Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[N:3]([C:9]1[N:14]([CH3:15])[C:13](=[O:16])[C:12]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)=[C:11]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)[N:10]=1)[CH2:4][C:5](NC)=[O:6].[CH3:33][O:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[CH2:38][Mg]Cl.O.C(OCC)(=O)C>C1COCC1>[CH3:33][O:34][C:35]1[CH:36]=[C:37]([CH2:38][C:5](=[O:6])[CH2:4][NH:3][C:9]2[N:14]([CH3:15])[C:13](=[O:16])[C:12]([C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=3)=[C:11]([C:27]3[CH:28]=[CH:29][N:30]=[CH:31][CH:32]=3)[N:10]=2)[CH:41]=[CH:42][CH:43]=1
Reactant: COc1cccc(C[Mg]Cl)c1
Reactant: CNC(=O)CN(OC)c1nc(-c2ccncc2)c(-c2ccc3ccccc3c2)c(=O)n1C
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(CC(=O)CNc2nc(-c3ccncc3)c(-c3ccc4ccccc4c3)c(=O)n2C)c1
Reaction time: 3 h

Procedure:
To a solution of 2-(N′-methoxy-N′-methylaminocarbonylmethylamino)-3-methyl-5-naphthalen-2-yl-6-pyridin-4-yl-3H-pyrimidin-4-one (400 mg, 0.93 mmol) in THF (10 mL) at 0° C. was slowly added 3-methoxybenzylmagnesium chloride (Rieke Metal, 0.25 M in THF, 20 mL). After 3 h, water (100 mL) and ethyl acetate (200 mL) were added. The layers were separated. The organic layer was washed with brine (3×80 mL), dried, and evaporated to give crude product. Column chromatograph purification (silica gel, 1-2% MeOH/CH2Cl2) gave the product as a solid. M+1=491.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2[C:15]([O:17][CH3:18])=[O:16])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:23]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2[C:15]([O:17][CH3:18])=[O:16])[CH3:23])(=[O:10])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccccc1NS(=O)(=O)c1ccc(Cl)c(Cl)c1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1ccccc1N(C)S(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 40 °C

Procedure:
Methyl 2-(3,4-dichlorophenylsulfonamido)benzoate (21.3 g, 59.1 mmol) was dissolved in acetone (300 ml), and K2CO3 (16.3 g, 118.3 mmol, 2 eq.) was added thereto. Methyl iodide (7.4 ml, 118.3 mmol, 2 eq.) was then added, and the suspension was heated overnight at 40° C. The solid materials were filtered off and the filtrate was concentrated using a rotary evaporator. Purification was carried out by filtration over silica gel (DCM).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16].[CH2:17]([O:19][CH:20]([C:27]1[CH:32]=[CH:31][C:30]([C:33]2[O:34][C:35]([CH3:38])=[N:36][N:37]=2)=[CH:29][CH:28]=1)[C:21](N(OC)C)=[O:22])[CH3:18]>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][C:12]([C:21](=[O:22])[CH:20]([O:19][CH2:17][CH3:18])[C:27]3[CH:28]=[CH:29][C:30]([C:33]4[O:34][C:35]([CH3:38])=[N:36][N:37]=4)=[CH:31][CH:32]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COc1cc(-c2ccco2)cc(OC)c1Cl
Reactant: CCOC(C(=O)N(C)OC)c1ccc(-c2nnc(C)o2)cc1
Product: CCOC(C(=O)c1ccc(-c2cc(OC)c(Cl)c(OC)c2)o1)c1ccc(-c2nnc(C)o2)cc1

Procedure:
1-(5-(4-Chloro-3,5-dimethoxyphenyl)furan-2-yl)-2-ethoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)ethanone was prepared from 2-(4-chloro-3,5-dimethoxyphenyl)furan and 2-ethoxy-N-methoxy-N-methyl-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamide according to the procedure used in Example 30. Purification by chromatography (60% EtOAc-hexanes) gave the product as a pale yellow solid (0.122 g, 25% yield). MS: m/z 483.1 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]1=[CH:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[C:22](O)=[O:23].[C:25]1([C@@H:31]([NH2:40])[CH2:32][C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:25]1([C@@H:31]([NH:40][C:22]([C@H:10]2[CH2:9][CH2:8][C@H:7]3[C@H:6]4[C@H:15]([CH2:14][CH2:13][C@:11]23[CH3:12])[C@:16]2([CH3:21])[C:3]([N:2]([CH3:1])[C:19](=[O:20])[CH2:18][CH2:17]2)=[CH:4][CH2:5]4)=[O:23])[CH2:32][C:33]2[CH:34]=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1ccc(C[C@H](N)c2ccccc2)cc1
Reactant: CN1C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC[C@@H]12
Product: Cc1ccc(C[C@H](NC(=O)[C@H]2CC[C@H]3[C@@H]4CC=C5N(C)C(=O)CC[C@]5(C)[C@H]4CC[C@]23C)c2ccccc2)cc1
Yield: 58 %

Procedure:
The title compound was prepared in a yield of 58% in a similar manner to that described in Example 1 by reacting 4-methyl-3-oxo-4-azaandrost-5-ene-17β-carboxylic acid (prepared as described in Preparation 5) and (S)-1-phenyl-2-(4-methylphenyl)ethylamine.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:12][CH2:13][CH2:14][CH2:15][C:16]([N:18]([CH3:20])[CH3:19])=[O:17])=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[CH2:28]([O:35][C:36]1[CH:41]=[CH:40][C:39]([C:42](=[O:45])[CH2:43]Br)=[CH:38][CH:37]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[BH4-].[Na+]>CN(C)C=O.C(O)C>[CH2:28]([O:35][C:36]1[CH:37]=[CH:38][C:39]([CH:42]([OH:45])[CH2:43][NH:1][C@H:2]2[CH2:11][CH2:10][C:9]3[C:4](=[CH:5][C:6]([O:12][CH2:13][CH2:14][CH2:15][C:16]([N:18]([CH3:20])[CH3:19])=[O:17])=[CH:7][CH:8]=3)[CH2:3]2)=[CH:40][CH:41]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CN(C)C(=O)CCCOc1ccc2c(c1)C[C@@H](N)CC2
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)C(=O)CCCOc1ccc2c(c1)C[C@@H](NCC(O)c1ccc(OCc3ccccc3)cc1)CC2
Temperature: 0 °C
Yield: 26.5 %

Procedure:
(S)-4-(2-Amino-1,2,3,4-tetrahydronaphthalen-7-yloxy)-N,N-dimethylbutyramide (196 mg) and triethylamine (270 μl) were dissolved in N,N-dimethylformamide (3 ml), and a solution of 4'-benzyloxy-2-bromoacetophenone (195 mg) in N,N-dimethylformamide (2 ml) was added to the solution under ice-cooling with stirring. After reaction for 15 minutes, sodium borohydride (240 mg) and ethanol (3 ml) were added to the reaction mixture under ice-cooling with stirring. After reaction for 2 hours, the reaction mixture was poured into ice-water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo. To the resulting residue was added a solution of triethanolamine (200 mg) in tetrahydrofuran (5 ml), and the mixture was heated under reflux for 16 hours. After cooling, water was poured into the reaction mixture and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo. Purification of the residue by medium pressure liquid column chromatography on silica gel (eluent: ethyl acetate/ethanol=6/1) gave 4-[(2S)-2-[[(2RS)-2-(4-benzyloxyphenyl)-2-hydroxyethyl]amino]-1,2,3,4-tetrahydronaphthalen-7-yloxy]-N,N-dimethylbutyramide (85 mg) as an amorphous.
Reaction SMILES: [H-].[Na+].[C:3]1([N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10]2=[O:18])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:19][O:20][C:21](=[O:33])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br>CN(C=O)C>[CH3:19][O:20][C:21](=[O:33])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:10]1=[O:18]
Reactant: O=c1[nH]c2ccccc2n1-c1ccccc1
Reactant: COC(=O)CCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCCCCn1c(=O)n(-c2ccccc2)c2ccccc21

Procedure:
The product is produced as described in example 1 from 1.3 g. of NaH (80% suspension in mineral oil), 10 g. of 1-phenylbenzimidazolin-2-one, 200 cc. of DMF, 13.3 g. of 11-bromoundecanoic acid methyl ester and 1.3 g. of NaJ. Eluant in chromatographic purification: hexane/ethylacetate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:57])[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[N:21]=[C:20]3[C:16]([N:17]=[CH:18][N:19]3[C@@H:22]3[CH2:26][C@H:25]([NH:27][C:28](=[O:39])[C@H:29]([O:31][CH2:32][C:33]4C=CC=CC=4)[CH3:30])[C@@H:24]([OH:40])[C@H:23]3[OH:41])=[C:15]([NH:42][CH2:43][CH:44]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C([O:65][C@H](C)C(N[C@H]1C[C@@H](N2C=NC3C2=NC(Cl)=NC=3NCC(C2C=CC=CC=2)C2C=CC=CC=2)[C@H](O)[C@@H]1O)=O)C1C=CC=CC=1>>[C:1]([O:5][C:6]([NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[N:21]=[C:20]3[C:16]([N:17]=[CH:18][N:19]3[C@@H:22]3[CH2:26][C@H:25]([NH:27][C:28]([C@@H:29]([O:31][C:32](=[O:65])[CH3:33])[CH3:30])=[O:39])[C@@H:24]([OH:40])[C@H:23]3[OH:41])=[C:15]([NH:42][CH2:43][CH:44]([C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)[C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[N:14]=2)[CH2:9]1)=[O:57])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H](OCc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: C[C@@H](OCc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)OC(C)(C)C)C4)nc32)[C@H](O)[C@@H]1O
Product: CC(=O)O[C@@H](C)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)OC(C)(C)C)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound is prepared analogously to {(R)-1-[9-[(1R,2S,3R,4S)-4-((R)-2-benzyloxy-propionylamino)-2,3-dihydroxy-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (Example 181, step 3), by substituting acetic acid (S)-1-{(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentylcarbamoyl}-ethyl ester (Example 182, step 2) for (R)-2-benzyloxy-N-{(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide (Example 181, step 2).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH3:16])[C:12]([C:17]([F:20])([F:19])[F:18])=[CH:11][N:10]=2)=[C:4]([O:21][CH3:22])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:28]1[S:32][CH:31]=[N:30][CH:29]=1)CCC>>[CH3:22][O:21][C:4]1[CH:3]=[C:2]([C:28]2[S:32][CH:31]=[N:30][CH:29]=2)[N:7]=[CH:6][C:5]=1[NH:8][C:9]1[N:14]=[C:13]([NH:15][CH3:16])[C:12]([C:17]([F:20])([F:19])[F:18])=[CH:11][N:10]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncs1
Reactant: CNc1nc(Nc2cnc(Cl)cc2OC)ncc1C(F)(F)F
Product: CNc1nc(Nc2cnc(-c3cncs3)cc2OC)ncc1C(F)(F)F

Procedure:
N2-(4-Methoxy-6-(thiazol-5-yl)pyridin-3-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine was prepared by the procedure described in Example 7, using N2-(6-chloro-4-methoxypyridin-3-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine and 5-(tributylstannyl)thiazole. LCMS (10 cm_ESCI_Formic_MeCN): [MH+]=383 at 2.60 min. 1H NMR δ (ppm) (CDCl3): 9.65 (1H, s), 8.9 (1H, d, J=2.1), 8.2 (1H, d, J=1.1), 8.1 (1H, d, J=2.1), 7.75 (1H, s), 7.55 (1H, s), 5.27 (1H, s), 4.1 (3H, s), 3.2 (3H, d, J=4.7).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:13]=[C:12]([CH:14]=[CH2:15])[N:11]=[C:10]([CH3:16])[N:9]=2)[N:3]=1.Cl[C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1.C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:9]=[C:10]([CH3:16])[N:11]=[C:12](/[CH:14]=[CH:15]/[C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)[CH:13]=2)[N:3]=1
Reactant: Clc1ccc2ccccc2n1
Reactant: C=Cc1cc(-n2nc(C)nc2C)nc(C)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(/C=C/c2ccc3ccccc3n2)cc(-n2nc(C)nc2C)n1
Temperature: 100 °C

Procedure:
To a solution of 4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-methyl-6-vinylpyrimidine (1-3) (200 mg, 0.93 mmol, 1.0 eq.) in degassed DMF (4.0 mL) was added 2-chloroquinoline (148 mg, 0.93 mmol, 1.0 eq.) followed by palladium acetate (32.0 mg, 47.5 mol, 0.050 eq.) and triethylamine (1.20 mL, 4.65 mmol, 5.0 eq.). The reaction was heated at 100° C. for 48 hours and cooled to room temperature. The reaction was quenched by the addition of water (5.0 mL) and ethyl acetate (5.0 mL) was added and the mixture was filtered through Celite. The organic layer was separated and the aqueous layer was washed with ethyl acetate (2×5.0 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (10-40% ethyl acetate in hexanes) to afford (E)-2-(2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-methylpyrimidin-4-yl)vinyl)quinoline (1-4) as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 8.19 (br d, 1H, J=8.5 Hz), 8.13 (d, 1H, J=16.0 Hz), 8.11 (br d, 1H, J=8.3 Hz), 7.87 (br s, 111), 7.81 (br dd, 1H, J=8.0, 1.0 Hz), 7.78-7.68 (m, 3H), 7.55 (ddd, 1H, J=8.0, 7.0, 1.0 Hz), 2.94 (s, 3H), 2.77 (s, 3H), 2.44 (s, 3H). LRMS mz (M+H+) 343 found, 343 required. m.p. 153-155° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([S:24](Cl)(=[O:26])=[O:25])[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH-].[NH4+:30]>>[CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([S:24](=[O:26])(=[O:25])[NH2:30])[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: O=C(O)c1cc(NCc2ccccc2)c(-c2ccccc2)c(S(=O)(=O)Cl)c1
Agent: Cl
Agent: [OH-]
Product: NS(=O)(=O)c1cc(C(=O)O)cc(NCc2ccccc2)c1-c1ccccc1

Procedure:
3-Benzylamino-5-chlorosulfonyl-4-phenylbenzoic acid (1.0 g) is in portions added to conc. ammonium hydroxide (10 ml) while stirring at 10°-12° C. After additional stirring at room temperature for about 18 hours, the resulting solution is dropwise added to an excess of icecold 4 N hydrochloric acid. The resulting precipitate is collected by filtration, washed with water and dried. After recrystallization from aqueous ethanol, 3-benzylamino-4-phenyl-5-sulfamylbenzoic acid is obtained with a melting point of 221°-222° C.
Reaction SMILES: [C:1]1(C2C=CC=CC=2)[CH:6]=[CH:5][C:4]([S:7]([NH:10][C:11]([NH:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[C:26]4=[N:27][C:28]([CH3:32])=[CH:29][C:30]([CH3:31])=[C:25]4[N:24]=[C:23]3[CH2:33][CH3:34])=[CH:18][CH:17]=2)=[O:12])(=[O:9])=[O:8])=CC=1.[S:41]1C=CC=C1S(N)(=O)=O>>[CH2:33]([C:23]1[N:22]([C:19]2[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][NH:13][C:11]([NH:10][S:7]([C:4]3[S:41][CH:1]=[CH:6][CH:5]=3)(=[O:9])=[O:8])=[O:12])=[CH:17][CH:18]=2)[C:26]2=[N:27][C:28]([CH3:32])=[CH:29][C:30]([CH3:31])=[C:25]2[N:24]=1)[CH3:34]
Reactant: NS(=O)(=O)c1cccs1
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(-c3ccccc3)cc2)cc1
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2cccs2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 18 from phenyl 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate (step 1 of Example 18) and 2-thiophenesulfonamide (Huang, H. C.; Reinhard, E. J.; Reitz, D. B. Tetrahedron Lett., 1994, 35, 7201.; Graham, S. L.; Scholz, T. H. Synthesis, 1986, 1031).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:4].[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][C:11]([C:22]1[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=1)=[CH:10][CH:9]=2)=[O:4]
Reactant: OB(O)c1ccc(F)cc1
Reactant: COC(=O)c1c(O)c2cc(Br)ccc2sc1=O
Product: COC(=O)c1c(O)c2cc(-c3ccc(F)cc3)ccc2sc1=O

Procedure:
6-(4-Fluoro-phenyl)-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester was prepared from 6-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester under conditions analogous to Example 7(a) using 4-fluorophenylboronic acid. 1H NMR (200 MHz, CDCl3): δ (ppm)=8.515 (s, 1H), 7.765 (d, 1H), 7.586 (m, 2H), 7.427 (d, 1H), 7.381-7.120 (m, 2H), 4.026 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([F:29])=[CH:25][C:26]=3[F:28])[N:21]=[C:20]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[C:19]=2[CH3:36])[C:5]([C:8]2[C:13]([F:14])=[CH:12][N:11]=[C:10]([O:15][CH3:16])[CH:9]=2)=[N:6][CH:7]=1.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.C1(P(C2CCCCC2)C2(C(C)C)CC(C(C)C)=CC(C(C)C)=C2C2C=CC=CC=2)CCCCC1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:28][C:26]1[CH:25]=[C:24]([F:29])[CH:23]=[C:22]2[C:27]=1[C:18]([NH:17][C:4]1[C:5]([C:8]3[C:13]([F:14])=[CH:12][N:11]=[C:10]([O:15][CH3:16])[CH:9]=3)=[N:6][CH:7]=[C:2]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[CH:3]=1)=[C:19]([CH3:36])[C:20]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)=[N:21]2
Reactant: COc1cc(-c2ncc(Br)cc2Nc2c(C)c(-c3ccccn3)nc3cc(F)cc(F)c23)c(F)cn1
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)C1=CC(C(C)C)=C(c2ccccc2)C(C(C)C)(P(C2CCCCC2)C2CCCCC2)C1
Solvent: Cc1ccccc1
Product: COc1cc(-c2ncc(N3CCOCC3)cc2Nc2c(C)c(-c3ccccn3)nc3cc(F)cc(F)c23)c(F)cn1
Temperature: 90 °C
Reaction time: 21.5 h

Procedure:
A mixture of N-(5-bromo-5′-fluoro-2′-methoxy-2,4′-bipyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine (50.2 mg, 0.091 mmol), morpholine (0.03 mL, 0.34 mmol), 2-dicyclohexylphosphino-2,4,6,-triisopropylbiphenyl (9.1 mg, 0.019 mmol), tris(dibenzylideneacetone)dipalladium (0) (8.5 mg, 9.28 μmol), and sodium tert-butoxide (26.7 mg, 0.28 mmol) in dry Toluene (3 mL) was degassed by nitrogen. The mixture was heated to 90° C. After 21.5 h, the reaction was cooled to rt, then treated with water. After extracting twice with EtOAc, the organic layer was combined and dried over anhydrous magnesium sulfate. After filtration and concentration, the light orange film was purified with HPLC 10-60% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution. The impure fractions were further purified with SFC chromatography to afford a white solid as 5,7-difluoro-N-(5′-fluoro-2′-methoxy-5-morpholino-2,4′-bipyridin-3-yl)-3-methyl-2-(pyridin-2-yl)quinolin-4-amine. 1H NMR (400 MHz, CDCl3) δ ppm 8.68 (1H, br. s.), 8.10 (2H, t, J=2.0 Hz), 7.96 (2H, m), 7.66 (1H, m.), 7.38 (1H, m), 7.07 (2H, m), 6.61 (1H, m), 3.96 (3H, s), 3.91 (4H, m), 3.30 (4H, m), 2.17 (3H, s). Mass Spectrum (pos.) m/e: 559.2 (M+1).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:33][C:34]([O:36]CC)=[O:35])[C:9]([C:11]1[CH:32]=[CH:31][C:14]2[N:15]([CH3:30])[C:16]([CH2:18][N:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=3)[CH3:20])=[N:17][C:13]=2[CH:12]=1)=[O:10].[OH-].[Na+]>>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:33][C:34]([OH:36])=[O:35])[C:9]([C:11]1[CH:32]=[CH:31][C:14]2[N:15]([CH3:30])[C:16]([CH2:18][N:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:28])[NH2:29])=[CH:23][CH:22]=3)[CH3:20])=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(CN(C)c1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CN(Cc1nc2cc(C(=O)N(CC(=O)O)c3ccccn3)ccc2n1C)c1ccc(C(=N)N)cc1

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[N-(4-amidinophenyl)-N-methylaminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)amide hydrochloride and sodium hydroxide solution.
Reaction SMILES: Cl.[C:2]([C:5]1[S:6][CH:7]=[C:8]([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[C:9]=1[Cl:10])([OH:4])=O.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26][C:27](=[O:36])[C:28]2[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=2[NH2:35])=[N:24][CH:25]=1>S(Cl)(Cl)=O.N1C=CC=CC=1>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26][C:27](=[O:36])[C:28]2[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=2[NH:35][C:2]([C:5]2[S:6][CH:7]=[C:8]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[C:9]=2[Cl:10])=[O:4])=[N:24][CH:25]=1
Reactant: CN1CCN(Cc2csc(C(=O)O)c2Cl)CC1
Reactant: Nc1ccc(Cl)cc1C(=O)Nc1ccc(Cl)cn1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CN1CCN(Cc2csc(C(=O)Nc3ccc(Cl)cc3C(=O)Nc3ccc(Cl)cn3)c2Cl)CC1
Temperature: 25 °C
Reaction time: 90 h
Yield: 78.5 %

Procedure:
A suspension of 2-carboxy-3-chloro-4-(4-methylpiperazin-1-yl)methylthiophene HCl salt (2.0 g, 5.8 mmol) in thionyl chloride (50 mL) was heated at reflux. After 90 hours, the mixture was cooled to ambient temperature and concentrated of all volatiles in vacuo. To a suspension of the resulting solid in pyridine (20 mL) at 0° C. was added N-(5-chloropyridin-2-yl)-2-amino-5-chlorobenzamide (1.5 g, 5.2 mmol) in pyridine (5 mL). The mixture was stirred and allowed to warm gradually to ambient temperature. After 16 hours, the mixture was concentrated of all volatiles in vacuo. Purification by flash chromatography on silica gel afforded 2.2 g (80% yield) of N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide, as a tan foam; NMR (DMSO-d6/TFA) 11.4 (s, 1), 11.0 (s, 1), 7.6-8.4 (m, 7), 4.4 (s, 2), 3.0-4.0 (br m, 8), 2.9 (s, 3) ppm.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([OH:21])=O)=[CH:15]2)(=[O:8])=[O:7].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C.CN(C)C=O>[N:22]1([C:19]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9][S:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)(=[O:7])=[O:8])=[O:21])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C1CCNC1
Reactant: O=C(O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1)N1CCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
To a mixture of 7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (200 mg), pyrrolidine (65 μL), 1H-1,2,3-benzotriazol-1-ol (150 mg) and N,N-dimethylformamide (8 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (190 mg) at 4° C., and the mixture was stirred at room temperature for 18 hr. The reaction mixture was diluted with ethyl acetate, washed with aqueous citric acid solution, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were washed with ethyl acetate-hexane to give the title compound (210 mg, yield 90%) as pale-yellow needle crystals. melting point 248-249° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:24])([F:23])[F:22])[CH:5]=[C:6]([CH:12]=1)[O:7][CH2:8][CH2:9][CH2:10][OH:11].C(N(CC)C(C)C)(C)C.CS(C)=O>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:22])([F:24])[F:23])[CH:5]=[C:6]([CH:12]=1)[O:7][CH2:8][CH2:9][CH:10]=[O:11]
Reactant: Cc1cc(OCCCO)cc(OCc2ccccc2C(F)(F)F)c1
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(OCCC=O)cc(OCc2ccccc2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
Sulfur trioxide pyridine complex (1.3 g, 8.0 mmol) was added to a solution of 3-[5-methyl-3-(2-trifluoromethylbenzyloxy)phenoxy]propanol (680 mg, 2.0 mmol), as prepared in the preceding step, N,N-diisopropylethylamine (0.7 mL, 5.5 mmol) and anhydrous dimethyl sulfoxide (0.4 mL, 5.6 mmol) in anhydrous dichloromethane (20 mL). The reaction mixture was stirred at ambient temperature for 1 hour and then quenched with 10% aqueous citric acid (50 mL). The mixture was extracted into dichloromethane (3×50 mL), and the dichloromethane solution was washed with 10% aqueous citric acid (40 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane) to give the title compound as a white solid (575 mg, 85%). 1H-NMR (300 MHz, CDCl3) δ 9.85 (s, 1 H), 7.75 (d, J=7.8 Hz, 1 H), 7.69 (d, J=7.8 Hz, 1 H), 7.56 (t, J=7.6 Hz, 1 H), 7.41 (t, J=7.6 Hz, 1 H), 6.42 (s, 1H), 6.37 (s, 1 H), 6.35 (s, 1 H), 5.23 (s, 2 H), 4.27 (t, J=6.1 Hz, 2 H), 2.87 (t, J=6.1 Hz, 2 H), 2.29 (s, 3 H).