Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[CH:51][C:52]([C:58]5[NH:59][N:60]=[CH:61][CH:62]=5)=[CH:53][CH:54]=4)[O:49][C:48]=3[C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C>>[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[CH:51][C:52]([C:58]5[NH:59][N:60]=[CH:61][CH:62]=5)=[CH:53][CH:54]=4)[O:49][C:48]=3[C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)=[CH:45][CH:46]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4cc(-c5ccn[nH]5)ccc4c3=O)cc2)CCC1
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4cc(-c5ccn[nH]5)ccc4c3=O)cc2)CCC1
Yield: 92 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, (1-{-4-[4-oxo-2-phenyl-7-(2H-pyrazol-3-yl)-4H-chromen-3-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester was reacted to give the title compound as a cream solid (27 mg, 92%). 1H NMR (400 MHz, DMSO-d6): δ 13.36-13.12 (br s, 1H), 8.14-8.11 (m, 2H), 8.05-8.00 (m, 1H), 7.90-7.83 (br s, 1H), 7.48-7.33 (m, 7H), 7.21-7.17 (m, 2H), 7.00 (d, J=3 Hz, 1H), 2.47-2.39 (m, 2H), 2.24-2.15 (m, 2H), 2.08-1.97 (m, 1H), 1.73-1.64 (m, 1H). LCMS (Method F): RT=8.99 min, [M+H]+=434.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25]([OH:27])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O[N:29]=[C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[NH2:31]>>[C:32]1([C:30]2[N:31]=[C:25]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[O:8])[CH2:10]3)[O:27][N:29]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: NC(=NO)c1ccccc1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3ccccc3)no2)C1

Procedure:
250 mg (0.65 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 49A) and 97 mg (0.71 mmol) of N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 35 mg (12% of theory)
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH2:6][CH2:7][C:8](=[O:30])[C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([C:24](=[O:28])[CH2:25]2)[C@:21]2([CH3:22])[C@H:16]([CH2:17][C@H:18]([OH:29])[CH2:19][CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)=[O:4].[I-:31].[Na+]>CC(C)=O>[OH:29][C@@H:18]1[CH2:19][CH2:20][C@@:21]2([CH3:22])[C@@H:16]([CH2:15][CH2:14][C@@H:13]3[C@@H:23]2[C:24](=[O:28])[CH2:25][C@@:26]2([CH3:27])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C:8](=[O:30])[CH2:7][CH2:6][O:5][C:3](=[O:4])[CH2:2][I:31])[CH2:17]1
Reactant: [I-]
Reactant: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CCOC(=O)CCl)[C@@]3(C)CC(=O)[C@@H]12
Agent: [Na+]
Solvent: CC(C)=O
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CCOC(=O)CI)[C@@]3(C)CC(=O)[C@@H]12
Yield: 103.4 %

Procedure:
21-Chloroacetoxymethyl-3α-hydroxy-5α-pregnane-11,20-dione (400 mg.) in acetone (40 ml) was treated with sodium iodide (420 mg.) and the mixture was refluxed for 40 mins. The filtered solution was evaporated to a yellow solid which was partitioned between water and ether/ethyl acetate 1:1. The organic layer was washed with water, dried over sodium sulphate and evaporated to give title compound (500 mg) as a yellow foam.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=3)=[CH:9][N:8]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:28][N:29]([C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1)[C:30](=[O:32])[CH3:31].OC1C=CC=C2C=1N=CC=C2>[Cu]Cl.CC(N(C)C)=O>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:39][C:36]4[CH:35]=[CH:34][C:33]([N:29]([CH3:28])[C:30](=[O:32])[CH3:31])=[CH:38][CH:37]=4)=[CH:13][CH:12]=3)=[CH:9][N:8]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(C)(C)n1cc(-c2ccc(I)cc2)c2c(N)ncnc21
Reactant: CC(=O)N(C)c1ccc(O)cc1
Agent: Cl[Cu]
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CC(=O)N(C)C
Product: CC(=O)N(C)c1ccc(Oc2ccc(-c3cn(C(C)(C)C)c4ncnc(N)c34)cc2)cc1

Procedure:
In a similar manner to Example 9, a mixture of 4-amino-5-(4-iodophenyl)-7-(tert-butyl)pyrrolo[2,3-d]pyrimidine (100 mg), potassium carbonate (104 mg), N-methyl-(4-acetamido)phenol (120 mg), 8-hydroxyquinoline (8 mg), copper (I) chloride (5 mg) and dimethylacetamide (8 ml) gave N-{4-[4-(4-amino-7-tert-butylpyrrolo[2,3-d]-pyrimidin-5-yl)phenoxy]phenyl}-N-methylacetamide. This structure was confirmed by 1H nmr.
Reaction SMILES: [ClH:1].Cl.[CH3:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.[Br:16]Br>C(O)(=O)C.O>[ClH:1].[Br:16][C:9]1[CH:8]=[CH:7][C:6]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:5][C:4]=1[CH3:3]
Reactant: BrBr
Reactant: Cc1cccc(N2CCNCC2)c1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(N2CCNCC2)ccc1Br
Reaction time: 1 h

Procedure:
To a solution of 966 mg (4.0 mmol) of 1-(3-Methylphenyl)piperazine dihydrochloride in 9 mL of acetic acid and 1 mL of water at 0° C. was added 640 mg (4.0 mmol) of bromine. After 1 hour, the reaction was concentrated to an oil in vacuo, and the oil was partitioned between ethyl acetate and 1M NaOH. The phases were separated, and the ethyl acetate phase was washed once each with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to an oil in vacuo. The oil was dissolved in a minimum volume of methanol, and the solution was acidified with 2M HCl in ether. The product was isolated by filtration. 1H NMR (D2O, 400 MHz) 7.37 (d, 1H), 6.85 (s, 1H), 6.76 (d, 1H), 3.37 (m, 8H), 2.17 (s, 3H) ppm.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26](O)=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C1CN([P+](O[N:49]2N=N[C:51]3C=CC=[CH:55][C:50]2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CC(N)C>C(Cl)Cl.CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([NH:49][CH:50]([CH3:55])[CH3:51])=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)NC(=O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Reaction time: 0.5 h

Procedure:
A suspension of 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (70 mg, 0.14 mmol), PyBOP® (40 mg, 0.077 mmol), DIEA (24 μL, 0.14 mmol) in dry CH2Cl2:DMF (2:0.1 mL) was stirred at RT for 15 minutes. To this solution of activated acid was added propan-2-amine (5.4 mg, 0.091 mmol). After 30 minutes, 1.0 equivalent of DIEA and 0.55 equivalents of PyBOP® were added. After stirring the solution for 15 minutes, 0.65 equivalents of propan-2-amine were added and the mixture was stirred for an additional 30 minutes. The solvent was removed in vacuo and the crude product was purified using prep HPLC (25-50—90 mins) to afford 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-isopropylacetamide. (40 mg, 0.086 mmol, 61%).
Reaction SMILES: [OH:1][CH:2]([C:24]1[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=1)[C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=2[C:6]([CH3:14])=[C:5]([NH:15][C:16](=[O:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:4]=1[CH3:23]>ClCCl.[O-2].[O-2].[Mn+4]>[CH:30]([C:27]1[CH:26]=[CH:25][C:24]([C:2]([C:3]2[C:11]3[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=3[C:6]([CH3:14])=[C:5]([NH:15][C:16](=[O:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:4]=2[CH3:23])=[O:1])=[CH:29][CH:28]=1)([CH3:32])[CH3:31]
Reactant: Cc1c2c(c(C(O)c3ccc(C(C)C)cc3)c(C)c1NC(=O)CC(C)(C)C)OC(C)(C)C2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1c2c(c(C(=O)c3ccc(C(C)C)cc3)c(C)c1NC(=O)CC(C)(C)C)OC(C)(C)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.6 %

Procedure:
To a solution of N-(7-(hydroxy(4-isopropylphenyl)methyl)-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (209 mg, 0.48 mmol) obtained in Example 341 in dichloromethane (7 mL) was added manganese dioxide (415 mg, 4.8 mmol) and the mixture was stirred at room temperature for 8 hours. The reaction solution was filtered and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:3) to obtain 156 mg (yield: 75%) of the title compound. Melting point: 194-195° C. (ethyl acetate-hexane).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:18](=[N:20][NH:21][C:22]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[O:23])[CH3:19])=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1.CO.[OH-].[Na+].Cl>O>[OH:1][C:2]1[C:3]([C:18](=[N:20][NH:21][C:22]([C:24]2[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=2)=[O:23])[CH3:19])=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:8]=1
Reactant: COC(=O)c1ccc(C(=O)NN=C(C)c2nn(C)c(-c3cccc(C(F)(F)F)c3)c2O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=NNC(=O)c1ccc(C(=O)O)cc1)c1nn(C)c(-c2cccc(C(F)(F)F)c2)c1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 54.8 %

Procedure:
To methyl 4-{[2-(1-{4-hydroxy-1-methyl-5-[3-(trifluoromethyl)phenyl]-1H-pyrazol-3-yl}ethylidene)hydrazino]carbonyl}benzoate (0.072 mmol, 33.1 mg), methanol (2 mL) was added, and 1 M aqueous sodium hydroxide (5 eq., 0.360 mL) was added at room temperature. After 30 minutes of stirring at room temperature and 1.5 hours of stirring at 60° C., the reactor was cooled to 0° C., and 1 M hydrochloric acid (5 eq., 0.360 mL) and water were added. The precipitated solid was recovered by filtration, washed with water and dried by means of a vacuum pump to give the desired product as a yellow solid (17.6 mg, yield 55%).
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][N:14]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].N>O1CCCC1>[N:14]1([CH2:13][CH2:12][O:11][C:8]2[CH:7]=[CH:6][C:5]([CH2:4][OH:3])=[CH:10][CH:9]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CCOC(=O)c1ccc(OCCN2CCCCCC2)cc1
Agent: N
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1ccc(OCCN2CCCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
To a solution of 4-(2-azepan-1-ylethoxy)benzoic acid ethyl ester (6.0 g) in tetrahydrofuran (60 ml) was added lithium aluminum hydride (1.5 g) under a nitrogen atmosphere, the solution was stirred overnight at room temperature, tetrahydrofuran and aqueous ammonia were then sequentially added thereto on an ice bath, the solution was filtered through celite pad, the solvent was evaporated in vacuo to provide [4-(2-azepan-1-ylethoxy)phenyl]methanol (3.6 g). The title compound (194 mg) was obtained according to an analogous synthetic method to Preparation Example 13 using the above compound (200 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1.C1(C)C=CC(S([O:37][CH:38]2[CH2:42][CH2:41][CH:40](O)[CH2:39]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][CH:40]2[CH2:41][CH2:42][CH:38]([OH:37])[CH2:39]2)=[CH:25][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)OC2CCC(O)C2)cc1
Reactant: OC[C@H]1O[C@](O)(c2ccc(Cl)c(Cc3ccc(O)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: OC[C@H]1O[C@](O)(c2ccc(Cl)c(Cc3ccc(OC4CCC(O)C4)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 70 °C
Reaction time: 16 h

Procedure:
A mixture of 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene (0.25 g), 3-hydroxy-cyclopent-1-yl p-tolylsulfonate (0.19 g) and cesium carbonate (0.33 g) in dimethylformamide (1.5 mL) is stirred at 70° C. for 16 h. After cooling to ambient temperature, water is added and the resultant mixture is extracted with ethyl acetate. The combined organic phases are dried (Na2SO4), the solvent is removed and the residue is purified by chromatography on silica gel (dichloromethane/methanol 1:0→4:1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]([NH2:18])=[O:17])=[C:11]3[NH:10][CH2:9][CH:8]=2)[CH:2]=1.[C:19](N1C=CN=C1)(N1C=CN=C1)=[O:20]>O1CCOCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]3[C:11]4[N:10]([C:19](=[O:20])[NH:18][C:16](=[O:17])[C:15]=4[CH:14]=[N:13]3)[CH2:9][CH:8]=2)[CH:2]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NC(=O)c1cnn2c1NCC=C2c1cccnc1
Solvent: C1COCCO1
Product: O=c1[nH]c(=O)n2c3c1cnn3C(c1cccnc1)=CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.1 %

Procedure:
A mixture of 4.0 g of 4,5-dihydro-7-(3-pyridinyl)pyrazolo(1,5-a)pyrimidine-3-carboxamide (Example 10), 80 ml of dry p-dioxane and 10.0g of 1,1'- carbonyldiimidazole is heated at reflux for 5 hours. Then an additional 5.0 g of 1,1'-carbonyldiimidazole is added and heating is continued for 16 hours. After cooling to room temperature the precipitated solid is collected by filtration, washed with water and dried in vacuo to give 2.0 g of the desired product as a white solid, mp 292-295° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH2:13])=[O:12])=[CH:8][CH:9]=2)[C:4]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][C:21](O)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[CH:3]1>Cl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH2:13])=[O:12])=[CH:8][CH:9]=2)[C:4]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:19][CH:20]=[C:21]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:22][CH2:23]2)=[CH:3]1
Reactant: Cn1cc(CCCCN2CCC(O)(c3ccccc3)CC2)c2cc(C(N)=O)ccc21
Agent: Cl
Product: Cn1cc(CCCCN2CC=C(c3ccccc3)CC2)c2cc(C(N)=O)ccc21

Procedure:
4.05 g of 1-methyl-3-[4-(4-hydroxy-4-phenyl-1-piperidyl)-butyl]-indole-5-carboxamide [obtainable by reacting 1-methyl-3-(4-bromobutyl)-indole-5carboxamide with 4-piperidone, followed by reaction with C6H5Li and hydrolysis] are heated at 50° with 40 ml of hydrochloric acid for 2 hours, and the mixture is worked up in the customary manner to give 1-methyl-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl]-indole-5-carboxamide.
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=2[O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[C:11]([OH:13])=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:25][Li]>CCOCC>[CH3:1][C:2]1([C:8]2[CH:9]=[C:10]([C:11](=[O:13])[CH3:25])[CH:14]=[CH:15][C:16]=2[O:17][Si:18]([C:21]([CH3:22])([CH3:24])[CH3:23])([CH3:19])[CH3:20])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC1(c2cc(C(=O)O)ccc2O[Si](C)(C)C(C)(C)C)CCCCC1
Reactant: [Li]C
Solvent: CCOCC
Product: CC(=O)c1ccc(O[Si](C)(C)C(C)(C)C)c(C2(C)CCCCC2)c1
Reaction time: 8 h

Procedure:
28.82 g (0.083 mol) of 3-(1-methylcyclohexyl)-4-tert-butyldimethylsilyloxybenzoic acid, in 300 ml ether, are treated at -20° C. under nitrogen, with 0.166 mol of methyllithium (1.6M in ether). The reaction mixture is stirred under nitrogen overnight and it is then treated as for Example 25(a). After filtration of the residue on silica, 22 g (76%) of the expected product are isolated in the form of a yellow oil.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[O:9]=[C:10]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11]1.[Cl-].[Na+]>CS(C)=O>[O:9]1[C:10]2([CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11]2)[CH2:2]1
Reactant: CCOC(=O)N1CCC(=O)C1
Reactant: C[S+](C)(C)=O
Agent: [Cl-]
Agent: [H-]
Agent: [I-]
Solvent: CS(C)=O
Product: CCOC(=O)N1CCC2(CO2)C1
Temperature: 25 °C

Procedure:
23.5 g (107 mmol) of trimethylsulphoxonium iodide and 3.3 g of sodium hydride (80% strength in paraffin oil) are initially introduced and 80 ml of absolute dimethyl sulphoxide are added dropwise at 10° C. The mixture is stirred for an hour at room temperature and 15.7 g (100 mmol) of ethyl 3-oxopyrrolidine-1-carboxylate [J. Med. Pharm. Chem. 5, 752 (1962)] in 20 ml of absolute dimethyl sulphoxide are then added dropwise in the course of 15 minutes. The mixture is stirred for one hour at room temperature, poured onto a mixture of ice and saturated sodium chloride solution and extracted using diethyl ether. The ether solutions are washed with sodium chloride solution, dried over Na2SO4, concentrated and distilled.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:15][C:6]2=[N:7][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:10]=[C:5]2[C:4](=O)[CH2:3]1.[CH3:18][C:19]([S@:22]([NH2:24])=[O:23])([CH3:21])[CH3:20].[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CC1CCCO1.C(O[Ti](OCC)(OCC)OCC)C>[CH3:1][C:2]1([CH3:17])[O:15][C:6]2=[N:7][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:10]=[C:5]2[C@H:4]([NH:24][S:22]([C:19]([CH3:21])([CH3:20])[CH3:18])=[O:23])[CH2:3]1
Reactant: CC1(C)CC(=O)c2ccc(C(F)(F)F)nc2O1
Reactant: CC(C)(C)[S@](N)=O
Agent: CCO[Ti](OCC)(OCC)OCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Solvent: CC1CCCO1
Product: CC1(C)C[C@@H](NS(=O)C(C)(C)C)c2ccc(C(F)(F)F)nc2O1
Temperature: -10 °C
Reaction time: 2 h
Yield: 98.5 %

Procedure:
A solution of Example 62B (1.52 g, 6.20 mmol), (R)-2-methylpropane-2-sulfinamide (1.127 g, 9.30 mmol), 2-methyltetrahydrofuran (20 mL), and tetraethoxytitanium (5.20 mL, 24.8 mmol) was heated to 70° C. After 3 hours the solution was cooled to −10° C. and sodium borohydride (0.469 g, 12.4 mmol) was added. The mixture was warmed to room temperature, stirred for 2 hours then cooled to 0° C. and 10% aqueous citric acid (50 mL) was added. The mixture was stirred vigorously overnight then diluted with methyltetrahydrofuran (300 mL). The layers were separated and the organic extract was washed with water and brine, dried (Na2SO4), filtered, and concentrated. Purification by flash chromatography (SiO2, 20-100% hexane/ethyl acetate gradient) provided the title compound (2.14 g, 6.11 mmol, 99% yield). MS (DCI+) m/z 349 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](N)[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.N([O-])=O.[Na+].[OH-].[NH4+].[Cl:19]CCl>Cl.[Cu]Cl>[Br:1][C:2]1[CH:3]=[C:4]([Cl:19])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: ClCCl
Reactant: Nc1cc(Br)c2ncccc2c1
Agent: Cl[Cu]
Agent: Cl
Agent: O=N[O-]
Product: Clc1cc(Br)c2ncccc2c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
8-Bromoquinolin-6-amine (300 mg, 1.34 mmol) was taken up in concentrated hydrochloric acid (8 ml) and cooled to 0° C. (ice bath). Sodium nitrite (1.86 gm, 26.9 mmol) was added in three equal portions over 10 minutes. The mixture was removed from the cooling bath and copper (I) chloride (3.33 g, 33.6 mmol) was added in 3 portions, over about 6 minutes. On stirring a green-black rising foam developed. Stirring was continued for 45 minutes and then the reaction mixture was cooled to 0° C. (ice bath). A mixture of ice water (75 ml) and ammonium hydroxide (75 ml) was added with vigorous stirring. Dichloromethane (150 ml) was added and the material was shaken in a reparatory funnel. The organic phase was collected and shaken with an equal volume of brine. The aqueous phases were back extracted with dichloromethane (2×120 ml). The organics were combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative thin layer chromatography (2 plates), eluting first with 1% methanol/dichloromethane and then re-developing the plate with 25% ethyl acetate/hexane. The product band was collected, providing the desired product as a light yellow-white solid (287 mg). (M+H)+=242/244 m/e.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH2:15])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][C:22]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=4)=[CH:23][CH:24]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(-c2ccc(CN)cc2)ccn1
Reactant: O=C(O)c1ccc(-c2ccccn2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2ccc(CNC(=O)c3ccc(-c4ccccn4)cc3)cc2)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (4-(2-methylpyridin-4-yl)phenyl)methanamine 13-3 (10 mg, 0.05 mmol), 4-(pyridin-2-yl)benzoic acid 13-4 (10 mg, 0.05 mmol), and HATU (23 mg, 0.06 mmol) were added N,N-diisopropylethylamine (DIEA, 17 μL, 0.1 mmol) and DMF (0.5 mL). The solution was stirred overnight at room temperature and was subjected directly to reverse phase preparative HPLC to yield N-(4-(2-methylpyridin-4-yl)benzyl)-4-(pyridin-2-yl)benzamide 13 as white powder. MS m/z 380.2 (M+1). 1H NMR 400 MHz (CDCl3) δ 8.65-8.60 (m, 1H), 8.41 (d, 1H), 7.99-7.85 (m, 4H), 7.80-7.70 (m, 2H), 7.65-7.50 (m, 3H), 7.45 (d, 2H), 7.34 (bs, 1H), 7.32-7.27 (m, 2H), 4.66 (d, 2H), 2.56 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].P([O-])(O)(O)=[O:14].[Na+].Cl([O-])=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O.CS(C)=O>[Cl:1][C:2]1[C:3]([OH:12])=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[C:5]([OH:14])=[O:6]
Reactant: O=P([O-])(O)O
Reactant: COc1ccc(C=O)c(O)c1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(C(=O)O)c(O)c1Cl
Temperature: 15 °C
Reaction time: 16 h
Yield: 61.6 %

Procedure:
To a solution of 3-chloro-2-hydroxy-4-methoxybenzaldehyde (16.6 g) and sodium dihydrogenphosphate (34.7 g) in a mixed solvent of DMSO (180 mL)-water (45.0 mL) was added an aqueous solution (35.0 mL) of sodium chlorite (27.2 g) under ice-cooling, and the mixture was stirred at 15° C. for 16 hr. The reaction mixture was poured into saturated aqueous sodium carbonate solution, the mixture was diluted with water, and filtered, and the filtrate was extracted with petroleum ether/ethyl acetate=5:1. The aqueous layer was acidified with conc. hydrochloric acid to adjusted pH=1, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (11.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.[C:16]([O:19][CH2:20][C:21]1[CH:25]=[CH:24][O:23][C:22]=1[C:26](=[O:29])[CH2:27]Br)(=[O:18])[CH3:17]>>[C:16]([O:19][CH2:20][C:21]1[CH:25]=[CH:24][O:23][C:22]=1[C:26]([C:27]1[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4]2[C:5]([C:6]=1[NH2:7])=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=2)=[O:29])(=[O:18])[CH3:17]
Reactant: CC(=O)OCc1ccoc1C(=O)CBr
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Product: CCOC(=O)n1c(C(=O)c2occc2COC(C)=O)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in Step 2 of Example 1 from 4-chloro-2-(ethoxycarbonylamino)benzonitrile (Example 1, step 1) and 3-acetoxymethyl-2-(bromoacetyl)furan (Example 372, step 1).