Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:9]=[C:8]([C:10](O)=[O:11])[C:7]=2[CH:13]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>CCOCC>[CH3:1][O:2][C:3]1[CH:13]=[C:7]2[CH:8]([CH2:10][OH:11])[CH2:9][C:6]2=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(C(=O)O)=C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: COc1ccc2c(c1)C(CO)C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 5-methoxybenzocyclobutene-1-carboxylic acid (32.0 g) in ether (1.2 l) is added dropwise to a stirred suspension of LAH (15.5 g) in ether (650 ml) under nitrogen. The reaction mixture is stirred at RT for 4 hours, after which, water (15.5 ml), 15% NaOH (15.5 ml) and a second portion of water added (46 ml) sequentially to the reaction mixture resulting in the formation of a precipitate. The ethereal layer is filtered, dried over Na2SO4, filtered and concentrated in vacuo yielding the desired product as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[S:15][C:14]([CH3:17])([CH3:16])[C:13](=[O:18])[NH:12][C:11]2[N:19]([CH3:23])[N:20]=[C:21]([CH3:22])[C:10]1=2.[OH-].[Na+].[CH3:26]OS(OC)(=O)=O.[NH4+].[OH-].C(=O)(O)[O-].[Na+]>C1COCC1.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[S:15][C:14]([CH3:17])([CH3:16])[C:13](=[O:18])[N:12]([CH3:26])[C:11]2[N:19]([CH3:23])[N:20]=[C:21]([CH3:22])[C:10]1=2
Reactant: COS(=O)(=O)OC
Reactant: Cc1nn(C)c2c1C(c1ccc(Cl)cc1Cl)SC(C)(C)C(=O)N2
Agent: O=C([O-])O
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nn(C)c2c1C(c1ccc(Cl)cc1Cl)SC(C)(C)C(=O)N2C
Temperature: 25 °C
Reaction time: 24 h
Yield: 72 %

Procedure:
To 4-(2,4-dichlorophenyl)-1,3,6,6-tetramethyl-4,8-dihydropyrazolo[3,4-e][1,4]thiazepin-7-one (0.150 g, 0.4 mmol, made in the same manner as Preparation C.2) dissolved in THF/H2O (1:1, 10 mL), was added NaOH (0.81 mL, 2 M aqueous). The reaction mixture was stirred for about 24 h at rt. Subsequently, dimethylsulfate (0.077 mL, 0.8 mmol) was added, and the reaction mixture was stirred for about 1 hr at rt. To the reaction mixture was added NH4OH (1 mL, 25% aqueous), followed by 5% aqueous sodium bicarbonate (5 mL) and ethyl acetate (25 mL). The layers were separated and the organic layer was washed with water (25 mL), dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, ethyl acetate/DCM (1:9)), to afford 4-(2,4-dichlorophenyl)-1,3,6,6,8-pentamethyl-4H-pyrazolo[3,4-e][1,4]thiazepin-7-one (0.110 g, 0.28 mmol, 72%), as a white solid. LC-MS (Table 1, Method a) Rt=5.05 min, m/z 384 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 1.05 (3 H, br. s.) 1.51 (3 H, br. s.) 2.32 (3 H, br. s.) 2.87 (3 H, br. s.) 3.65 (3 H, br. s.) 5.32 (1 H, br. s.) 7.29 (1 H, dd, J=8.3, 1.9 Hz) 7.34 (1 H, br. s.) 7.72 (1 H, d, J=8.3 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([N+:12]([O-])=O)=[C:8]([CH:11]=1)[C:9]#[N:10])[CH3:2]>CO.Cl.[Fe]>[NH2:12][C:7]1[CH:6]=[C:5]([C:15]([F:17])([F:18])[F:16])[C:4]([O:3][CH2:1][CH3:2])=[CH:11][C:8]=1[C:9]#[N:10]
Reactant: CCOc1cc(C#N)c([N+](=O)[O-])cc1C(F)(F)F
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: CCOc1cc(C#N)c(N)cc1C(F)(F)F
Temperature: 50 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
Iron powder (40.96 g, 733 mmol) was added in small portions over 5 min to a stirred suspension of finely grinded 5-ethoxy-2-nitro-4-trifluoromethyl-benzonitrile from step 3 (42.79 g, 164.5 mmol) in MeOH (85 mL) and conc. HCl (102 mL) with water bath cooling keeping the internal temperature at 40-50° C. The resulting mixture was stirred for further 1 h at ca. 50° C. and then poured into ice cold H2O (700 mL). The precipitate was filtered, washed with water, dried, and dissolved in boiling EtOH (800 mL), activated carbon (ca. 10 g) was added, the mixture was refluxed for 45 min, the hot solution was filtered and evaporated to dryness to leave a yellow solid (31.81 g, 84%), which was used without further purification. MS (EI) 230.1 [M].
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[C:13]1[CH:17]=[CH:16][NH:15][CH:14]=1.[Cl:18][C:19]1[N:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>C(Cl)Cl.C(OCC)(=O)C>[Cl:18][C:19]1[C:20]([C:21]([C:16]2[NH:15][CH:14]=[C:13]([C:7]3[C:6]([Cl:5])=[CH:11][CH:10]=[CH:9][C:8]=3[Cl:12])[CH:17]=2)=[O:22])=[CH:24][CH:25]=[CH:26][N:27]=1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: Clc1cccc(Cl)c1-c1cc[nH]c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(c1cc(-c2c(Cl)cccc2Cl)c[nH]1)c1cccnc1Cl
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Aluminum chloride (1.4 g, 10.5 mmol) was added to a mixture of 3-(2,6-dichloro-phenyl)-1H-pyrrole (2 g, prepared as described in Journal of Organic Chemistry, 62: 2650 (1997) (incorporated herein by reference) and 2-chloronicotinoyl chloride (1.8 g, 10.5 mmol) in DCM (55 mL) at 0° C. The mixture was stirred at 0° C. for 30 mins and at room temperature for 1.5 hours. The reaction was diluted with ethyl acetate and washed with brine, 2N NaOH, brine, dried and concentrated. The residue was purified on silica gel column to give 168 mg of (2-chloro-pyridin-3-yl)-[4-(2,6-dichloro-phenyl)-1H-pyrrol-2-yl]-methanone.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH:10][CH:11]=[O:12].C(N(CC)CC)C.[C:20]1([C:26](Cl)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[CH3:7][N:6]1[C:2]([NH:1][C:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[C:3]([CH2:8][CH2:9][NH:10][CH:11]=[O:12])[CH:4]=[N:5]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1ncc(CCNC=O)c1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1ncc(CCNC=O)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.6 %

Procedure:
To a solution of N-[2-(5-amino-1-methylpyrazol-4-yl)ethyl]formamide (2.7 g, 16 mmol) and triethylamine (2.5 ml, 17.6 mmol) in methylene chloride (50 ml) was added triphenylmethyl chloride (5.2 g, 17.6 mmol), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was washed with successively 10% aqueous citric acid solution and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was triturated with diisopropyl ether and dried in vacuo to give N-[2-(1-methyl-5-triphenylmethylaminopyrazol-4-yl)ethyl]formamide (4.7 g) as a colorless solid.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15](Br)=[CH:16][CH:17]=3)[C:12]3[CH:20]=[C:21]([Cl:24])[CH:22]=[N:23][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:25]([O-:28])([O-])=O.[K+].[K+].O>O1CCOCC1.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>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15](/[CH:11]=[CH:12]/[C:13]4[CH:18]=[CH:17][C:16]([O:28][CH3:25])=[CH:15][CH:14]=4)=[CH:16][CH:17]=3)[C:12]3[CH:20]=[C:21]([Cl:24])[CH:22]=[N:23][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C([O-])[O-]
Reactant: O=S(=O)(c1ccccc1)n1c2ccc(Br)cc2c2cc(Cl)cnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(/C=C/c2ccc3c(c2)c2cc(Cl)cnc2n3S(=O)(=O)c2ccccc2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 135.6 %

Procedure:
To a solution of 9-benzenesulfonyl-6-bromo-3-chloro-9H-pyrido[2,3-b]indole (250 mg, 0.59 mmol, 1 equiv.) in anhydrous dioxane (25 ml) under Argon, Pd(PPh3)4 (102 mg, 0.09 mmol, 0.15 equiv.), K2CO3 (244 mg, 1.77 mmol, 3 equiv.), (E)-2′-(4-methoxyphenyl)ethenylboronic acid (110 mg, 0.77 mmol, 1.3 equiv.) and H2O (5 ml) are added respectively. The mixture is stirred at 100° C. overnight and then filtered over celite which is washed with AcOEt (20 ml) and THF (10 ml). The filtrate is concentrated under reduced pressure and the crude residue is purified over silica gel column (eluant CH2Cl2/PE 7:3). The product is obtained as a white solid (212 mg, 0.40 mmol) in 68% yield.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C@@H:7]2[O:13][C@H:12]([CH2:14][OH:15])[C@@H:10]([OH:11])[C@H:8]2[OH:9])[C:5]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:4]=2[N:3]=1.[Br:21]Br.O>O>[Br:21][C:17]1[C:18]([Cl:20])=[CH:19][C:4]2[N:3]=[C:2]([Cl:1])[N:6]([C@@H:7]3[O:13][C@H:12]([CH2:14][OH:15])[C@@H:10]([OH:11])[C@H:8]3[OH:9])[C:5]=2[CH:16]=1
Reactant: BrBr
Reactant: OC[C@H]1O[C@@H](n2c(Cl)nc3cc(Cl)ccc32)[C@H](O)[C@@H]1O
Solvent: O
Product: OC[C@H]1O[C@@H](n2c(Cl)nc3cc(Cl)c(Br)cc32)[C@H](O)[C@@H]1O
Reaction time: 6 h

Procedure:
To a suspension of 0.110 g (0.313 mmol, as C12H12Cl2N2O4MeOH) of 2,5-dichloro-1-β-D-ribofuranosylbenzimidazole (73) in 3 mL of H2O was added dropwise 10 mL of a sat. solution of Br2/H2O at room temperature. After the addition had been completed, stirring was continued for 6 hr. The reaction mixture was filtered and the solid was washed with portions of H2O, and then recrystallized from MeOH to give 0.091 g (73%, 2 crops) of 99 as white crystalline needles. MP 158°-159° C. MS (EI) m/e 395.9274 (5% M+ =395.9279). 1H NMR (DMSO-d6): δ 8.69 (s, 1, 7-H), 7.96 (s, 1, 4-H), 5.88 (d, 1, 1'-H, J1'-2' =8.0 Hz), 5.51 (d, 1, 2'-OH, J2'-2'OH =6.5 Hz), 5.41 (t, 5'-OH, J5'-5'OH =4.5 Hz), 5.30 (d, 1, 3'-OH, J3'-3'OH =4.5 Hz), 4.42 (m, 1, 2'-H, J2'-3' =5.5 Hz), 5.30 (d, 1, 3'-OH, J3'-4' =1.5 Hz), 4.01 (m, 1, 4'-H, J4'-5' =J4'-5'=2.5 Hz), 371 (m, 2, 5'-H, and 5"-H, J5'-5" =1.20 Hz). Anal. Calcd. for C12H11BrCl2N2O4 : C, 36.21; H, 2.79; N, 7.04. Found: C, 36.14; H, 2.90; N, 6.90.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[CH:6][C:7]=1[CH2:8][OH:9])[CH3:2]>C(OCC)C.O1CCCC1.[O-2].[O-2].[Mn+4]>[CH2:1]([C:3]1[O:4][C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:12][CH:11]=2)=[CH:6][C:7]=1[CH:8]=[O:9])[CH3:2]
Reactant: CCc1oc(-c2ccc(C(F)(F)F)cc2)cc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C=O
Temperature: 40 °C
Reaction time: 8 h
Yield: 24.6 %

Procedure:
A suspension of {2-ethyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methanol (2.7 g) and manganese dioxide (6.8 g) in diethyl ether (20 mL) and tetrahydrofuran (20 mL) was stirred overnight at 40° C. Manganese dioxide was filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel chromatography (5% ethyl acetate/hexane to 20% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (0.66 g, 24%) as a yellow solid.
Reaction SMILES: C[N:2]1[C:6]([NH:7][C:8]([O:10][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[C:5]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4([C:34]([OH:36])=[O:35])[CH2:33][CH2:32]4)=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[N:4]=[N:3]1.Br[C:38]1C=CC(C2N(C)N=NC=2C(O)=O)=CC=1>>[CH3:38][N:4]1[C:5]([C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4([C:34]([OH:36])=[O:35])[CH2:33][CH2:32]4)=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)=[C:6]([NH:7][C:8]([O:10][C@@H:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH3:12])=[O:9])[N:2]=[N:3]1
Reactant: Cn1nnc(C(=O)O)c1-c1ccc(Br)cc1
Reactant: C[C@@H](OC(=O)Nc1c(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)nnn1C)c1ccccc1
Product: C[C@@H](OC(=O)Nc1nnn(C)c1-c1ccc(-c2ccc(C3(C(=O)O)CC3)cc2)cc1)c1ccccc1

Procedure:
This compound was prepared using the same method as described for the preparation of 1-{4′-[1-methyl-5-((R)-1-phenyl-ethoxycarbonylamino)-1H-[1,2,3]triazol-4-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid in Example 2, except that 5-(4-bromo-phenyl)-1-methyl-1H-[1,2,3]triazole-4-carboxylic acid (from step 4b in Example 1) was used. LC/MS calcd for C28H26N4O4 (m/e) 482.0, obsd 483.0 (M+H); 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.15-1.30 (m, 2.4H), 1.32-1.62 (m, 4.6H), 4.05 (s, 3H), 5.69 (br m, 1H), 7.20-7.40 (br m, 5H), 7.46 (d, J=8.1 Hz, 2H), 7.59 (d, J=−8.1 Hz, 2H), 7.66 (d, J=8.1 Hz, 2H), 7.77 (d, J=7.6 Hz, 2H), 9.34 (br s, 1H), 12.39 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22]C(=O)C)=[CH:18][CH:17]=1.Cl>C(O)C>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH2:14][CH2:13][CH2:12][N:3]2[C:2](=[O:1])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]2=[O:11])=[CH:17][CH:18]=1
Reactant: CC(=O)Nc1ccc(OCCCN2C(=O)c3ccccc3C2=O)cc1
Agent: Cl
Solvent: CCO
Product: Nc1ccc(OCCCN2C(=O)c3ccccc3C2=O)cc1
Reaction time: 18 h
Yield: 98.2 %

Procedure:
A solution of 10.0 g of N-[4-[3-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)propoxy]phenyl]acetamide (Example 94) in 500 ml of ethanol is treated with 100 ml of HCl and refluxed for 8 hours and allowed to stand at room temperature for 18 hours. The precipitate is collected, washed with 50 ml of ethanol and air dried to give 8.6 g of solid as the hydrochloride salt. A 1.5 g sample is crystallized from ethanol: water to give 1.2 g of the HCl salt of the title compound, m.p. 250°-260° C.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[C:12]([C:13]2[C:21]3[C:20]([NH2:22])=[N:19][CH:18]=[N:17][C:16]=3[N:15]([CH3:23])[CH:14]=2)=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][NH:8]2.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.[F:57][C:58]1[CH:63]=[CH:62][C:61]([CH2:64][C:65](O)=[O:66])=[CH:60][C:59]=1[C:68]([F:71])([F:70])[F:69]>CN(C=O)C.CO.C(Cl)Cl>[F:3][C:4]1[C:12]([C:13]2[C:21]3[C:20]([NH2:22])=[N:19][CH:18]=[N:17][C:16]=3[N:15]([CH3:23])[CH:14]=2)=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][N:8]2[C:65](=[O:66])[CH2:64][C:61]1[CH:62]=[CH:63][C:58]([F:57])=[C:59]([C:68]([F:69])([F:71])[F:70])[CH:60]=1
Reactant: O=C(O)Cc1ccc(F)c(C(F)(F)F)c1
Reactant: Cn1cc(-c2ccc3c(c2F)CCN3)c2c(N)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2ccc3c(c2F)CCN3C(=O)Cc2ccc(F)c(C(F)(F)F)c2)c2c(N)ncnc21
Reaction time: 1 h
Yield: 66.3 %

Procedure:
To a suspension of 5-(4-fluoro-2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine dihydrochloride (200 mg, 0.56 mmol, 1 equiv) and HATU (235 mg, 0.62 mmol, 1.1 equiv) in DMF (2 mL) at room temperature was added DIEA (314 uL, 1.80 mmol, 3.2 equiv) in one portion. To this mixture was added [4-fluoro-3-(trifluoromethyl)phenyl]acetic acid (125 mg, 0.56 mmol, 1 equiv) portionwise over a 1 h period. After an additional 1 hour, the mixture was poured into ice cold water to give a suspension, which was filtered. The cake was washed with water and dried under house vacuum to afford crude product, which was dissolved in 10% MeOH in DCM and absorbed onto a dryload cartridge. Purification was done on an Analogix SF25-40 g silica gel cartridge using gradient elution of 1% A in CHCl3 to 65% A in CHCl3 (A was a mixture of 3200/800/80 CHCl3/MeOH/NH4OH, gradient: 0-5 min: 1% A, 5-35 min 5-60% A). The desired product eluted from 30-36% A. The combined fractions were concentrated in vacuo. The residue was dissolved in 10% MeOH in DCM and absorbed onto a dryload cartridge. Purification was done on an Analogix SF25-60 g silica gel cartridge using gradient elution of 1% A in EtOAc 75% A (A was a mixture of 20% MeOH in EtOAc). The desired product eluted from 34-64% A. The combined fractions were concentrated in vacuo. The residue was dissolved in 20 mL of 10% MeOH in DCM and concentrated in vacuo. The volume was reduced down to about 4 mL, and the mixture was diluted with 10 mL of MTBE. The resulting suspension was concentrated in vacuo to a wet paste, which was diluted with another 10 mL of MTBE. The suspension was filtered. The cake was washed with MTBE (3×4 mL) and dried under vacuum at 65° C. for 18 h to afford 5-(4-fluoro-1-{[4-fluoro-3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (181 mg) as white solids. LC-MS (ES) m/z=488 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.28 (s, J=8.3 Hz, 2H), 3.74 (s, 3H), 4.03 (s, 2H), 4.34 (t, J=8.3 Hz, 2H), 5.87-6.19 (br s, 1.6H), 7.20 (t, J=8.0 Hz, 1H), 7.27 (s, 1H), 7.45-7.55 (m, 1H), 7.63-7.70 (m, 1H), 7.73 (d, J=7.1 Hz, 1H), 7.91 (d, J=8.1 Hz, 1H), 8.14 (s, 1H).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=[O:11])[CH2:5][CH2:4][CH:3]=[CH:2]1.Cl([O-])=[O:18].[Na+].P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.CC(=CC)C>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[C:10]([OH:18])=[O:11])[CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: COc1ccc(C=O)cc1OC1C=CCC1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Product: COc1ccc(C(=O)O)cc1OC1C=CCC1
Reaction time: 8 h
Yield: 71.3 %

Procedure:
A solution of 3-cyclopent-2-enyloxy-4-methoxybenzaldehyde (7.70 g) in t-butanol (160 mL) and 2-methyl-2-butene (40 mL) is treated dropwise with an aqueous solution (150 mL) containing sodium chlorite (80% technical grade; 4.39 g) and sodium dihydrogen phosphate (38.49 g), and left to stand overnight. The resulting mixture is extracted with dichloromethane (2×250 mL), and the combined organic layers are dried over sodium sulfate, the solvent is removed under reduced pressure, and the resulting residue is recrystallized from ethyl acetate, to give 3-cyclopent-2-enyloxy-4-methoxybenzoic acid (5.89 g), in the form of a colorless solid. m.p. 160-163° C. [Elemental analysis: C,66.4; H,6.0%; calculated: C,66.7; H,6.0%].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[O:13]=[C:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:16][CH2:15]1>C1COCC1>[OH:13][C:14]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:15][CH2:16][N:17]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:18][CH2:19]1
Reactant: Brc1ccccn1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(O)(c2ccccn2)CC1
Temperature: -60 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-bromopyridine (0.47 mL, 5 mmol) in THF (20 mL) was cooled to −60° C. and treated dropwise with nBuLi (1.6M in hexanes, 5.2 ml, 5.2 mmol). The reaction mixture was stirred for 30 minutes at −60° C. and then benzyl 4-oxo-1-piperidine carboxylate 1.14 g, 4.9 mmol) in THF (10 mL) was slowly added to the reaction mixture. The reaction mixture was stirred at −60° C. for 15 minutes and then quenched with saturated NH4Cl. The cooling bath was removed and reaction mixture was allowed to warm to room temperature. The mixture was were extracted with CH2Cl2 and the organics were dried (MgSO4), filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography using hexane:ethyl acetate (1:1) to provide the title compound, 400 mg (27%). 1H NMR (d6-DMSO, 300 MHz) δ 1.54 (m, 4H), 2.05 (m, 4 H), 3.25 (m, 4H), 3.95 (m, 4H), 5.11 (s, 2H), 5.35 (s, 1H), 7.25 (m, 2H), 7.35 (m, 5H), 7.68 (m, 1H), 7.79 (m, 1H), 8.5 (m, 1H); MS (DCI/NH3) m/z 313 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-])=O.[BH4-].[Na+]>C(O)C.S([O-])([O-])(=O)=O.[Cu+2]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH2:13]
Reactant: O=[N+]([O-])c1ccccc1-c1ccccn1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Solvent: CCO
Product: Nc1ccccc1-c1ccccn1
Yield: 47.1 %

Procedure:
Next, 0.96 g (4.8 mmols) of the ortho-(2-pyridyl)nitrobenzene, 0.072 g (0.48 mmol) of copper sulfate and 0.91 g (24.0 mmols) of sodium borohydride were suspended in 30 ml of ethyl alcohol and allowed to react at room temperature. After 5 hours from the start of the reaction, the reaction mixture was filtered through celite, 50 ml of ether was added to the filtrate, the organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated. The liquid thus obtained was purified by column chromatography and concentrated to give 0.38 g (2.26 mmoles, 47%) of ortho-(2-pyridyl)aniline as a brown liquid.
Reaction SMILES: Br[C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[O:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[Li+].[Cl-].[CH3:27][C:28]1([CH3:43])[CH2:33][CH2:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][CH2:29]1>COCCOC.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>[CH3:27][C:28]1([CH3:43])[CH2:33][CH2:32][C:31]([C:2]2[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([CH:9]3[CH2:14][C:13]([CH3:16])([CH3:15])[O:12][C:11]([CH3:18])([CH3:17])[CH2:10]3)[N:3]=2)=[CH:30][CH2:29]1
Reactant: CC1(C)CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CC1(C)CC(c2ccc(N)c(Br)n2)CC(C)(C)O1
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: [Cl-]
Solvent: COCCOC
Product: CC1(C)CC=C(c2nc(C3CC(C)(C)OC(C)(C)C3)ccc2N)CC1
Temperature: 80 °C
Yield: 80 %

Procedure:
To a solution of 2-bromo-6-(2,2,6,6-tetramethyl-tetrahydro-pyran-4-yl)-pyridin-3-ylamine (as prepared in the previous step, 17.0 g, 0.054 mol ) in DME (200 mL) was added 2 M aq Na2CO3 (214 mL, 0.428 mol), LiCl (2.70 g, 0.0600 mol ) and 2-(4,4-dimethyl-cyclohex-1-enyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (15.3 g, 0.064 mol). The resulting mixture was degassed by sonication under Ar and Pd(PPh3)4 (6.20 g, 5.30 mmol) was added and the reaction heated at 80° C. under Ar overnight. The reaction mixture was allowed to cool to RT and was extracted with EtOAc. After concentrating, the resulting residue was purified on silica gel with 2-20% EtOAc:hexane to give the title compound as a white solid (14.8 g, 80%). Mass spectrum (ESI, m/z): Calcd. for C22H34N2O, 343.2 (M+H), found 343.3.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][CH2:20][N:21]3[S:24]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=3)(=[O:26])=[O:25])=[CH:16][CH:15]=2)=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:36]1C=C(S(Cl)(=O)=O)C=CC=1Cl>>[CH3:36][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][CH2:20][N:21]3[S:24]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=3)(=[O:26])=[O:25])=[CH:16][CH:15]=2)=[O:13])=[CH:10][C:2]=1[Cl:1]
Reactant: O=C(Nc1ccc(C(=O)O)c(Cl)c1)c1ccc2c(c1)N(S(=O)(=O)c1ccc(Cl)c(Cl)c1)CCC2
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Product: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2ccc(Cl)c(Cl)c2)CCC3)cc1Cl

Procedure:
2-Chloro-4-{[1-(3,4-dichloro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid, m/z (ES+): 539.18 (M+H+.), was prepared in analogy to example 40, steps 1 to 5. Step 4 was performed using 3,4-dichloro-benzenesulfonyl chloride, yielding 2-chloro-4-{[1-(3,4-dichloro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid methyl ester, which was hydrolyzed in step 5.