Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21](=[O:38])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[NH:28][CH:29]([C:31]3[CH:36]=[CH:35][N:34]=[C:33]([NH2:37])[N:32]=3)[CH3:30])=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[NH2:37][C:33]1[N:32]=[C:31]([CH:29]([NH:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:21]([NH:20][C:12]2[CH:11]=[C:10]3[C:15]([C:16]([CH3:19])([CH3:18])[CH2:17][NH:8][CH2:9]3)=[CH:14][CH:13]=2)=[O:38])[CH3:30])[CH:36]=[CH:35][N:34]=1
Reactant: CC(Nc1ccccc1C(=O)Nc1ccc2c(c1)CN(C(=O)OC(C)(C)C)CC2(C)C)c1ccnc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(Nc1ccccc1C(=O)Nc1ccc2c(c1)CNCC2(C)C)c1ccnc(N)n1

Procedure:
To a solution of 7-{2-[1-(2-amino-pyrimidin-4-yl)-ethylamino]-benzoylamino}-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (Example 125) (80 mg, 0.154 mmol) in CH2Cl2 (3 mL) was added TFA (2 mL). The resulting mixture was stirred at RT for 18 h and basified with 5 N NaOH and extracted with CH2Cl2 (2×15 mL). The combined organic layers were washed with saturated NaHCO3, water, brine, dried over MgSO4, and evaporated in vacuo to give the product. MS m/z: 417.5 (M+H). Calc'd. for C24H29N6O-417.51.
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([N+:14]([O-])=O)=[C:9]([F:17])[CH:8]=2)([CH3:4])([CH3:3])[CH3:2]>CO.[Ni]>[C:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([NH2:14])=[C:9]([F:17])[CH:8]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc2cc([N+](=O)[O-])c(F)cc2[nH]1
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)c1cc2cc(N)c(F)cc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.6 %

Procedure:
A suspension of 2-tert-butyl-6-fluoro-5-nitro-1H-indole (1.5 g, 6.36 mmol) and Ni (0.5 g) in MeOH (20 mL) was stirred under H2 atmosphere (1 atm) at the room temperature for 3 h. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to dryness. The residue was recrystallized in ether to give 2-tert-butyl-6-fluoro-1H-indol-5-amine (520 mg, 38%). 1H-NMR (300 MHz, DMSO-d6) δ 10.46 (brs, 1H), 6.90 (d, J=8.7 Hz, 1H), 6.75 (d, J=9.0 Hz, 1H), 5.86 (s, 1H), 4.37 (brs, 2H), 1.29 (s, 9H); MS (ESI) m/e 206.6.
Reaction SMILES: [CH:1]12[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[C:8]([K])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:10])[CH3:9]>>[CH3:9][C:8]([C@@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6][C@H:1]1[OH:7])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10]
Reactant: C1CCC2OC2C1
Reactant: CC(C)([K])c1ccccc1
Product: CC(C)(c1ccccc1)[C@@H]1CCCC[C@H]1O

Procedure:
The next step in the synthesis was the addition of cyclohexene oxide to α-cumylpotassium to produce trans-2-cumylcyclohexanol. Dropwise addition of 105 mL (1.0 mol) of cyclohexene oxide (available from Lancaster Synthesis, Ltd., Windham, N.H., U.S.A.) followed; as before, the cyclohexene oxide addition was controlled so that the bath temperature did not rise above 30° C. As cyclohexene oxide was added, the reaction mixture thinned and became black. After this addition, the mixture was stirred for 3 hours. The reaction flask was cooled in an ice bath and 750 mL of saturated aqueous ammonium chloride was added slowly to the reaction mixture, which changed in color from light brown to bright orange to light brown again; concurrently, a white precipitate that had formed during the initial stages of the addition dissolved.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](N(OC)C)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C[Mg]Br.[CH2:17](OCC)[CH3:18]>C1COCC1.Cl>[Cl:1][C:2]1[C:7]([C:8](=[O:9])[CH2:17][CH3:18])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CON(C)C(=O)c1cccnc1Cl
Reactant: CCOCC
Agent: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CCC(=O)c1cccnc1Cl
Temperature: 50 °C
Reaction time: 1 h

Procedure:
2-Chloro-N-methoxy-N-methylpyridine-3-carboxamide (1.0 g) was dissolved in THF (30 ml), 3 Methylmagnesium bromide-diethyl ether solution (2.0 ml) was added dropwise at room temperature, and the mixture was stirred at 50° C. for 1 hr. The reaction mixture was diluted with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (630 mg).
Reaction SMILES: C1(C(=[N:14][C:15]2[N:20]=[CH:19][C:18]3[N:21]=[CH:22][N:23]([CH:24]4[CH2:29][CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]4)[C:17]=3[CH:16]=2)C2C=CC=CC=2)C=CC=CC=1.[ClH:37]>C1COCC1>[ClH:37].[NH:26]1[CH2:27][CH2:28][CH2:29][CH:24]([N:23]2[C:17]3[CH:16]=[C:15]([NH2:14])[N:20]=[CH:19][C:18]=3[N:21]=[CH:22]2)[CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCCC(n2cnc3cnc(N=C(c4ccccc4)c4ccccc4)cc32)C1
Agent: Cl
Solvent: C1CCOC1
Product: Nc1cc2c(cn1)ncn2C1CCCNC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
To a solution of tert-butyl 3-(6-((diphenylmethylene)amino)-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate (400 mg, 0.83 mmol, 1.0 eq) in THF (4 mL) was added HCl (4 N solution in 1,4 dioxane, 4 mL). The mixture was stirred at rt for 3 h and concentrated in vacuo to afford a residue which was washed with EtOAc (10 mL×3) to give crude title compound (180 mg, 95%) as brown solid. 1H NMR (400 MHz, DMSO-d6) δ: 9.82 (s, 1H), 8.73-8.65 (m, 1H), 7.74-7.70 (m, 1H), 7.58-7.56 (m, 1H), 4.04-4.02 (m, 1H), 3.67-3.66 (m, 0.5H), 3.48-3.32 (m, 2H), 2.95-2.79 (m, 1.5H), 2.18 (s, 1H), 1.99-1.96 (m, 3H), 1.75-1.73 (m, 1H). ESI-MS (M+H+): 218.0.
Reaction SMILES: [Br:1][C:2]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:13][CH:14]1[CH2:19][C:18](=[O:20])[CH2:17][C:16](=O)[CH2:15]1>>[C:4]([C:3]1[C:2]([Br:1])=[C:11]([CH:10]=[CH:9][CH:8]=1)[NH:12][C:16]1[CH2:15][CH:14]([CH3:13])[CH2:19][C:18](=[O:20])[CH:17]=1)([O:6][CH3:7])=[O:5]
Reactant: CC1CC(=O)CC(=O)C1
Reactant: COC(=O)c1cccc(N)c1Br
Product: COC(=O)c1cccc(NC2=CC(=O)CC(C)C2)c1Br
Temperature: 125 °C
Yield: 66.6 %

Procedure:
A mixture of methyl 2-bromo-3-aminobenzoate (10.2 g, 44.3 mM) and 5-methyl-1,3-cyclohexanedione (6.15 g, 48.7 mM) was heated at 125° C. under a stream of nitrogen for 1.5 hours. The resultant solid was triturated with ethyl acetate to afford 9.98 g (67%) of 3-(3-carbomethoxy-2-bromoanilino)-5-methyl-cyclohex-2-en-1-one. 1H NMR (CDCl3) δ7.55 (m, 2H), 7.35 (dd, J=8 and 8 Hz, 1H), 6.4 (bs, 1H), 5.55 (s, 1H), 3.95 (s, 3H), 2.6-2.0 (m, 5H), 1.15 (d, J=7 Hz, 3H). MS (ES) m/e 338, 340.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH:5]=[CH:4][C:3]=1[NH2:17].[C:18]([OH:26])(=[O:25])[C:19]([CH2:21][C:22](O)=[O:23])=[CH2:20]>>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH:5]=[CH:4][C:3]=1[N:17]1[C:22](=[O:23])[CH2:21][CH:19]([C:18]([OH:26])=[O:25])[CH2:20]1
Reactant: Nc1ccc(OCc2cccc(F)c2)cc1F
Reactant: C=C(CC(=O)O)C(=O)O
Product: O=C(O)C1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2F)C1

Procedure:
The title compound is prepared in analogy to Example 20c) from 2-fluoro-4-(3-fluoro-benzyloxy)-phenylamine and itaconic acid. Yield: 67% of a purple solid. MS: m/e=346.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[C:10](Cl)=[CH:9][C:8]([Cl:12])=[N:7][CH:6]=1)[CH3:2].[CH2:14]([O:16][C:17](=[O:30])[CH2:18][CH2:19][NH:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[CH2:26][CH2:25][CH2:24]2)[CH3:15].C(N(CC)CC)C>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[C:10]([N:20]([CH2:19][CH2:18][C:17]([O:16][CH2:14][CH3:15])=[O:30])[C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[CH2:26][CH2:25][CH2:24]3)=[CH:9][C:8]([Cl:12])=[N:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Reactant: CCOC(=O)CCNc1ccc2c(c1)CCC2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCN(c1ccc2c(c1)CCC2)c1cc(Cl)ncc1C(=O)OCC
Temperature: 100 °C
Reaction time: 48 h
Yield: 42.6 %

Procedure:
To a solution of 4,6-dichloro-nicotinic acid ethyl ester (2 g, 9 mmol) and 3-(indan-5-ylamino)-propionic acid ethyl ester (from Example 1 (A), 2.3 g, 10 mmol) in 5 mL of DMF was added triethylamine (2 g, 20 mmol). The mixture was stirred at 100° C. for 48 hours. The reaction was cooled, quenched with water, and extracted 3 times with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo. Flash chromatography (EtOAc/Hexanes, 2:10 v/v) afforded the title compound as a white solid (1.6 g, 44%). 1H NMR (400 MHz, CDCl3) δ (ppm): 8.22 (s, 1H), 7.15 (d, J=8.0 Hz, 1H), 6.92 (s, 1H), 6.85 (m, 2H), 4.03-4.15 (m, 4H), 3.74 (q, J=7.1 Hz, 2H), 2.85 (t, J=7.4 Hz, 4H), 2.64 (m, 2H), 2.07 (m, 2H), 1.23 (t, J=7.1 Hz, 3H), 1.08 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].C(Cl)Cl.[C:15]([NH2:19])([CH3:18])([CH3:17])[CH3:16].CCN(C(C)C)C(C)C>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:19][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:10])=[O:9]
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)c1ccccc1Br
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)NS(=O)(=O)c1ccccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
2-Bromobenzenesulfonyl chloride (100.9 g, 394.9 mmol) was dissolved in methylene chloride (500 mL, 8.0 mol) and cooled at 0° C. t-Butylamine (41.3 mL, 395 mmol) was added in 3 portions over approximately 1 minute. DIPEA (75.7 mL, 434 mmol) was immediately added in 3 portions over approximately 1 minute. The mixture was warmed to room temperature and stirred overnight. The product was washed with 1M H3PO4 (2×), with saturated. NaHCO3, and with saturated aqueous NaCl, then dried over MgSO4, filtered, and concentrated to yield 2-bromo-N-t-butyl-benzenesulfonamide (112 g) as a light brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:17][C:18]1[NH:22][N:21]=[C:20]([CH:23]=O)[CH:19]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][NH:16][CH2:23][C:20]3[CH:19]=[C:18]([CH3:17])[NH:22][N:21]=3)[CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NCCN1CCN(c2cccc(Cl)c2)CC1
Reactant: Cc1cc(C=O)n[nH]1
Product: Cc1cc(CNCCN2CCN(c3cccc(Cl)c3)CC2)n[nH]1
Yield: 60.4 %

Procedure:
Compound 73 was prepared using the same method as that of Example 1 except that 4-(3-chlorophenyl)piperazin-1-ylethylamine and 5-methylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[C@@H:19]([CH3:20])[CH2:18][C:17]2[C:16]([O:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[NH:27][CH:26]=[CH:25]4)=[N:15][CH:14]=[N:13][C:12]=2[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[C:31]([O:35][C:36]([N:38]1[C:42]([NH:43][C:44](OC2C=CC=CC=2)=[O:45])=[CH:41][C:40]([C:53]2([CH3:56])[CH2:55][CH2:54]2)=[N:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[C@@H:19]([CH3:20])[CH2:18][C:17]2[C:16]([O:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[N:27]([C:44](=[O:45])[NH:43][C:42]3[N:38]([C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:37])[N:39]=[C:40]([C:53]5([CH3:56])[CH2:55][CH2:54]5)[CH:41]=3)[CH:26]=[CH:25]4)=[N:15][CH:14]=[N:13][C:12]=2[CH2:11]1)=[O:9])([CH3:4])([CH3:5])[CH3:6]
Reactant: CC(C)(C)OC(=O)n1nc(C2(C)CC2)cc1NC(=O)Oc1ccccc1
Reactant: C[C@H]1Cc2c(ncnc2Oc2ccc3[nH]ccc3c2)CN1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H]1Cc2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cc(C4(C)CC4)nn3C(=O)OC(C)(C)C)c2)CN1C(=O)OC(C)(C)C

Procedure:
Sodium hydride (0.024 g, 0.990 mmol; 60% in oil) is added to a solution of (S)-4-(1H-Indol-5-yloxy)-6-methyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylic acid tert-butyl ester, Example 53-B-1, (0.126 g, 0.330 mmol) and DMF (7.5 mL) at it. After 5 min 3-(1-Methyl-cyclopropyl)-5-phenoxycarbonylamino-pyrazole-1-carboxylic acid tert-butyl ester, Example 5-D, (0.178 g, 0.495 mmol) is then added. After 1 h the mixture is quenched by the addition of saturated aqueous NH4Cl and then concentrated. The residue is separated directly via FCC (20-70% EtOAc/heptane). MS (ESI) m/z 644.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]#[N:23])[CH:20]=3)[N:15]=[CH:14][C:13]=2C(O)=O)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C1(OC2C=CC=CC=2)C=CC=CC=1>CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]#[N:23])[CH:20]=3)[N:15]=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CNc2c(C(=O)O)cnc3ccc(C#N)cc23)cc1Cl
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1ccc(CNc2ccnc3ccc(C#N)cc23)cc1Cl
Temperature: 240 °C
Yield: 75.3 %

Procedure:
To 2.16 g (5.87 mmol) 4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinolinecarboxylic acid was added 50 mL diphenyl ether (Aldrich), and nitrogen was vigorously bubbled through this mixture for 20 minutes. The resulting mixture was then heated to 240° C. under nitrogen for 30 minutes. During the course of the reaction, the dispersed starting material slowly dissolved, and gas evolution was observed. The resulting solution was poured into 200 mL hexane, and a precipitated solid was filtered to yield 1.43 g (4.42 mmol, 75% yield) of the title compound as a off-white solid: LC/MS: M/Z 324 (M+H) observed, 96% purity; mp: decomposed 227–230° C. LC: 2.84′.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]3[C:11]([CH:12]=[N:13][C:14]([S:17][CH3:18])=[N:15]3)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(Cl)Cl.ClC1C=CC=C(C(OO)=[O:30])C=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]3[C:11]([CH:12]=[N:13][C:14]([S:17]([CH3:18])=[O:30])=[N:15]3)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CSc1ncc2ccc(-c3cccc(Cl)c3)n2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1ncc2ccc(-c3cccc(Cl)c3)n2n1
Temperature: 25 °C

Procedure:
Into a 100 mL round bottom flask, [7-(3-Chloro-phenyl)-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (1.60 g, 0.00580 mol) was dissolved in Methylene chloride (60 mL, 1 mol) and the mixture was treated with m-Chloroperbenzoic acid (1.35 g, 0.00783 mol). The reaction was allowed to stir at room temperature until HPLC showed consumption of starting material. The reaction was partitioned between sodium bicarbinate and DCM. The organic layer was separated, washed with water subsequently with Brine and dried over sodium sulfate. The solution was filtered and reduced. The solid was then triturated with ether to afford 7-(3-Chloro-phenyl)-2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazine as a yellow solid. The product was used as is with mixture of sulfone by-product.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[Br:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][N:9]2[CH2:10][CH2:11][C:6]([S:20]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)(=[O:22])=[O:21])([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)=[CH:18][CH:17]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(Cc2ccc(Br)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccc(Br)cc3)CC2)cc1

Procedure:
1-(4-Bromo-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared starting from 1-(4-bromo-benzyl)-4-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester (16.5 g, 33.3 mmol) dissolved in THF:methanol 3:1 and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 6.18 g (40%); tan solid; mp 215° C.; MS: 469.7 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([F:10])[N:3]=1.ClC(Cl)C.[NH:15]1[CH2:20][CH2:19][S:18](=[O:22])(=[O:21])[CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>>[Cl:1][C:2]1[N:3]=[C:4]([F:10])[C:5]([CH2:6][N:15]2[CH2:20][CH2:19][S:18](=[O:22])(=[O:21])[CH2:17][CH2:16]2)=[CH:8][CH:9]=1
Reactant: O=S1(=O)CCNCC1
Reactant: O=Cc1ccc(Cl)nc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: O=S1(=O)CCN(Cc2ccc(Cl)nc2F)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
6-Chloro-2-fluoronicotinaldehyde (116 mg, 0.73 mmol) was added to a 200 mL round bottom under argon. Dichloroethane (2.9 ml) was added followed by thiomorpholine 1,1-dioxide (98 mg, 0.73 mmol). The mixture was stirred for 45 min at room temperature, at which time sodium triacetoxyborohydride (216 mg, 1.02 mmol) was added. The resulting slurry was stirred for 72 hours at room temperature. Saturated aqueous sodium bicarbonate was added and the resulting mixture was extracted twice with ethyl acetate. The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (silica, 0-100% ethyl acetate/hexanes) to afford the title compound.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([N:9]([C:11]2[CH:16]=[CH:15][C:14]3[O:17][CH2:18][CH2:19][O:20][C:13]=3[CH:12]=2)N)=[O:8])=[CH:5][CH:4]=1.[C:23]([OH:30])(=[O:29])[CH2:24][CH2:25][C:26]([CH3:28])=O>O>[CH3:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([N:9]2[C:11]3[C:16](=[CH:15][C:14]4[O:17][CH2:18][CH2:19][O:20][C:13]=4[CH:12]=3)[C:25]([CH2:24][C:23]([OH:30])=[O:29])=[C:26]2[CH3:28])=[O:8])=[CH:5][CH:4]=1
Reactant: Cc1ccc(C(=O)N(N)c2ccc3c(c2)OCCO3)cc1
Reactant: CC(=O)CCC(=O)O
Agent: Cl
Solvent: O
Product: Cc1ccc(C(=O)n2c(C)c(CC(=O)O)c3cc4c(cc32)OCCO4)cc1
Temperature: 25 °C

Procedure:
A mixture of 5 g of N1 -(p-methylbenzoyl)3,4-ethylenedioxyphenylhydrazine hydrochloride and 30 g of levulinic acid was heated for 3 hours at 85° - 90° C. The reaction mixture was cooled to a room temperature, and poured into 200 ml of water. crude product was recrystallized twice from ethyl acetate to give 1-(p-methylbenzoyl)-2-methyl-5,6-ethylenedioxy-3-indolylacetic acid having a melting point of 170° - 171° C.
Reaction SMILES: [N:1]([O-])=O.[Na+].[CH3:5][C:6]([C:8]1[C:13]([NH2:14])=[CH:12][C:11]([O:15][CH3:16])=[C:10]([O:17][CH3:18])[CH:9]=1)=[O:7]>C(O)(=O)C.S(=O)(=O)(O)O>[OH:7][C:6]1[C:8]2[C:13](=[CH:12][C:11]([O:15][CH3:16])=[C:10]([O:17][CH3:18])[CH:9]=2)[N:14]=[N:1][CH:5]=1
Reactant: COc1cc(N)c(C(C)=O)cc1OC
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc2nncc(O)c2cc1OC
Temperature: 80 °C
Yield: 87.3 %

Procedure:
The starting material, 4-hydroxy-6,7-dimethoxycinnoline was obtained by adding a solution of sodium nitrite (1.9 g, 27 mmol) to a solution of 2-amino-4,5-dimethoxyacetophenone (5 g, 0.025 mol) in acetic acid (90 ml) and sulphuric acid (15 ml) at a rate to maintain the temperature below 20° C. The mixture was heated at 80° C. for 90 minutes. After cooling and concentrating the solution to half its original volume, the residue was poured into ether (800 ml). The solid was collected by filtration and suspended in water (200 ml). After adjusting to pH7 with sodium hydroxide the solid was filtered, washed with water, methanol and methylene chloride to give 4-hydroxy-6,7-dimethoxycinnoline (4.5 g, 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:15][C:16]1[N:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[Cl:15][C:16]1[C:17]([C:18]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=3)[CH:4]=2)=[O:19])=[CH:21][CH:22]=[C:23]([Cl:25])[N:24]=1
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(Cl)nc1Cl

Procedure:
Procedure G was used to couple 4-chloro-3-(pyridin-2-yl)aniline (50 mg) and 2,6-dichloronicotinic acid to produce 2,6-dichloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)pyridine-3-carboxamide. MS (Q1) 378.1 (M)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]([OH:27])=[O:26])=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:30][OH:31].C(=O)([O-])O.[Na+]>>[OH:31]/[N:30]=[C:8](/[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1)\[CH2:9][C@H:10]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([OH:27])=[O:26])=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(CC(=O)O)cc2)c2ccccc2C)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@H](c2ccc(CC(=O)O)cc2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 132, step 6, from {4-[(R)-3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-phenyl}-acetic acid and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a white foam, MS (ESI+): m/z=389.4 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([C:42]#[N:43])[CH:37]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([C:42]#[N:43])[CH:37]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(C#N)c2)c1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C#N)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (218 mg, 0.75 mmol) and 3-[3-(2-cyano-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K24) (242 mg, 0.75 mmol) according to the general procedure M. Obtained as a white solid (275 mg, 68%).
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([Cl:18])[CH:13]=2)[CH:9]=[C:8]([CH3:19])[N:7]=1)=[O:5])C.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][N:22]=1>>[CH3:27][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:4]([C:6]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([Cl:18])[CH:13]=3)[CH:9]=[C:8]([CH3:19])[N:7]=2)=[O:5])=[N:22][CH:23]=1
Reactant: Cc1ccc(N)nc1
Reactant: CCOC(=O)c1cc(-c2ccnc(Cl)c2)cc(C)n1
Product: Cc1ccc(NC(=O)c2cc(-c3ccnc(Cl)c3)cc(C)n2)nc1

Procedure:
The title compound, was prepared from 2′-Chloro-6-methyl-[4,4′]bipyridinyl-2-carboxylic acid ethyl ester in accordance with the general method of example 26, step 6 using 2-amino-5methylpyridine instead of 3-chloroaniline to yield the final compound as a white crystalline, MS (ISP): m/e=339.2, 341.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Cl:10])[C:3]=1[CH2:11][OH:12].CO>C1C=CC=CC=1.O=[Mn]=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Cl:10])[C:3]=1[CH:11]=[O:12]
Reactant: COc1cc(Cl)c(CO)c(Cl)c1
Agent: O=[Mn]=O
Solvent: c1ccccc1
Solvent: CO
Product: COc1cc(Cl)c(C=O)c(Cl)c1
Temperature: 25 °C

Procedure:
A suspension of (2,6-dichloro-4-methoxy-phenyl)-methanol (5.69 g, 27.49 mmol) and MnO2 (15 g) in benzene (100 mL) was stirred at reflux, utilizing a Dean-Stark trap, overnight. The suspension was cooled to room temperature, filtered through Celite, and the solvent was removed by evaporation to yield 4.69 g (83%) of crude white solid. An analytical sample was obtained by recrystallization from methanol to yield white needle crystals: mp 104-106° C.; 1H NMR (DMSO-d6): δ 3.90 (3H, s), 7.21 (2H, s), 10.29 (1H, s); MS (EI) m/z 204/206/218 (M+−).