Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](O)/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]CC.C1(P([N:28]=[N+:29]=[N-:30])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[N:28]([CH2:1]/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[N+:29]=[N-:30]
Reactant: CCCCCCC/C=C/C=C/CO
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCC/C=C/C=C/CN=[N+]=[N-]

Procedure:
(2E,4E)-Dodeca-2,4-dien-1-ol (4.95 g) was dissolved in dry toluene (110 ml) and diphenylphosphinyl azide (7.92 g) was added. DBU (4.91 ml) was added dropwise. The mixture turned opaque under evolution of heat. The solvent was evaporated and diethyl ether was added to the residue. The reaction mixture was washed with 1M HCl, 1M NaOH and brine and the organic layer was dried over sodium sulfate, filtered and concentrated to give a light yellow liquid. The crude product was filtered over silica gel.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[NH:11][CH:12]=1.[CH3:18][O-:19].[Na+].CO>>[CH3:18][O:19][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[NH:11][CH:12]=1
Reactant: NCCCCc1nc(-c2cnccc2Cl)c[nH]1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccncc1-c1c[nH]c(CCCCN)n1
Temperature: 70 °C
Yield: 96 %

Procedure:
To a solution of 4-[4-(4-chloro-3-pyridyl)imidazolyl]butylamine (400 mg, mmoles) was added sodium methoxide, 5.3 M in methanol (10 ml, 53 mmoles). The reaction mixture was heated at 70° C. for 2 hours. Upon cooling the reaction mixture was concentrated to around 4 ml and then was taken up in dichloromethane (125 ml) and was washed with water (20 ml). The aqueous layer was extracted further with dichloromethane (125 ml), the combined organics were dried over MgSO4, filtered, and concentrated yielding 4-[4-(4-methoxy-3-pyridyl)imidazolyl]butylamine (379 mg, 96%). MH+(247)
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH2:9](I)[C:10]([CH3:13])([CH3:12])[CH3:11]>>[CH2:9]([S:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8])[C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: Oc1ccccc1S
Reactant: CC(C)(C)CI
Product: CC(C)(C)CSc1ccccc1O
Yield: 58 %

Procedure:
This compound was prepared in 58% yield from 2-mercaptophenol and neopentyl iodide according to the procedure for 1p in Example VIII. 1H NMR (CDCl3): δ 1.03 (s, 9H), 2.70 (s, 2H), 6.72 (s, 1H), 6.83-6.87 (m, 1H), 6.96 (dd, J=2.2 Hz, J=7.95, 1H), 7.21-7.26 (m, 1H), 7.46-7.48 (m, 1H); 13C NMR (CDCl3): δ 28.90, 32.56, 52.64, 114.82, 120.94, 130.74, 135.61, 156.60, 158.89;
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:10](=[C:11]([OH:16])[CH:12]=[CH:13][CH:14]=2)[C:9]([OH:17])=[C:8]2[C:3]=1[C:4](=[O:19])[CH:5]=[CH:6][C:7]2=[O:18].[H-].[Na+].[CH3:22]I>CS(C)=O>[Cl:1][C:2]1[C:15]2[C:10](=[C:11]([O:16][CH3:22])[CH:12]=[CH:13][CH:14]=2)[C:9]([OH:17])=[C:8]2[C:3]=1[C:4](=[O:19])[CH:5]=[CH:6][C:7]2=[O:18]
Reactant: CI
Reactant: O=C1C=CC(=O)c2c1c(Cl)c1cccc(O)c1c2O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cccc2c(Cl)c3c(c(O)c12)C(=O)C=CC3=O
Reaction time: 0.08 h

Procedure:
10-Chloro-8, 9-dihydroxy-1,4-anthracenedione (compound 3) (100 mg) was dissolved with stirring in dry dimethyl sulfoxide (25 ml) under a nitrogen atmosphere. Sodium hydride (80% dispersion, 28.5 mg) was added to the solution in one aliquot. The resulting dark blue solution was stirred for 5 min then methyl iodide (156 mg, 0.1 ml) was added in one lot. Stirring was continued for 10 min then another aliquot of methyl iodide (0.1 ml) was added to the mixture. After a further 5 min the dark blue solution was quenched with ice-cold phosphate buffer (pH 7) to give a red suspension which was extracted with chloroform. The combined organic extracts were dried and evaporated to a crude solid which was chromatographed on a column of silica gel 60 with chloroform as eluant. The mobile red band gave the product (compound 12) as a red solid (84 mg, 88%).
Reaction SMILES: OC1NC2C=CC=CC=2N=1.BrN1C(=O)CCC1=O.[Br:19][C:20]1[CH:29]=[CH:28][C:23]2[N:24]=[C:25]([OH:27])[NH:26][C:22]=2[C:21]=1Br.[OH-].[Na+].Cl>CN(C=O)C>[Br:19][C:20]1[CH:29]=[CH:28][C:23]2[N:24]=[C:25]([OH:27])[NH:26][C:22]=2[CH:21]=1
Reactant: Oc1nc2ccc(Br)c(Br)c2[nH]1
Agent: Cl
Agent: O=C1CCC(=O)N1Br
Agent: Oc1nc2ccccc2[nH]1
Solvent: CN(C)C=O
Product: Oc1nc2ccc(Br)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 4 %

Procedure:
The procedure of Mitchell et at., J. Org. Chem. 44(25):4733 (1979) was adapted. To a stirred suspension of 2-hydroxybenzimidazole (134 mg, 1.00 mmol, Aldrich) in dry DMF (3 mL) was added dropwise a solution of N-bromosuccinimide (187 mg, 1.05 mmol, Aldrich) in dry DMF (1 mL) and then it was stirred at 25° C. for 0.5 h resulting a light yellow solution. The solution was allowed to stand at 25° C. for 24 h to give a brown yellow solution which was poured into 20 mL ice water and collected by filtration and washed with distilled water (2×1 mL) followed by 95% ethanol (2×1 mL), affording 188 mg (88%) of crude title compound containing 5% dibromo-2-hydroxybenzimidazole by NMR. A 188 mg sample of crude product was dissolved into 1N NaOH (5 ml) and then acidified to pH=2 with 4N HCl giving a white creamy precipitate. It was collected by filtration and washed with distilled water (2×1 mL) followed by 95% ethanol (2×1 mL) and dried in the air at 50° C. for 8 h, giving 180 mg of title compound (containing 4% di-bromo-2-hydroxybenzimidazole by NMR) as a white powder. Crystallization from hot methanol gave white microcrystals of purer title compound (containing 3% di-bromo-2-hydroxy-benzimidazole by NMR). Mp: 305°-7° C.; IR (KBr, cm-1): 3425, 3181, 3012, 1756, 1693, 1481. 1H NMR (DMSO-d6): δ 6.854 (d, J=8.1 Hz, 1H); 7.038-7.082 (m, 2H); 10.768 (s, 2H). HRMS: calcd for C7H5BrN2O (M+) m/z: 211.9584 found: 211.9591. Potency relative to DCK: 1%.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4]SC.C(O)[C@H]1[O:16][C@H:15]([O:17][C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O>O>[CH2:3]([CH:2]([NH2:1])[C:7]([OH:9])=[O:8])[CH2:4][C:15]([OH:17])=[O:16]
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Reactant: CSCC[C@H](N)C(=O)O
Solvent: O
Product: NC(CCC(=O)O)C(=O)O

Procedure:
An excipients solution is prepared according to a protocol similar to that of Preparation 3 using 0.02 g of methionine, 0.96 g of sucrose and 9.01 g of water for injection (WFI). 8.42 g of the previous excipients solution were added to 9.66 g of water for injection (WFI) and to 7.31 g of polymer P2 solution (46.7 mg/mL polymer P2 solution) obtained by the method described in Preparation 7. This solution was gently stiffed for at least 15 min at room temperature.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:4][C:3]=1[C:21]1[C:30](=[O:31])[N:29]([CH3:32])[C:28]2[N:27]=[C:26](Cl)[N:25]=[CH:24][C:23]=2[N:22]=1.[CH3:34][NH2:35].C1COCC1>CS(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:4][C:3]=1[C:21]1[C:30](=[O:31])[N:29]([CH3:32])[C:28]2[N:27]=[C:26]([NH:35][CH3:34])[N:25]=[CH:24][C:23]=2[N:22]=1
Reactant: CN
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1nc2cnc(Cl)nc2n(C)c1=O
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CNc1ncc2nc(-c3cc(NC(=O)c4cccc(C(F)(F)F)c4)ccc3C)c(=O)n(C)c2n1

Procedure:
A Smith vial (2-5 mL) is charged with N-[4-methyl-3-(2-chloro-8-methyl-7-oxo-7,8-dihydropteridin-6-yl)-pheny]-3-trifluoromethyl-benzamide (15 mg, 0.032 mmol), 2M methylamine solution in THF (160 μL, 0.32 mmol), and DMSO (0.5 mL). After purging with Argon, the vial is sealed and irradiated at 100° C. for 45 minutes in a Smith Synthesizer. The resulting solution is subjected to purification by reverse-phase LC-MS to yield the title compound; 1H NMR 400 MHz (DMSO-d6) δ 10.51 (s, 1H), 8.68 (s, 1H), 8.31 (s, 1H), 8.26 (d, J=8.0 Hz, 1H), 8.02 (bs, 1H), 7.96 (d, J=7.2 Hz, 1H), 7.80-7.76 (m, 3H), 7.27 (d, J=8.2 Hz, 1H), 3.56 (s, 3H), 2.94 (s, 3H), 2.19 (s, 3H); MS m/z 469.3 (M+1).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[N:17]=[C:18]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:19][C:20]=3[C:21]([F:24])([F:23])[F:22])=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=[O:36]>C(Cl)Cl>[O:36]=[S:4]1[CH2:3][CH2:2][N:1]([C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[N:17]=[C:18]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:19][C:20]=3[C:21]([F:23])([F:24])[F:22])=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(Nc1ccc(N2CCSCC2)nc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(N2CCS(=O)CC2)nc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Temperature: -78 °C
Reaction time: 2 h

Procedure:
2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-thiomorpholin-4-yl-pyridin-3-yl)-amide (30 mg, 0.07 mmol) was dissolved in 3 mL of methylene chloride, and cooled down to −78° C. One equivalent of 3-chloroperoxybenzoic acid (12 mg, 0.07 mmol) was added. The reaction mixture was warmed up to room temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and then purified by flash chromatography (Merck silica gel 60, 230-400 mesh, 0-20% methanol in methylene chloride for 25 min) to gave 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(1-oxo-1λ4-thiomorpholin-4-yl)-pyridin-3-yl]-amide as an off-white solid. LCMS calcd for C20H17F3N4O3S (m/e) 450, obsd 451 (M+H).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1.[O:15]1C2(CCNCC2)O[CH2:17][CH2:16]1.C12OC1CCCC2>C(O)C>[O:15]1[C:11]2([CH2:12][CH2:13][N:8]([C@@H:3]3[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]3[OH:1])[CH2:9][CH2:10]2)[O:14][CH2:17][CH2:16]1
Reactant: O=C1CCN([C@@H]2CCCC[C@H]2O)CC1
Reactant: C1CC2(CCN1)OCCO2
Agent: C1CCC2OC2C1
Solvent: CCO
Product: O[C@@H]1CCCC[C@H]1N1CCC2(CC1)OCCO2
Temperature: 25 °C
Yield: 91 %

Procedure:
Preparation of (+/−)-trans-1-(2-hydroxy-cyclohexyl)-piperidin-4-one. To a solution of 1,4-dioxa-8-azaspiro[4,5]decane (14.7 g, 100 mmol) in ethanol (75 ml) was added cyclohexene oxide (10.0 g, 100 mmol). The reaction mixture was refluxed for 40 hours then cooled to room temperature and concentrated. The residue was chromatographed over silica gel (hexane/ethylacetate 4:1) to provide (+/−)-trans-2-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-cyclohexanol (22.1 g, 91%) as a white solid, MS (ISP): m/e=241.2 (M+).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:15][C:16]([NH:18][C:19]1[CH:20]=[C:21]([C:25]2[CH:34]=[N:33][C:32]3[C:31]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)=[N:30][C:29]([C:41]4[CH:42]=[N:43][C:44]([NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[N:45][CH:46]=4)=[N:28][C:27]=3[CH:26]=2)[CH:22]=[CH:23][CH:24]=1)=[O:17]>CN(C=O)C>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:15][C:16]([NH:18][C:19]2[CH:20]=[C:21]([C:25]3[CH:34]=[N:33][C:32]4[C:31]([N:35]5[CH2:40][CH2:39][O:38][CH2:37][CH2:36]5)=[N:30][C:29]([C:41]5[CH:42]=[N:43][C:44]([NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[N:45][CH:46]=5)=[N:28][C:27]=4[CH:26]=3)[CH:22]=[CH:23][CH:24]=2)=[O:17])[CH2:4][CH2:3]1
Reactant: OC1CCNCC1
Reactant: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3ncc(-c4cccc(NC(=O)CCl)c4)cc3n2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3ncc(-c4cccc(NC(=O)CN5CCC(O)CC5)c4)cc3n2)cn1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 86.8 %

Procedure:
To a 25 mL round bottom flask, 4-hydroxy piperidine (0.021 g, 0.00021 mol) and DMF (1.5 mL) were added and then cooled to 0-10° C. To the same reaction flask, potassium carbonate (0.058 g, 0.00042 mol) was added and the reaction mixture was stirred at 0-10° C. for 30 minutes. To the same flask, a solution of tert-butyl (5-(7-(3-(2-chloroacetamido)phenyl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)pyrimidin-2-yl)carbamate (0.08 g, 0.00014 mol) in DMF (1 mL) was added and then stirred at room temperature for 12 hours. The reaction was quenched with water to provide the precipitate. The precipitate was collected by filtration to provide the title compound (0.078 g, 88%). The compound was used in the next step without purification. 1H NMR (300 MHz, DMSO-d6): δ 10.43 (s, 1H), 9.84 (s, 1H), 9.49 (s, 1H), 9.12 (d, J=2.1 Hz, 1H), 8.38 (s, J=2.1 Hz, 1H), 8.21 (br s, 1H), 7.87 (d, J=7.8 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.54 (t, J=8.1 Hz, 1H), 4.63 (d, J=3.9 Hz, 1H), 4.58 (br s, 4H), 3.84 (s, 4H), 3.51-3.49 (m, 1H), 3.28 (s, 2H), 3.13-2.75 (m, 2H), 2.29 (t, J=8.7 Hz, 2H), 1.78 (d, J=9.3 Hz, 2H), 1.58 (d, J=9.3 Hz, 2H), 1.49 (s, 9H): LCMS (ESI): Calculated. 641.3, Observed mass [M+H]+: 642.2, (RT=0.22 min).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=1.CC1(C)C(C)(C)OB([C:31]2[CH:39]=[CH:38][C:34]3[NH:35][CH:36]=[N:37][C:33]=3[CH:32]=2)O1.B(O)O>>[NH:35]1[C:34]2[CH:38]=[CH:39][C:31]([C:2]3[C:3]4[CH2:16][CH2:15][N:14]([C:17]5[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=5)[C:4]=4[N:5]=[C:6]([N:8]4[CH2:13][CH2:12][O:11][CH2:10][CH2:9]4)[N:7]=3)=[CH:32][C:33]=2[N:37]=[CH:36]1
Reactant: CC1(C)OB(c2ccc3[nH]cnc3c2)OC1(C)C
Reactant: Clc1nc(N2CCOCC2)nc2c1CCN2c1cccnc1
Agent: OBO
Product: c1cncc(N2CCc3c(-c4ccc5[nH]cnc5c4)nc(N4CCOCC4)nc32)c1

Procedure:
In the same manner as Example 1-B-10, using 4-chloro-2-morpholin-4-yl-7-pyridin-3-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine, and 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-benzimidazole as a boronic acid, the desired compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17](N)=[C:16]([S:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]1[Cl:24].[CH3:25][S:26]SC.C(ON=O)(C)(C)C>C(Cl)(Cl)Cl.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([S:26][CH3:25])=[C:16]([S:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]1[Cl:24]
Reactant: Nc1c(SC(F)(F)F)nc(Cl)n1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: CSSC
Agent: CC(C)(C)ON=O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CSc1c(SC(F)(F)F)nc(Cl)n1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 58.7 %

Procedure:
To a solution of 700 mg (1.77 mmole) of 1-(2,6-dichloro-4-trifluoromethylphenyl)-5-amino-2-chloro-4-trifluoromethylsulfenylimidazole in 8 ml of chloroform was added 0.26 ml (2.54 mmole) of dimethyl disulfide and 0.32 ml (0.89 mmole) of t-butylnitrite at 0° C. The resulting mixture was stirred at 0° C. for 15 min. and then at RT for 45 min. The mixture was diluted with 75 ml of methylene chloride and partitioned between water and methylene chloride. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was purified by preparative TLC using 5% ethyl acetate in hexane to give 480 mg (58.74% yield) of the desired product. 1H NMR (CDCl3): δ2.26 (s, 3H), 7.82 (s, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[C:11]([O:15][C:16](=O)[O:17]C(C)(C)C)([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C.C(O)(C)(C)C>O>[C:11]([O:15][C:16]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: NCCc1ccc(O)cc1
Solvent: CC(C)(C)O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Yield: 97.9 %

Procedure:
A mixture of 68.59 grams (0.5 mol) of tyramine (β-hydroxyphenylethylamine), 109.13 grams (0.5 mol) of di-t-butylcarbonate, 27.83 grams (0.275 mol) of triethylamine and 2700 ml of 80:20 t-butanol:deionized water solution was stirred for 16 hours at room temperature. The volume of the reaction mixture was reduced to 500-600 ml using a rotary evaporator. The viscous solution was extracted three times with 500 ml portions of chloroform. The chloroform extractions were combined, dried with anhydrous sodium sulfate, filtered and the chloroform was removed under reduced pressure. The product crystallized slowly to form a waxy solid and was recrystallized from acetonitrile. Based on method of preparation, there was obtained 116.13 grams (98% yield) of N-t-butoxycarbonyl tyramine (N-BOC-tyramine). The identity of the chainstopper was further confirmed by 1H NMR analysis.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:12][CH2:13][CH2:14][CH2:15][C@H:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:23]=[CH:24][C:25]3[S:30][CH2:29][C:28](=[O:31])[NH:27][C:26]=3[CH:32]=2)[CH2:17]1>>[NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:12][CH2:13][CH2:14][CH2:15][C@H:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:23]=[CH:24][C:25]3[S:30][CH2:29][C:28](=[O:31])[NH:27][C:26]=3[CH:32]=2)[CH2:17]1)=[O:6]
Reactant: NCCC[C@@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1
Reactant: Nc1cc(F)ccc1C(=O)O
Product: Nc1cc(F)ccc1C(=O)NCCC[C@@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1
Yield: 78 %

Procedure:
Starting from 2-amino-4-fluorobenzoic acid and 6-[(R)-5-(3-amino-propyl)-2-oxo-oxazolidin-3-yl]-4H-benzo[1,4]thiazin-3-one (described in WO 2010/041219) and using Procedure D, the title compound was obtained as a beige solid (130 mg; 78% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([C:22]3[CH2:26][CH2:25][CH2:24][CH:23]=3)=[CH:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1>C(O)C.C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)=[CH:14]2)(=[O:11])=[O:12])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)n2cc(C3=CCCC3)c3ccccc32)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)c1ccc(S(=O)(=O)n2cc(C3CCCC3)c3ccccc32)cc1

Procedure:
Dissolve 4-(3-cyclopent-1-enyl-indole-1-sulfonyl)-benzoic acid methyl ester (2.2 g, 5.77 mmol) in ethanol (25 mL) and ethyl acetate (25 mL) and hydrogenate with 10% palladium on carbon (300 mg) at 33 psi for 16 h. Filter the catalyst over celite and back-wash with 1:1 ethanol/ethyl acetate (50 mL). Concentrate to give a dark solid and dissolve in 1:1 ethyl acetate/hexanes (50 mL) and pass through a silica gel plug. Back-wash the plug with 1:1 ethyl acetate/hexanes (100 mL) and concentrate the filtrate to an oil, which solidifies upon standing and found to be pure title compound (2.0 g, 90%); 1H NMR DMSO-d6) δ8.10 (m, 4H), 7.93 (d, J=8.2 Hz, 1H), 7.55 (d, J=7.7 Hz, 1H), 7.53 (s, 1H), 7.36 (t, J=7.1 Hz, 1H), 7.28 (t, J=7.7 Hz, 1H), 3.84 (s, 3H), 3.16 (m, 1H), 2.08 (m, 2H), 1.62 (m, 6H); MS (ESI) m/z 384 (m+H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[O:4][N:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH:18]1([CH2:21][C:22]2[C:27]([C:28]3[CH:33]=[CH:32][N:31]=[C:30](S(C)=O)[N:29]=3)=[CH:26][N:25]=[C:24]([NH2:37])[N:23]=2)[CH2:20][CH2:19]1>C1COCC1>[CH:18]1([CH2:21][C:22]2[C:27]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([NH:7][C:5]4[O:4][N:3]=[C:2]([CH3:1])[CH:6]=4)[N:29]=3)=[CH:26][N:25]=[C:24]([NH2:37])[N:23]=2)[CH2:19][CH2:20]1
Reactant: Cc1cc(N)on1
Reactant: CS(=O)c1nccc(-c2cnc(N)nc2CC2CC2)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(Nc2nccc(-c3cnc(N)nc3CC3CC3)n2)on1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-methyl-isoxazol-5-ylamine in THF was added LiHMDS at −78° C., then the solution was stirred for 15 minutes, and 4′-(cyclopropylmethyl)-2-(methylsulfinyl)-4,5′-bipyrimidin-2′-amine (5-2) in THF was added to the reaction mixture. The reaction was warmed to rt and stirred for 1 hour. The reaction mixture was quenched with saturated ammonium chloride, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to give a crude product which was further purified by reverse-phase HPLC to give the desired product.
Reaction SMILES: [F:1][CH:2]([F:33])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([NH:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[N:9]=2)[C:6]2[CH:27]=[CH:28][CH:29]=[C:30]([O:31][CH3:32])[C:5]=2[N:4]=1.[H-].[Na+].I[CH3:37].N>CN(C=O)C.O.C(Cl)Cl.CCOC(C)=O.C(O)(=O)C>[F:33][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]([CH3:37])[C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[N:9]=2)[C:6]2[CH:27]=[CH:28][CH:29]=[C:30]([O:31][CH3:32])[C:5]=2[N:4]=1
Reactant: CI
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Nc2cccnc2)nc(N2CCOCC2)n1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(C)c2cccnc2)n1
Reaction time: 0.17 h
Yield: 53 %

Procedure:
A solution of 4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-(3-pyridinyl)-1,3,5-triazin-2-amine (0.544 g, 1 mmol) in 15 mL DMF was treated with of NaH and then a slight excess iodomethane was added. After 10 min, the reaction was neutralized with acetic acid and diluted with water. After the pH was made slightly alkaline with aq. NH3, the precipitate was collected and dried. Chromatography on alumina eluting with CH2Cl2/EtOAc (9:1) gave 0.26 g (53% yield) of 4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-methyl-6-(4-morpholinyl)-N-(3-pyridinyl)-1,3,5-triazin-2-amine: mp (MeOH) 200-201° C.; 1H NMR (DMSO-d6) δ 8.67 (d, J=2.2 Hz, 1H), 8.55 (d, J=4.1 Hz, 1H), 7.89 (ddd, J=8.1, 2.6, 1.5 Hz, 1H), 7.70-7.29 (m, 3H), 6.90 (d, J=8.0 Hz, 1H), 3.94 (s, 3H), 3.84-3.61 (m, 8H), 3.55 (s, 3H); Anal. Calcd. for C22H22F2N8O2: C, 56.4; H, 4.7; N, 23.9. Found: C, 56.5; H, 4.75; N, 24.5%.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([CH:13]=[O:14])=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].O>C(O)C>[C:1]1([C:7]2[N:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1cnc(-c2ccccc2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OCc1cnc(-c2ccccc2)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
2-Phenylpyrimidine-5-carbaldehyde (2.0 g) was dissolved in ethanol (20 mL), sodium tetrahydroborate (411 mg) was added under ice-cooling, and the mixture was stirred at 0° C. for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution and then saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (1.75 g) as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([CH3:8])[O:5][N:4]=1.[CH:9]([N:12]1[CH2:17][CH2:16][CH:15]([NH:18][S:19]([CH2:22][CH2:23][NH:24][C:25]([C:27]2[S:28][C:29]([Cl:32])=[CH:30][CH:31]=2)=[O:26])(=[O:21])=[O:20])[CH2:14][CH2:13]1)([CH3:11])[CH3:10]>>[CH:9]([N:12]1[CH2:17][CH2:16][CH:15]([N:18]([CH2:2][C:3]2[CH:7]=[C:6]([CH3:8])[O:5][N:4]=2)[S:19]([CH2:22][CH2:23][NH:24][C:25]([C:27]2[S:28][C:29]([Cl:32])=[CH:30][CH:31]=2)=[O:26])(=[O:20])=[O:21])[CH2:14][CH2:13]1)([CH3:11])[CH3:10]
Reactant: CC(C)N1CCC(NS(=O)(=O)CCNC(=O)c2ccc(Cl)s2)CC1
Reactant: Cc1cc(CCl)no1
Product: Cc1cc(CN(C2CCN(C(C)C)CC2)S(=O)(=O)CCNC(=O)c2ccc(Cl)s2)no1

Procedure:
5-Chloro-thiophene-2-carboxylic acid {2-[(1-isopropyl-piperidin-4-yl)-(5-methyl-isoxazol-3-ylmethyl)-sulfamoyl]-ethyl}-amide was prepared by an analogous procedure as described in example 15 starting from 67 mg (1 equiv.) 3-chloromethyl-5-methyl-isoxazole and 200 mg (0.50 mmol) 5-chloro-thiophene-2-carboxylic acid [2-(1-isopropyl-piperidin-4-ylsulfamoyl)-ethyl]-amide (reaction temperature: 60° C.). Final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.1% TFA) gave pure 5-chloro-thiophene-2-carboxylic acid {2-[(1-isopropyl-piperidin-4-yl)-(5-methyl-isoxazol-3-ylmethyl)-sulfamoyl]-ethyl}-amide. The title compound was obtained as its trifluoroacetate in form of a colorless amorphous material.