Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][CH:5]=1.[CH2:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([N:22]2[CH2:23][CH2:24][N:19]([CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:20][CH2:21]2)=[CH:6][CH:5]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: COC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(N2CCN(Cc3ccccc3)CC2)cc1

Procedure:
4-Fluorobenzoic acid methyl ester (200 mmol), 1-benzyl-piperazine (300 mmol), and potassium carbonate (300 mmol) are suspended in acetonitrile (400 ml) and stirred under reflux for 6 days. After evaporation of the solvent, the residue is dissolved in water and extracted three times with diethylether. The extract is dried over sodium sulfate and evaporated. The residue is purified by flash chromatographic on silica gel with (CH2Cl2 first, then CH2Cl2/MeOH=15:1) as mobile phase. The product containing fractions are combined and evaporated. The residue is suspended in diethylether/pentane and the solid filtered of and dried (vacuum). A powder with mp. 105-107° C. is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][C:10]([O:17][CH3:18])=[C:11]([OH:16])[CH:12]=2)[CH:7]1[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:34](I)[CH2:35][CH2:36][CH3:37].C(OCC)(=O)C.CCCCCC>CN(C)C=O>[CH2:1]([O:3][C:4]([N:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][C:10]([O:17][CH3:18])=[C:11]([O:16][CH2:34][CH2:35][CH2:36][CH3:37])[CH:12]=2)[CH:7]1[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1C=Cc2cc(O)c(OC)cc2C1Cc1cccc(OC)c1
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCOc1cc2c(cc1OC)C(Cc1cccc(OC)c1)N(C(=O)OCC)C=C2
Temperature: 85 °C
Reaction time: 18 h
Yield: 57.7 %

Procedure:
To a stirred solution of 6-hydroxy-7-methoxy-1-(3-methoxy-benzyl)-1H-isoquinoline-2-carboxylic acid ethyl ester (840 mg, 2.28 mmol) in anhydrous N,N-dimethylformamide (25 mL) was added potassium carbonate (1.89 g, 13.6 mmol) and butyl iodide (0.78 mL, 6.83 mmol) dropwise. The reaction mixture was heated with stirring at 85° C. for 18 hrs. The solvent was evaporated and the residue was diluted with ethyl acetate (50 mL) and water (50 mL). The aqueous phase was extracted with ethyl acetate (3×50 mL). The combined extracts were washed with saturated aqueous sodium chloride solution (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 20% ethyl acetate/hexane) afforded 6-Butoxy-7-methoxy-1-(3-methoxy-benzyl)-1H-isoquinoline-2-carboxylic acid ethyl ester (560 mg, 56% yield) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][CH:34]([F:36])[F:35])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[C:17]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][NH:10][N:9]=2)[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:43]([O:47][C:48](=[O:51])[CH2:49]Br)([CH3:46])([CH3:45])[CH3:44]>CN(C=O)C.O>[C:43]([O:47][C:48](=[O:51])[CH2:49][N:10]1[CH:11]=[C:12]([NH:13][C:14]([C:16]2[C:17]([NH:25][C:26]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:32])=[N:18][N:19]3[CH:24]=[CH:23][CH:22]=[N:21][C:20]=23)=[O:15])[C:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:33][CH:34]([F:36])[F:35])=[N:9]1)([CH3:46])([CH3:45])[CH3:44]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)OC(=O)Nc1nn2cccnc2c1C(=O)Nc1c[nH]nc1-c1cc(Cl)ccc1OC(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)Cn1cc(NC(=O)c2c(NC(=O)OC(C)(C)C)nn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 74.8 %

Procedure:
A solution of tert-butyl (3-((3-(5-chloro-2-(difluoromethoxy)phenyl)-1H-pyrazol-4-yl)carbamoyl)pyrazolo[1,5-a]pyrimidin-2-yl)carbamate (1.0 g, 1.92 mmol) in DMF (10 mL) was treated with cesium carbonate (0.69 g, 2.12 mmol) and tert-butyl-bromoacetate (0.43 g, 2.12 mmol) and was left to stir at room temperature for 2.5 hours. The reaction mixture was diluted with water and the resultant precipitate was collected by filtration. The resultant solid was purified by flash chromatography on silica eluting with 0-70% EtOAc in cyclohexane. Appropriate fractions were combined and evaporated to afford [4-[(2-tert-butoxycarbonylamino-pyrazolo[1,5-a]pyrimidine-3-carbonyl)-amino]-3-(5-chloro-2-difluoromethoxy-phenyl)-pyrazol-1-yl]-acetic acid tert-butyl ester as a white solid (0.91 g, 74%). LCMS (Method 3) [M+H]+=633.9, RT=4.46 min. 1H NMR (400 MHz, CDCl3) δ: (ppm) 9.78 (s, 1H), 9.70 (s, 1H), 8.76 (dd, 1H, J=1.8, 6.8 Hz), 8.47 (dd, 1H, J=1.8, 4.3 Hz), 8.34 (s, 1H), 7.69 (d, 1H, J=2.5 Hz), 7.41 (dd, 1H, J=2.7, 8.7 Hz), 7.28 (d, 1H, J=8.8 Hz), 6.92 (dd, 1H, J=4.4, 6.9 Hz), 6.47 (t, 1H, J=74.0 Hz), 4.85 (s, 2H), 1.56 (s, 9H), 1.49 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[N:26](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[C:46]([C:50]([O:52][CH:53]([O:55][C:56]([O:58][CH:59]3[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60]3)=[O:57])[CH3:54])=[O:51])=[CH:47][CH:48]=[CH:49][C:6]=2[N:5]=1)[CH3:2].C(O)C>CO>[CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:23][N:24]=[N:25][N:26]=3)=[CH:14][CH:15]=2)[C:7]2[C:46]([C:50]([O:52][CH:53]([O:55][C:56]([O:58][CH:59]3[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64]3)=[O:57])[CH3:54])=[O:51])=[CH:47][CH:48]=[CH:49][C:6]=2[N:5]=1)[CH3:2]
Reactant: CCOc1nc2cccc(C(=O)OC(C)OC(=O)OC3CCCCC3)c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: CO
Product: CCOc1nc2cccc(C(=O)OC(C)OC(=O)OC3CCCCC3)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 95.4 %

Procedure:
Using 10.0 g of (+)-1-(cyclohexyloxycarbonyloxy)-ethyl 2-ethoxy-1-[2'-(N-triphenylmethyl-1H-tetrazol-5-yl)biphenyl-4-yl]methylbenzimidazole-7-carboxylate, the reaction and after-treatment of Example 1 was repeated except that ethanol was used in lieu of methanol. The procedure provided 6.83 g of (±)-1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methylbenzimidazole-7-carboxylate (yield 91%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:10][C:11]3[C:12]4[CH:30]=[CH:29][N:28](S(C5C=CC(C)=CC=5)(=O)=O)[C:13]=4[N:14]=[C:15]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=4)[N:16]=3)[CH:8]=2)[CH:3]=[N:2]1.[OH-].[K+]>O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:10][C:11]3[C:12]4[CH:30]=[CH:29][NH:28][C:13]=4[N:14]=[C:15]([NH:17][C:18]4[CH:19]=[CH:20][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:22][CH:23]=4)[N:16]=3)[CH:8]=2)[CH:3]=[N:2]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc5cn[nH]c5c4)nc(Nc4ccc(S(N)(=O)=O)cc4)nc32)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: NS(=O)(=O)c1ccc(Nc2nc(Nc3ccc4cn[nH]c4c3)c3cc[nH]c3n2)cc1
Temperature: 70 °C
Yield: 19.8 %

Procedure:
To a solution of 4-(4-(1H-indazol-6-ylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzenesulfonamide (105 mg, 0.18 mmol) in dioxane (5 mL), aq. 1N KOH (1.50 mL, 1.50 mmol) was added. The mixture was then heated at 70° C. for 4 h. before it was concentrated in vacuo. The residue was then acidified with acetic acid (HOAc) (2.0 mL) and purified by HPLC to give the title compound (15 mg). MS 421.1 (M+H) (Compound 11-1).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N:10]2[CH2:21][CH2:20][N:19]3[C:12](=[CH:13][C:14]4[CH2:15][C:16]([CH3:23])([CH3:22])[CH2:17][C:18]=43)[C:11]2=[O:24])[C:7]=1[CH:8]=[O:9].[CH3:25][O:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][N:32]2[N:35]=[C:36]([NH:38][C:39]3[C:40](=[O:55])[N:41]([CH3:54])[CH:42]=[C:43](B4OC(C)(C)C(C)(C)O4)[CH:44]=3)[CH:37]=[C:31]2[CH2:30]1.C([O-])(=O)C.[Na+].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C.O>[CH3:22][C:16]1([CH3:23])[CH2:15][C:14]2[CH:13]=[C:12]3[N:19]([CH2:20][CH2:21][N:10]([C:6]4[CH:5]=[N:4][CH:3]=[C:2]([C:43]5[CH:44]=[C:39]([NH:38][C:36]6[CH:37]=[C:31]7[CH2:30][N:29]([CH2:28][CH2:27][O:26][CH3:25])[CH2:34][CH2:33][N:32]7[N:35]=6)[C:40](=[O:55])[N:41]([CH3:54])[CH:42]=5)[C:7]=4[CH:8]=[O:9])[C:11]3=[O:24])[C:18]=2[CH2:17]1
Reactant: COCCN1CCn2nc(Nc3cc(B4OC(C)(C)C(C)(C)O4)cn(C)c3=O)cc2C1
Reactant: CC1(C)Cc2cc3n(c2C1)CCN(c1cncc(Br)c1C=O)C3=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: COCCN1CCn2nc(Nc3cc(-c4cncc(N5CCn6c(cc7c6CC(C)(C)C7)C5=O)c4C=O)cn(C)c3=O)cc2C1
Temperature: 100 °C
Yield: 31.5 %

Procedure:
A sealed tube equipped with a magnetic stirrer was charged with 3-bromo-5-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyri-dine-4-carbaldehyde 107f (100 mg, 0.26 mmol), 328a (110 mg, 0.26 mmol), Pd(dppf)Cl2 (10 mg, 0.026 mmol), sodium acetate (50 mg, 0.50 mmol), K3PO4 (100 mg, 0.50 mmol), and acetonitrile/water (5 mL/1 mL). After three cycles of vacuum/nitrogen flush, the mixture was heated at 100° C. for 2 h. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 10:1 dichloromethane/methanol to afford 328b (50 mg, 32%) as a brown solid. MS-ESI: [M+H]+ 611.3.
Reaction SMILES: [Li+].[OH-].[NH2:3][C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:7]([CH2:14][C@@H:15]([O:36][C:37]([N:39]2[CH2:44][CH2:43][CH:42]([N:45]3[CH2:51][CH2:50][C:49]4[CH:52]=[CH:53][CH:54]=[CH:55][C:48]=4[NH:47][C:46]3=[O:56])[CH2:41][CH2:40]2)=[O:38])[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][C@H:25]3[C:31]([O:33]CC)=[O:32])[CH2:20][CH2:19]2)=[O:17])=[CH:6][C:5]=1[Cl:57]>C1COCC1>[NH2:3][C:4]1[C:9]([C:10]([F:11])([F:13])[F:12])=[CH:8][C:7]([CH2:14][C@@H:15]([O:36][C:37]([N:39]2[CH2:40][CH2:41][CH:42]([N:45]3[CH2:51][CH2:50][C:49]4[CH:52]=[CH:53][CH:54]=[CH:55][C:48]=4[NH:47][C:46]3=[O:56])[CH2:43][CH2:44]2)=[O:38])[C:16]([N:18]2[CH2:19][CH2:20][CH:21]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][C@H:25]3[C:31]([OH:33])=[O:32])[CH2:22][CH2:23]2)=[O:17])=[CH:6][C:5]=1[Cl:57]
Reactant: CCOC(=O)[C@@H]1CN(C)CCN1C1CCN(C(=O)[C@@H](Cc2cc(Cl)c(N)c(C(F)(F)F)c2)OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN1CCN(C2CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)[C@H](C(=O)O)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
0.5 mL (1.00 mmol) 2 M LiOH solution were added to 80.0 mg (0.10 mmol) ethyl (S)-1-(1-{(R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]-propionyl}-piperidin-4-yl)-4-methyl-piperazine-2-carboxylate in 1 mL THF and the reaction mixture was stirred for 20 h at RT. This was purified by HPLC without working up; the fractions containing the product were combined and lyophilised.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:17]=[C:16]2[C:12]([N:13]=[C:14]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:22][CH2:21]3)[N:15]2[CH3:18])=[C:11]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:10]=1.[C:36](O)(=O)[CH2:37][CH3:38]>>[CH2:37]([C:38]1[N:8]([C:9]2[N:17]=[C:16]3[C:12]([N:13]=[C:14]([CH2:19][N:20]4[CH2:21][CH2:22][CH:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:24][CH2:25]4)[N:15]3[CH3:18])=[C:11]([N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)[N:10]=2)[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1)[CH3:36]
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Nc3ccccc3N)nc21
Reactant: CCC(=O)O
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1

Procedure:
Following the procedures for 180, 2-(1-((2-(2-aminophenylamino)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol and propanoic acid were reacted to give 158. LCMS: M+H+=519.3. 1H-NMR (400 MHz, DMSO-d6): δ 8.02 (m, 1H), 7.63 (m, 1H), 7.26 (m, 2H), 4.24 (s, br, 4H), 4.02 (s, 1H), 3.82 (s, 3H), 3.77 (m, 4H), 3.73 (s, 2H), 3.28 (q, 2H), 2.90 (m, 2H), 2.00 (m, 2H), 1.66 (m, 2H), 1.34 (t, 3H), 1.22 (m, 3H), 1.02 (s, 6H)
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[NH:34][C:16]4=[N:17][CH:18]=[CH:19][C:20]([CH2:21][NH:22][CH:23]5[CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24]5)=[C:15]4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:35][CH3:36].[ClH:37]>O1CCOCC1>[ClH:37].[NH:25]1[CH2:26][CH:23]([NH:22][CH2:21][C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[NH:34][C:13]([C:9]4[C:7]5=[N:8][C:3]([O:2][CH3:1])=[C:4]([O:35][CH3:36])[CH:5]=[C:6]5[N:11]([CH3:12])[CH:10]=4)=[CH:14][C:15]=23)[CH2:24]1
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(CNC4CN(C(=O)OC(C)(C)C)C4)ccnc3[nH]1)cn2C
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc2c(nc1OC)c(-c1cc3c(CNC4CNC4)ccnc3[nH]1)cn2C

Procedure:
The product is prepared by following the procedure described in example 51, starting with 0.075 g of tert-butyl 3-{[2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]amino}azetidine-1-carboxylate instead of the tert-butyl (2-{[2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]amino}ethyl)carbamate used in example 51 and 1.2 cm3 of 5N hydrochloric acid in dioxane. 0.077 g of azetidin-3-yl-[2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]amine hydrochloride is obtained with the following characteristics:
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[C:13]([N:20]3[CH2:29][CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)[N:14]=[C:15]([C:17]([OH:19])=[O:18])[CH:16]=[C:11]2[C:10]([CH3:30])=[C:9]1[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].I[CH3:35].O>CN(C)C=O>[CH3:35][O:18][C:17]([C:15]1[CH:16]=[C:11]2[C:10]([CH3:30])=[C:9]([CH3:31])[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:12]2=[C:13]([N:20]2[CH2:29][CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21]2)[N:14]=1)=[O:19]
Reactant: CI
Reactant: Cc1c(C)n(Cc2ccccc2)c2c(N3CCc4ccccc4C3)nc(C(=O)O)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc2c(C)c(C)n(Cc3ccccc3)c2c(N2CCc3ccccc3C2)n1
Yield: 35 %

Procedure:
A solution of 1-benzyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid (20 mg, 0.05 mmol) prepared in Example 733, potassium hydroxide (10.1 mg, 0.07 mmol) and iodomethane (4.3 μl, 0.07 mmol) in anhydrous N,N-dimethylformamide (1 ml) was stirred for 10 hours at room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/10, v/v) to give the titled compound as a white solid. (Yield: 35%)
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([N:7]([CH3:10])[O:8][CH3:9])=[O:6].C([O-])([O-])=O.[K+].[K+].[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>CC#N>[CH3:10][N:7]([O:8][CH3:9])[C:5](=[O:6])[CH2:4][CH2:3][CH2:2][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: C1COCCN1
Reactant: CON(C)C(=O)CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CON(C)C(=O)CCCN1CCOCC1
Temperature: 105 °C
Yield: 44.2 %

Procedure:
To a solution of the product from Step 1 (3.01 g, 18.1 mmol) in MeCN (40 mL), was added K2CO3 (10 g, 72.4 mmol) and morpholine (1.58 mL, 18.1 mmol). This mixture was then heated to 105° C. in a sealed tube for overnight. The reaction mixture then diluted with MeCN (50 mL), then filtered and concentrated. Residue was taken up in Et2O (100 mL), washed with brine, dried over Na2SO4, filtered and concentrated to afford the title compound as a colorless oil (1.73 g, 44%), which was used directly to next step without further purification. MS (ES+) m/e 217 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[Br:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=S)=[C:21]([Cl:28])[CH:20]=1.NC(N)=S.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>O1CCCC1.C(=O)([O-])O.[Na+]>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]2[N:13]([CH2:14][CH2:15][CH2:16][OH:17])[C:3]3[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=[C:11]([Cl:12])[C:2]=3[N:1]=2)=[C:21]([Cl:28])[CH:20]=1
Reactant: S=C=Nc1ccc(Br)cc1Cl
Reactant: COC(=O)c1ccc(Cl)c(N)c1NCCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NC(N)=S
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(Cl)c2nc(Nc3ccc(Br)cc3Cl)n(CCCO)c12
Temperature: 25 °C
Reaction time: 60 h
Yield: 64.6 %

Procedure:
To a solution of methyl 3-amino-4-chloro-2-[(3-hydroxypropyl)amino]benzoate (7.67 g, 29.72 mmol) in tetrahydrofuran (200 mL) was added 4-bromo-2-chloro-1-isothiocyanatobenzene (8.86 g, 35.66 mmol). The reaction mixture was stirred at room temperature for 2.5 d. The starting material wasn't consumed completely. To the mixture was added 4-bromo-2-chloro-1-isothiocyanatobenzene (1.47 g, 5.91 mmol). The reaction mixture was stirred at room temperature for 5 hrs. The solvent was removed by concentration. The residue was washed with diisopropyl ether to give a mixture contained the thiourea. The mixture was subject to next step without further purification. The mixture was dissolved into tetrahydrofuran (200 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (4.41 g, 22.97 mmol) and triethylamine (3.50 mL, 25.27 mmol). The reaction mixture was stirred at 50° C. for 13 hrs. After cooling, the mixture was diluted with aqueous sodium hydrogen carbonate and extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was washed with diisopropyl ether/ethyl acetate to give the title compound as a colorless solid (9.08 g, 19.19 mmol, 65% (2 steps)).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:9]([NH:18][S@@](C(C)(C)C)=O)([CH2:11][C@H:12]([OH:17])[C:13]([F:16])([F:15])[F:14])[CH3:10].CO.Cl.O1CCOCC1>C(Cl)Cl>[NH2:18][C@@:9]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[F:1])([CH3:10])[CH2:11][C@H:12]([OH:17])[C:13]([F:14])([F:15])[F:16]
Reactant: CC(C)(C)[S@@](=O)N[C@@](C)(C[C@H](O)C(F)(F)F)c1cccc(F)c1F
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: C[C@](N)(C[C@H](O)C(F)(F)F)c1cccc(F)c1F
Reaction time: 0.67 h

Procedure:
(R)-N-((2S,4S)-2-(2,3-difluorophenyl)-5,5,5-trifluoro-4-hydroxypentan-2-yl)-2-methylpropane-2-sulfinamide (7.18 g, 19.23 mmol) was dissolved in DCM (50 mL) and MeOH (25 mL) to form a clear solution. To this solution was added hydrogen chloride, 4M in 1,4-dioxane (48.1 ml, 192 mmol) via syringe. After stirred for 40 min, the mixture was concentrated, basified with 1N NaOH and diluted with DCM (400 ml) and water (50 ml). The separated organic layer was washed with brine (2×), dried over Na2SO4 and then filtered. The filtrate was concentrated and dried in vacuum to afford (2S,4S)-4-amino-4-(2,3-difluorophenyl)-1,1,1-trifluoropentan-2-ol as white solid with MS+=270 (M+1). This crude product was dissolved in THF (100 ml) and then treated with benzoyl isothiocyanate (2.85 ml, 21.15 mmol). After stirred for 40 min, triethylamine (3.21 ml, 23.08 mmol) and N1-((ethylimino)methylene)-N3,N-3-dimethylpropane-1,3-diamine hydrochloride (4.05 g, 21.15 mmol) were added. The resulted suspension was brought up to 70° C. for 40 min. Then the reaction mixture was partitioned between EtOAc and water. The separated organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated and purified by silica gel column (0-20% EtOAc/hexane) to afford N-((4S,6S)-4-(2,3-difluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (7.0 g, 17.57 mmol, 91% yield) as white solid. MS m/z=399.0 [M+H]+. Calculated for C19H15F5N2O2: 398.3
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-])=O)=[C:5]([NH2:18])[CH:4]=1.IC1C=CC(SC)=CC=1N>O=[Pt]=O.C(O)C>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:15])=[C:5]([NH2:18])[CH:4]=1
Reactant: CSc1ccc(-c2ccccc2[N+](=O)[O-])c(N)c1
Agent: O=[Pt]=O
Agent: CSc1ccc(I)c(N)c1
Solvent: CCO
Product: CSc1ccc(-c2ccccc2N)c(N)c1
Reaction time: 0.17 h

Procedure:
A flask was charged with ca. 1 mmol of 4-Methylsulfanyl-2′-nitro-biphenyl-2-ylamine, 15 mL of ethanol, and 0.1 mmol of PtO2, and stirred under hydrogen atmosphere at 40 psi for 10 minutes. The reaction mixture was filtered through diatomaceous earth, washed with ethanol, and the combined organic layer was evaporated to dryness. The crude material was purified by preparative HPLC. The same material can also be prepared by the previous method, (Suzuki coupling conditions) starting from 4-iodo-3-aminothioanisole, and purified by preparative HPLC.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:4]=2[S:5][CH:6]=1.Cl.Cl[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[F:20].O>CN1CCCC1=O>[F:11][C:8]1[CH:9]=[CH:10][C:3]2[C:2]([NH:1][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[F:20])=[CH:6][S:5][C:4]=2[CH:7]=1
Reactant: Fc1cnccc1Cl
Reactant: Nc1csc2cc(F)ccc12
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Product: Fc1ccc2c(Nc3ccncc3F)csc2c1
Yield: 82.6 %

Procedure:
A solution of 3-amino-6-fluorobenzo[b]thiophene (10 g, 60 mmol) and 4-chloro-3-fluoropyridine hydrochloride (12 g, 71 mmol) in 150 mL of 1-methyl-2-pyrrolidinone was stirred at 90-95° for 2.5 h, and thereafter cooled, stirred with water and extracted with ether. The aqueous layer was basified with 30% aqueous ammonium hydroxide and extracted with ether. The organic extract was washed with water and saturated sodium chloride solution, and dried (anhydrous magnesium sulfate), filtered and concentrated to give 13 g of a solid. Elution through silica with 10% ethyl acetate in dichloromethane via flash column chromatography yielded 7 g (44.6%) of a white solid, mp 155-157° C. Recrystallization of 2 g from acetonitrile afforded 1.3 g (29%) of white needles, mp 158-159° C.