Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[N:12]=[C:11]([C:26]([C:32]([F:35])([F:34])[F:33])([C:28]([F:31])([F:30])[F:29])[OH:27])[CH2:10]1.[CH:36]1([S:39](Cl)(=[O:41])=[O:40])[CH2:38][CH2:37]1.C(N(CC)CC)C>ClCCl>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[N:13]([C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:25][CH2:24][N:23]([S:39]([CH:36]4[CH2:38][CH2:37]4)(=[O:41])=[O:40])[CH2:22][CH2:21]3)=[CH:18][CH:19]=2)[N:12]=[C:11]([C:26]([C:28]([F:30])([F:31])[F:29])([C:32]([F:33])([F:35])[F:34])[OH:27])[CH2:10]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: OC(C1=NN(c2ccc(N3CCNCC3)cc2)C(c2ccccc2Cl)C1)(C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(C1CC1)N1CCN(c2ccc(N3N=C(C(O)(C(F)(F)F)C(F)(F)F)CC3c3ccccc3Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.4 %

Procedure:
5-(2-Chloro-phenyl)-1-[4-(piperazin-1-yl)-phenyl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole hydrochloride (20.0 mg, 0.04 mmol) prepared in Example 428, cyclopropanesulfonyl chloride (6.0 uL, 0.06 mmol), and triethylamine (25.0 uL, 0.18 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 16 hours, washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/1) to give 15.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([C:16]2[CH:17]=[C:18]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][NH:33][CH2:34][C@H:35]([O:48][Si](C(C)(C)C)(C)C)[C:36]4[CH:45]=[CH:44][C:43]([OH:46])=[C:42]5[C:37]=4[CH:38]=[CH:39][C:40](=[O:47])[NH:41]5)=[CH:27][CH:26]=3)[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])[CH:13]=[CH:14][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F.F.F.C(N(CC)CC)C>C1COCC1.CO>[CH2:1]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([C:16]2[CH:17]=[C:18]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][NH:33][CH2:34][C@H:35]([OH:48])[C:36]4[CH:45]=[CH:44][C:43]([OH:46])=[C:42]5[C:37]=4[CH:38]=[CH:39][C:40](=[O:47])[NH:41]5)=[CH:27][CH:26]=3)[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])[CH:13]=[CH:14][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(Nc2ccc(CCNC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(O)c4[nH]c(=O)ccc34)cc2)cc1-c1cccc(CNCc2ccccc2)c1
Agent: F
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc(Nc2ccc(CCNC[C@H](O)c3ccc(O)c4[nH]c(=O)ccc34)cc2)cc1-c1cccc(CNCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
N-{2-[4-(3-(3-(N-benzylamino)methylphenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-tert-butyldimethylsilyloxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine (55 mg, 0.73 mmol) was dissolved in THF/MeOH (5 mL:2 mL). Triethylamine-trihydrofluoride (0.5 mL) was added, and the reaction mixture was stirred at room temperature for 5 h. The solvent was then evaporated, and the residue purified by HPLC to afford N-{2-[4-(3-(3-(N-benzylamino)methylphenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine (114). m/z: [M+H+] calcd for C40H41N4O4 641.31. found 641.3
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([Cl:11])=[CH:9][C:8](Cl)=[CH:7][N:6]=1)=[O:4].ClC1C(C(O)=O)=NC=C(Cl)C=1.IC.C(=O)([O-])[O-].[K+].[K+].[F:32][C:33]([F:44])([F:43])[C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(COC)OC>[CH3:1][O:2][C:3]([C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:38]2[CH:37]=[CH:36][CH:35]=[C:34]([C:33]([F:44])([F:43])[F:32])[CH:39]=2)=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ncc(Cl)cc1Cl
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: O=C(O)c1ncc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: COCCOC
Solvent: CN(C)C=O
Product: COC(=O)c1ncc(-c2cccc(C(F)(F)F)c2)cc1Cl
Temperature: 25 °C
Yield: 20 %

Procedure:
To a degassed solution of 10.48 g (50.9 mmol) of 3,5-dichloro-pyridine-2-carboxylic acid methyl ester [prepared in analogy to the procedure described for the preparation of intermediate 5A from 3,5-dichloro-pyridine-2-carboxylic acid and iodomethane, potassium carbonate in DMF] in 400 ml of dimethoxyethane were added 14.49 g (76.3 mmol) of 3-(trifluoromethyl)phenyl boronic acid and 49.73 g (152.6 mmol) of caesium carbonate. While stirring, 0.77 g (1.50 mmol) of [(t-Bu)2P(OH)]2PdCl2 (POPd) was added and the reaction mixture was stirred at reflux for 7 hours. It was then cooled down to RT, poured into crashed ice and extracted twice with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (heptane/EtOAc 98:2 to 1:1) to give 3.22 g (20%) of 3-chloro-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid methyl ester as light yellow oil; [MS: 316.0 (MH+, 1Cl)] and 2.80 g (12.9%) of 3,5-bis-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid methyl ester as light yellow solid; [MS: 426.1 (MH+)] and 3.21 g (20.0%) of 5-chloro-3-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid methyl ester as light yellow oil. [MS: 316.0 (MH+, 1Cl)].
Reaction SMILES: [NH2:1][CH:2]([CH:10]([OH:26])[CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:27]([C:29]1[CH:30]=[C:31]([N:35]=[C:36]=[O:37])[CH:32]=[CH:33][CH:34]=1)#[N:28]>C1COCC1>[C:27]([C:29]1[CH:30]=[C:31]([NH:35][C:36]([NH:1][CH:2]([CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:10]([OH:26])[CH2:11][N:12]2[CH2:13][CH2:14][CH:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:16][CH2:17]2)=[O:37])[CH:32]=[CH:33][CH:34]=1)#[N:28]
Reactant: NC(Cc1ccccc1)C(O)CN1CCC(Cc2ccc(F)cc2)CC1
Reactant: N#Cc1cccc(N=C=O)c1
Solvent: C1CCOC1
Product: N#Cc1cccc(NC(=O)NC(Cc2ccccc2)C(O)CN2CCC(Cc3ccc(F)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-amino-4-[4-(4-fluorophenyl)methyl-1-piperidinyl]-1-phenyl-butan-3-ol (50 mg, 0.14 mmoles) in 2.5 mL of dry THF was added 3-cyanophenyl isocyanate (20.2 mg, 0.14 mmoles) and the mixture was stirred for 15 minutes at room temperature. Then the solvent was evaporated off to give an oily residue. It was purified by column chromatography on silica gel with elution by EtOAc to give pure titled compound as an amorphous solid. MS (ES+) for C30H33FN4O2: 501.
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]([CH3:35])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:28])[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:27])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:16]([O:18]CC)=[O:17])C.[OH-].[K+]>C(O)C.O>[O:28]=[C:10]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:27])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:16]([OH:18])=[O:17])[CH2:9][CH2:8][CH2:7][CH2:6][C:5]([CH3:35])([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:4]([OH:36])=[O:3]
Reactant: CCOC(=O)C(C)(CCCCC(=O)CCCCC(C)(C(=O)OCC)c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(CCCCC(=O)CCCCC(C)(C(=O)O)c1ccccc1)(C(=O)O)c1ccccc1
Reaction time: 8 h
Yield: 90.6 %

Procedure:
To a solution of 7-oxo-2,12-dimethyl-2,12-diphenyl-tridecanedioic acid diethyl ester (3.93 g, 7.55 mmol) in ethanol (60 mL) was added a solution of KOH (4.0 g, 85%, mmol) in water (10 mL). The reaction mixture was heated under reflux for 3 h and then kept overnight at rt. The solution was concentrated under reduced pressure. The residue was dissolved in water (100 mL) and washed with ether (2×75 mL). The aqueous layer was acidified with concd. HCl (ca. 12 mL) until pH 1. The product was extracted with diethyl ether (3×75 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo to give 7-oxo-2,12-dimethyl-2,12-diphenyl-tridecanedioic acid as an oil (3.0 g, 90%). 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 7.40-7.10 (m, 10H), 2.32 (t, J=7.2 Hz, 4H), 2.10-1.80 (m, 4H), 1.6-1.45 (m, 10H), 1.25-1.10 (m, 4H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm): 211.1, 182.5, 142.8, 128.4, 126.9, 126.0, 49.9, 42.3, 38.7, 24.2, 24.0, 22.3. HRMS (LSIMS, nba): Calcd. for C27H35O5 (MH+): 439.2484, found 439.2497.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[CH2:15]([Sn](CCCC)(CCCC)CCCC)[CH:16]=[CH2:17].[Cl-].[Li+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([CH2:17][CH:16]=[CH2:15])=[C:3]([C:11]([F:14])([F:13])[F:12])[CH:4]=1)([O-:10])=[O:9]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: O=[N+]([O-])c1ccc(Br)c(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=CCc1ccc([N+](=O)[O-])cc1C(F)(F)F

Procedure:
A mixture of 1-bromo-4-nitro-2-(trifluoromethyl)benzene (1.0 g, 3.7 mmol), Allyl Tri-n-butyltin (1.4 mL, 4.4 mmol), Lithium Chloride (470 mg, 11 mmol), and Palladium Tetrakis (210 mg, 0.18 mmol) in toluene (30 mL) was heated to reflux for 16 hours under nitrogen. TLC showed complete reaction at that point. The reaction was diluted with ethyl acetate, adsorbed onto silica gel, and purified by silica gel chromatography to afford the title product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[N:19]3[CH2:20][CH2:21][CH2:22][C:23]([O:29][C:30]4[CH:35]=[C:34]([F:36])[C:33]([F:37])=[C:32]([F:38])[CH:31]=4)(C(OCC)=O)[C:18]3=[N:17][N:16]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][C:12]([CH3:14])=[N:11][CH:10]=1.C[Mg]Br>C1COCC1.C(OCC)(=O)C.[Cl-].[NH4+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[N:19]3[CH2:20][CH2:21][CH2:22][C:23]([C:3]([OH:2])([CH3:4])[CH3:8])([O:29][C:30]4[CH:35]=[C:34]([F:36])[C:33]([F:37])=[C:32]([F:38])[CH:31]=4)[C:18]3=[N:17][N:16]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][C:12]([CH3:14])=[N:11][CH:10]=1
Reactant: CCOC(=O)C1(Oc2cc(F)c(F)c(F)c2)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(-c2nnc3n2CCCC3(Oc2cc(F)c(F)c(F)c2)C(C)(C)O)ccc1-c1cnc(C)o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 117.4 %

Procedure:
Under a nitrogen atmosphere, to a mixture of ethyl 3[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-8-(3,4,5-trifluorophenoxy)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate (0.28 g) in THF (5 ml) was added methylmagnesium bromide (1M THF solution, 2.61 ml) at 0° C., and the mixture was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate and saturated aqueous ammonium chloride solution, the mixture was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and further recrystallized from ethyl acetate/hexane to give the title compound (0.16 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][CH2:12][CH2:13][OH:14])(=[O:10])=[O:9].[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[C:17]=1Br.C([O-])([O-])=O.[K+].[K+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C(#N)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:14][CH2:13][CH2:12][NH:11][S:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:17]1[C:16]([Cl:15])=[CH:21][C:20]([Cl:22])=[CH:19][C:18]=1[Cl:23])(=[O:10])=[O:9]
Reactant: Nc1ccccc1S(=O)(=O)NCCO
Reactant: Clc1cc(Cl)c(Br)c(Cl)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC#N
Product: O=S(=O)(NCCO)c1ccccc1Nc1c(Cl)cc(Cl)cc1Cl
Temperature: 160 °C
Reaction time: 2 h
Yield: 16.7 %

Procedure:
To a stirred solution of 2-Amino-N-(2-hydroxyethyl)-benzene sulfonamide (160 mg, 0.74 mmol), 1,3,5-trichloro-2-bromobenzene (241 mg, 0.93 mmol), K2CO3 (256 mg, 1.85 mmol) and xantphos (43 mg, 0.074 mmol) in acetonitrile (2 ml) under nitrogen in a microwave tube was added Pd2dba3 (34 mg, 0.037 mmol) in one portion and the tube sealed. The reaction was heated with stirring in a microwave at 160° C. for 120 minutes. The reaction was cooled before filtering through celite. The crude reaction mixture was part-purified by column chromatography eluting with ethyl acetate:hexane and the concentrated fractions further purified by preparative chromatography under acidic conditions to afford the named product (49.0 mg, 17%); δH (400 MHz, DMSO) 7.83 (3H, m), 7.75+7.45 (1H, d), 7.59+7.10 (1H, s), 7.55+7.38 (1H, t), 7.16+6.95 (1H, t), 7.10+6.40 (1H, d), 4.73 (1H, m), 3.35 (2H, m) and 2.83 (2H, m); LCMS Rt=7.92 min, m/z (ES+) 397 (M+H).
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19](O)[CH:20]2[CH2:22][CH:21]2[C:23]#[N:24])=[CH:15][CH:14]=1.[F:26][C:27]1[CH:28]=[C:29]2[C:33](=[C:34]([CH2:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:35]=1)[NH:32][CH:31]=[CH:30]2>ClCCCl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:30]2[C:29]3[C:33](=[C:34]([CH2:36][S:37]([CH3:40])(=[O:38])=[O:39])[CH:35]=[C:27]([F:26])[CH:28]=3)[NH:32][CH:31]=2)[CH:20]2[CH2:22][CH:21]2[C:23]#[N:24])=[CH:15][CH:14]=1
Reactant: N#CC1CC1C(O)c1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cc1cc(F)cc2cc[nH]c12
Agent: [Cl-]
Agent: [In+3]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)Cc1cc(F)cc2c(C(c3ccc(Cl)cc3)C3CC3C#N)c[nH]c12

Procedure:
128 mg (0.58 mmol) of indium(III) chloride and 0.07 ml (0.87 mmol) of trifluoroacetic acid were added to 100 mg (0.48 mmol) of the compound from Example 167A and 149 mg (0.58 mmol) of the compound from Example 87A with a purity of 88% under argon in 5 ml of 1,2-dichloroethane, and the mixture was heated under reflux overnight. It was concentrated and the residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 130 mg (65% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [CH2:1]([C:3]([C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[C:23]([CH3:29])[CH:22]=1)([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([OH:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[C:8]([CH3:20])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].[S:30]1[CH2:34][C:33](=[O:35])[NH:32][C:31]1=[O:36].C(O)(=O)C.N1CCCCC1>C1(C)C=CC=CC=1>[CH2:1]([C:3]([C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[C:34]2[S:30][C:31](=[O:36])[NH:32][C:33]2=[O:35])=[C:23]([CH3:29])[CH:22]=1)([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([OH:19])[C:15]([CH3:17])([CH3:18])[CH3:16])=[C:8]([CH3:20])[CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)(c1ccc(C=O)c(C)c1)c1ccc(OCC(O)C(C)(C)C)c(C)c1
Reactant: O=C1CSC(=O)N1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CCC(CC)(c1ccc(C=C2SC(=O)NC2=O)c(C)c1)c1ccc(OCC(O)C(C)(C)C)c(C)c1
Yield: 82.6 %

Procedure:
To a mixture of enantiomer 2 of 4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzaldehyde (048 g, 1.21 mmol) and toluene (15 mL) is added 90% 2,4-thiazolidinedione (0.19 g, 1.45 mmol), and piperidine acetate (0.03 g, 0.18 mmol). The solution is heated to a reflux overnight and the water removed by a Dean-Stark trap. The solution is diluted with EtOAc (60 mL), washed with water (50 mL), brine (50 mL), dried over MgSO4, filtered and concentrated. Purified by ISCO (20%-40% EtOAc gradient) to furnish the title compound (0.50 g, 1.00 mmol, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([CH:28]=[O:29])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[CH3:30][Mg]Br.O.C(OCC)(=O)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([CH:28]([OH:29])[CH3:30])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: C[Mg]Br
Reactant: O=Cc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(O)c1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1

Procedure:
In 30 mL of tetrahydrofuran was dissolved 620 mg of 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-formylquinazoline (IV-1), the solution was cooled to 0° C. under the nitrogen atmosphere, and 4.9 mL of methylmagnesium bromide (0.93M tetrahydrofuran solution) was added dropwise. After the reaction at 0° C. for 1 hour under the nitrogen atmosphere, water and ethyl acetate were added to separate the layers. The organic layer was washed sequentially with water and aqueous saturated sodium chloride solution, and dried over magnesium sulfate. After concentration, the resulting crystal was washed with chloroform to obtain 330 mg of 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-hydroxyethan-1-yl)quinazoline (VI-1).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17](/[C:22](/[CH3:29])=[CH:23]/[C:24](OCC)=[O:25])[CH:16]=[CH:15]2.[NH4+].[Cl-]>C1(C)C=CC=CC=1.C1COCC1>[CH3:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17](/[C:22](/[CH3:29])=[CH:23]/[CH2:24][OH:25])[CH:16]=[CH:15]2
Reactant: CCOC(=O)/C=C(\C)c1ccc2cc(C)ccc2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C/C(=C\CO)c1ccc2cc(C)ccc2c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 84.1 %

Procedure:
A solution of diisobutylaluminum hydride in toluene (1.5M, 30 ml) was added dropwise to a solution of ethyl (E)-3-(6-methyl-2-naphthyl)crotonate (3.62 g) in THF (50 ml) at −78° C. and the mixture was stirred at −78° C. for 15 minutes. Saturated aqueous solution of NH4Cl was added to the mixture and organic layer was washed with 1N HCl and brine, dried and concentrated. The residue was crystallized from hexane-cyclohexane gave the titled compound (2.54 g) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[O:6][C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15](Cl)=[N:16][OH:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.O1CCCC1.[C:24]([C:26]1[C:27]([NH2:32])=[N:28][CH:29]=[CH:30][CH:31]=1)#[CH:25].C(N(CC)CC)C>O>[Cl:1][C:2]1[O:6][C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[CH:25]=[C:24]([C:26]4[C:27]([NH2:32])=[N:28][CH:29]=[CH:30][CH:31]=4)[O:17][N:16]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: ON=C(Cl)Cc1ccc(Cc2ccc(Cl)o2)cc1
Reactant: C#Cc1cccnc1N
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: Nc1ncccc1-c1cc(Cc2ccc(Cc3ccc(Cl)o3)cc2)no1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
To a mixture of (4-(5-chloro-furan-2-ylmethyl)-phenyl)-acetohydroximoyl chloride (25 mg, 0.088 mmol) described in Manufacturing Example 62-1-6 and tetrahydrofuran (1 mL) were added 3-ethynyl-pyridin-2-ylamine (8.0 mg, 0.068 mmol) described in Manufacturing Example 1-2-3 and triethylamine (19 μL, 0.14 mmol) at room temperature, which was stirred for 1 hour at 55° C. The mixture was cooled to room temperature and water was added at the same temperature, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoracetic acid) to obtain the title compound as a crude product, and this was then purified by NH silica gel column chromatography (ethyl acetate:heptane=1:1) to obtain the title compound (3.8 mg, 15%).
Reaction SMILES: O1[CH2:6][CH2:5]OCC1.BrC1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[N+:17]([O-:19])=[O:18])[N:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]([CH3:29])[CH3:28])[N:22]=2)[N:9]=1.CB(O)O.C(=O)([O-])[O-].[K+].[K+]>O.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>[CH:27]([C:23]1[N:22]=[C:21]([CH2:20][N:10]2[C:11]3[C:16](=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][CH:12]=3)[C:5]([CH3:6])=[N:9]2)[CH:26]=[CH:25][CH:24]=1)([CH3:29])[CH3:28]
Reactant: CC(C)c1cccc(Cn2nc(Br)c3c([N+](=O)[O-])cccc32)n1
Reactant: C1COCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB(O)O
Agent: O=C([O-])[O-]
Solvent: O
Product: Cc1nn(Cc2cccc(C(C)C)n2)c2cccc([N+](=O)[O-])c12
Temperature: 120 °C
Yield: 73 %

Procedure:
A 3 liter heavy walled reaction flask was charged with dioxane (1 liter), 3-bromo-1-((6-isopropylpyridin-2-yl)methyl)-4-nitro-1H-indazole (90 g, 0.24 mol), methyl boronic acid (72 g, 1.20 mol), Pd(PPh3)4 (9.7 g, 0.0084 mol), potassium carbonate (99.5 g, 0.719 mol), followed by 200 mL of water. This mixture was purged with argon for 10 minutes, flask sealed and heated to 120° C. for 16 hours. Another 1.5 mol % of Pd(PPh3)4 was added followed by another 2 equivalents of methyl boronic acid, and the mixture warmed to 120° C. for 24 hours. The mixture was diluted with water and extracted with EtOAc. The combined organic extracts were dried over sodium sulfate and concentrated. Column chromatography (5% ethyl acetate/hexane to 10% ethyl acetate/hexane) gave 54 g (73%) of 1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole as an orange/yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([N:19]3[CH2:27][C:26]4[CH:25]=[CH:24][N:23]=[CH:22][C:21]=4[CH2:20]3)=[O:18])[C:7](=[O:28])[CH:6]3[CH2:29][CH:30]4[CH2:31][CH2:32][O:33][C:5]34[C:4]=2[CH:3]=1.[OH-].[Na+].Cl>CN(C)C=O.O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([N:19]3[CH2:27][C:26]4[CH:25]=[CH:24][N:23]=[CH:22][C:21]=4[CH2:20]3)=[O:18])[C:7](=[O:28])[C:6]3[CH2:29][CH:30]([CH2:31][CH2:32][OH:33])[C:5]=3[C:4]=2[CH:3]=1
Reactant: O=C(NCCCCN1C(=O)C2CC3CCOC32c2cc(Cl)ccc21)N1Cc2ccncc2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCCCCn1c(=O)c2c(c3cc(Cl)ccc31)C(CCO)C2)N1Cc2ccncc2C1
Reaction time: 18 h

Procedure:
To a solution of N-[4-(9-chloro-5-oxo-2,3,3a,4,4a,5-hexahydro-6H-furo[2′,3′:2,3]cyclobuta[1,2-c]quinolin-6-yl)butyl]-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxamide (30 mg, 0.064 mmol) in dimethylformamide (292 uL) and water (292 uL) was added sodium hydroxide (1.679 μl, 0.064 mmol). The solution was stirred for 18 hours and then brought to pH ˜7 by dropwise addition of 1M HCl. Column chromatography of the wet, crude mixture provided the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 8.58 (s, 1H), 8.54 (d, J=5.1 Hz, 1H), 7.54 (d, J=2.4 Hz, 1H), 7.46 (dd, J=9.1, 2.4 Hz, 1H), 7.37 (d, J=9.1 Hz, 1H), 7.25 (m, 1H), 5.06 (t, J=5.7 Hz, 1H) 4.77 (bs, 2H), 4.75 (bs, 2H), 4.33 (t, J=7.4 Hz, 2H), 3.87 (m, 2H), 3.74 (m, 2H), 3.46 (m, 2H), 3.37 (dd, J=14.0, 4.5 Hz, 1H), 2.86 (dd, J=14.0, 1.3 Hz, 1H), 2.27 (m, 1H), 1.97 (m, 1H), 1.82 (m, 2H), 1.71 (m, 2H); MS (ESI(+)) m/e 467 (M+H)+.