Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[C:5]([OH:16])=[C:6]2[C:11](=[C:12]([CH3:14])[CH:13]=1)[NH:10][C:9](=[O:15])[CH:8]=[CH:7]2)[CH:2]=[CH2:3].[C:17](O)(=[O:19])[CH3:18]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[C:17]([O:16][C:5]1[C:4]([CH2:1][CH:2]=[CH2:3])=[CH:13][C:12]([CH3:14])=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:15])[NH:10]2)(=[O:19])[CH3:18]
Reactant: CC(=O)O
Reactant: C=CCc1cc(C)c2[nH]c(=O)ccc2c1O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: C=CCc1cc(C)c2[nH]c(=O)ccc2c1OC(C)=O
Temperature: 25 °C
Yield: 91.3 %

Procedure:
To a solution of 6-allyl-5-hydroxy-8-methylcarbostyril (3.2 g, 14.9 mmol) in pyridine (50 ml), acetic acid (3.5 34.3 mmol) was added and stirred at room temperature for hour. The mixture was condensed and dissolved in chloroform. The resultant solution was washed with saturated aqueous sodium bicarbonate solution, aqueous 2N-HCl solution, and water, and dried and condensed. As a result, 3.5 g of 5-acetoxy-6-allyl-8-methylcarbostyril was obtained as colorless crystals (91.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30]C)[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28]C)=[N:13][C:14]=1[CH2:15]C.ClC1C=C(Cl)C=CC=1C1N=C(C)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1C.CI>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH3:30])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH3:28])=[N:13][C:14]=1[CH3:15]
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Agent: Cc1nc(-c2ccc(Cl)cc2Cl)c(C)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: CI
Product: CO[C@H]1Cc2ccccc2[C@H]1Nc1nc(C)c(-c2ccc(Cl)cc2Cl)nc1C

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-dimethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol and methyl iodide, and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ) 7.51, 7.43, 7.37–7.25, 5.86, 5.40, 4.28, 3.43, 3.23, 3.06, 2.42, 2.25; HRMS (FAB) calcd for C22H21Cl2N3O+H 414.1140, found 414.1143.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:16])=[C:7]([CH:15]=1)[C:8]([O:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[O:9])=[CH2:2].I[C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:27][C:28]2[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][N:29]=2)(=[O:26])=[O:25])=[CH:20][CH:19]=1.C(N(CCCC)CCCC)CCC>[Pd].CC(N(C)C)=O>[OH:16][C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[CH:2][C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH:27][C:28]3[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][N:29]=3)(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[CH:15][C:7]=1[C:8]([O:10][CH2:11][CH:12]([CH3:13])[CH3:14])=[O:9]
Reactant: C=Cc1ccc(O)c(C(=O)OCC(C)C)c1
Reactant: Cc1cccnc1NS(=O)(=O)c1ccc(I)cc1
Agent: [Pd]
Solvent: CC(=O)N(C)C
Solvent: CCCCN(CCCC)CCCC
Product: Cc1cccnc1NS(=O)(=O)c1ccc(C=Cc2ccc(O)c(C(=O)OCC(C)C)c2)cc1
Yield: 51.4 %

Procedure:
10% Palladium on charcoal (0.5g) was added to a solution of isobutyl 5-ethenyl-2-hydroxybenzoate (6.6 g, 30mmol) and 4-iodo-N-(3-methyl-2-pyridinyl)benzenesulfonamide (11.2 g, 30 mmol) in dimethylacetamide (10 ml) and tributylamine (10 ml, 42 mmol) at 110° C. After 90 min. the solution was filtered and diluted with isopropanol (0.3 l) and chilled in a freezer. The product was filtered off, dried and dissolved in boiling formic acid (100 ml). The solution was filtered and water (65 ml) was added. After cooling to refrigerator temperature the product was filtered off and dried to yield 7.2 g (51%) product
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[C:25]([O:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=[CH:22][C:21]=3[N:32]([CH3:34])[CH3:33])[CH2:15][CH2:14]2)[C:9]2[C:4](=[CH:5][C:6]([O:37][CH3:38])=[C:7]([O:35][CH3:36])[CH:8]=2)[N:3]=1.[NH2:39][CH2:40][CH:41]1[CH2:44][N:43](C(OC(C)(C)C)=O)[CH2:42]1.C(=O)([O-])N.C(C(O)=O)(F)(F)F>>[NH:43]1[CH2:44][CH:41]([CH2:40][NH:39][C:2]2[N:11]=[C:10]([NH:12][CH:13]3[CH2:18][CH2:17][N:16]([CH2:19][C:20]4[C:25]([O:26][CH2:27][CH2:28][N:29]([CH3:30])[CH3:31])=[CH:24][CH:23]=[CH:22][C:21]=4[N:32]([CH3:33])[CH3:34])[CH2:15][CH2:14]3)[C:9]3[C:4](=[CH:5][C:6]([O:37][CH3:38])=[C:7]([O:35][CH3:36])[CH:8]=3)[N:3]=2)[CH2:42]1
Reactant: COc1cc2nc(Cl)nc(NC3CCN(Cc4c(OCCN(C)C)cccc4N(C)C)CC3)c2cc1OC
Reactant: CC(C)(C)OC(=O)N1CC(CN)C1
Agent: NC(=O)[O-]
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2nc(NCC3CNC3)nc(NC3CCN(Cc4c(OCCN(C)C)cccc4N(C)C)CC3)c2cc1OC

Procedure:
Following General Procedure D, Compound 75 (100 mg, 0.18 mmol) and tert-butyl 3-(aminomethyl)azetidine-1-carboxylate (62 mg, 0.31 mmol) were converted into the carbamate product. The crude carbamate product was treated with CF3CO2H and purified using neutral alumina prep TLC, eluting with 5% NH3-MeOH and 95% CH2Cl2 to isolate the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([CH:16]3[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.[O:21]([C:28]([NH:30][C:31]1[CH:32]=[C:33]([CH:47]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:49]=1)[O:34][CH2:35][CH:36]1[CH2:39][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:37]1)=O)C1C=CC=CC=1.CCN(C(C)C)C(C)C>C1COCC1>[CH:16]1([C:14]([NH:13][C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:19]=[CH:20][C:2]([NH:1][C:28]([NH:30][C:31]4[CH:32]=[C:33]([CH:47]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:49]=4)[O:34][CH2:35][CH:36]4[CH2:37][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:39]4)=[O:21])=[CH:3][CH:4]=3)[CH:12]=[CH:11][N:10]=2)=[O:15])[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CC(COc2cc(NC(=O)Oc3ccccc3)cc(C(F)(F)F)c2)C1
Reactant: Nc1ccc(Oc2ccnc(NC(=O)C3CC3)c2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(COc2cc(NC(=O)Nc3ccc(Oc4ccnc(NC(=O)C5CC5)c4)cc3)cc(C(F)(F)F)c2)C1
Temperature: 70 °C
Reaction time: 12 h
Yield: 52.7 %

Procedure:
Dissolve N-[4-(4-aminophenoxy)-2-pyridyl]cyclopropanecarboxamide (200 mg, 0.74 mmol) and tert-butyl 3-[[3-(phenoxycarbonylamino)-5-(trifluoromethyl)phenoxy]methyl]-azetidine-1-carboxylate (415 mg, 0.89 mmol) in THF (10 mL), add DIEA (200 mg, 1.48 mmol), stir under N2 at 70° C. for 12 hrs. Concentrate under reduced pressure to give the crude product. Purification by chromatography (silica gel, EtOAc:PE=2:1) affords the title compound (250 mg, 52.4%). MS: (M+1): 642.3.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:3]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21]1.C(N(CC)CC)C>C(Cl)Cl>[OH:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:4]1[N:3]=[C:2]([N:20]2[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:21]2)[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: Cc1ccc2c(Cl)nc(-c3ccccc3O)nc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.5 %

Procedure:
To a solution of 2-(4-chloro-7-methylquinazolin-2-yl)phenol (0.5 g, 1.84 mmol) in CH2Cl2 (10 mL) at 0° C. was added dropwise a solution of tert-butyl(R)-piperidin-3-ylcarbamate (0.37 g, 1.84 mmol) in CH2Cl2 (5 mL), then triethylamine (0.51 mL, 3.68 mmol). The mixture was allowed to warm to room temperature and was stirred for 3 h. After quenching with water, it was extracted with CH2Cl2. The organic layers were combined, dried over MgSO4, and concentrated. Purification via silica gel chromatography using 5:1 CH2Cl2: hexanes gave tert-butyl(R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-ylcarbamate (0.54 g, 68%). LC/MS: m/z 435.5 (M+H)+ at 2.80 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: COC1C=CC(C[S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([OH:29])=O)[CH2:10]2)=CC=1.[N+:32]([C:35]1[CH:63]=[CH:62][C:38]([CH2:39][O:40][C:41]([CH:43]2[CH2:48][NH:47][CH2:46][CH2:45][N:44]2[C:49]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][C:56]([N+:59]([O-:61])=[O:60])=[CH:55][CH:54]=2)=[O:50])=[O:42])=[CH:37][CH:36]=1)([O-:34])=[O:33]>>[SH:8][C@@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=2)=[O:15])[C@H:11]([C:27]([N:47]2[CH2:46][CH2:45][N:44]([C:49]([O:51][CH2:52][C:53]3[CH:54]=[CH:55][C:56]([N+:59]([O-:61])=[O:60])=[CH:57][CH:58]=3)=[O:50])[CH:43]([C:41]([O:40][CH2:39][C:38]3[CH:62]=[CH:63][C:35]([N+:32]([O-:34])=[O:33])=[CH:36][CH:37]=3)=[O:42])[CH2:48]2)=[O:29])[CH2:10]1
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)C1CNCCN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)C1CN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CCN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 34.1 %

Procedure:
Following a procedure similar to that described in Preparation 8, but using 0.47 g of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid, 0.20 g of N,N'-carbonyldiimidazole and 0.70 g of 2-(4-nitrobenzyloxycarbonyl)-1-(4-nitrobenzyloxycarbonyl)piperazine, 270 mg of the title compound were obtained as an amorphous solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:12]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH2:11][C:5]1[CH:6]=[CH:10][CH:2]=[CH:3][CH:4]=1)=[O:8])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: Cc1ccc(O)cc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(OCc2ccccc2)cc1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 168.6 %

Procedure:
To a solution of 5-hydroxy-2-methylbenzoic acid (1.52 g) in DMF (25 mL) were added benzyl bromide (3.40 g) and potassium carbonate (4.14 g), and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the precipitated crystals were collected by filtration, and dried to give the title compound (2.80 g) as a white solid. This compound was used for the next step without further purification.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[S:6][C:5]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=2)=[CH:15][CH:14]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=C(O)C=Cc1ccc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C(O)C=Cc1ccc(-c2ccc(Cl)cc2)s1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.250 g (1.1 mmol) of 3-(5-bromo-thiophen-2-yl)-acrylic acid and 61.9 mg (0.1 mmol) of tetrakis(triphenylphosphine)palladium were dissolved in 5 ml of degassed DME and stirred at room temperature for 10 min. 0.251 g (1.6 mmol) of 4-chlorophenylboronic acid and 1 ml of a 2 M aqueous sodium carbonate solution were added together with an additional 5 ml of degassed DME. The resulting solution was heated to 95° C. for 4 h and then stirred at room temperature for 16 h. Solids were removed by filtration, and the resulting solution was evaporated to dryness. The residue was dissolved in ethyl acetate and washed three times with a saturated sodium hydrogencarbonate solution and once with a saturated sodium chloride solution. The organic phase was dried with sodium sulfate, filtered, and the solvent was removed under reduced pressure. The product was purified by silica gel chromatography. Yield: 0.12 g.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5]([Si:9]([CH3:12])([CH3:11])Cl)([CH3:8])([CH3:7])[CH3:6].CCN(CC)CC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:5]([Si:9]([CH3:12])([CH3:11])[O:2][CH2:1][CH2:3][NH2:4])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: NCCO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCN
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of ethanolamine (0.5 mL, 8.1 mmol), tert-butyldimethylchlorosilane (1.42 g, 8.9 mmol), Et3N (1.25 mL, 8.9 mmol) and DMAP (51 mg, 0.41 mmol) in DCM (25 mL) is stirred at RT for 18 h. The reaction mixture is quenched by H2O, DCM is added and the organic layer is washed with brine, dried over MgSO4 and evaporated in vacuo. Silica gel flash chromatography of the residue affords the title compound as a colorless oil; ES-MS: M+=176.2; 1HNMR (CDCl3) 3.95-3.85 (m, 2H), 3.15-3.10 (m, 2H), 0.90 (s, 9H), 0.05 (s, 6H), NH2 is missing.
Reaction SMILES: [CH:1]1([CH2:5][O:6][C:7]2[C:12]3[C:13]([O:16][CH2:17][CH:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=[N:14][O:15][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH2:4][CH2:3][CH2:2]1.O=[CH:25][CH2:26][C:27]1([C:33]([O:35][CH3:36])=[O:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(C1(C(OC)=O)CCC1)=O>>[CH:1]1([CH2:5][O:6][C:7]2[C:12]3[C:13]([O:16][CH2:17][CH:18]4[CH2:19][CH2:20][N:21]([CH2:25][CH2:26][C:27]5([C:33]([O:35][CH3:36])=[O:34])[CH2:28][CH2:29][O:30][CH2:31][CH2:32]5)[CH2:22][CH2:23]4)=[N:14][O:15][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: c1cc(OCC2CCC2)c2c(OCC3CCNCC3)noc2c1
Reactant: COC(=O)C1(CC=O)CCOCC1
Agent: COC(=O)C1(C=O)CCC1
Product: COC(=O)C1(CCN2CCC(COc3noc4cccc(OCC5CCC5)c34)CC2)CCOCC1

Procedure:
The title compound was prepared according to the procedure described in Step 3 of EXAMPLE 2 using 4-(cyclobutylmethoxy)-3-(piperidin-4-ylmethoxy)-1,2-benzisoxazole (EXAMPLE 17, Step 4) and methyl 4-(2-oxoethyl)tetrahydro-2H-pyran-4-carboxylate (WO 2004/043958) instead of 3-(piperidin-4-ylmethoxy)-4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazole and methyl 1-formylcyclobutanecarboxylate.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[F:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=2)[NH2:7])=[CH:15][CH:14]=1
Reactant: Oc1ccc(F)cc1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(Oc2ccc(F)cc2)ccc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 24 h
Yield: 102.7 %

Procedure:
A mixture of 5-chloro-2-nitroaniline (345 mg, 2.00 mmol), 4-fluorophenol (224 mg, 2 mmol), potassium carbonate (549 mg, 4 mmol) and DMF (8 mL) was stirred at 120° C. for 1 day. The mixture was cooled and then water (10 mL) was added. The mixture was extracted with ethyl acetate (4×2 mL). The combined extract was dried over magnesium sulfate and concentrated. Product was purified from the residue by silica gel column chromatography (eluted with a 6:1 mixture of hexane/EtOAc) to give 5-(4-fluorophenoxy)-2-nitroaniline (510 mg, quant) as a yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH2:7][C:8]([OH:10])=O.CCN(C(C)C)C(C)C.[NH2:23][CH2:24][CH:25]([OH:37])[CH2:26][N:27]1[CH2:36][CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28]1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(Cl)Cl>[CH2:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:35][CH2:36][N:27]1[CH2:26][CH:25]([OH:37])[CH2:24][NH:23][C:8](=[O:10])[CH2:7][O:6][C:5]1[CH:11]=[CH:12][CH:13]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: COc1cccc(OCC(=O)O)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(OCC(=O)NCC(O)CN2CCc3ccccc3C2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30 %

Procedure:
To a stirred mixture of 2-(3-methoxyphenoxy)acetic acid (100 mg, 0.549 mmol) in DCM (5 mL) was added DIEA (106 mg, 0.824 mmol), 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (113 mg, 0.549 mmol) and Bop-Cl (168 mg, 0.66 mmol). The mixture was stirred at 25° C. for 16 hours then the reaction mixture was quenched with water (20 mL), extracted with DCM (3×20 mL). The combined extracts were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-HPLC to afford the desired product (61 mg, Yield 32%). 1H NMR (400 MHz, MeOD) δ 7.21 (dd, J1=J2=8.0 Hz, 1H), 7.17-7.03 (m, 4H), 6.59-6.51 (m, 3H), 4.52 (s, 2H), 4.05-4.01 (m, 1H), 3.77 (s, 3H), 3.73 (d, J=2.8 Hz, 2H), 3.47-3.37 (m, 2H), 2.92 (d, J=5.2 Hz, 2H), 2.87 (d, J=5.2 Hz, 2H), 2.61 (d, J=6.0 Hz, 2H). LCMS (m/z): 371.1 (M+1).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:18][CH:19]([C:24]2([CH3:29])[CH2:28]CC[CH2:25]2)[CH2:20][C:21]([OH:23])=[O:22])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][N:9]=2)=[N:6][CH:7]=1.ClC1N=C(N[C@@H](C(C)(C)C)CC(OC)=O)C(F)=CN=1.C(O)=O>C(#N)C>[F:1][C:2]1[C:3]([NH:18][C@@H:19]([C:24]([CH3:29])([CH3:28])[CH3:25])[CH2:20][C:21]([OH:23])=[O:22])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][N:9]=2)=[N:6][CH:7]=1
Reactant: CC1(C(CC(=O)O)Nc2nc(-c3n[nH]c4ncc(F)cc34)ncc2F)CCCC1
Agent: COC(=O)C[C@@H](Nc1nc(Cl)ncc1F)C(C)(C)C
Solvent: CC#N
Solvent: O=CO
Product: CC(C)(C)[C@@H](CC(=O)O)Nc1nc(-c2n[nH]c3ncc(F)cc23)ncc1F

Procedure:
Compound 5 was synthesized in a manner similar to compound 12, starting with compound 6a: 1H NMR (400 MHz, d6-DMSO) δ 12.65 (s, 1H), 9.43 (s, 1H), 9.15 (s, 1H), 8.44 (d, J=4.7 Hz, 1H), 8.41-8.29 (m, 2H), 3.93 (s, 1H), 3.54 (s, 1H), 1.19 (d, J=20.0 Hz, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=2.70 min, (M+H) 393.32.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[N:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)[C:3]=1[C:4]#[N:5].ClC1C=CC=C(C(OO)=[O:31])C=1>ClCCl>[Cl:1][C:2]1[CH:9]=[N+:8]([O-:31])[CH:7]=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:14][CH:15]=2)[C:3]=1[C:4]#[N:5]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: N#Cc1c(Cl)cncc1-c1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Product: N#Cc1c(Cl)c[n+]([O-])cc1-c1ccc(Oc2ccccc2)cc1
Reaction time: 22 h
Yield: 63.1 %

Procedure:
A solution of 3-chloro-5-(4-phenoxyphenyl)isonicotinonitrile (0.495 g, 1.614 mmol) and 77% 3-chloroperbenzoic acid (1.808 g, 8.07 mmol) in dichloromethane (20 mL) was stirred at room temperature. After 22 h at room temperature, the mixture was diluted with dichloromethane (100 mL), washed with 1 M sodium sulfite (25 mL), 1 N NaOH (2×25 mL), brined (25 mL), dried (MgSO4) and concentrated. Silica gel chromatography, loading with dichloromethane and eluting with 20-50% ethyl acetate in hexanes, gave 3-chloro-4-cyano-5-(4-phenoxyphenyl)pyridine 1-oxide as white solid (328.8 mg, 63% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.25 (1H, δ, J=1.51 Hz), 8.16 (1H, δ, J=1.51 Hz), 7.46-7.58 (2H, m), 7.36-7.45 (2H, m), 7.21 (1H, t, J=7.40 Hz), 7.03-7.16 (4H, m); MS (ES+) m/z: 323 (M+H); LC retention time: 3.863 min (analytical HPLC Method A).
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][C:9]([CH2:10][NH2:11])=[C:4]2[CH:3]=[CH:2]1.Cl[C:13]1[N:18]=[C:17]([NH:19][C:20]2[CH:24]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[NH:22][N:21]=2)[CH:16]=[CH:15][N:14]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][C:9]([CH2:10][NH:11][C:13]3[N:18]=[C:17]([NH:19][C:20]4[CH:24]=[C:23]([CH:25]5[CH2:27][CH2:26]5)[NH:22][N:21]=4)[CH:16]=[CH:15][N:14]=3)=[C:4]2[CH:3]=[CH:2]1
Reactant: Clc1nccc(Nc2cc(C3CC3)[nH]n2)n1
Reactant: NCc1cncc2[nH]ccc12
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: c1cc(Nc2cc(C3CC3)[nH]n2)nc(NCc2cncc3[nH]ccc23)n1
Temperature: 120 °C
Reaction time: 18 h
Yield: 11.1 %

Procedure:
A mixture of (1H-pyrrolo[2,3-c]pyridin-4-yl)methanamine (236 mg, 1.61 mmol), 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (344 mg, 1.46 mmol) and DIPEA (565 mg, 4.38 mmol) in IPA (2 mL) was stirred in a sealed tube at 120° C. for 18 h. The reaction mixture was cooled to RT and concentrated in vacuo. The crude residue was purification by preparative HPLC to afford 56 mg (11.1%) of the title compound as white solid: 1H NMR (500 MHz, CD3OD) δ 8.64 (s, 1H), 8.06 (s, 1H), 7.85 (s, 1H), 7.59 (d, J=3.0, 1H), 6.72 (d, J=3.0, 1H), 6.17-5.96 (m, 2H), 4.92 (s, 2H), 1.75 (s, 1H), 0.85 (d, J=4.5, 2H), 0.51 (s, 2H); MS (ESI) m/z: 347.2 [M+1]+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([CH:13]3[CH2:17][NH:16][C:15](=[O:18])[CH2:14]3)=[CH:10][CH:11]=2)[N:6]([CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:5]=1.[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CN1C(=O)N(C)CCC1>O1CCCC1>[CH2:28]([N:16]1[CH2:17][CH:13]([C:9]2[CH:8]=[C:7]3[C:12]([C:4]([CH3:3])=[CH:5][N:6]3[CH2:19][CH2:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:11][CH:10]=2)[CH2:14][C:15]1=[O:18])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Cc1cn(CCCc2ccccc2)c2cc(C3CNC(=O)C3)ccc12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: Cc1cn(CCCc2ccccc2)c2cc(C3CC(=O)N(Cc4ccccc4)C3)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
A solution of sodium hydride (0.013 g) in tetrahydrofuran at 0° C., under argon, was treated with a solution of 4-[3-methyl-1-(3-phenyl-propyl)-1H-indole-6-yl]-pyrrolidine-2-one (0.184 g, Example 20) and benzyl bromide (0.094 g) in dry tetrahydrofuran. The mixture was allowed to warm to room temperature then treated with N,N′-dimethylpropyleneurea (0.05 g). After stirring at room temperature overnight the solution was partitioned between ethyl acetate (15 ml)and 1N hydrochloric acid (15 ml). The organic phase was dried over magnesium sulphate then evaporated. The residue was subjected to preparative layer chromatography on silica using a mixture of ethyl acetate and hexane (3:7, v/v) as eluent to yield the title compound (0.18 g) as an oil. [Elemental analysis:—C, 79.16; H, 6.98; N, 6.14%. Calculated for C29H30N2O.H2O:—C, 79.04; H, 7.33; N, 6.36%].
Reaction SMILES: Br.Br.[N:3]1([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(O)C.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C(=O)([O-])O.[Na+]>O>[OH:15][C:12]1[CH:11]=[CH:10][C:9]([N:3]2[CH2:4][CH2:5][N:6]([S:26]([C:23]3[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=3)(=[O:28])=[O:27])[CH2:7][CH2:8]2)=[CH:14][CH:13]=1
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)N2CCN(c3ccc(O)cc3)CC2)cc1
Reaction time: 0.5 h

Procedure:
To a stirred mixture of 15.5 parts of 4-(1-piperazinyl)phenol dihydrobromide, 40 parts of ethanol and 75 parts of water are added 15.2 parts of 4-methylbenzenesulfonyl chloride and stirring is continued for 30 minutes at room temperature. Then there are added portionwise 12.6 parts of sodium hydrogen carbonate at 0° C. Upon completion, stirring is continued overnight at room temperature. The precipitated product is filtered off and taken up in alkaline water. The mixture is filtered over hyflo and the filtrate is acidified with acetic acid. The precipitated product is filtered off and taken up in water. The free base is liberated in the conventional manner with a sodium hydroxide solution. The whole is filtered over hyflo and the filtrate is acidified with acetic acid. The precipitated product is filtered off and dried, yielding 4.8 parts of 1-(4-hydroxyphenyl)-4-(4-methylphenylsulfonyl)piperazine; mp. 193.1° C.