc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4 M HCl in dioxane (5 ml) is added to a solution of 4-{2-[(E)-3,5-diamino-6-chloro-pyrazine-2-carbonylimino]-1,3,8-triaza-spiro[4.5]decane-8-carbonyl}-piperidine-1-carboxylic acid tert-butyl ester (Intermediate BA) (0.14 g, 0.26 mmol) in dioxane (10 ml) and the reaction mixture is stirred at room temperature for 3 hours. The reaction mixture is concentrated in vacuo and the yellow solid obtained is triturated with DCM. The DCM layer is decanted and the compound is washed with MeOH and dried under vacuum to afford the title compound as yellow solid; [M+H]+ 436
Reaction SMILES: C1N2CN3CN(C2)CN1C3.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[C:19]([CH3:27])([C:23]([F:26])([F:25])[F:24])[O:18][CH2:17][CH2:16]2.O.[C:29]([O:33]C)(C)(C)C>FC(F)(F)C(O)=O>[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[CH:29]=[O:33])[C:19]([CH3:27])([C:23]([F:26])([F:24])[F:25])[O:18][CH2:17][CH2:16]2
Reactant: COc1ccc2c(c1)CCOC2(C)C(F)(F)F
Reactant: COC(C)(C)C
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(cc1C=O)C(C)(C(F)(F)F)OCC2
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To hexamethylenetetramine (31.3 g, 223 mmol) was added trifluoroacetic acid (400 mL) and the mixture was heated to 70° C. for 90 minutes. A solution of 6-methoxy-1-methyl-1-trifluoromethyl-isochroman (50.0 g, 203 mmol) in trifluoroacetic acid (100 mL) was then added to the reaction mixture over 40 minutes. The solution was stirred for 3 hours and water was added (450 mL). The reaction mixture was stirred 16 hours, cooled to room temperature, and poured into methyl tert-butyl ether (500 mL). The organic layer was separated and washed with water (3×300 mL). The organic layer was poured into a round bottom flask and cooled to 0° C. 6N Sodium hydroxide was added in portions until the pH raised to 10 (˜500 mL). The organic layer was separated, washed with water (200 mL), dried over magnesium sulfate, filtered, and concentrated to afford 6-methoxy-1-methyl-1-trifluoromethyl-isochroman-7-carbaldehyde as an oil (54.2 g of a 12:1 mixture of regioisomers, 97%). 1H NMR (400 MHz, CDCl3) δ1.71 (s, 3), 2.95 (dt, 2, J=2.6, 5.3), 3.90-3.97 (m, 1), 3.97 (s, 3), 4.19 (dt, 1, J=11.2, 5.6), 6.81 (d, 1, J=1.2), 10.4 (s, 1). 13C NMR (75 MHz, CDCl3) δ23.07, 29.98, 55.73, 60.83, 76.03 (q, J=27.4), 111.81, 112.50, 123.65, 125.32, 125.64 (q, J=287), 127.06, 160.89, 188.92. IR 1683, 1616, 1498, 1296, 1271, 1163, 1149, 1120, 1096, 874 cm−1. Analysis calculated for C13H13F3O3: C, 57.13; H, 5.05. Found: C, 56.94; H, 4.78.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[S:5][C:4]=1[C:14]([NH2:16])=[O:15].[CH3:17][CH2:18][C:19](=O)[CH2:20][CH3:21].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH2:18]([C:19]1([CH2:20][CH3:21])[N:2]([CH3:1])[C:3]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=3)[S:5][C:4]=2[C:14](=[O:15])[NH:16]1)[CH3:17]
Reactant: CNc1cc(-c2ccncc2)sc1C(N)=O
Reactant: CCC(=O)CC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCC1(CC)NC(=O)c2sc(-c3ccncc3)cc2N1C
Temperature: 120 °C
Reaction time: 1 h
Yield: 23 %

Procedure:
A mixture of 3-(methylamino)-5-(pyridin-4-yl)thiophene-2-carboxamide (0.094 g, 0.40 mmol), 3-pentanone (2.5 mL), p-toluenesulfonic acid monohydrate (0.0095 g, 0.050 mmol) and acetic acid (2.0 mL) was stirred for 1 h at 120° C. in a sealed tube. Then, this mixture was stirred for 1.5 h at 150° C. in a sealed tube. The mixture was poured into sat. aqueous sodium hydrogen carbonate (150 mL). Extraction with ethyl acetate (100 mL), drying over magnesium sulfate, filtration and concentration at reduced pressure gave an oil. This oil was purified by column chromatography (Combiflash, 40 g silica gel, dichloromethane to 95:5 dichloromethane/methanol), then triturated with ethyl acetate/hexanes (1:1), and the precipitate was collected by filtration to afford the title compound (0.0281 g, 23%) as a yellow solid:
Reaction SMILES: [CH:1]([N:4](CC)[CH:5](C)C)(C)C.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([OH:21])[C:18](O)=[O:19])=[C:13]([F:22])[CH:12]=1.CNC.C1COCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([OH:21])[C:18]([N:4]([CH3:5])[CH3:1])=[O:19])=[C:13]([F:22])[CH:12]=1
Reactant: O=C(O)C(O)c1ccc(Br)cc1F
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)C(=O)C(O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N,N-Diisopropylethylamine (0.8 g, 0.006 mol) was added to a mixture of (4-bromo-2-fluorophenyl)(hydroxy)acetic acid (Oakwood, Cat. No. 019267) (0.5 g, 0.002 mol), dimethylamine in THF (2.4 mmol, 2.0 M, 1.2 mL), and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.1 g, 0.0024 mol) in methylene chloride (10 mL). The mixture was stirred at r.t. overnight, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-40%) to afford the desired product. LCMS (M+H)+=276.2/278.2. 1H NMR (300 MHz, DMSO-d6) δ: 9.50 (d, J=1.1 Hz, 1H), 7.97 (dd, J=8.0, 1.5 Hz, 1H), 7.83 (dd, J=11.4, 1.5 Hz, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.51 (d, J=1.1 Hz, 1H), 7.01 (s, 1H), 5.70 (s, 1H), 5.65 (s, 1H), 3.96 (s, 6H), 2.94 (s, 3H), 2.88 (s, 3H).
Reaction SMILES: [CH2:1]([CH:3]([CH2:7][CH3:8])[C:4](Cl)=[O:5])[CH3:2].[C:9]([CH2:11][C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])#[N:10].C(N(CC)CC)C>C(Cl)Cl>[OH:5]/[C:4](/[CH:3]([CH2:7][CH3:8])[CH2:1][CH3:2])=[C:11](/[C:9]#[N:10])\[C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13]
Reactant: CC(C)OC(=O)CC#N
Reactant: CCC(CC)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(CC)/C(O)=C(\C#N)C(=O)OC(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 67.7 %

Procedure:
22.2 g (0.16 mol) of 2-ethylbutyryl chloride were added to a solution of 21 g (0.16 mol) of isopropyl cyanoacetate in CH2Cl2, and the reaction mixture was cooled to 0° C. At this temperature, with ice-cooling, 33.5 g (0.33 mol) of triethylamine were added dropwise, and the mixture was then stirred at 25° C. for 2 h. Following subsequent acidic hydrolysis, the organic phase was washed, dried and concentrated. Purification by customary methods gave 24.4 g of the title compound (68% of theory) as a colorless oil (b.p. 70-75° C./1.5 mbar).
Reaction SMILES: [C:1]1([NH2:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH2:11])[CH:4]=[CH:3][CH:2]=1.[C:13]1(C)[CH:18]=CC(S(O)(=O)=O)=C[CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[CH3:14][C:13]1([CH3:18])[NH:11][C:9]2[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=2)=[CH:4][CH:3]=[CH:2][C:1]=3[NH:12]1
Reactant: Nc1cccc2cccc(N)c12
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC1(C)Nc2cccc3cccc(c23)N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29096.4 %

Procedure:
A solution of 1,8-naphthalene diamine (3.5 g, 22 mmol), distilled as in Example 1, acetone (25 ml) and p-toluene sulfonic acid (10 mg) was prepared and stirred at room temperature for 0.5 hour under a nitrogen atmosphere. The mixture was basified with concentrated sodium carbonate (2 ml) and concentrated to about 5 ml volume. The mixture was diluted with ether (150 ml), washed with water and brine, and dried over potassium carbonate. Concentration gave 3.35 g (77%) 2,3-dihydro-2,2-dimethyl perimidine as a pale pink solid. Recrystallization from hexane-ether gave crystals: mp 114°-115° C.; NMR (CDCl3) 7.07(m, 4H), 6.33(m, 2H), 4.06(bs, 2H), 1.42(s, 6H); IR (KBr) 3364, 3290, 1618, 1595 cm-1.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31]Cl)(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1.[NH2:33][C:34]([CH3:38])([CH3:37])[CH2:35][OH:36]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][NH:33][C:34]([CH3:38])([CH3:37])[CH2:35][OH:36])(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Reactant: CC(C)(N)CO
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCNC(C)(C)CO)CC2)nc1N

Procedure:
The compound was prepared from [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (Example 242) and 2-amino-2-methyl-1-propanol (Aldrich) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C24H36N6O5SF [(M+H)+] 539.2447, observed 539.2449.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7](O)[CH:6]=[C:5]([C:14]([F:17])([F:16])[F:15])[N:4]=1.N1C(C)=CC=CC=1C.O=P(Cl)(Cl)[Cl:30]>>[F:1][C:2]([F:19])([F:18])[C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([Cl:30])[CH:6]=[C:5]([C:14]([F:17])([F:16])[F:15])[N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1c(O)cc(C(F)(F)F)nc1C(F)(F)F
Solvent: Cc1cccc(C)n1
Product: COC(=O)c1c(Cl)cc(C(F)(F)F)nc1C(F)(F)F
Yield: 19.7 %

Procedure:
A mixture of 6.7 g (0.0232 mol) of product of Example 4, 2.8 g (0.026 mol) of 2,6-lutidine, and 50 ml of POCl3 was held at reflux for 18 hours and concentrated. The residue was treated with water and extracted with ether. The ether extract was washed with 10% NaOH and then with saturated NaCl, dried, and concentrated. The residue was kugelrohr distilled at 133 Pa (pot temperature 90° C.). The distillate was recrystallized from hexane at low temperature to give 1.4 g (19.7%) of product; mp 48°-49° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=2[C:13]2[C:14]3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([CH3:30])=[C:19]([C:31](O)=[O:32])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1.[NH2:34][CH:35]1[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=2[C:13]2[C:14]3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([CH3:30])=[C:19]([C:31]([NH:34][CH:35]4[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:39][CH2:40]4)=[O:32])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c1
Product: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methylphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c7) and commercially available tert-butyl 4-amino-piperidine-1-carboxylate the title compound is obtained as pale yellow viscous oil.