Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][OH:3].[H-].[Na+].[C:10]([O:14][C:15]([NH:17][CH2:18][C:19]([N:21]([CH2:23][C:24]1[CH:25]=[C:26]([C:30]2[CH:31]=[N:32][C:33]([N:36]3[CH2:41][CH2:40][N:39]([C:42](OC4C=CC([N+]([O-])=O)=CC=4)=[O:43])[CH2:38][CH2:37]3)=[N:34][CH:35]=2)[CH:27]=[CH:28][CH:29]=1)[CH3:22])=[O:20])=[O:16])([CH3:13])([CH3:12])[CH3:11].O>CN(C=O)C>[C:10]([O:14][C:15]([NH:17][CH2:18][C:19]([N:21]([CH2:23][C:24]1[CH:25]=[C:26]([C:30]2[CH:31]=[N:32][C:33]([N:36]3[CH2:41][CH2:40][N:39]([C:42]([O:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])=[O:43])[CH2:38][CH2:37]3)=[N:34][CH:35]=2)[CH:27]=[CH:28][CH:29]=1)[CH3:22])=[O:20])=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CCOC(=O)CO
Reactant: CN(Cc1cccc(-c2cnc(N3CCN(C(=O)Oc4ccc([N+](=O)[O-])cc4)CC3)nc2)c1)C(=O)CNC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COC(=O)N1CCN(c2ncc(-c3cccc(CN(C)C(=O)CNC(=O)OC(C)(C)C)c3)cn2)CC1
Reaction time: 0.17 h
Yield: 10.9 %

Procedure:
Ethyl glycolate (116 mg) was dissolved in DMF (4 ml), and NaH (73 mg) was added thereto under ice-cooling. After stirring at the same temperature for 10 minutes, a solution of 4-nitrophenyl 4-{5-[3-({[N-(tert-butoxycarbonyl)glycyl](methyl)amino}methyl)phenyl]pyrimidin-2-yl}piperazine-1-carboxylate (340 mg) in DMF (3 ml) was added thereto, followed by stirring at room temperature overnight. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was dried over MgSO4, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 2-ethoxy-2-oxoethyl 4-{5-[3-({[N-(tert-butoxycarbonyl)glycyl](methyl)amino}methyl)phenyl]pyrimidin-2-yl}piperazine-1-carboxylate (35 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](/[C:6](=[C:11](\[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)/[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)/[CH2:7][C:8](O)=[O:9])=[O:5])[CH3:2].CO>O1CCCC1>[Cl:28][C:25]1[CH:24]=[CH:23][C:22](/[C:11](/[C:12]2[CH:13]=[CH:14][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:16][CH:17]=2)=[C:6](/[CH2:7][CH2:8][OH:9])\[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:27][CH:26]=1
Reactant: CCOC(=O)/C(CC(=O)O)=C(\c1ccc(Cl)cc1)c1ccc(S(C)(=O)=O)cc1
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)/C(CCO)=C(\c1ccc(Cl)cc1)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
To a solution of 32.8 g (0.0775 mole) of (Z)-3-ethoxycarbonyl-4-(4-chlorophenyl)-4-(4-methanesulphonylphenyl)but-3-enoic acid, prepared in example 3, in 90 ml of anhydrous tetrahydrofuran are added dropwise 15.5 ml (0.155 mole) of borane/dimethyl sulphide complex. The mixture is stirred at room temperature for 8 hours and 23.5 ml of methanol are added dropwise. The mixture is evaporated to dryness in vacuo and the residue is dissolved in ethyl acetate. After washing with potassium carbonate solution, the organic phase is separated, dried over magnesium sulphate and evaporated in vacuo to give 30.8 g of ethyl (Z)-3-(4-chlorophenyl)-3-(4-methanesulphonylphenyl)-2-(2-hydroxyethyl)prop-2-enoate as crystals with a melting point of 128° C. after recrystallisation from isopropanol.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.[CH3:7][CH:8]([CH3:27])[CH2:9][N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][C:18](O)=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:12]=[C:11]1[CH2:24][CH2:25][CH3:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:7][CH:8]([CH3:27])[CH2:9][N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][C:18]([O:1][CH:2]4[CH2:6][CH2:5][O:4][CH2:3]4)=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:12]=[C:11]1[CH2:24][CH2:25][CH3:26]
Reactant: OC1CCOC1
Reactant: CCCc1nc2cnc3cc(O)ccc3c2n1CC(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCc1nc2cnc3cc(OC4CCOC4)ccc3c2n1CC(C)C
Reaction time: 48 h
Yield: 88.9 %

Procedure:
3-Hydroxytetrahydrofuran (0.375 mL, 4.64 mmol) was added to a suspension of 1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-7-ol (1.0 g, 3.5 mmol) and triphenylphosphine (1.5 g, 5.7 mmol) in THF. Diisopropyl azodicarboxylate (1.1 mL, 5.6 mmol) was added dropwise over a period of three minutes, and the reaction was stirred for 48 hours. The solvent was removed under reduced pressure, the residue was purified by column chromatography on silica gel (eluting with 98:2 dichloromethane:methanol) to provide 1.1 g of 1-(2-methylpropyl)-2-propyl-7-(tetrahydrofuran-3-yloxy)-1H-imidazo[4,5-c]quinoline as an off-white, crystalline solid.
Reaction SMILES: O=S(Cl)Cl.[Cl:5][C:6]1[C:14]([I:15])=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][N:7]=1.[F:16][C:17]([F:27])([F:26])[O:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1.C1COCC1.CN(C=O)C>[Cl:5][C:6]1[C:14]([I:15])=[CH:13][C:9]([C:10]([NH:23][C:22]2[CH:24]=[CH:25][C:19]([O:18][C:17]([F:16])([F:26])[F:27])=[CH:20][CH:21]=2)=[O:12])=[CH:8][N:7]=1
Reactant: O=C(O)c1cnc(Cl)c(I)c1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(I)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
DMF (0.13 mL) and SOCl2 (0.734 mL, 10.05 mmol) were added to a mixture of 6-chloro-5-iodonicotinic acid (1.00 g, 3.35 mmol) and 4-(trifluoromethoxy)aniline (0.623 mg, 3.52 mmol) in toluene (7 mL) and the RM was stirred at 80° C. for 1 h. The solvent was evaporated off under reduced pressure and under argon the residue was dissolved in THF (7.00 mL) and DIPEA (1.17 mL, 6.7 mmol), cooled to −15° C. treated dropwise with a solution of 4-(trifluoromethoxy)aniline (0.476 mL, 3.52 mmol) in THF (7.00 mL) and stirred at RT for 1 h. The solvent was evaporated off under reduced pressure and the residue treated with aq. 1N HCl (30 mL) and extracted with TBME (100 mL). The combined extracts were washed with sat. aq. Na2CO3 (30 mL) and brine (30 mL), dried over Na2SO4 and the solvent was evaporated off under reduced pressure until crystallization commenced. The product was triturated with n-heptane, filtered and dried to afford the title compound as an off-white solid. HPLC (Condition 4) tR=6.36 min, UPLC-MS (Condition 3) tR=1.23 min, m/z=441.1 [M−H]−.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[C:24][CH2:25][CH2:26][OH:27])=[CH:19][C:18]=2[F:28])=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]>CCO.[Pd]>[F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][OH:27])=[CH:19][C:18]=2[F:28])=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: O=C(NOCCO)c1ccc(F)c(F)c1Nc1ccc(C#CCCO)cc1F
Agent: [Pd]
Solvent: CCO
Product: O=C(NOCCO)c1ccc(F)c(F)c1Nc1ccc(CCCCO)cc1F
Yield: 46 %

Procedure:
The product of Example 11, 3,4-Difluoro-2-[2-fluoro-4-(4-hydroxy-1-butynyl)anilino]-N-(2-hydroxyethoxy)-benzamide was hydrogenated in absolute EtOH in the presence of 5% Pd/C by the procedure of Example 1, Step D. Purification of the resulting oil was carried out by filtration through a plug of silica gel (EtOAc as eluant) to afford 3,4-difluoro-2-[2-fluoro-4-(4-hydroxybutyl)anilino]-N-(2-hydroxyethoxy)benzamide as a white crystalline solid (46%); m.p. (Et2O/EtOAc) 65-69° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.90 (br s, 1 H), 8.83 (br s, 1 H), 7.44–7.38 (m, 1 H), 7.13–7.07 (m, 1 H), 7.03 (dd, J=12.5, 1.6 Hz, 1 H), 6.88 (dd, J=8.2, 1.7 Hz, 1 H), 6.82 (ddd, J=8.7, 8.7, 4.3 Hz, 1 H), 4.76 (v br s, 1 H), 4.35 (t, J=5.2 Hz, 1H), 3.84 (t, J=4.8 Hz, 2 H), 3.56 (t, J=4.9 Hz, 2 H), 3.43–3.34 (m, 2 H), 2.55–2.47 (m, 2 H), 1.61–1.51 (m, 2 H), 1.46–1.37 (m, 2 H). Anal. calcd. for C19H21F3N2O4: C, 57.3; H, 5.3; N, 7.0. Found C, 57.4; H, 5.4; N, 6.9.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=2[O:24][CH2:25][C:26]([O:28]C)=[O:27])[CH:5]=[CH:6][C:7]=1[S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9].C1COCC1.CO>[OH-].[Na+]>[F:1][C:2]1[CH:3]=[C:4]([C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=2[O:24][CH2:25][C:26]([OH:28])=[O:27])[CH:5]=[CH:6][C:7]=1[S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9]
Reactant: COC(=O)COc1ccc(C(F)(F)F)cc1-c1ccc(S(=O)(=O)C(C)C)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)S(=O)(=O)c1ccc(-c2cc(C(F)(F)F)ccc2OCC(=O)O)cc1F

Procedure:
A solution of the product from step e) (140 mg) in NaOH (0.35 ml, 1 M), THF (2 ml) and MeOH (1 ml) was stirred for 2 h. The solvent was removed in vacuo and the residue was washed with ether, acidified (2M HCl) and extracted with DCM (thrice). The organic extracts were dried (MgSO4), evaporated and crystallised from isohexane-DCM to give the title compound (105 mg). M.p. 170-1° C.
Reaction SMILES: [CH2:1]([N:8]([CH3:12])[CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CS(C)=O.N1C=CC=CC=1.S(=O)(=O)=O>C(Cl)Cl>[CH2:1]([N:8]([CH2:9][CH:10]=[O:11])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(CCO)Cc1ccccc1
Agent: O=S(=O)=O
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: CN(CC=O)Cc1ccccc1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
To a 3-necked 2-L flask was added N-benzyl-N-methylethanolamine (30.5 g, 0.182 mol), DCM (0.5 L), DIPEA (95 mL, 0.546 mol) and DMSO (41 mL, 0.728 mol). Using an ice bath, the mixture was cooled to about −10° C. and sulfur trioxide pyridine-complex (87 g, 0.546 mol) was added in 4 portions over 5 minute intervals. The reaction was stirred at −10° C. for 2 hours. Before removing the ice-bath, the reaction was quenched by adding water (0.5 L). The aqueous layer was separated and the organic layer was washed with water (0.5 L) and brine (0.5 L) and then dried over magnesium sulfate and filtered to provide the title compound which was used without further purification.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:18])[C@@H:6]([CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)[NH2:7])[CH:2]=[CH2:3].C(N(CC)CC)C.[CH2:26]([O:33][C:34]([NH:36][C:37]([CH3:42])([C:39](O)=[O:40])[CH3:38])=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.C(OCC)(=O)C>[CH2:26]([O:33][C:34]([NH:36][C:37]([CH3:42])([CH3:38])[C:39]([NH:7][C@H:6]([CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)[C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:18])=[O:40])=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: C=CCOC(=O)[C@H](N)Cc1c[nH]c2ccccc12
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)C(C)(C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.5 %

Procedure:
D-Tryptophan allyl ester (250 mg; 0.822 mmol), triethylamine (230 μl; 1.650 mmol) and N-benzyloxycarbonyl-α-methylalanine (167.9 mg; 0.826 mmol) were dissolved in dry methylene chloride (5 ml) and BOP (363.7 mg; 0.822 mmol) added. The reaction mixture was stirred at room temperature for 16 h and then the reaction quenched with saturated brine (5 ml). The methylene chloride layer was separated, dried with magnesium sulfate and filtered then the volatiles removed under reduced pressure to leave a dark brown oil. Chromatography of this oil on silica gel using ethyl acetate and hexanes 2:1 v/v afforded 322 mg (84.5%) of the desired product. FAB-MS:- calculated for C26H29N3O5 463.2; found 464.5 (M+1).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>C1(C)C=CC=CC=1>[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:33][CH2:34][N:35]([CH2:2][CH2:3][CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=34)[S:6]2(=[O:18])=[O:17])[CH2:36][CH2:37]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CCN(c2ccccn2)CC1
Temperature: 20 °C

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]-isothiazole 1,1-dioxide (8.5 g), triethylamine (4.2 cc) and 1-(2-pyridyl)piperazine (4.7 cc) in toluene (8cc). The mixture is heated for 2 hours at boiling point, then cooled to a temperature of about 20° C. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with ethyl acetate as eluant, and recrystallization from boiling acetonitrile (30 cc), 2-{3-[4-(2-pyridyl)-1-piperazinyl]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (4.2 g) is obtained, m.p. 101° C.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[C:6](=[O:18])[NH:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)=[N:9][N:10]=1)[CH2:3][CH3:4].[C:19]([C@@H:23]1[CH2:28][CH2:27][C@H:26]([C:29](Cl)=O)[CH2:25][CH2:24]1)([CH3:22])([CH3:21])[CH3:20]>>[Br:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[NH:7][C:6](=[O:18])[C:5]3=[C:2]([CH2:3][CH3:4])[N:1]=[C:29]([C@H:26]4[CH2:27][CH2:28][C@@H:23]([C:19]([CH3:20])([CH3:22])[CH3:21])[CH2:24][CH2:25]4)[N:10]3[N:9]=2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)[C@H]1CC[C@@H](C(=O)Cl)CC1
Reactant: CCC(N)c1nnc(-c2ccc(Br)cc2)[nH]c1=O
Product: CCc1nc([C@H]2CC[C@@H](C(C)(C)C)CC2)n2nc(-c3ccc(Br)cc3)[nH]c(=O)c12

Procedure:
In analogy to the procedure for Example 23A, 7.6 g (24.6 mmol) 6-(1-aminopropyl)-3-(4-bromophenyl)-1,2,4-triazin-5(4H)-one (Example 29A), 4.98 g (24.55 mmol) cis-4-tert-butylcyclohexylcarbonyl chloride (Example 42A) and proportionate amounts of the other reagents are used.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[OH:9].[Cl:10][CH2:11][CH2:12][C:13](O)=[O:14].C(OCC)(=O)C>FC(F)(F)S(O)(=O)=O>[Cl:10][CH2:11][CH2:12][C:13]([C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([OH:9])=[CH:4][C:5]=1[OH:8])=[O:14]
Reactant: O=C(O)CCCl
Reactant: Oc1ccc(Cl)c(O)c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=C(CCCl)c1cc(Cl)c(O)cc1O
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of 4-chlorobenzene-1,3-diol (100 g, 692 mmol) and 3-chloropropanoic acid (75.1 g, 692 mmol) in trifluoromethanesulfonic acid (295 mL) was stirred at 75° C. for 30 minutes. The reaction was cooled to ambient temperature and slowly poured into a 2 L beaker filled with ice. To the slurry was added ethyl acetate (1200 mL) with stirring until all solids dissolved. The mixture was poured into a reparatory funnel, the aqueous layer was removed and the organic layer was washed with water. The organic layer was dried over magnesium sulfate, filtered and concentrated. The crude material was purified by silica gel column chromatography eluting with a solvent system mixture of 15% ethyl acetate/hexanes to provide the desired product (162.6 g, 86%).
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]#N)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[H-].C([Al+]CC(C)C)C(C)C.C(OCC)(=[O:25])C.C(O)(=O)C(C(C(O)=O)O)O>C1(C)C=CC=CC=1>[F:1][C:2]1[C:10]([CH:11]=[O:25])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2
Reactant: CCOC(C)=O
Reactant: N#Cc1ccc2[nH]ncc2c1F
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C(O)C(O)C(O)C(=O)O
Agent: [H-]
Solvent: Cc1ccccc1
Product: O=Cc1ccc2[nH]ncc2c1F
Temperature: -40 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
805 mg (5 mmols) 4-fluoro-1H-indazole-5-carbonitrile (see EP 1510516, Example 85) were suspended in 25 mL toluene and cooled to −40° C. During 15 minutes 8 mL of a 1.5 M solution of diisobutylaluminium hydride in toluene (12 mmols) were added dropwise. The mixture was stirred for 2 hours at −40° C. At this temperature 5 mL ethyl acetate were added and the mixture was stirred for 20 minutes. 5 mL of a 1 M aqueous solution of tartaric acid were added and the mixture was stirred for 30 minutes at −20 to 0° C. The insolubles were removed by filtration. A small amount of dilute aqueous citric acid was added and the mixture was extracted with ethyl acetate. The extracts were washed with saturated sodium chloride and sodium hydrogen carbonate solutions and dried over sodium sulfate. The crude product was purified with column chromatography to yield 4-fluoro-1H-indazole-5-carbaldehyde 762 mg (92.9%). 1H-NMR (DMSO-d6): 13.82 (br s, 1H); 10.32 (s, 1H); 8.44 (s, 1H); 7.74 (dd, 1H); 7.49 (d, 1H) ppm.
Reaction SMILES: [CH3:1]O.[N+:3]([C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1)[C:9]([OH:11])=[O:10])([O-:5])=[O:4].S(=O)(=O)(O)O>>[N+:3]([C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1)[C:9]([O:11][CH3:1])=[O:10])([O-:5])=[O:4]
Reactant: CO
Reactant: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Yield: 91.9 %

Procedure:
In a 72-liter, round-bottomed flask equipped with mechanical stirrer and condenser were combined methyl alcohol (27.97 kg, 873 moles, 35.4 liters), 3,5-dinitrobenzoic acid (15 kg, 70.72 moles), and sulfuric acid (2.6 kg, 26.56 moles, 1.42 liters). The mixture was heated and stirred at reflux by means of a heating mantle for approximately 26 hours and then was allowed to cool to 25° (approximately 18 hours). The precipated solid was isolated by centrifugation (Tolhurst 12-in. centrifuge); each of the four loads collected was washed with methyl alcohol (4 liters). The wet solid was air dried for 16-18 hours to give 14.7 kg (92% of theory) of methyl 3,5-dinitrobenzoate (I). Tlc analysis (toluene/acetone/HOAc; 90/5/2; utilizing a plate marketed by Mallinckrodt under the trade designation ChromAR 7GF plate) showed the product to be homogenous and identical to an authentic sample.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][C:9]2[N:13]([CH3:14])[N:12]=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.Cl[C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[C:33]([C:37]1([C:40]([F:43])([F:42])[F:41])[CH2:39][CH2:38]1)=[N:32][N:31]=[CH:30]2>>[CH3:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][C:9]2[N:13]([CH3:14])[N:12]=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[C:33]([C:37]1([C:40]([F:43])([F:42])[F:41])[CH2:39][CH2:38]1)=[N:32][N:31]=[CH:30]2
Reactant: Cc1ccc(C(=O)Nc2ccnn2C)cc1B1OC(C)(C)C(C)(C)O1
Reactant: FC(F)(F)C1(c2nncc3cc(Cl)ccc23)CC1
Product: Cc1ccc(C(=O)Nc2ccnn2C)cc1-c1ccc2c(C3(C(F)(F)F)CC3)nncc2c1

Procedure:
The title compound was prepared according to a procedure analogous to that described in Example 225, using 4-methyl-N-(1-methyl-1H-pyrazol-5-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide and 6-chloro-1-(1-(trifluoromethyl)cyclopropyl)phthalazine as the starting materials. MS (ESI, pos. ion) m/z: 452.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:25])[N:7]2[C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([C:21]([O:23][CH3:24])=[O:22])[CH:15]=1.FC1C=CC(F)=CC=1B(O)O.ClC1C=CC=C(Cl)C=1N1C2C(=C([C:57]3[CH:62]=[CH:61][C:60]([F:63])=[CH:59][C:58]=3[F:64])C=C(OC)C=2)CCC1=O>>[F:63][C:60]1[CH:59]=[C:58]([F:64])[CH:57]=[CH:62][C:61]=1[C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:25])[N:7]2[C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([C:21]([O:23][CH3:24])=[O:22])[CH:15]=1
Reactant: COC(=O)c1ccc(C)c(N2C(=O)CCc3c(Br)cc(OC)cc32)c1
Reactant: COc1cc(-c2ccc(F)cc2F)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)CC2
Agent: OB(O)c1cc(F)ccc1F
Product: COC(=O)c1ccc(C)c(N2C(=O)CCc3c(-c4ccc(F)cc4F)cc(OC)cc32)c1

Procedure:
5-(2,4-Difluorophenyl)-3,4-dihydro-7-methoxy-1-(3-methoxycarbonyl-6-methylphenyl)-2(1H)-quinolinone was prepared from 5-bromo-3,4-dihydro-7-methoxy-1-(3-methoxycarbonyl-6-methylphenyl)-2(1H)-quinolinone (INTERMEDIATE 14) and 2,5-difluorophenylboronic acid by a procedure analogous to that described in INTERMEDIATE 2. Mass spectrum (ESI) 438.1 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.06 (d, J=5.0 Hz, 1H); 7.89 (s, 1H); 7.42 (d, J=5.0 Hz, 2H); 7.01 (m, 2H); 6.49 (s, 1H); 5.86 (s, 1H); 3.95 (s, 3H); 3.68 (s, 3H); 2.81 (m, 4H); 2.21 (s, 3H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18]Cl)=[CH:14][N:13]=1.C(N(CC)CC)C>C(O)C>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:9]([C:6]2[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=2)[NH2:10])=[CH:14][N:13]=1
Reactant: NNc1ccc(F)cc1
Reactant: ClCc1ccc(Cl)nc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: NN(Cc1ccc(Cl)nc1)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of (4-fluorophenyl)hydrazine hydrochloride (2.52 g, 20 mmol; Aldrich) and 2-chloro-5-(chloromethyl)pyridine (3.24 g, 20.00 mmol; Aldrich) in ethanol (120 mL) was treated with triethylamine (9.76 mL, 70.0 mmol; Aldrich), and the mixture was heated at 80° C. with stirring for 16 hours. The solvent was removed and the residue was purified by flash chromatography (silica gel, 10:1 CH2Cl2—CH3OH) to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 4.53 (s, 2H), 6.93-6.99 (m, 2H), 7.02-7.10 (m, 2H), 7.40 (d, J=8 Hz, 1H), 7.77 (dd, J=8, 3 Hz, 1H), 8.30 (d, J=3 Hz, 1H); MS (DCI/NH3) m/z 252 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([OH:17])=O)[N:13]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:20][N:21]([CH3:31])[C:22](=[O:30])[CH2:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([N:27]3[CH2:26][CH2:25][N:24]([CH2:23][C:22](=[O:30])[N:21]([CH3:20])[CH3:31])[CH2:29][CH2:28]3)=[O:17])[N:13]=2)=[O:7])=[CH:18][CH:19]=1
Reactant: O=C(O)Cc1csc(NC(=O)c2ccc(Cl)cc2)n1
Reactant: CN(C)C(=O)CN1CCNCC1
Product: CN(C)C(=O)CN1CCN(C(=O)Cc2csc(NC(=O)c3ccc(Cl)cc3)n2)CC1

Procedure:
In analogy to example 1.3, [2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetic acid (example 1.2) was coupled with piperazino-acetic acid N,N-dimethylamide to give 4-chloro-N-{4-[2-(4-dimethylcarbamoylmethyl-piperazin-1-yl)-2-oxo-ethyl]-thiazol-2-yl}-benzamide, using general procedure A. Amorphous white solid. MS 450.0 ([M+H]+)
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[C:18]([F:35])=[C:19](/[CH:23]=[C:24](/[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[CH3:34])\[C:25]#[N:26])[CH:20]=[CH:21][CH:22]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([Cl:16])[C:18]=2[F:35])[C:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[CH3:34])([C:25]#[N:26])[CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Reactant: Cc1cc(Cl)ccc1/C(C#N)=C/c1cccc(Cl)c1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(Cl)ccc1C1(C#N)C(CC(C)(C)C)NC(C(=O)OC(C)(C)C)C1c1cccc(Cl)c1F
Yield: 48.8 %

Procedure:
In a manner similar to the method described in Example 1c, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 1a (2.1 g, 10 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-methyl-phenyl)-acrylonitrile (2.3 g, 7.5 mmol) prepared in Example 57a, AgF (1.3 g, 10 mmol), and triethylamine (2.8 g, 28 mmol) in dichloromethane (100 mL) at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-methyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.9 g, 49%).