Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:41]=[CH:40][C:9]2[N:10]([CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[C:18]([C:23](=[O:33])NCC3C=CC(Cl)=CC=3)[CH:17]=[CH:16]4)=[N:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2].[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([NH:49][CH:50]2[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]2)=[CH:45][CH:44]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:41]=[CH:40][C:9]2[N:10]([CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[C:18]([C:23](=[O:33])[N:49]([C:46]3[CH:45]=[CH:44][C:43]([Cl:42])=[CH:48][CH:47]=3)[CH:50]3[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]3)[CH:17]=[CH:16]4)=[N:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3nc(C(=O)NCc4ccc(Cl)cc4)ccc3c1)n2C1CCCCC1
Reactant: Clc1ccc(NC2CCCCC2)cc1
Product: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3nc(C(=O)N(c4ccc(Cl)cc4)C4CCCCC4)ccc3c1)n2C1CCCCC1

Procedure:
The title compound was prepared as described for Compound 546c using Compound 546b in place of 4-chloro-N-methylaniline. MS: 635.31 (M+H+).
Reaction SMILES: [N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:23][C:24]1[C:29]([OH:30])=[CH:28][CH:27]=[CH:26][N:25]=1>>[N:1]1([S:11]([C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH:23][C:24]3[C:29]([OH:30])=[CH:28][CH:27]=[CH:26][N:25]=3)=[O:19])=[CH:21][CH:22]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1
Reactant: Nc1ncccc1O
Product: O=C(Nc1ncccc1O)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1

Procedure:
4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32 mmol) was treated with 2-aminopyridin-3-ol (29 mg, 0.26 mmol) using method C. The residue was purified using flash chromatography eluting with 0-60% EtOAc in hexanes. The resulting solid was triturated with dichloromethane/hexanes to give 4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(3-hydroxypyridin-2-yl)benzamide as an off-white solid. Yield: 23 mg (21%). 1H-NMR: 8.08 (d, J=8.5 Hz, 2H), 7.93 (dd, J=5.0, 1.5 Hz, 1H), 7.72 (d, J=8.5 Hz, 2H), 7.63 (d, J=8.5 Hz, 1H), 7.31 (dd, J=8.0, 1.5 Hz, 1H), 7.23-7.18 (m, 2H), 7.12-7.08 (m, 2H), 3.84-3.79 (m, 2H), 2.44 (J=7.0 Hz, 2H), 1.66-1.58 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][C:4](=[O:20])[CH:3]=1.CCN(CC)CC.[Cl:28][CH2:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](Cl)=O.CC(C)(O)C#N.C([BH3-])#N.[Na+]>C(O)(=O)C.C(#N)C.C(Cl)Cl>[Cl:28][CH2:29][C:30]1[CH:31]=[C:32]([CH2:33][C:3]2[C:4](=[O:20])[O:5][C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:7][C:2]=2[OH:1])[CH:36]=[CH:37][CH:38]=1
Reactant: O=C1C=C(O)CC(c2ccccc2)(c2ccccc2)O1
Reactant: O=C(Cl)c1cccc(CCl)c1
Agent: CC(C)(O)C#N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: ClCCl
Product: O=C1OC(c2ccccc2)(c2ccccc2)CC(O)=C1Cc1cccc(CCl)c1

Procedure:
The title compound was prepared as described in General Method 8 using the following: 5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (0.300 g, 1.13 mmol), Et3N (0.17 mL, 1.2 mmol), 3-(chloromethyl)benzoyl chloride (0.13 mL, 1.13 mmol), CH2Cl2 (5.0 mL), acetonitrile (5.0 mL), acetone cyanohydrin (0.05 mL, 0.5 mmol), Et3N (0.35 mL, 2.5 mmol), glacial acetic acid (6.0 mL), sodium cyanoborohydride (0.50 g, 7.9 mmol). Purification was achieved by submitting the final residue to column chromatograpy (SiO2, 4/1 hexane/ethyl acetate to 3/2 hexane/ethyl acetate) to provide a solid (0.118 g, 135-137° C.). 1H NMR (400 MHz, DMSO-d6) δ 11.211 (s, 1 H), 7.418-7.280 (m, 10 H), 7.088 (d, 1 H, 7.5 Hz), 6.975 (t, 1 H, J=7.5 Hz), 6.689 (s, 1 H), 6.513 (d, 1 H, J=7.5 Hz), 4.498 (s, 2 H), 3.540 (s, 2 H), 3.447 (s, 2 H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:10][CH:9]=[C:8]([C:11]([NH:13][C:14]3[C:23]([CH3:24])=[CH:22][CH:21]=[C:20]4[C:15]=3[CH:16]=[CH:17][N:18]=[C:19]4[NH:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([N:36]4[CH:40]=[C:39]([CH3:41])[N:38]=[CH:37]4)[CH:27]=3)=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH:42]1(NC2C3SC=C(C(O)=O)C=3N=CN=2)[CH2:44][CH2:43]1>>[CH:42]1([NH:1][C:2]2[C:3]3[S:10][CH:9]=[C:8]([C:11]([NH:13][C:14]4[C:23]([CH3:24])=[CH:22][CH:21]=[C:20]5[C:15]=4[CH:16]=[CH:17][N:18]=[C:19]5[NH:25][C:26]4[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([N:36]5[CH:40]=[C:39]([CH3:41])[N:38]=[CH:37]5)[CH:27]=4)=[O:12])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:44][CH2:43]1
Reactant: O=C(O)c1csc2c(NC3CC3)ncnc12
Reactant: Cc1cn(-c2cc(Nc3nccc4c(NC(=O)c5csc6c(N)ncnc56)c(C)ccc34)cc(C(F)(F)F)c2)cn1
Product: Cc1cn(-c2cc(Nc3nccc4c(NC(=O)c5csc6c(NC7CC7)ncnc56)c(C)ccc34)cc(C(F)(F)F)c2)cn1
Yield: 54.2 %

Procedure:
The procedures of <Step 3> of Example 1 were repeated, except for using 6-methyl-N1-(3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl)-isoquinolin-1,5-diamine (0.012 g, 0.03 mmol) obtained in Example 5 and 4-cyclopropylamino-thieno[3,2-d]pyrimidine-7-carboxylic acid (see WO 2011009687, 0.04 mmol) to obtain the title compound (10 mg, 57%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[O:11])=[CH:4][CH:3]=1.[Br-:20]>>[Br:20][CH:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:10]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)=[O:11]
Reactant: COc1ccc(C(=O)CCc2ccc(F)cc2)cc1
Reactant: [Br-]
Product: COc1ccc(C(=O)C(Br)Cc2ccc(F)cc2)cc1
Yield: 95 %

Procedure:
A procedure similar to step 3 of Example 1 was used. 3-(4-fluoro-phenyl)-1-(4-methoxy-phenyl)-propan-1-one prepared in the step 2 and bromide were used as starting materials, and anhydrous AlC3 was used as catalyst. The obtained product was a white solid in a yield of 95.0%, mp: 76-77 └. 1H-NMR (CDCl3, 400 MHz) δ: 3.31 (1H, dd, J=14.28, 7.00 Hz), 3.66 (1H, dd, J=14.28, 7.28 Hz), 3.87 (3H, s, OCH3), 5.23 (1H, t, J=7.56 Hz, CHBr), 6.93 (2H, d, J=8.96 Hz, ArH), 6.96 (2H, t, 3JFH=3JHH=8.72 Hz, ArH), 7.23 (2H, dd, 3JHH=8.68 Hz, 4JFH=5.60 Hz, ArH), 7.95 (2H, d, J=8.96 Hz, ArH); ESI-MS: 339.2 (M+2, 89), 337.0 (M, 70), 257.2 (100).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[CH:6][N:5]=[CH:4][N:3]=1.O[Li].O>C1COCC1.CO>[OH:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cncnc1O
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1cncnc1O
Reaction time: 8 h

Procedure:
Ethyl 4-hydroxypyrimidine-5-carboxylate can be prepared following the procedure of M. Pesson et al., Eur. J. Med. Chem.—Chim. Ther. 1974, 9, 585. A solution of this ester (500 mg, 3 mmol) in THF (10 mL) and MeOH (5 mL) was treated with LiOH.H2O (373 mg, 8.9 mmol) and stirred overnight. The mixture was quenched with conc. HCl (1 mL) and extracted with EtOAc (2×20 mL). The combined organic extract was dried (MgSO4) and concentrated to give 260 mg of the title compound 19 as an orange solid, m.p. 220° C. (dec). 4-HYDROXY-2-METHYLPYRIMIDINE-5-CARBOXYLIC ACID (20).
Reaction SMILES: [N:1]1([CH:10]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH3:24])=[CH:19][CH:18]=2)[CH2:11][C:12]([O:14]CC)=[O:13])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C(#N)C.CO>Cl>[N:1]1([CH:10]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH3:24])=[CH:19][CH:18]=2)[CH2:11][C:12]([OH:14])=[O:13])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CCOC(=O)CC(c1ccc(CC)cc1)n1cnc2ccccc21
Agent: Cl
Solvent: CO
Solvent: CC#N
Product: CCc1ccc(C(CC(=O)O)n2cnc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A suspension of ethyl 3-(1H-benzimidazol-1-yl)-3-(4-ethylphenyl)propanoate (180 mg, 559 μmol) in hydrochloric acid (10 mL of a 5N solution) was stirred at room temperature for 72 hours. A mixture of acetonitrile and methanol (10:1, 11 mL) was added, and the resulting solution stirred at room temperature for 110 hours. The solution was warmed to reflux for 24 hours, and evaporated in vacuo. The residue was taken up into aqueous sodium carbonate, and the resulting solution extracted with diethyl ether. The aqueous phase was acidified with dilute hydrochloric acid (pH<4), and extracted with dichloromethane. The combined dichloromethane extracts were evaporated in vacuo to afford the title compound, [LCMS (Method A, Mobile Phase I) RT=4.20 min, MH+ 296].
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]([O:13][CH2:14][CH3:15])=[O:12].[CH3:16][C:17]([CH3:51])([O:19][C:20]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][CH:31]2[CH2:36][CH2:35][N:34]([C:37]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[O:38])[CH2:33][CH2:32]2)=[C:26]([C:47]([O:49][CH3:50])=[O:48])[CH:25]=1)=[O:21])[CH3:18]>C(Cl)Cl>[CH3:18][C:17]([CH3:51])([O:19][C:20]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:31]2[CH2:36][CH2:35][N:34]([C:37]([O:39][CH2:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)=[O:38])[CH2:33][CH2:32]2)=[C:26]([C:47]([O:49][CH3:50])=[O:48])[CH:25]=1)=[O:21])[CH3:16]
Reactant: COC(=O)c1cc(CNC(=O)OC(C)(C)C)ccc1NC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CCOC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)N(c1ccc(CNC(=O)OC(C)(C)C)cc1C(=O)OC)C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 96 h
Yield: 47.8 %

Procedure:
2.08 g of DIEA and then 1.745 g of ethyl chloroformate are added to a solution of 1.6 g of benzyl 4-{[4-({[(1,1-dimethylethoxy)carbonyl]amino}methyl)-2-(methoxycarbonyl)phenyl]amino}piperidine-1-carboxylate obtained in stage 5.2 in 11 ml of DCM. The mixture is stirred at AT for 4 days. It is evaporated under reduced pressure. The residue is taken up in 10 ml of pyridine (10 ml) and 0.7 g of ethyl chloroformate is added. The mixture is stirred at AT for 4 h 00. It is evaporated under reduced pressure. The residue is chromatographed on silica gel, elution being carried out with an AcOEt/heptane mixture, (10/90, v/v) as far as (30/70, v/v), to give 0.875 g of the expected product.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH2:23]([NH:25][CH2:26][CH2:27][OH:28])[CH3:24]>>[Br:1][C:2]1[C:3]([N:25]([CH2:23][CH3:24])[CH2:26][CH2:27][OH:28])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: CCNCCO
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Product: CCN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1Br
Temperature: 140 °C

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 22.1 using 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 6.2) and 2-(ethylamino)ethanol to afford a white solid. (The RM was heated at 140° C. for 18 h). HPLC (Condition 4) tR=5.92 min, UPLC-MS (Condition 3) tR=1.19 min, m/z=450.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][CH2:20]Br)[CH:15]=2)[CH:10]=[C:9]1[C:22]1[C:23]2[S:36][C:35]([CH2:37][OH:38])=[CH:34][C:24]=2[N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[N:26]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[NH:48]1[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1>C(#N)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][CH2:20][N:48]3[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]3)[CH:15]=2)[CH:10]=[C:9]1[C:22]1[C:23]2[S:36][C:35]([CH2:37][OH:38])=[CH:34][C:24]=2[N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[N:26]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1nc(-c2cc3ccc(OCCCBr)cc3n2C(=O)OC(C)(C)C)c2sc(CO)cc21
Reactant: C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1nc(-c2cc3ccc(OCCCN4CCCCC4)cc3n2C(=O)OC(C)(C)C)c2sc(CO)cc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 73.3 %

Procedure:
To 6-(3-bromo-propoxy)-2-(1-tert-butoxycarbonyl-5-hydroxymethyl-1H-thieno[3,2-c]pyrazol-3-yl)-indole-1-carboxylic acid tert-butyl ester [990 mg, 1.63 mmol, Intermediate (77)] in acetonitrile (20 mL) were added polymer supported DIEA (3.83 mmol/g, 850 mg, 3.26 mmol) and piperidine (0.32 mL, 3.26 mmol). The mixture was stirred gently at 60° C. for 4 hours. The PS-DIEA was filtered and the solvent was removed. The residue was chromatographed through silica gel (dichloromethane/1.0M ammonia in methanol, 95/05) to produce 2-(1-tert-butoxycarbonyl-5-hydroxymethyl-1H-thieno[3,2-c]pyrazol-3-yl)-6-(3-piperidin-1-yl-propoxy)-indole-1-carboxylic acid tert-butyl ester [730 mg, 74%, Intermediate (78)] as a white foam. LC/MS: 611.2 (M+H), RT=3.05 minutes.
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]([CH3:25])[S:8]([N:11]1[CH:15]=[C:14]([CH2:16][C:17]([CH3:24])([C:20]([F:23])([F:22])[F:21])[CH:18]=[CH2:19])[N:13]=[CH:12]1)(=[O:10])=[O:9].[F:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][C:40](OC)=[O:41])=[CH:35][CH:34]=2)=[N:31][CH:32]=1>O1CCCC1>[F:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][C:40]([C:12]3[N:11]([S:8]([N:7]([CH3:6])[CH3:25])(=[O:10])=[O:9])[CH:15]=[C:14]([CH2:16][C:17]([CH3:24])([C:20]([F:23])([F:22])[F:21])[CH:18]=[CH2:19])[N:13]=3)=[O:41])=[CH:35][CH:34]=2)=[N:31][CH:32]=1
Reactant: COC(=O)Cc1ccc(-c2ccc(F)cn2)cc1
Reactant: C=CC(C)(Cc1cn(S(=O)(=O)N(C)C)cn1)C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CC(C)(Cc1cn(S(=O)(=O)N(C)C)c(C(=O)Cc2ccc(-c3ccc(F)cn3)cc2)n1)C(F)(F)F
Temperature: -10 °C
Reaction time: 3 h

Procedure:
n-Butyllithium (1.6 M in hexane) (4.19 mL, 6.7 mmol) was added to a −78° C. solution of N,N-dimethyl-4-[2-methyl-2-(trifluoromethyl)but-3-en-1-yl]-1H-imidazole-1-sulfonamide (Intermediate 4) (1.74 g, 5.59 mmol) in tetrahydrofuran (6 mL). After warming to −10° C. over 1 h, methyl [4-(5-fluoropyridin-2-yl)phenyl]acetate (1.14 g, 5.59 mmol) in tetrahydrofuran (6 mL) was added and the reaction allowed to warm to ambient temperature. After stirring at ambient temperature for 3 h, the reaction mixture was quenched with water and extracted with methylene chloride and ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-100% ethyl acetate/hexane afforded 2-{[4-(5-fluoropyridin-2-yl)phenyl]acetyl}-N,N-dimethyl-4-[2-methyl-2-(trifluoromethyl)but-3-en-1-yl]-1H-imidazole-1-sulfonamide.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH:16]([CH3:20])[C:17]([OH:19])=[O:18].Cl.[CH2:22](O)[CH3:23]>>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH:16]([CH3:20])[C:17]([O:19][CH2:22][CH3:23])=[O:18]
Reactant: CCO
Reactant: CC(C(=O)O)c1ccc2c(c1)CCc1ccccc1S2
Agent: Cl
Product: CCOC(=O)C(C)c1ccc2c(c1)CCc1ccccc1S2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 100 mg of 2-(10,11-dihydro dibenzo[b,f]thiepin-2-yl)-propionic acid was added 2 ml of ethanol containing 17% of hydrogen chloride and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off to obtain the residue, to which was added ice-water and extracted with ethyl acetate, and the extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain pale brown oil, which was chromatographed over silica gel and eluted with benzene-chloroform. There was obtained 96 mg of ethyl 2-(10,11-dihydro dibenzo[b,f]thiepin-2-yl)-propionate as pale yellow oil.
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:40][CH2:41][CH2:42][N:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:13][CH2:14][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:20]=2[CH2:21]1)[CH3:2]
Reactant: ClCCCN1CCCCC1
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCCN2CCCCC2)c(F)c1)c1cc(OC)ccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 49.4 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 1-(3-chloropropyl)piperidine (19 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (13 mg) was obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH:13]=[O:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C-:16]#[N:17].[K+].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.O>[OH:14][CH:13]([CH:10]1[CH2:11][CH2:12][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9]1)[C:16]#[N:17]
Reactant: O=CC1CCN(Cc2ccccc2)C1
Reactant: [C-]#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: N#CC(O)C1CCN(Cc2ccccc2)C1
Reaction time: 2 h
Yield: 84.7 %

Procedure:
To a solution of 12.45 g of crude 1-benzyl-3-formylpyrrolidine in a mixture of 23 ml of tetrahydrofuran and 23 ml of water is added 11.4 ml (2 equivalents) of concentrated hydrochloric acid and then 8.39 g (2 equivalents) of potassium cyanide powder in a period of 15 minutes under ice-cooling. The mixture is stirred at the same temperature for 2 hours, adjusted to pH 10 with 10% aqueous sodium carbonate solution, and extracted thrice with methylene chloride. The extract is washed with water, dried over sodium sulfate and evaporated under reduced pressure to yield 12.05 g of 2-hydroxy-2-(1-benzylpyrrolidin-3-yl) acetonitrile.
Reaction SMILES: [CH3:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH2:3][C:4]1([C:7]([F:10])([F:9])[F:8])[CH2:6][O:5]1.[NH2:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH:21]=[CH:22][C:23]([CH3:29])=[N:24]2>CCCCCC.C(OCC)(=O)C>[CH3:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH2:3][C:4]([C:7]([F:10])([F:9])[F:8])([OH:5])[CH2:6][NH:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH:21]=[CH:22][C:23]([CH3:29])=[N:24]2
Reactant: CC(C)(CC1(C(F)(F)F)CO1)c1ccccc1
Reactant: Cc1ccc2c(N)cccc2n1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc2c(NCC(O)(CC(C)(C)c3ccccc3)C(F)(F)F)cccc2n1
Yield: 58.8 %

Procedure:
Analogously to Example 1, 500 mg (2.05 mmol) of 2-(2-methyl-2-phenylpropyl)-2-(trifluoromethyl)oxirane and 650 mg (4.10 mmol) of 5-amino-2-methylquinoline are reacted. After chromatography on silica gel with hexane-ethyl acetate (0-70%), 485 mg of product is obtained.
Reaction SMILES: [C:1]([O:9][C:10]1[N:15]=[C:14]([OH:16])[C:13]([C:17]#[N:18])=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:17]([C:13]1[C:14]([O:16][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:15][C:10]([O:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:11][CH:12]=1)#[N:18]
Reactant: N#Cc1ccc(OC(=O)c2ccccc2)nc1O
Reactant: O=C(Cl)c1ccccc1
Product: N#Cc1ccc(OC(=O)c2ccccc2)nc1OC(=O)c1ccccc1
Yield: 80.9 %

Procedure:
The general procedure of Example 90 was followed using 1.00 g of 6-benzoyloxy-3-cyano-2-hydroxypyridine and 0.58 g of benzoyl chloride, thereby producing 1.15 g of the title compound in a yield of 80%.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]2[C:13]([CH3:18])=[N:14][CH:15]=[C:16]([CH3:17])[C:5]=12.Br[N:20]1[C:24](=[O:25])[CH2:23][CH2:22][C:21]1=[O:26].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[Cl:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]2[C:13]([CH3:18])=[N:14][C:15]([N:20]3[C:24](=[O:25])[CH2:23][CH2:22][C:21]3=[O:26])=[C:16]([CH3:17])[C:5]=12
Reactant: Cc1cnc(C)n2c1c(CCCl)c1ccccc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: Cc1c(N2C(=O)CCC2=O)nc(C)n2c1c(CCCl)c1ccccc12

Procedure:
To a refluxing solution of 5-(2-chloroethyl)-1,4-dimethylpyrimido[1,6-a]indole (13 g, described in Example 12), in chloroform (400 ml) is added N-bromosuccinimide (9.4 g) and anhydrous potassium carbonate (7 g). The reaction mixture is stirred and refluxed for 45 minutes. The resulting slurry is cooled and washed with water, and the organic phase is separated and evaporated. The residue is chromatographed on silica gel using chloroform and the eluates are evaporated. The residue (6.6 g) is crystallized from ethyl acetate to give 1-[5-(2-chloro)ethyl-1,4-dimethylpyrimido[1,6-a]indol-3-yl]pyrrolidine-2,5-dione; mp 232°-234° C.; ir (CHCl3) 1780 (weak) and 1705 cm-1 ; uv (MeOH) λmax 299, 310, and 324 nm; ε=6300, 10180, and 13170, respectively; nmr (CDCl3) δ2.31(s), 2.82(s), 2.91(s), 3.55(m), 7.0(m) and 8.0(m).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)([O-:12])=[O:11].O.C(O)(=O)C>N1C=CC=CC=1>[N+:10]([C:13]1[CH:14]=[CH:15][C:16]([S:19]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=2[CH3:9])(=[O:21])=[O:20])=[CH:17][CH:18]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc(O)ccc1N
Solvent: CC(=O)O
Solvent: O
Solvent: c1ccncc1
Product: Cc1cc(O)ccc1NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Yield: 84.3 %

Procedure:
To a stirred mixture of 4-amino-3-methylphenol (24 g, 0.2 mole) in 600 ml of pyridine was added all at once p-nitrobenzenesulfonyl chloride (Eastman) (45 g, 0.2 mole) followed by heating on a steam bath for 2 hours. The dark oily solution was poured into 4 liters of water and then treated with glacial acetic acid until acid. The tar crystallized on standing to give after filtration 67 g (100%) of brown solid. The entire sample was recrystallized from CH3NO2 to give 52 g of pure intermediate.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][CH2:8][N:9]2[CH:13]=[CH:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=3)[C:10]2=[O:23])[CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].C(OCC)(=O)C>[NH2:20][C:17]1[CH:16]=[CH:15][C:14]([N:11]2[CH2:12][CH2:13][N:9]([CH2:8][CH2:7][CH2:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:10]2=[O:23])=[CH:19][CH:18]=1
Reactant: O=c1n(CCCC2CCCC2)ccn1-c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(N2CCN(CCCC3CCCC3)C2=O)cc1
Reaction time: 8 h
Yield: 59.8 %

Procedure:
A mixture of the product from Example 49 (3.7 g, 11.7 mmol) and 10% palladium on activated carbon (0.74 g) in ethyl acetate (200 mL) was placed under an atmosphere of hydrogen overnight. The mixture was filtered through a pad of Celite with excess ethyl acetate, and the filtrate was concentrated to a crude brown oil. The crude was purified by silica gel chromatography (gradient elution from 2:1 hexanes/ethyl acetate to 1:1 hexanes/ethyl acetate) to afford a pale orange solid (2.01 g, 60%). Mp 97-99° C.; Rf=0.1 (2:1 hexanes/ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ 7.20 (d, 2H), 6.72 (d, 1H), 6.63 (d, 1H), 6.57 (d, 2H), 5.09 (br s, 1H), 3.50 (t, 2H), 1.72 (m, 3H), 1.59 (m, 6H), 1.26 (m, 2H), 1.03 (m, 2H); MS (FAB) m/z 286 (MH+).