Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:26])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:34][C:33]([C:35]2[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=2)[C:38]#[N:39])=[CH:32][C:31](=O)[O:30]1>>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH:26][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:42]=[CH:41][CH:40]=[C:37]([C:38]#[N:39])[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(-c3ccccc3)cc2)cc1N
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(-c3ccccc3)cc2)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Yield: 66.7 %

Procedure:
Prepared from (3″-amino-[1,1′;4′,1″]terphenyl-4″-yl)-carbamic acid tert.-butyl ester (Example G32) (159 mg, 0.44 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) (111 mg, 0.49 mmol) according to the general procedure K. Obtained as an off-white solid (156 mg).
Reaction SMILES: [C:1]([NH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:26]([CH3:33])([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[CH3:32][C:26]([O:24][C:21]1[CH:20]=[CH:19][C:18]([C:15]2[CH:16]=[CH:17][C:12]([CH2:11][CH2:10][NH:9][C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:13][CH:14]=2)=[CH:23][CH:22]=1)([CH3:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: O=C(NCCc1ccc(-c2ccc(O)cc2)cc1)c1ccccc1
Reactant: CCOC(=O)C(C)(C)Br
Product: CCOC(=O)C(C)(C)Oc1ccc(-c2ccc(CCNC(=O)c3ccccc3)cc2)cc1
Yield: 16 %

Procedure:
Ethyl 2-Methyl-2-{4-[2-benzamido-ethyl]-biphenyl-4'-oxy}-propionate was prepared from 4-(2-benzamido-ethyl)-4'-hydroxybiphenyl and ethyl 2-bromo-2-methyl-propionate analogous to Example 1. Yield: 16% of theory; m.p. 100° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)[N:5]=[C:4]([NH:15][C@H:16]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH3:17])[CH:3]=1.[NH:25]1[CH2:29][CH2:28][C@H:27]([NH:30][C:31](=[O:33])[CH3:32])[CH2:26]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C(OCC)(=O)C.C1(C)C=CC=CC=1>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C@@H:16]([NH:15][C:4]2[CH:3]=[C:2]([N:25]3[CH2:29][CH2:28][C@H:27]([NH:30][C:31](=[O:33])[CH3:32])[CH2:26]3)[CH:7]=[C:6]([NH:8][C:9]3[CH:14]=[N:13][CH:12]=[CH:11][N:10]=3)[N:5]=2)[CH3:17])=[CH:19][CH:20]=1
Reactant: CC(=O)N[C@H]1CCNC1
Reactant: C[C@H](Nc1cc(Cl)cc(Nc2cnccn2)n1)c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)N[C@H]1CCN(c2cc(Nc3cnccn3)nc(N[C@@H](C)c3ccc(F)cc3)c2)C1
Temperature: 100 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
100 mg of (S)-4-chloro-N2-[1-(4-fluorophenyl)ethyl]-N6-(pyrazin-2-yl)pyridine-2,6-diamine (Reference Example 2), 112 mg of (S)—N-(pyrrolidin-3-yl)acetamide, 69 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 92 mg of sodium t-butoxide and 30 mg of tris (dibenzylideneacetone)(chloroform)dipalladium were added in turn to 6 ml of degassed toluene, and the mixture was stirred at 100° C. for 2 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 115 mg of N-{(S)-1-[2-{[(S)-1-(4-fluorophenyl)ethyl]amino}-6-(pyrazin-2-ylamino)pyridin-4-yl]pyrrolidin-3-yl}acetamide as pale brown powder. The obtained compound was subjected to hydrochlorination using a conventional method to obtain 67 mg of the objective compound as brown powder.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].O.[F:8][C:9]1[CH:33]=[C:32]([Br:34])[CH:31]=[CH:30][C:10]=1[CH2:11][N:12]1[N:21]=[C:20]([CH2:22][C:23]([O:25]CC)=[O:24])[C:19]2[C:14](=[C:15]([F:28])[CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:29]>O1CCOCC1>[F:8][C:9]1[CH:33]=[C:32]([Br:34])[CH:31]=[CH:30][C:10]=1[CH2:11][N:12]1[N:21]=[C:20]([CH2:22][C:23]([OH:25])=[O:24])[C:19]2[C:14](=[C:15]([F:28])[CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:29]
Reactant: CCOC(=O)Cc1nn(Cc2ccc(Br)cc2F)c(=O)c2c(F)cccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)Cc1nn(Cc2ccc(Br)cc2F)c(=O)c2c(F)cccc12
Yield: 53.4 %

Procedure:
A mixture of potassium carbonate (1.5 g.), water (16 ml.), dioxan (50 ml.) and ethyl 2-(2-fluoro-4-bromobenzyl)-8-fluoro-1,2-dihydro-1-oxophthalazin-4-ylacetate (1.0 g.) was heated under reflux for 24 hours, and then evaporated. The residue was dissolved in water (100 ml.) and the solution washed with ether (2×100 ml.). The aqueous phase was acidified to pH 2 by addition of concentrated hydrochloric acid. The solid which formed was collected by filtration, washed with water, and recrystallised from a 7:1:5 v/v/v mixture of toluene/isopropanol/petrol (60-80) to give 2-(2-fluoro-4-bromobenzyl)-8-fluoro-1,2-dihydro-1-oxophthalazin-4-ylacetic acid (Example 36) (0.5 g.), m.p. 173°-l75° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH:22][C:23]2[CH:24]=[C:25]([CH:44]=[CH:45][CH:46]=2)[C:26]([C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]([CH2:37][CH2:38][C:39]([O:41]CC)=[O:40])[CH:29]=2)=[O:27])[C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[OH-].[Na+]>O1CCOCC1.CO>[CH2:18]([C:15]1[CH:16]=[CH:17][C:12]([CH:11]([NH:22][C:23]2[CH:24]=[C:25]([CH:44]=[CH:45][CH:46]=2)[C:26]([C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]([CH2:37][CH2:38][C:39]([OH:41])=[O:40])[CH:29]=2)=[O:27])[C:8]2[CH:7]=[CH:6][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:10][CH:9]=2)=[CH:13][CH:14]=1)[CH:19]([CH3:20])[CH3:21]
Reactant: CCOC(=O)CCn1cc(C(=O)c2cccc(NC(c3ccc(CC(C)C)cc3)c3ccc(CC(C)C)cc3)c2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)Cc1ccc(C(Nc2cccc(C(=O)c3cn(CCC(=O)O)c4ccccc34)c2)c2ccc(CC(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.5 %

Procedure:
To a solution of ethyl 3-[3-[3-[bis(4-isobutylphenyl)methylamino]benzoyl]indol-1-yl]propionate (507 mg) in a mixture of 1,4-dioxane (8 ml) and methanol (2 ml) was added 1N aqueous sodium hydroxide (2 ml), and the mixture was stirred at 25° C. for 5 hours. After evaporation of the organic solvent, the residue was acidified (pH 2) with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water and dried over magnesium sulfate. After evaporation of the solvent, the residue was chromatographed on silica gel (20 g) eluting with chloroform to give 3-[3-[3-[bis(4-isobutylphenyl)methylamino]benzoyl]indol-1-yl]propionic acid (375 mg) as an oil.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[CH:5][S:6][CH:7]=1.[OH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[O:26][CH2:27][CH2:28][N:29]([CH3:33])[C:30](=[O:32])[CH3:31])[N:19]=[CH:18][N:17]=2)=[CH:11][C:10]=1[CH3:34]>>[CH3:33][N:29]([CH2:28][CH2:27][O:26][C:24]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:25]=1[C:16]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:2][C:3]3[N:4]=[CH:5][S:6][CH:7]=3)=[C:10]([CH3:34])[CH:11]=1)=[N:17][CH:18]=[N:19]2)[C:30](=[O:32])[CH3:31]
Reactant: CC(=O)N(C)CCOc1cccc2ncnc(Nc3ccc(O)c(C)c3)c12
Reactant: ClCc1cscn1
Product: CC(=O)N(C)CCOc1cccc2ncnc(Nc3ccc(OCc4cscn4)c(C)c3)c12
Yield: 5 %

Procedure:
The procedure described in Example 3 was repeated using 4-(chloromethyl)-1,3-thiazole and N-[2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5-yl}oxy)ethyl]-N-methylacetamide (obtained as described in Example 75, preparation of starting materials) to give the title compound as an off-white solid in 5% yield; NMR spectrum (DMSO-d6 373K) 1.94 (s, 3H), 2.24 (s, 3H), 2.99 (s, 3H), 3.87 (t, 2H), 4.46 (m, 2H), 5.25 (s, 2H), 7.08 (d, 1H), 7.17 (d, 1H), 7.35 (d, 1H), 7.47 (d, 1H), 7.54 (dd, 1H), 7.70 (m, 2H), 8.41 (s, 1H), 9.07 (d, 1H), 9.63 (s, 1H); Mass spectrum MH+ 464.
Reaction SMILES: [C:1]([N:8]([CH3:17])[C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[CH2:40]([O:47][C:48](=[O:65])[C@H:49]([CH3:64])[NH:50][C:51](=[O:63])[C@H:52]([CH3:62])[N:53]([C:55](=[O:61])[C@H:56]([CH:58]([CH3:60])[CH3:59])[NH2:57])[CH3:54])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>ClCCl>[CH2:40]([O:47][C:48](=[O:65])[C@H:49]([CH3:64])[NH:50][C:51](=[O:63])[C@H:52]([CH3:62])[N:53]([C:55](=[O:61])[C@H:56]([CH:58]([CH3:60])[CH3:59])[NH:57][C:14](=[O:16])[C@H:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH3:17])[CH3:54])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CC(C)[C@H](N)C(=O)N(C)[C@@H](C)C(=O)N[C@@H](C)C(=O)OCc1ccccc1
Reactant: CC(C)C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H](C(=O)N[C@H](C(=O)N(C)[C@@H](C)C(=O)N[C@@H](C)C(=O)OCc1ccccc1)C(C)C)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 13.17 g (0.0537 mole) of Boc-N-methyl-L-leucine in 370 ml of dry dichloromethane was stirred and cooled at 0° C. as one-half of 13.15 g. (0.130 mole) of dry triethylamine was added, followed by 15.05 g (0.0591 mole) of BOP-Cl. This was stirred at 0° C. for 3 hours. The remainder of the triethylamine was added, followed by a solution of 13 g (0.0358 mole) of L-valyl-N-methyl-L-alanyl-L-alanine benzyl ester in 50 ml of dry dichloromethane. The reaction was stirred at ice temperature for 22 hours, then washed with 125 ml of a 10% solution of potassium bisulfate. The organic layer was further washed with 2×100 ml of saturated sodium bicarbonate solution, dried over magnesium sulfate, concentrated to a small volume, and chromatographed on silica gel eluting with 1:1 ether/hexane gradually increasing the ether to 2:1. The product weighed 15.8 g (75% of theory), and the FAB m.s. showed a molecular ion peak at 591.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]4[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][C:26]=4[F:34])[N:13]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:35][CH2:36][C:37]([CH3:48])([CH3:47])[CH2:38][NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:21])[F:22])[N:15]=[C:14]([NH:24][C:25]4[CH:33]=[CH:32][C:28]([C:29]([NH:35][CH2:36][C:37]([CH3:48])([CH3:47])[CH2:38][NH:39][C:40](=[O:46])[O:41][C:42]([CH3:43])([CH3:45])[CH3:44])=[O:30])=[CH:27][C:26]=4[F:34])[N:13]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(CN)CNC(=O)OC(C)(C)C
Reactant: O=C(O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(CNC(=O)OC(C)(C)C)CNC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.2 %

Procedure:
To a solution of 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-3-fluorobenzoic acid (200 mg, 0.42 mmol) in DCM (3 mL) was added tert-butyl 3-amino-2,2-dimethylpropylcarbamate (98 mg, 0.48 mmol), HATU (229 mg, 0.60 mol) and iPr2NEt (0.35 mL, 2.00 mmol). The mixture was stirred at r.t. for 16 hours before all the solvents were removed under vacuum. All solvents were removed under vacuum and the residue was purified by silica gel column (EtOAC/Hexanes=20% to 40%) to give tert-butyl 3-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-3-fluorobenzamido)-2,2-dimethylpropylcarbamate (270 mg, 100%) as a white solid.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=2)[NH:12][CH:11]=[C:10]3[CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:32][CH2:33][CH2:34][CH2:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[Cl:32][CH2:33][CH2:34][CH2:35][S:36]([N:22]1[CH2:23][CH2:24][CH:19]([C:10]2[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:8]=3)[NH:12][CH:11]=2)[CH2:20][CH2:21]1)(=[O:38])=[O:37]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)c[nH]c12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
To a solution of 5-phenyl-3-(4-piperidinyl)-1H-indole-7-carboxamide (404 mg, 1.26 mmol) in CH2Cl2 at 0° C., triethylamine (0.7 mL, 5.04 mmol) and 3-chloropropanesulfonyl chloride (0.23 mL, 1.89 mmol) were added. The reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was partitioned between CH2Cl2 (100 mL) and water (50 mL). The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (2×100 mL). The combined organic phase washed with brine (50 mL), dried over magnesium sulfate and filtered. The solvent was removed under reduced pressure and purified via filtration through an SPE Cartridge (Aminopropyl NH2, 500 mg/6 mL) to give the title compound (370 mg, 64%).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([CH:17]([CH3:19])[CH3:18])=[C:15]([C:20]([OH:22])=O)[N:14]=[N:13]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].C1C=C[C:26]2N(O)N=[N:29][C:27]=2[CH:28]=1.C1(N)CC1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C>[CH:27]1([NH:29][C:20]([C:15]2[N:14]=[N:13][N:12]([C:9]3[CH:10]=[CH:11][C:6]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=3)[C:16]=2[CH:17]([CH3:19])[CH3:18])=[O:22])[CH2:28][CH2:26]1
Reactant: On1nnc2ccccc21
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2C(C)C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2C(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 164.1 %

Procedure:
1-{4-[(Ethylamino)carbonyl]phenyl}-5-isopropyl-1H-1,2,3-triazole-4-carboxylic acid (512 mg, 1.69 mmol) obtained in Example 92a), HOBt (116 mg, 0.847 mmol, 0.5 eq.) and cyclopropylamine (0.157 ml, 2.20 mmol, 1.3 eq.) were dissolved in acetonitrile-DMF (2:1, 9.0 ml), WSC (398 mg, 2.03 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated, the residue was diluted with ethyl acetate-hexane (2:1, 45 ml), and the mixture was washed with 2% aqueous sodium carbonate solution, 10% aqueous ammonium chloride solution and saturated brine. The aqueous layers were each extracted with ethyl acetate-hexane (3:2, 30 ml). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated, and diethyl ether was added to the residue. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (476 mg, 1.39 mmol, 91.4%).
Reaction SMILES: C(S[C:4](=[S:16])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])C.[NH2:17][CH2:18][CH2:19][CH2:20][NH2:21]>C1(C)C=CC=CC=1>[NH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:4](=[S:16])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: NCCCN
Reactant: CCCCCCCCCCCC(=S)SCC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCC(=S)NCCCN
Temperature: 10 °C

Procedure:
10.4 g of ethyl-dodecanedithioate is dissolved in 100 ml of toluene and the solution obtained is mixed with a solution of 30 g of 1,3-diaminopropane in 200 ml of toluene. The mixture is maintained at about 10° C. for 1 hour, with stirring.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[N:12]=[C:11]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[ClH:27]>C1COCC1.CO.[Pd]>[ClH:27].[NH2:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[N:12]=[C:11]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:10]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cc(-c2ccc(C#N)cc2)n(-c2ccc(OC)cc2)n1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(-c2ccc(CN)cc2)n(-c2ccc(OC)cc2)n1
Reaction time: 6.5 h

Procedure:
A mixture of 10% Pd-C 50% wet (100 mg) and ethyl 5-(4-cyanophenyl)-1-(4-methoxyphenyl)-1H-pyrazole-3-carboxylate (1 g) in THF (10 ml), MeOH (5 ml), and 1M HCl (2.9 ml) was hydrogenated under H2 latmat ambient temperature for 6.5 hours. The catalyst was filtered off through a celite pad and the pad was washed with MeOH. The filtrate and combined washings were concentrated in vacuo. The residue was dissolved in EtOH and concentrated in vacuo. The residue was crystallized from AcOEt to give ethyl 5-[4-(aminomethyl)phenyl]-1-(4-methoxyphenyl)-1H-pyrazole-3-carboxylate hydrochloride (984 mg) as a powder.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Cl:8].[S:9]1[CH:13]=[CH:12][N:11]=[C:10]1[S:14](Cl)(=[O:16])=[O:15]>>[Cl:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:14]([C:10]1[S:9][CH:13]=[CH:12][N:11]=1)(=[O:16])=[O:15]
Reactant: Cc1noc(N)c1Cl
Reactant: O=S(=O)(Cl)c1nccs1
Product: Cc1noc(NS(=O)(=O)c2nccs2)c1Cl
Yield: 33 %

Procedure:
N-(4-chloro-3-methyl-5-isoxazolyl)thiazole-2-sulfonamide was prepared in the same manner as described in Example 2 from 5-amino-4-chloro-3-methylisoxazole and thiazole-2-sulfonyl chloride in 33% yield. This was purified by HPLC (5% CH3CN to 100% CH3CN over 30 min.) to give a solid, m.p. 171-173° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[F:16][C:17]1[CH:18]=[N:19][CH:20]=[C:21]([CH:23]=[CH2:24])[CH:22]=1.[OH-].[K+]>CN1C(=O)CCC1>[F:16][C:17]1[CH:22]=[C:21]([CH2:23][CH2:24][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)[CH:20]=[N:19][CH:18]=1
Reactant: C=Cc1cncc(F)c1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2cncc(F)c2)CCN(C)C1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole, 3-fluoro-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: C(OC([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:22][CH2:23][C:24]3([C:36]#[N:37])[CH2:29][CH2:28][N:27]([C:30]4[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=4)[CH2:26][CH2:25]3)=[CH:16][CH:17]=2)[CH2:12]1)=O)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[C].[Pd]>[C:36]([C:24]1([CH2:23][CH2:22][O:21][C:15]2[CH:14]=[C:13]3[C:18]([CH2:19][CH2:20][NH:11][CH2:12]3)=[CH:17][CH:16]=2)[CH2:25][CH2:26][N:27]([C:30]2[CH:31]=[CH:32][N:33]=[CH:34][CH:35]=2)[CH2:28][CH2:29]1)#[N:37]
Reactant: N#CC1(CCOc2ccc3c(c2)CN(C(=O)OCc2ccccc2)CC3)CCN(c2ccncc2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: N#CC1(CCOc2ccc3c(c2)CNCC3)CCN(c2ccncc2)CC1
Yield: 90.2 %

Procedure:
To a solution of 7-[2-[4-cyano-1-(pyridin-4-yl)piperidin-4-yl]ethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester (585 mg) in ethanol (5 ml) were added 7.5% palladium carbon (220 mg) and ammonium formate (220 mg), and the mixture was stirred under reflux for 3 hours. After completion of the reaction, the reaction mixture was filtrated and the solvent was evaporated. To the obtained residue was added aqueous sodium hydrogencarbonate and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dried under reduced pressure to give the title compound (385 mg).
Reaction SMILES: [CH3:1][N:2]([CH2:20][C:21]([OH:23])=O)[C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][N:11]=2)=[C:5]([CH3:19])[CH:4]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[CH2:47]([N:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1)[C:48]1[CH:56]=[CH:55][C:54]2[O:53][CH2:52][O:51][C:50]=2[CH:49]=1>CN(C=O)C.O>[CH2:47]([N:57]1[CH2:62][CH2:61][N:60]([C:21](=[O:23])[CH2:20][N:2]([CH3:1])[C:3]2[CH:8]=[CH:7][C:6]([O:9][C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][N:11]=3)=[C:5]([CH3:19])[CH:4]=2)[CH2:59][CH2:58]1)[C:48]1[CH:56]=[CH:55][C:54]2[O:53][CH2:52][O:51][C:50]=2[CH:49]=1
Reactant: Cc1cc(N(C)CC(=O)O)ccc1Oc1ccc([N+](=O)[O-])cn1
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(N(C)CC(=O)N2CCN(Cc3ccc4c(c3)OCO4)CC2)ccc1Oc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of {methyl[3-methyl-4-(5-nitropyridin-2-yloxy)phenyl]amino}acetic acid (0.93 g, 2.9 mmol) in DMF (40 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.67 g, 3.5 mmol), 1-hydroxybenzotriazole monohydrate (0.54 g, 3.5 mmol), and 1-piperonylpiperazine (0.68 g, 3.08 mmol). The reaction mixture was stirred for 15 hours at room temperature under a nitrogen atmosphere. To the resulting solution was added water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1→dichloromethane:methanol=100:1), to thereby yield 1.2 g of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=1[O:23][CH3:24])([O-:3])=[O:2].[H-].[Na+].[C:27](OC(=O)C)(=[O:29])[CH3:28].Cl>CN(C)C=O>[C:27]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[C:7]([CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=2[O:23][CH3:24])=[CH:8]1)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(C(=O)O)ccc1Cc1c[nH]c2ccc([N+](=O)[O-])cc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)O)ccc1Cc1cn(C(C)=O)c2ccc([N+](=O)[O-])cc12
Reaction time: 0.33 h
Yield: 67.4 %

Procedure:
A solution of 4-(5-nitroindol-3-ylmethyl)-3-methoxybenzoic acid (0.6 g.) in N,N-dimethylformamide (DMF), (3 ml.) was added to a stirred suspension of oil-free sodium hydride (0.088 g.) in DMF (8 ml.) under a nitrogen atmosphere at ambient temperature. The red solution was stirred for 20 minutes, and acetic anhydride (0.187 g.) added. After 1 hour, the mixture was poured into hydrochloric acid (1N, 30 ml.), extracted with ethyl acetate (3×50 ml), the combined extracts washed with water (2×20 ml.), brine, dried (MgSO4) and evaporated. The product was crystallized from a mixture of tetrahydrofuran and ether to give 4-(1-acetyl-5-nitroindol-3-ylmethyl)-3-methoxybenzoic acid (0.455 g., 67%) as a yellow powder; partial NMR (250 MHz, DMSO-d6): 2.68(s,3H, NCOCH3); 3.95(s,3H, OMe); 4.13(s,2H, ArCH3).