Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5]1.[ClH:21].S(Cl)([Cl:24])=O>C(Cl)Cl>[ClH:24].[CH2:13]([O:12][C:10]([C:7]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][Cl:21])[CH2:5][CH2:6]1)=[O:11])[CH3:14]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)C1(c2ccccc2)CCN(CCO)CC1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)C1(c2ccccc2)CCN(CCCl)CC1

Procedure:
A solution is prepared from 5.9 parts of the ester obtained in the preceding paragraph and 134 parts of methylene chloride. This solution is saturated with hydrogen chloride gas at below 10° and 5.1 parts of thionyl chloride is added. The mixture is refluxed for 1 hour and then cooled and volatile material is removed under reduced pressure. The residue is dissolved in 88 parts of benzene, and the solution evaporated under reduced pressure. The residue is then crystallized from a mixture of ethanol and ether to give 1-(2-chloroethyl)-4-phenyl-4-piperidinecarboxylic acid ethyl ester hydrochloride melting at about 216°-218°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:16][C:17]([OH:19])=[O:18])[CH:12]=[CH:13][C:14]=1[Cl:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:21][CH2:22]O>>[CH2:21]([O:18][C:17](=[O:19])[CH2:16][C:11]1[CH:12]=[CH:13][C:14]([Cl:15])=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1)[CH3:22]
Reactant: CCO
Reactant: O=C(O)Cc1ccc(Cl)c(OCc2ccccc2)c1
Agent: Cl
Product: CCOC(=O)Cc1ccc(Cl)c(OCc2ccccc2)c1

Procedure:
(3-Benzyloxy-4-chloro-phenyl)-acetic acid (8 g) was treated with hydrogen chloride (4N in 1,4-dioxane; 6 mL) in EtOH (100 mL) at 80° C. for 3 hours. After concentrating to dryness, the residue was purified by silica gel chromatography to give (3-benzyloxy-4-chloro-phenyl)-acetic acid ethyl ester.
Reaction SMILES: [S:1]([Cl:4])([Cl:3])=[O:2].[NH2:5][C@@H:6]([CH2:10][NH2:11])[C:7]([OH:9])=[O:8].[CH3:12]O>>[S:1]([Cl:4])([Cl:3])=[O:2].[ClH:3].[NH2:5][C@@H:6]([CH2:10][NH2:11])[C:7]([O:9][CH3:12])=[O:8]
Reactant: NC[C@H](N)C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H](N)CN
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methanol (400 mL) was cooled to 0° C. and thionyl chloride (217 mL, 3.0 moles, 20 eq) was added dropwise under argon. After addition was completed, the solution was warmed to RT for 20 min. 2(S),3-Diaminopropanoic acid 2-1 (20 g, 0.143 mole) (Schweizerhall Chemicals) was crushed to a fine powder and added to the solution. The reaction was heated to reflux for 48 h, at which time TLC showed a small amount of starting material remaining. An additional portion of methanol (100 mL) and thionyl chloride (72 mL) was prepared as before and added to the reaction at RT; the reaction was then stirred overnight at RT. The reaction was worked up by removal of solvent at 40° C. in vacuo to give 2-2 as foam. Rf 0.72 (9:1:1 EtOH/H2O/NH4OH). 1H NMR (400 MHz, D2O) δ4.55 (dd, J=5.4 8.2 Hz, 1H), 3.92 (s, 3H), 3.64 (dd, J=8.2, 13.8 Hz, 1H), 3.55 (dd, J=5.4, 13.8 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=1[C:19]([F:22])([F:21])[F:20].C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>C(#N)C.O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:2]2[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=2)=[CH:14][C:13]=1[C:19]([F:20])([F:21])[F:22]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cn1
Temperature: 80 °C
Reaction time: 10 h
Yield: 34 %

Procedure:
To a solution of 5-bromo-2-nitropyridine (15 g, 73.9 mmol) and 4-chloro-3-(trifluoromethyl)phenol (14.52 g, 73.9 mmol) in acetonitrile (200 mL) was added potassium carbonate (18.38 g, 133 mmol) and the reaction mixture was stirred at 80° C. for 10 hr. Then, 200 mL of EtOAc and 200 mL of H2O were added. The organic layer was separated and concentrated under reduced pressure. The crude product was purified by a silica gel column chromatography eluting and was eluted with Hex/EtOAc (5:1) to provide 5-(4-chloro-3-(trifluoromethyl)phenoxy)-2-nitropyridine (8 g, 32.8%),
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[CH3:11][C:12]1([CH3:25])[CH2:17][CH:16](OS(C)(=O)=O)[CH2:15][C:14]([CH3:24])([CH3:23])[O:13]1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH:16]2[CH2:15][C:14]([CH3:24])([CH3:23])[O:13][C:12]([CH3:25])([CH3:11])[CH2:17]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: CC1(C)CC(OS(C)(=O)=O)CC(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)CC(Oc2ccc(Cl)cc2C=O)CC(C)(C)O1

Procedure:
In a manner similar to the method described in example 4a, 5-chlorosalicylaldehyde (4.6 g, 30 mmol) (Aldrich) reacted with methanesulfonic acid 2,2,6,6-tetramethyl-tetrahydro-pyran-4-yl ester (8 g, 34 mmol) and K2CO3 in N,N-dimethylformamide to give 5-chloro-2-(2,2,6,6-tetramethyl-tetrahydro-pyran-4-yloxy)-benzaldehyde as a off white solid (Yield 0.94 g, 10%).
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][C:8]=2[CH:9]=1)C.C(O)=O>O>[CH:4]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][C:8]=2[CH:9]=1)=[O:3]
Reactant: CCOC(OCC)c1cc2cc(C(=O)OC)ccc2o1
Solvent: O=CO
Solvent: O
Product: COC(=O)c1ccc2oc(C=O)cc2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 99.1 %

Procedure:
Methyl 2-(diethoxymethyl)-1-benzofuran-5-carboxylate (2.6 g, 8.5 mmol) is combined with formic acid (15 ml) and water (3.8 ml). The reaction is stirred 6 h at RT, the volatiles are removed in vacuo, and the residue is neutralized with 50 ml saturated NaHCO3. The mixture is extracted with CH2Cl2 (4×20 ml), the organic layer is dried (K2CO3), and is concentrated in vacuo to provide 1.72 g (99%) of methyl 2-formyl-1-benzofuran-5-carboxylate as amber flakes. HRMS (EI) calcd for C11H8O4: 204.0423, found 204.0418 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[C:22]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][N:27]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]([OH:20])=O)[CH:8]=1)=[O:5].[CH2:33]([CH2:35][NH2:36])[OH:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C)C=O>[NH3:6].[Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[C:22]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][N:27]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]([NH:36][CH2:35][CH2:33][OH:34])=[O:20])[CH:8]=1)=[O:5]
Reactant: O=C(O)c1cc(NC(=O)c2cc(-c3ccc(F)cn3)c(Cl)cc2Cl)n(-c2ccccc2)n1
Reactant: NCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N
Product: O=C(NCCO)c1cc(NC(=O)c2cc(-c3ccc(F)cn3)c(Cl)cc2Cl)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 144.9 %

Procedure:
5-(2,4-dichloro-5-(5-fluoropyridin-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylic acid (Example 102, 100 mg, 0.212 mmol), ethanolamine (0.2 mL, 0.32 mmol) and HATU (121 mg, 0.32 mmol) were dissolved in dimethylformamide (5 mL) under nitrogen. Triethylamine (0.12 mL, 0.85 mmol) was added and the reaction stirred at room temperature for 1 hour. The reaction was concentrated in vacuo. The residue was partitioned between ethyl acetate (50 mL) and water (30 mL), the organic layer was collected, dried over magnesium sulphate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 95:5:0.5 dichloromethane:methanol:ammonia to afford the title compound as a white solid (79 mg, 73%).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH:13]3[CH2:15][O:14]3)=[CH:7][C:5]=2[N:6]=1.[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[NH:24][C:25](=[O:34])[CH2:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][C:28]1=[O:33].CC1C=CC=C(C)C=1NC(=O)CN1CCNCC1>>[CH3:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([CH3:16])[C:18]=1[NH:24][C:25](=[O:34])[CH2:26][N:27]1[CH2:32][CH2:31][N:30]([CH2:15][CH:13]([OH:14])[CH2:12][O:11][C:8]2[CH:9]=[CH:10][C:4]3[S:3][C:2]([CH3:1])=[N:6][C:5]=3[CH:7]=2)[CH2:29][C:28]1=[O:33]
Reactant: Cc1cccc(C)c1NC(=O)CN1CCNCC1=O
Reactant: Cc1nc2cc(OCC3CO3)ccc2s1
Agent: Cc1cccc(C)c1NC(=O)CN1CCNCC1
Product: Cc1nc2cc(OCC(O)CN3CCN(CC(=O)Nc4c(C)cccc4C)C(=O)C3)ccc2s1

Procedure:
Compound 64 was prepared in the manner of compound 7 substituting compound 33 for compound 6 and compound 32 for compound 5 in part D of compound 7: Mass Spectrum (MH+)=483.3.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([N:9]2[CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[OH:20])[CH2:12][C:11]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[N:10]2)=[O:8])=[CH:4][CH:3]=1.O.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[N:38][NH:39][CH:40]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>CO.CN(C=O)C.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>[NH:38]1[CH:37]=[C:36]([C:2]2[S:6][C:5]([C:7]([N:9]3[CH:13]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[OH:20])[CH2:12][C:11]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)=[N:10]3)=[O:8])=[CH:4][CH:3]=2)[CH:40]=[N:39]1
Reactant: O=C(c1ccc(Br)s1)N1N=C(c2cccnc2)CC1c1ccccc1O
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
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: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(c1ccc(-c2cn[nH]c2)s1)N1N=C(c2cccnc2)CC1c1ccccc1O
Reaction time: 0.25 h
Yield: 23.8 %

Procedure:
To a solution of 2-{1-[(5-bromo-2-thienyl)carbonyl]-3-pyridin-3-yl-4,5-dihydro-1H-pyrazol-5-yl}phenol (0.209 g, 0.488 mmol) in MeOH (1 mL), DMF (1 mL), and water (1 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.110 g, 0.567 mmol), tetrakis(triphenylphosphine)palladium(0) (0.032 g, 0.028 mmol) and cesium carbonate (0.318 g, 0.976 mmol). The reaction mixture was subjected to MWI at 100° C. for 15 minutes. A precipitate formed and was filtered and washed with water to give 0.197 grams of crude product as a tan solid. The crude material was purified by column chromatography to give 2-(1-{[5-(1H-pyrazol-4-yl)-2-thienyl]carbonyl}-3-pyridin-3-yl-4,5-dihydro-1H-pyrazol-5-yl)phenol (I-45) (0.048 g, 0.116 mmol) as a white solid. LCMS: (FA) ES+ 416.3, ES 414.3. 1H NMR (400 MHz, d6-DMSO) δ: 9.73-9.82 (bs, 1H), 9.11 (s, 1H), 8.78 (d, 1H), 8.54 (d, 1H), 8.12 (s, 2H), 7.96 (d, 1H), 7.74-7.80 (m, 1H), 7.29 (d, 1H), 7.08 (t, 1H), 6.92 (d, 1H), 6.85 (d, 1H), 6.72 (t, 1H), 5.85 (dd, 1H), 3.90 (dd, 1H), and 3.21 (dd, 1H).
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[C:27](O)(=[O:32])[CH2:28]/[CH:29]=[CH:30]/[CH3:31]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:27](=[O:32])[CH2:28]/[CH:29]=[CH:30]/[CH3:31])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: C/C=C/CC(=O)O
Agent: Cl
Product: C/C=C/CC(=O)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1

Procedure:
The title compound, white solid (71 mg, 70%), MS (ISP) m/z=409.4 [(M+H)+], mp 165° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and (E)-pent-3-enoic acid.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:6]=[N:7][C:8]([C:11]#[CH:12])=[CH:9][CH:10]=2)[CH2:3][CH2:2]1.[Cl:13][C:14]1[CH:38]=[CH:37][C:17]([C:18]([NH:20][C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([N:31]3[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32]3)[CH:22]=2)=[O:19])=[CH:16][C:15]=1I>>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([NH:20][C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:24]=[C:23]([N:31]3[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32]3)[CH:22]=2)=[O:19])=[CH:37][C:38]=1[C:12]#[C:11][C:8]1[N:7]=[N:6][C:5]([NH:4][CH:1]2[CH2:3][CH2:2]2)=[CH:10][CH:9]=1
Reactant: C#Cc1ccc(NC2CC2)nn1
Reactant: Cc1cn(-c2cc(NC(=O)c3ccc(Cl)c(I)c3)cc(C(F)(F)F)c2)cn1
Product: Cc1cn(-c2cc(NC(=O)c3ccc(Cl)c(C#Cc4ccc(NC5CC5)nn4)c3)cc(C(F)(F)F)c2)cn1

Procedure:
The title compound was synthesized from N-cyclopropyl-6-ethynylpyridazin-3-amine and 4-chloro-3-iodo-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl) benzamide in a manner similar to that described for in Example 1. The intermediate compound 4-chloro-3-iodo-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide was made as for Example 24 (Step 1 to 2) with the spectra below: 1H NMR (300 MHz, DMSO-d6) δ: 10.78 (1 H, s), 8.55 (1 H, d, J=2.1 Hz), 8.26 (1 H, s), 8.22 (1 H, s), 8.11 (1 H, s), 7.99-8.03 (1 H, dd, J=2.1 and 8.1 Hz), 7.76-7.80 (2 H, m), 7.49 (1 H, s), 2.19 (3 H, s). LCMS: m/z [M+H]+ 505.9663.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14]Br.[SH:16][C:17]1[CH:18]=[C:19]([CH2:23][C:24]([OH:26])=[O:25])[CH:20]=[CH:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][S:16][C:17]1[CH:18]=[C:19]([CH2:23][C:24]([OH:26])=[O:25])[CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)Cc1cccc(S)c1
Reactant: Cc1oc(-c2ccccc2)nc1CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1oc(-c2ccccc2)nc1CCSc1cccc(CC(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(5-methyl-2-phenyloxazol-4-yl)ethylbromide (136 mg) and 3-mercaptophenylacetic acid.methyl ester (78 mg) were dissolved in acetonitrile (5 ml) and thereto was added potassium carbonate and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water and the mixture was extracted with ether. The extract was washed with an aqueous solution of sodium hydroxide, water and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (chloroform:ethyl acetate=200:1→50:1) to give the compound of the present invention (92 mg) having the following physical data.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH2:13]Br)[C:7]([OH:9])=[O:8])([O-:3])=[O:2].CO.[CH3:17]N(C1C=CC=CN=1)C.Cl.[CH2:27]([O:29][C:30](=[O:33])[CH2:31][NH2:32])[CH3:28].C(=O)([O-])O.[Na+]>ClCCl.C1COCC1>[CH2:27]([O:29][C:30]([CH2:31][NH:32][CH2:13][C:12]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH3:17])=[O:8])=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2])=[O:33])[CH3:28]
Reactant: O=C(O)c1ccc(CBr)c([N+](=O)[O-])c1
Reactant: CCOC(=O)CN
Reactant: CN(C)c1ccccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)CNCc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.5 g (9.6 mmol) of 3-nitro-4-bromomethylbenzoic acid was dissolved in 100 ml of dichloromethane. 0.78 ml (19.2 mmol) of methanol, 2.2 g (11.5 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)-3-carbodiimide hydrochloride and 30 mg of dimethylaminopyridine were added to the obtained solution, and they were stirred at room temperature for 3 hours. The reaction mixture was treated with dichloromethane as the extracting solvent by an ordinary method to obtain the crude product. The crude product was dissolved in 50 ml of THF. 2.0 g (14.6 mmol) of glycine ethyl ester hydrochloride and 1.8 g (21.9 mmol) of sodium hydrogencarbonate were added to the obtained solution, and they were stirred at 80° C. for 4 hours. The insoluble matter was removed by the filtration, and the solvent was evaporated. After the extraction with ethyl acetate followed by the treatment by an ordinary method, the crude title compound was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:9]([C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)[C:10]2[C:15]([C:16]=1[N:17]=[C:18]=[O:19])=[C:14]([CH3:20])[C:13]([C:21]([F:24])([F:23])[F:22])=[CH:12][CH:11]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:30][O:31][C:32]([C:34]1[C:38]([NH2:39])=[CH:37][S:36][CH:35]=1)=[O:33].C(OCC)(=O)C>FC(C1C=CC=CC=1)(F)F>[C:1]([O:5][C:6]([C:8]1[N:9]([C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)[C:10]2[C:15]([C:16]=1[NH:17][C:18]([NH:39][C:38]1[C:34]([C:32]([O:31][CH3:30])=[O:33])=[CH:35][S:36][CH:37]=1)=[O:19])=[C:14]([CH3:20])[C:13]([C:21]([F:23])([F:22])[F:24])=[CH:12][CH:11]=2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(C(F)(F)F)ccc2c1c(N=C=O)c(C(=O)OC(C)(C)C)n2-c1ccsc1
Reactant: COC(=O)c1cscc1N
Solvent: FC(F)(F)c1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1cscc1NC(=O)Nc1c(C(=O)OC(C)(C)C)n(-c2ccsc2)c2ccc(C(F)(F)F)c(C)c12
Temperature: 150 °C
Yield: 59 %

Procedure:
To a solution of 3-isocyanato-1-thiophen-3-yl-methyl-5-trifluoromethyl-1H-indole-2-carboxylic acid tert-butyl ester 1F (˜4.39 mmol) in trifluoromethylbenzene (10 mL) was added 4-aminothiophene-3-carboxylic acid methyl ester 1G (1.38 g, 8.79 mmol). The reaction mixture was heated in a microwave reactor at 150° C. for 20 minutes. Ethyl acetate (100 mL) was added and the organic layer was washed with 1 N hydrochloric acid and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography to provide 3-[3-(4-methoxycarbonyl-thiophen-3-yl)-ureido]-1-thiophen-3-yl-methyl-5-trifluoromethyl-1H-indole-2-carboxylic acid tert-butyl ester 1H (1.50 g, 2.59 mmol).
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][O:8]N)[CH2:4][O:3]1.FC1C(NC2C=CC(I)=CC=2F)=C(C=CC=1F)C(O)=O.O[C@H](CO)CO[NH:35][C:36](=[O:54])[C:37]1[CH:42]=[CH:41][C:40]([F:43])=[C:39]([F:44])[C:38]=1[NH:45][C:46]1[CH:51]=[CH:50][C:49]([I:52])=[CH:48][C:47]=1[F:53]>CO>[OH:6][C@@H:5]([CH2:7][OH:8])[CH2:4][O:3][C:41]1[C:40]([F:43])=[C:39]([F:44])[C:38]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([I:52])=[CH:48][C:47]=2[F:53])=[C:37]([CH:42]=1)[C:36]([NH2:35])=[O:54]
Reactant: CC1(C)OC[C@@H](CON)O1
Reactant: O=C(NOC[C@H](O)CO)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Agent: O=C(O)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Solvent: CO
Product: NC(=O)c1cc(OC[C@@H](O)CO)c(F)c(F)c1Nc1ccc(I)cc1F

Procedure:
Prepared from (S)-O-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine and 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid by the procedure described above for N-[(R)-2,3-dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide: m.p. 116-118° C. (Form II of Compound C); and m.p. 116-118° C. (Form I of Compound C); [α]=+1.77° (c=1.13, methanol). Analysis: Calcd. For: C16H14F3I1N2O4: C, 39.85; H, 2.93; N, 5.81; F, 11.82, I, 26.32. Found: C, 40.01; H, 2.73; N, 5.84; F, 11.45; I, 26.42.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:8][NH:9]2)=[CH:5][CH:4]=1.[O:20]1[CH2:22][C@H:21]1[CH2:23][O:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1[CH:27]=[CH:28][NH:29]2>CO.CS(C)=O>[F:19][C:2]([F:1])([F:18])[C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH:12]3[CH2:13][CH2:14][N:15]([CH2:22][C@H:21]([OH:20])[CH2:23][O:24][C:25]4[CH:33]=[CH:32][CH:31]=[C:30]5[C:26]=4[CH:27]=[CH:28][NH:29]5)[CH2:16][CH2:17]3)=[CH:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Solvent: CO
Solvent: CS(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(c2c[nH]c3cc(C(F)(F)F)ccc23)CC1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 193 from 6-trifluoromethyl-3-(piperidin-4-yl)-1H-indole (0.50 g, 1.9 mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.35 g, 1.9 mmol). The product was isolated as a white foam. Yield 250 mg (29%). mp 100°-105° C. FDMS m/e=457 (M+ of free base). α[D]589 =+8.13 (c=1.01, methanol/dimethylsulfoxide).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[C:14]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=3[NH2:25])[NH:15]2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[Na+].C(O)(=O)C.[Cl:41][CH2:42][C:43](Cl)=[O:44]>O1CCCC1>[C:1]([NH:5][S:6]([C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]3)=[C:14]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=3[NH:25][C:43](=[O:44])[CH2:42][Cl:41])[NH:15]2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)CCl
Reactant: Cc1ccc(-c2[nH]c3cc(S(=O)(=O)NC(C)(C)C)ccc3c2C2CCCCC2)c(N)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1ccc(-c2[nH]c3cc(S(=O)(=O)NC(C)(C)C)ccc3c2C2CCCCC2)c(NC(=O)CCl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
To a suspension of N-tert-butyl-2-(2-amino-4-methylphenyl)-3-cyclohexyl-1H-indole-6-sulfonamide (2.14 g, 4.86 mmol), sodium acetate (472 mg, 5.75 mmol) and acetic acid (0.33 ml, 5.76 mmol) in tetrahydrofuran (20 ml) was added dropwise chloroacetyl chloride (0.45 ml, 5.64 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. the reaction mixture was concentrated under reduced pressure, and water was added to the residue. The precipitated solid was collected by filtration and dried in vacuo. A suspension of the obtained solid in diethyl ether was stirred at room temperature for 1 hr. The solid was collected by filtration and dried in vacuo to give N-tert-butyl-2-[2-(chloroacetylamino)-4-methylphenyl]-3-cyclohexyl-1H-indole-6-sulfonamide (2.22 g, yield 89.9%). The obtained crude product was used for Step 10 without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:21][C:6]2=[C:7]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[S:8][C:9]([S:10]([CH3:13])(=O)=O)=[C:5]2[C:4](=[O:22])[CH2:3]1.[Na].[C:25]1(S)[CH:30]=[CH:29]C=[CH:27][CH:26]=1>CCO>[CH3:1][C:2]1([CH3:23])[CH2:21][C:6]2=[C:7]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[S:8][C:9]([S:10][C:13]3[CH:29]=[CH:30][CH:25]=[CH:26][CH:27]=3)=[C:5]2[C:4](=[O:22])[CH2:3]1
Reactant: CC1(C)CC(=O)c2c(S(C)(=O)=O)sc(C(=O)N3CCCC3)c2C1
Reactant: Sc1ccccc1
Agent: [Na]
Solvent: CCO
Product: CC1(C)CC(=O)c2c(Sc3ccccc3)sc(C(=O)N3CCCC3)c2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of the 6,6-dimethyl-3-methanesulphonyl-1-(pyrrolidin-1-ylcarbonyl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one (400 mg, 1.1 mmol) in EtOH (15 mL) was added thiophenol sodium salt (297 mg, 2.2 mmol). The mixture was stirred at room temperature for 3 h then the solvent evaporated. The residue was partitioned between EtOAc (20 mL) and water (30 mL). The organic phase was separated, dried (Na2SO4) and evaporated. The resultant oil was triturated with ether/hexane and the colourless solid (330 mg, 76%) collected by filtration. mp 140° C. C21H23NO2S2 requires: C, 65.42; H, 6.01; N, 3.63%. Found: C, 65.55; H, 5.77; N, 3.980%,. 1H NMR (360 MHz, CDCl3) δ1.07 (6H, s), 1.86-1.90 (4H, m), 2.43 (2H, s), 2.78 (2H, s), 3.36-3.60 (4H, m), 7.43-7.51 (3H, m), 7.67-7.70 (2H, m). MS (ES+) 386 (M+1).