Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[CH:7][C:6]([F:10])=[C:5]([F:11])[C:3]=1[NH2:4].[CH2:12]([C:14]1[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=1)[CH3:13].CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.Cl>O.C1(C)C=CC=CC=1>[F:1][C:2]1[C:8]([F:9])=[CH:7][C:6]([F:10])=[C:5]([F:11])[C:3]=1[NH:4][C:17]1[CH:18]=[CH:19][C:14]([CH2:12][CH3:13])=[CH:15][CH:16]=1
Reactant: Nc1c(F)c(F)cc(F)c1F
Reactant: CCc1ccc(Br)cc1
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1ccc(Nc2c(F)c(F)cc(F)c2F)cc1
Temperature: 85 °C
Reaction time: 0.75 h

Procedure:
A mixture of 2,3,5,6-tetrafluoroaniline (4.5 g, 27.3 mmol), 4-ethylbromobenzene (5.0 g, 27 mmol), toluene (50 ml), sodium tert-butoxide (4.67 g, 48 mmol), tri-tert-butylphosphin (217 mg, 1.07 mmol) and bis-dibenzylideneacetone-palladium(0) (260 mg, 0.45 mmol) is heated under nitrogen to 85° C. for 15.5 h. The mixture is cooled to room temperature and water (30 ml), concentrated hydrochloric acid (20 ml) and hyflo are added. After stirring for 45 minutes, the mixture is filtered and the organic phase is washed with water three times. The solvent is evaporated in vacuo and the residue is chromatographed on silica using hexane/toluene (9:1 to 3:1) affording N-(2′,3′,5′,6′-tetrafluorophenyl)-4-ethylanilin as a liquid.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:13]([C:14]([O:16]C)=O)=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]1(=[O:23])[O:22][CH2:21][CH2:20][CH2:19]1.CC(C)([O-])C.[K+]>>[OH:23][CH2:18][CH2:19][C:20]1[C:21](=[O:22])[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[C:13]([C:14]=1[OH:16])=[CH:12][CH:11]=[CH:10][N:9]=2
Reactant: COC(=O)c1cccnc1Nc1ccccc1
Reactant: O=C1CCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: O=c1c(CCO)c(O)c2cccnc2n1-c1ccccc1
Temperature: 95 °C
Reaction time: 1 h

Procedure:
To a solution of 6.8 g. of methyl 2-phenylamino-3-pyridine carboxylate in 60 ml. of gamma-butyrolactone there was added, under nitrogen, 13.4 g. of potassium tertiary butoxide. The reaction mixture was heated and stirred for one hour at 95° C., poured on ice and stirred overnight. The mixture was extracted with ether, the aqueous layer acidified with acetic acid to pH 4.5 and the product was collected by filtration. Recrystallization from chloroform, acetone, isopropanol yielded the product of this example as a colorless solid; m.p. 235°-236° C.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9](Br)[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.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>[N+:1]([C:4]1[CH:10]=[C:9]([C:14]2[CH:13]=[CH:12][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2]
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Reactant: OB(O)c1ccc2ccccc2c1
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: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1ccc(-c2ccc3ccccc3c2)cc1[N+](=O)[O-]
Yield: 68 %

Procedure:
A suspension of 2-nitro-4-bromoaniline (5 g, 23 mmol) in toluene is admixed with 3.27 g (23 mmol) of 2-naphthylboronic acid, 9.5 g (0.069 mol) of potassium carbonate and 1.3 g of tetrakis(triphenylphosphine)palladium. The mixture is heated to reflux for 4 hours and the reaction is stopped by adding 100 ml of water. The mixture is extracted with ethyl acetate and dried over sodium sulphate, and the solvent is removed under reduced pressure. Purification by column chromatography gives 4.1 g (68% yield).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1.CCCCCC.CCOC(C)=O>CN(C1C=CN=CC=1)C.C1COCC1>[Cl:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6]([N:13]3[CH2:18][CH2:17][N:16]([C:27]([NH:26][C:23]4[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=4)=[O:28])[CH2:15][CH2:14]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Cc1c(Cl)ccc2c(N3CCNCC3)ccnc12
Agent: CN(C)c1ccncc1
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(Cl)ccc2c(N3CCN(C(=O)Nc4ccc(F)cc4)CC3)ccnc12

Procedure:
7-Chloro-8-methyl-4-(piperazin-1-yl)quinoline (80 mg, 0.31 mmol), 4-fluorophenyl isocyanate (57 μL, 0.5 mmol), and DMAP (2 mg) in THF (10 mL) are reacted according to method C yielding the product as a yellow solid after column chromatography with hexane-EtOAc.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([CH3:12])([CH3:11])[CH2:9][NH:10][C:4]=2[CH:3]=1.[C:13](OC([O-])=O)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].O>C1COCC1.CN(C)C1C=CN=CC=1>[C:16]([O:15][C:13]([N:10]1[C:4]2[CH:3]=[C:2]([Cl:1])[N:7]=[CH:6][C:5]=2[C:8]([CH3:12])([CH3:11])[CH2:9]1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: CC1(C)CNc2cc(Cl)ncc21
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(Cl)cc21
Reaction time: 2 h
Yield: 49.7 %

Procedure:
To a solution of 6-chloro-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine (1.3 g, 7.4 mmol) in THF (20 mL) were added tert-butyl dicarbonate (4.1 g, 18.6 mmol) and dimethyl-pyridin-4-yl-amine (2.22 g, 18.6 mmol) and the solution was stirred for 2 h. Water (60 mL) was added and the product was extracted with EtOAc. The organic phase was washed with brine, dried (MgSO4), filtered and evaporated. Chromatography (SiO2, eluted with petrol-EtOAc 0-40%) gave the title compound (1.04 g). 1H NMR (Me-d3-OD): 8.04 (1H, s), 7.60 (1H, s), 3.81 (2H, s), 1.59 (9H, s), 1.40 (6H, s). MS: [M+H]+=283.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16](C(C)(C)C)=[CH:15][CH:14]=2)=[N:7][CH:6]=1)[CH3:2].[C:24](C1C=CC(C#C)=CC=1)([CH3:27])([CH3:26])[CH3:25]>>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][CH:16]=[C:17]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:18]=2)=[N:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C(C)(C)C)cc2)nc1
Reactant: C#Cc1ccc(C(C)(C)C)cc1
Product: CCOC(=O)c1ccc(C#Cc2cccc(C(C)(C)C)c2)nc1

Procedure:
Using the same general procedure as described for Compound 3, but using instead 3-tert-butylphenylethyne (Compound 19), the title compound was synthesized as a white solid. PMR (CDCl3): & 1.34 (9H, s), 1.42 (3H, t, J~7.2 Hz), 4.43 (2H, q, J~7.2 Hz), 7.28-7.36 (1H, m), 7.40-7.46 (2H, m), 7.60 (1H, d, J~8.1 Hz), 7.67 (1H, s), 8.29 (1H, dd, J~8.1 Hz, 2.1 Hz), 9.21 (1H, d, J~2.1 Hz).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[B-](F)(F)F.N1(OC(=[N+](C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:32][CH2:33][CH:34]([OH:66])[CH2:35][O:36][C:37]1[C:42]([CH3:43])=[CH:41][C:40]([C:44]2[O:45][C:46]3[N:47]=[C:48]([CH2:57][C:58]4[CH:63]=[CH:62][C:61]([Cl:64])=[CH:60][CH:59]=4)[N:49]=[C:50]([O:53][CH2:54][CH2:55][CH3:56])[C:51]=3[N:52]=2)=[CH:39][C:38]=1[CH3:65].C(N(C(C)C)C(C)C)C>CN(C)C=O>[Cl:64][C:61]1[CH:60]=[CH:59][C:58]([CH2:57][C:48]2[N:49]=[C:50]([O:53][CH2:54][CH2:55][CH3:56])[C:51]3[N:52]=[C:44]([C:40]4[CH:39]=[C:38]([CH3:65])[C:37]([O:36][CH2:35][CH:34]([OH:66])[CH2:33][NH:32][C:1](=[O:9])[C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)=[C:42]([CH3:43])[CH:41]=4)[O:45][C:46]=3[N:47]=2)=[CH:63][CH:62]=1
Reactant: CCCOc1nc(Cc2ccc(Cl)cc2)nc2oc(-c3cc(C)c(OCC(O)CN)c(C)c3)nc12
Reactant: O=C(O)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCOc1nc(Cc2ccc(Cl)cc2)nc2oc(-c3cc(C)c(OCC(O)CNC(=O)c4ccccc4)c(C)c3)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 9.1 %

Procedure:
A mixture of 37 mg of benzoic acid, 110 mg of [(benzotriazol-1-yloxy)-dimethylamino-methylene]-dimethyl-ammonium tetrafluoroborate (TBTU), 100 mg of 1-amino-3-{4-[5-(4-chloro-benzyl)-7-propoxy-oxazolo[5,4-d]pyrimidin-2-yl]-2,6-dimethyl-phenoxy}-propan-2-ol (example 20) and 104 mg of ethyldiisopropylamine in 2 ml of dimethylformamide was stirred for 16 h at room temperature. After removal of the solvent the product was isolated via preparative HPLC (method HPLC2) to yield 11 mg of the title compound.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:22]=[CH:21][C:8]([CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH:18]([OH:20])[CH3:19])[CH2:12][CH2:11]2)=[CH:7][CH:6]=1)([O-])=O>CO.[Pd]>[ClH:1].[NH2:2][C:5]1[CH:22]=[CH:21][C:8]([CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH:18]([OH:20])[CH3:19])[CH2:12][CH2:11]2)=[CH:7][CH:6]=1
Reactant: CC(O)CCN1CCC(Cc2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(O)CCN1CCC(Cc2ccc(N)cc2)CC1
Reaction time: 18 h
Yield: 82.1 %

Procedure:
A mixture of 4-(4-nitrobenzyl)-1-(3-hydroxy-butyl) piperidine hydrochloride (0.17 g, 0.53 mmol) in methanol (10 mL) with Pd/C 10% (0.06 g) was hydrogenated at 1 atm and 25° C. for 18 h then, after filtration through a celite pad and concentration under reduced pressure, the crude compound was triturated with EtOAc (10 mL) for 15 h to afford the title compound (0.13 g, 80%) as a pale pink solid: mp 155-160° C.; 1H NMR (D2O) 1.038 (d, J=6.0, 3H), 1.28-1.36 (m, 2H), 1.58-1.82 (m, 5H), 2.342 (d, J=6.3, 2H), 2.65-2.80 (m, 2H), 2.90-3.10 (m, 2H), 3.32-3.43 (m, 2H), 3.65-3.80 (m, 1H), 6.64 (d, J=8.7, 2H), 6.909 (d, J=8.4, 2H) ; Anal calcd for C16H27ClN2O H2O: C 60.65, H 9.22, N 8.84, found C 61.45, H 8.76, N 8.81.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[NH:18][N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>C(Cl)(Cl)Cl>[C:32]([N:18]1[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:24]2[C:16]([C:7]2[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]([OH:11])=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:6]=2)=[N:17]1)(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)c1cc(-c2n[nH]c3ncccc23)cc(C(C)(C)C)c1O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)n1nc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c2cccnc21
Reaction time: 3 h
Yield: 77.6 %

Procedure:
To a solution of 6.5 g of the compound of Example 1 in 50 ml of chloroform and 2.4 g of triethylamine is added dropwise 1.9 g of acetyl chloride over 15 minutes under cooling and stirring. After addition, the resulting mixture is stirred under cooling for 2 hours and then at room temperature for 3 hours. The reaction solution is washed with water, dried and then concentrated. The obtained residue is recrystallized from ethanol to give 5.7 g of 1-acetyl-3-(3,5-di-tertiary butyl-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine as oale yellow crvstals. melting at 169°-171° C.
Reaction SMILES: [CH2:1]([OH:7])[CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1.[N+](=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N-]>ClCCl.CCCCCCC.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][O:7][CH2:1][CH:2]1[CH2:3][CH2:4][CH2:5][O:6]1)[CH3:15]
Reactant: OCC1CCCO1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh]
Solvent: CCCCCCC
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)COCC1CCCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.2 %

Procedure:
To a solution of tetrahydrofurfuryl alcohol (1.02 g, 10.0 mmol) in dichloromethane (20 mL) is added rhodium (II) acetate dimer (10 mg) followed by ethyl diazoacetate (0.95 mL, 9.0 mmol). The reaction mixture is stirred at rt for 30 min. The reaction mixture is diluted with heptane, filtered through celite, and the filtrate is evaporated and the residue is vacuum distilled at 130° C. to give 1.02 g of the product 477. 1H NMR (CDCl3) δ 4.11 (q, 2H), 4.10 (s, 2H), 3.93 (m, 1H), 3.72 (m, 1H), 3.61 (m, 1H), 3.44 (m, 2H), 1.95-1.75 (m, 3H), 1.61-1.53 (m, 1H), 1.20 (t, 3H)
Reaction SMILES: Br[C:2]1[C:3]2[C:4]([S:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[C:5]3[CH:14]([CH2:15][C:16]([OH:18])=[O:17])[CH2:13][CH2:12][N:6]3[C:7]=2[CH:8]=[C:9]([F:11])[CH:10]=1.C[Mg+].[Br-].[Li]C(CC)C.[F:35][C:36]([F:42])([F:41])[C:37](OC)=[O:38].[NH4+].[Cl-]>C1COCC1>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([S:19][C:4]2[C:3]3[C:2]([C:37](=[O:38])[C:36]([F:42])([F:41])[F:35])=[CH:10][C:9]([F:11])=[CH:8][C:7]=3[N:6]3[CH2:12][CH2:13][CH:14]([CH2:15][C:16]([OH:18])=[O:17])[C:5]=23)=[CH:25][CH:24]=1
Reactant: COC(=O)C(F)(F)F
Reactant: O=C(O)CC1CCn2c1c(Sc1ccc(Cl)cc1)c1c(Br)cc(F)cc12
Agent: C[Mg+]
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: O=C(O)CC1CCn2c1c(Sc1ccc(Cl)cc1)c1c(C(=O)C(F)(F)F)cc(F)cc12
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 53 %

Procedure:
To a solution of (+/−)-[8-bromo-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetic acid (Example 7, 250 mg, 0.6 mmol) in THF (8 mL) at −78° C. was added 3M MeMgBr (0.7 mmol) followed by the addition of sec-BuLi (0.8 mmol, 1.3M solution). The reaction mixture was stirred at −78° C. for 5 minutes and methyl trifluoroacetate (352 mg, 2.8 mmol) was added., The reaction mixture was warmed to r.t., stirred for 4 hours and saturated aqueous NH4Cl was added. The phases were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with EtOAc/Hexanes/AcOH (20:30:1) to provide 150 mg of the title compound as a white solid.
Reaction SMILES: CN(C)C=O.C(Cl)(=O)C(Cl)=O.[C:12]1([C:18]2[CH:19]=[C:20]([C:24]([OH:26])=O)[CH:21]=[N:22][CH:23]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[NH2:27][C:28]1[CH:40]=[C:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:38]=[CH:37][C:29]=1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>C(Cl)Cl.C(N(CC)CC)C>[C:41]1([C:39]2[CH:38]=[CH:37][C:29]([C:30]([O:32][C:33]([CH3:36])([CH3:34])[CH3:35])=[O:31])=[C:28]([NH:27][C:24]([C:20]3[CH:21]=[N:22][CH:23]=[C:18]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:19]=3)=[O:26])[CH:40]=2)[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1N
Reactant: O=C(O)c1cncc(-c2ccccc2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cncc(-c2ccccc2)c1
Reaction time: 1 h

Procedure:
N,N-Dimethylformamide (0.9 μL) and oxalyl chloride (0.023 mL) were added to a methylene chloride (0.5 mL) suspension of 5-phenylpyridine-3-carboxylic acid (44 mg) at room temperature, followed by stirring at the same temperature for 1 hour. The reaction mixture was added to a solution mixture of tert-butyl 2-amino-4-phenylbenzoate (40 mg) in methylene chloride (1 mL) and triethylamine (0.17 mL) at room temperature, followed by stirring at the same temperature for 1 hour. The solvent was evaporated under reduced pressure, and ethyl acetate and a 10% aqueous solution of citric acid were added to the residue. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Trikonex AB, FlashTube 2008, eluent: hexane/ethyl acetate=2:1] to obtain tert-butyl 4-phenyl-2-(5-phenylpyridine-3-carboxamido)benzoate.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)/[C:8](=[CH:16]/[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)/[C:7]1=[O:24])=[O:5])[CH3:2].[Br:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH:32]=[N:33][C:34]([O:36][Si](C)(C)C)=[CH2:35]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)[C:8]2([CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[CH2:35][C:34](=[O:36])[NH:33][CH:32]2[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[Br:25])[C:7]1=[O:24])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Cl)cc21
Reactant: C=C(N=Cc1ccccc1Br)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)N1C(=O)C2(c3ccc(Cl)cc31)C(c1cccc(Cl)c1)CC(=O)NC2c1ccccc1Br
Yield: 69.5 %

Procedure:
In a manner similar to the method described in example 4c, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester (0.4 g, 1.1 mmol) prepared in example 4b was reacted with 1-(2-bromophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (3.0 g, 10 mmol) prepared in example 22a, in toluene to give racemic (2′R,3R,4′S)-2′-(2-bromophenyl)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester (0.45 g, 69%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[F:15][C:16]([F:40])([F:39])[CH2:17][NH:18][C:19]([C:21]1([CH2:34][CH2:35][CH2:36][CH2:37]Br)[C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:20]>>[F:15][C:16]([F:39])([F:40])[CH2:17][NH:18][C:19]([C:21]1([CH2:34][CH2:35][CH2:36][CH2:37][N:12]2[CH2:13][CH2:14][N:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:10][CH2:11]2)[C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:20]
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3ccc(Cl)c(Cl)c3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 b from 1-(3,4-dichlorophenyl)-piperazine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11](=[O:30])[O:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[C:15]([N:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][OH:29])[CH2:22][CH2:21]1)[CH:14]=2.CCN(C(C)C)C(C)C.[S:40](Cl)([C:43]1[CH:49]=[CH:48][C:46]([CH3:47])=[CH:45][CH:44]=1)(=[O:42])=[O:41].C(=O)(O)[O-].[Na+]>ClCCl.CN(C1C=CN=CC=1)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11](=[O:30])[O:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[C:15]([N:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][O:29][S:40]([C:43]3[CH:49]=[CH:48][C:46]([CH3:47])=[CH:45][CH:44]=3)(=[O:42])=[O:41])[CH2:22][CH2:21]1)[CH:14]=2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=c1oc2cc(N3CCN(CCCO)CC3)ccc2cc1-c1nc2ccccc2s1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCN2CCN(c3ccc4cc(-c5nc6ccccc6s5)c(=O)oc4c3)CC2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
70 mg (0.16 mmol) 3-Benzothiazol-2-yl-7-[4-(3-hydroxy-propyl)-piperazin-1-yl]-chromen-2-one are dissolved in 15 mL dichloromethane under argon. 0.083 mL Hünig base and 10 mg DMAP are added to the stirred solution, followed by 46 mg (1.5 eq.) tosyl chloride. The reaction mixture is stirred for 20 h at room temperature, poured onto ice, treated with 2 mL aqueous sodium bicarbonate solution and extracted (dichloromethane, saline). The organic phase is evaporated and the residue column chromatographed (silica gel, dichloromethane/EtOH 98:2) to yield after evaporation and drying under high vacuum 73 mg (78%) desired product as a light brownish powder.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:7]=2B2OC(C)(C)C(C)(C)O2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].N#N.[CH3:33][N:34]([CH:36]=[O:37])[CH3:35]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:33]1([N:34]2[CH:35]=[C:3]([C:7]3[CH:8]=[C:9]([S:12]([CH3:15])(=[O:13])=[O:14])[CH:10]=[CH:11][C:6]=3[O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[CH:2]=[C:1]([CH3:4])[C:36]2=[O:37])[CH2:11][CH2:6][CH2:7]1
Reactant: CN(C)C=O
Reactant: CC1(C)OB(c2cc(S(C)(=O)=O)ccc2OCC2CC2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Product: Cc1cc(-c2cc(S(C)(=O)=O)ccc2OCC2CC2)cn(C2CCC2)c1=O
Reaction time: 2 h
Yield: 58 %

Procedure:
The title compound of step 4 (27 mg, 0.11 mmol), the title compound of Example 90, step 1 (46 mg, 0.13 mmol), K2CO3 (46 mg, 0.33 mmol) and Pd(dppf)2Cl2 (8 mg, 0.011 mmol) in DMF (2 mL) was N2 purged and microwaved at 100° C. After 2 h, the mixture was concentrated under vacuum and DCM was added which was washed with water, brine and dried over Na2SO4. Purification by preparative TLC gave the title compound (25 mg, 58%) as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:34])[C:5]([O:8][CH2:9][C:10]1[C:11]([CH3:33])=[N:12][C:13]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:15]=1)([CH3:7])[CH3:6])C.[Li+].[OH-].Cl>C1COCC1.O>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:14]2[CH:15]=[C:10]([CH2:9][O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:34])=[O:3])[C:11]([CH3:33])=[N:12][C:13]=2[C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=2)=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(C)(C)OCc1cc(-c2ccc(Cl)cc2)c(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)c(-c2ccc(Cl)cc2)cc1COC(C)(C)C(=O)O
Reaction time: 16 h

Procedure:
To a solution of 400 mg of 2-[5-(4-Chloro-phenyl)-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxy]-2-methyl-propionic acid ethyl ester in 2 ml THF was added a solution of 39 mg of LiOH in 2 ml water at room temperature. After 16 h, the mixture was brought to pH 2 by addition of 1 M hydrochloric acid. The reaction mixture was concentrated under reduced pressure and the aqueous layer was extracted with dichloromethane. The combined organic phases were dried over MgSO4 and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. Yield: 280 mg.
Reaction SMILES: C([O:8][N:9]1[CH2:15][CH:14]=[CH:13][CH2:12][C@@H:11]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)(=[O:19])=[O:18])[C:10]1=[O:34])C1C=CC=CC=1.CS(O)(=O)=O>O>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([O:26][C:23]2[CH:22]=[CH:21][C:20]([S:17]([NH:16][C@@H:11]3[CH2:12][CH:13]=[CH:14][CH2:15][N:9]([OH:8])[C:10]3=[O:34])(=[O:18])=[O:19])=[CH:25][CH:24]=2)=[CH:32][CH:31]=1
Reactant: O=C1[C@H](NS(=O)(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)CC=CCN1OCc1ccccc1
Agent: CS(=O)(=O)O
Solvent: O
Product: O=C1[C@H](NS(=O)(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)CC=CCN1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 257 mg of N-(1-benzyloxy-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-(R)-yl)-4-(4-chloro-phenoxy)-benzenesulfonamide from Step E was added 6 mL of methane sulfonic acid. The reaction was stirred at room temperature for 16 hours. The reaction was poured over ice, and 50 mL of H2O was added. The resulting solids were filtered, washed with H2O (4 times), and dried. The solids were dissolved in ethyl acetate, and Hexanes was added after solvent reduction under vacuum. The resulting solids were filtered and washed with Hexanes (3 times), followed by drying. Obtained was 195 mg of a white solid (Compound 1). MS: 839 (2M+Na), 431 (M+Na), 409 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([N+:21]([O-])=O)[CH:19]=3)[CH:14]=[N:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.O>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[C:3]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([NH2:21])[CH:19]=3)[CH:14]=[N:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc2cnn(-c3ncc(C(F)(F)F)cc3Cl)c2c1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc2cnn(-c3ncc(C(F)(F)F)cc3Cl)c2c1
Yield: 65.8 %

Procedure:
To a suspension of iron powder (5 g) in acetic acid (10 g), 1-(3-chloro-5-trifluoromethylpyridin-2-yl)-6-nitroindazole [Compound No. 3] (3 g) and water (10 g) were added, and the resultant mixture was refluxed for 3 hours. After completion of the reaction, the reaction mixture was filtered through celite, and the filtrate was poured into water and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with hexane-ethyl acetate (4:1) to give 1-(3-chloro-5-trifluoromethylpyridin-2-yl)-6-aminoindazole (1.8 g).