Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13](I)[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[CH3:16][N:17](C)C=O>[C-]#N.[Zn+2].[C-]#N.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>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([C:16]#[N:17])[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)c1cc(Br)cc(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)(C)OC(=O)c1cc(Br)cc(C#N)c1
Temperature: 80 °C
Yield: 73 %

Procedure:
A mixture of t-butyl 3-bromo-5-iodobenzoate (1.91 g, 5 mmol), zinc cyanide (585 mg, 5 mmol), and tetrakis(triphenylphosphine)palladium(0) (300 mg, 5 mol %) in dimethylformamide (20 ml) was heated at 80° C. for 2 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate (20 ml) and washed with water and brine. The organic phase was dried and evaporated. Chromatography with ethyl acetate/hexane (1:4) gave the title compound as a colourless oil (1.02 g, 73%).
Reaction SMILES: [Cl:1][C:2]1[C:28]([Cl:29])=[CH:27][C:5]([CH2:6][NH:7][C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH:16]3[CH2:19][N:18]([C:20](OC(C)(C)C)=[O:21])[CH2:17]3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([O:30][CH3:31])[CH:3]=1.[CH2:32](N(CC)CC)[CH3:33].C(Cl)(=O)C=C>Cl.CO.C(Cl)Cl>[C:20]([N:18]1[CH2:17][CH:16]([N:13]2[CH2:14][CH2:15][CH:10]([C:8]([NH:7][CH2:6][C:5]3[CH:27]=[C:28]([Cl:29])[C:2]([Cl:1])=[CH:3][C:4]=3[O:30][CH3:31])=[O:9])[CH2:11][CH2:12]2)[CH2:19]1)(=[O:21])[CH:32]=[CH2:33]
Reactant: COc1cc(Cl)c(Cl)cc1CNC(=O)C1CCN(C2CN(C(=O)OC(C)(C)C)C2)CC1
Reactant: CCN(CC)CC
Agent: C=CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: C=CC(=O)N1CC(N2CCC(C(=O)NCc3cc(Cl)c(Cl)cc3OC)CC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
A mixture of tert-butyl 3-(4-(4,5-dichloro-2-methoxybenzylcarbamoyl)piperidin-1-yl)azetidine-1-carboxylate (210 mg, 0.44 mmol) in HCl/MeOH (10 mL, 2.86 M) was stirred at room temperature for 1 h. The mixture was concentrated in vacuo to yield the crude residue. The residue was dissolved in DCM (5 mL), triethylamine (0.5 mL) and acryloyl chloride (40 mg, 0.43 mmol) were added. The reaction mixture was stirred at room temperature for 30 min and then partitioned between DCM and water. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=50:1) to afford the desired product (150 mg, 82% yield).
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.[C:29](Cl)(=[O:31])[CH3:30]>C(Cl)Cl>[C:29]([NH:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]2)[CH2:9]1)=[O:6])(=[O:31])[CH3:30]
Reactant: CC(=O)Cl
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a suspension of (R)-quinuclidin-3-yl 2-amino-2-phenylacetate dihydrochloride (I25) (140 mg, 0.42 mmol) in DCM (10 ml), were sequentially added triethylamine (175 μl, 1.26 mmol) and acetyl chloride (35.8 μl, 0.50 mmol). The reaction was stirred at RT for 2 hours, and then the solvent was evaporated. The residue was taken up with little EtOAc, and the insoluble was filtered off. The organic phase was evaporated to dryness achieving (R)-quinuclidin-3-yl 2-acetamido-2-phenylacetate (127 mg; quantitative yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1.[NH2:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[CH3:24].[OH-].[Na+]>Cl.C(O)CCC>[CH3:24][C:16]1[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:15]=1[NH:14][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccc(-c2cccnc2)n1
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Product: Cc1ccc([N+](=O)[O-])cc1Nc1nccc(-c2cccnc2)n1

Procedure:
A 250 ml reactor, equipped with a mechanical stirrer and a reflux condenser, was charged with 2-chloro-4-(3-pyridyl)-pyrimidine (0.5 g, 2.6 mmol), 2-amino-4-nitrotoluene (0.5 g, 3.2 mmol), n-butanol (15 ml) and concentrated HCl (5 drops) and the mixture was refluxed for 38 hours. Then, the mixture was cooled, and 6 N NaOH was added to pH 8. The solvent was evaporated under reduced pressure and water (20 ml) was added to the residue, followed by extraction with dichloromethane (2×20 ml). The combined organic phase was concentrated to dryness to give the crude N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-pyrimidine-amine, which was purified by column chromatography to yield a product having 80% purity. The residue was re-slurried twice in methanol (2×2 ml) and in water (3 ml) and dried under reduced pressure.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][OH:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[CH2:16](Br)[CH:17]=[CH2:18].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:18]([O:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][OH:15])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5])[CH:17]=[CH2:16]
Reactant: C=CCBr
Reactant: COC(=O)c1ccc(OCCO)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCOc1cc(OCCO)ccc1C(=O)O

Procedure:
The reaction of methyl 2-hydroxy-4-(2-hydroxy-ethoxy)-benzoate and allyl bromide in 2-butanone in the presence of potassium carbonate was performed as described in Example 2 to give 2-Allyloxy-4-(2-hydroxy-ethoxy)-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 12.12 (s, —CO2H); 7.65 (d, J=8.7, 1 arom. H); 6.55 (m, 2 arom. H); 5.97 (m, —CH═CH2); 5.48, 5.21 (2 d-like, CH═CH2); 4.84 (m, CH2CH2OH); 4.58 (d-like, CH2—CH═CH2); 3.99, 3.67 (2t, J=4.8, CH2CH2OH). 13C-NMR (100 MHz, d6-DMSO): 166.45 (C═O); 162.93; 159.39; 133.30; 133.24; 116.86; 112.86; 105.84; 100.43; 69.82; 68.58; 59.40.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[C:4]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-])=O)[CH:3]=1.C(O)(=O)C>[Pd].O1CCOCC1>[NH2:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][CH2:13][CH2:12][O:11][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[NH2:8]
Reactant: O=[N+]([O-])c1ccccc1OCCOc1cc(F)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Nc1ccccc1OCCOc1cc(F)ccc1N

Procedure:
9.48 g 4-fluoro-1-nitro-2-(2-(2-nitro-phenoxy)-ethoxy)-benzene and 1.5 g palladium on charcoal were suspended in 500 ml dioxane and 60 ml glacial acetic acid and hydrogenated at room temperature. After flashing three times with nitrogen the catalyst was filtered off under a nitrogen atmosphere and the remaining solution was evaporated and the product was dried under vacuum. Yield: 7.52 g.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([CH:28]=[C:29]([OH:31])[CH:30]=1)[CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:11]1)[CH3:4].Cl[CH2:33][C:34]1[N:35]=[C:36]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:37][C:38]=1[CH3:39].O>CN(C)C=O>[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([CH:28]=[C:29]([O:31][CH2:33][C:34]2[N:35]=[C:36]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[O:37][C:38]=2[CH3:39])[CH:30]=1)[CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:11]1)[CH3:4]
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: CCOC(=O)CCc1cn(Cc2cc(O)cc(OCC)c2)cc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2cc(OCC)cc(OCc3nc(-c4ccccc4)oc3C)c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.1 %

Procedure:
Sodium hydride (60%, oily, 50.0 mg) was added to a solution of ethyl 3-[1-(3-ethoxy-5-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (492 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 15 minutes. 4-Chloromethyl-5-methyl-2-phenyloxazole (260 mg) was added to the mixture, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[1-[3-ethoxy-5-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionate (622 mg, yield: 88%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][C:11](=O)[CH2:12][CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[N+:15]([O-:17])=[O:16].[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH:11]([N:22]3[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]3)[CH2:12][CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[N+:15]([O-:17])=[O:16]
Reactant: CN1CCNCC1
Reactant: COc1c([N+](=O)[O-])ccc2c1CCC(=O)CC2
Product: COc1c([N+](=O)[O-])ccc2c1CCC(N1CCN(C)CC1)CC2

Procedure:
1-(1-Methoxy-2-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-4-methyl-piperazine was prepared from 1-methoxy-2-nitro-5,6,8,9-tetrahydro-benzocyclohepten-7-one and 1-methylpiperazine in a similar manner to Example 907e. Product was isolated as a brown film.
Reaction SMILES: Br[C:2]1[CH:11]=[N:10][C:9]2[NH:8][C:7]3[CH:12]=[CH:13][C:14]([C:16]#[N:17])=[CH:15][C:6]=3[C:5]([C:23]([F:26])([F:25])[F:24])([CH2:18][O:19][CH:20]([CH3:22])[CH3:21])[C:4]=2[CH:3]=1.CCOC(C)=O.CCCCCC.[CH3:39][N:40](C=O)C>[C-]#N.[C-]#N.[Zn+2].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:39]([C:2]1[CH:11]=[N:10][C:9]2[NH:8][C:7]3[CH:12]=[CH:13][C:14]([C:16]#[N:17])=[CH:15][C:6]=3[C:5]([C:23]([F:26])([F:24])[F:25])([CH2:18][O:19][CH:20]([CH3:21])[CH3:22])[C:4]=2[CH:3]=1)#[N:40]
Reactant: CC(C)OCC1(C(F)(F)F)c2cc(C#N)ccc2Nc2ncc(Br)cc21
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)OCC1(C(F)(F)F)c2cc(C#N)ccc2Nc2ncc(C#N)cc21
Temperature: 100 °C
Yield: 60 %

Procedure:
A degassed mix of 3-bromo-7-cyano-5-trifluoromethyl-5-isopropoxymethyl-5,10-dihydrobenzo[b][1,8]naphthyridine (15) (73 mg, 0.171 mmol), Zn(CN)2 (20 mg, 0.171 mmol) and Pd(PPh3)4 (10 mg, 0.00855 mmol) in anhydrous DMF (2 mL) was heated at 100° C. for 16 h 30 min. The reaction mixture was cooled to room temperature, quenched 2 N NH4OH (20 mL), and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Flash chromatography (20%-30% EtOAc-Hexane) provided 17 (38 mg, 60% yield) as a white solid: m.p. 226-227° C.; low resolution mass spectrum (ESI) m/z 371.2 [(M−H)— calcd for C19H14F3N4O: 371.11].
Reaction SMILES: [BH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH2:9].[C:10]([C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11]>C(=O)=O>[BH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:20]([C:17]1[CH:18]=[CH:19][C:14]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:15][CH:16]=1)(=[O:22])=[O:21]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Bc1cc(Cl)ccc1N
Agent: O=C=O
Product: Bc1cc(Cl)ccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Reaction time: 4 h
Yield: 49 %

Procedure:
A 100 mL round-bottom flask was charged with 2-boranyl-4-chloro-phenylamine (1.1 g, 7.9 mmol) and 4-tert-butyl benzenesulfonyl chloride (2.7 g, 11.6 mmol). The flask was evacuated and purged with nitrogen, followed by the addition of pyridine (20 mL). The homogeneous light purple solution was stirred 4 hours, and then poured onto a rapidly stirring cold slurry of 6 M HCl (66 mL) (formed by placing the acidic solution in acetonic dry ice). The resultant precipitated sulfonamide was filtered, washed thoroughly with 10% HCl, and dried in vacuo to afford purplish solid. The crude product was purified by flash chromatograph to yield 1.3 g of product as colorless solid: MS (ES) M+H expected 336.5, found 336.5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[F:17][C:18]([F:33])([F:32])[C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:22](Cl)=[O:23].CO>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][N:11]([C:22](=[O:23])[C:21]3[CH:25]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:27]=[C:19]([C:18]([F:17])([F:32])[F:33])[CH:20]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CCNC1
Solvent: CO
Solvent: ClCCl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC(CCO)(c2ccc(Cl)c(Cl)c2)C1

Procedure:
The method of example 3.1 was used with 2-[3-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanol (1 mmol) and 3,5-bis(trifluoromethyl)-benzoyl chloride (1 mmol) to obtain a residue. Chromatography of the residue on silica gel eluting sequentially with 1% methanol in dichloromethane and then 6% methanol in dichloromethane gave the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[C:3]=1[OH:17].[C:18](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[Br:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[C:3]=1[O:17][CH3:18]
Reactant: O=C([O-])[O-]
Reactant: CCNC(=O)Nc1nc2ccc(Br)c(O)c2s1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCNC(=O)Nc1nc2ccc(Br)c(OC)c2s1
Yield: 2 %

Procedure:
A mixture of 1-(6-bromo-7-hydroxy-2-benzothiazolyl)-3-ethyl-urea 6, potassium carbonate and iodomethane in DMF was reacted to give 0.0034 g (2%) of the desired compound 10. 1H NMR (DMSO) δ 10.88 (br s, 1H, NH), 7.55 (d, 1H, J=8.5 Hz, ArH), 7.33 (d, 1H, J=8.5 Hz, ArH), 6.82 (br s, 1H, NH), 3.93 (s, 3H, CH3), 3.18 (m, 2H, CH2), 1.09 (t, 3H, J=7.2 Hz, CH3); LC/MS 330 (MH+); RP-HPLC RT 3.04 minutes.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3]O.[CH3:7][C:8]1[CH:12]=[C:11]([C:13]([O:15]CC)=[O:14])[NH:10][N:9]=1.CCOCC.[OH-].[NH4+]>C(O)C>[F:1][C:2]([F:6])([F:5])[CH2:3][N:10]1[C:11]([C:13]([OH:15])=[O:14])=[CH:12][C:8]([CH3:7])=[N:9]1
Reactant: CCOC(=O)c1cc(C)n[nH]1
Reactant: OCC(F)(F)F
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: Cc1cc(C(=O)O)n(CC(F)(F)F)n1
Temperature: 70 °C
Yield: 72 %

Procedure:
A mixture of 100 g (0.35 mol) of the trichloromethanesulfonate ester of 2,2,2-trifluoroethanol [J. Med. Chem. 16 1354 (1973)] and 55 g (0.35 mol) of ethyl 3-methylpyrazole-5-carboxylate is heated at 150°-155° C. for two hours. The cooled (70° C.) melt is poured with stirring into 400 ml of ether, 80 ml of conc. ammonium hydroxide, and 150 g ice. The ether layer is separated and distilled to give 48 g bp 100°-110°/11 mm. The ester is stirred under reflux two hours in 175 ml of ethanol and 40 ml of water containing 14 g of potassium hydroxide and evaporated in vacuo. The residue is dissolved in 60 ml of water and acidified with conc. HCl to give 32 g (72%) of 1-(2,2,2-trifluoroethyl)-3-methylpyrazole-5carboxylic acid, mp 135°-139° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[N:5][CH:6]=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9].[C:19]([O-:22])(=[O:21])[CH3:20].[Na+].O>CC(N(C)C)=O>[C:19]([O:22][CH2:2][C:3]1[C:4]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[N:5][CH:6]=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])(=[O:21])[CH3:20]
Reactant: COC(=O)c1cnc(OCC(F)(F)F)c(CBr)c1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)c1cnc(OCC(F)(F)F)c(COC(C)=O)c1
Temperature: 130 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
A mixture of methyl 5-(bromomethyl)-6-(2,2,2-trifluoroethoxy)nicotinate (0.68 g, 2.07 mmol, Step-2) and sodium acetate (0.51 g, 6.20 mmol) in DMA (10 mL) is stirred at 130° C. for 2 hours. After cooling to room temperature, the reaction mixture is poured into water, extracted with ethyl acetate and dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-Hexane/ethyl acetate (6:1) to give 0.35 g (56% yield) of the title compound as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SC)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[CH3:31][O:32][CH:33]1[CH2:36][NH:35][CH2:34]1>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:35]5[CH2:36][CH:33]([O:32][CH3:31])[CH2:34]5)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:28])[F:29])[CH:3]=1
Reactant: COC1CNC1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: COC1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)C1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-methoxy-azetidin-1-yl)-thiazol-4-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and 3-methoxy-azetidine following General Procedure B.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1.C(N(CC)C(C)C)(C)C.Cl[C:29]1[N:34]=[C:33]([Cl:35])[N:32]=[C:31]([Cl:36])[C:30]=1[Cl:37]>C1COCC1>[CH2:12]([O:11][C:9]([N:6]1[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][C:29]2[C:30]([Cl:37])=[C:31]([Cl:36])[N:32]=[C:33]([Cl:35])[N:34]=2)[CH2:4][CH2:5]1)=[O:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Clc1nc(Cl)c(Cl)c(Cl)n1
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)N1CCC(CNc2nc(Cl)nc(Cl)c2Cl)CC1
Reaction time: 0.75 h

Procedure:
To a solution of benzyl 4-(aminomethyl)piperidine-1-carboxylate (EXAMPLE 13, Step 1) and N,N-diisopropylethylamine (2.6 g, 20 mmol) in THF (40 mL) at −78° C. was added a solution of tetrachloropyrimidine (4.4 g, 20 mmol). The cooling bath was removed and the solution was stirred for 45 min. The solution was concentrated and purified by filtering through a pad of silica gel using ether.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([N+:10]([O-])=O)[N:3]=1.O.C([O-])(O)=O.[Na+]>C(O)C>[Br:1][C:2]1[N:3]=[C:4]([NH2:10])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc([N+](=O)[O-])nc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(N)nc1Br
Temperature: 25 °C
Yield: 63 %

Procedure:
To a solution of 2-bromo-3-methoxy-6-nitropyridine (2.0 g, 8.6 mmol) in ethanol (20 mL) was added SnCl2-2H2O (3.9 g, 17 mmol) at room temperature. The reaction was heated at reflux for 2 h. After cooling to room temperature, the reaction mixture was poured into water (50 mL), basified to pH to 8 with saturated NaHCO3 and extracted with ethyl acetate (50×3 mL). The combined organic layers were dried over Na2SO4, evaporated in vacuo and purified by chromatography on silica gel (20% ethyl acetate in petroleum ether) to afford 6-bromo-5-methoxypyridin-2-amine (1.1 g, 65%). 1H-NMR (300 MHz, CDCl3) δ 7.09 (d, J=8.4, 1H), 6.43 (d, J=8.4, 1H), 4.27 (br s, 2H), 3.82 (s, 3H).
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[CH3:47][C:48]1[CH:56]=[CH:55][C:51]([C:52](Cl)=[O:53])=[CH:50][CH:49]=1.O>N1C=CC=CC=1>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:41]=[C:42]([NH:46][C:52]([C:51]3[CH:55]=[CH:56][C:48]([CH3:47])=[CH:49][CH:50]=3)=[O:53])[CH:43]=[CH:44][CH:45]=2)=[N:17]1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(C(=O)Nc2cccc(-c3n[nH]c4ccc(-c5nc[nH]n5)cc34)c2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 66.1 %

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.140 g, 0.23 mmol) in pyridine (2 mL) was 0.35 added 4-methylbenzoyl chloride (0.053 mL, 0.40 mmol). The reaction was stirred at room temperature for 15 h. Water (10 mL) was added and the solid collected by suction filtration. The solid was dried in a vacuum oven for 3 h. The residue was dissolved in 4 N hydrochloric acid in 1,4-dioxane (10 mL) and the mixture was stirred at room temperature for 2 h. After neutralization with aqueous sodium bicarbonate, the reaction mixture was extracted with ethyl acetate. The combined organic fractions were dried over anhydrous sodium sulfate, filtered and evaporated. Addition of dichloromethane (10 mL) to the residue gave the title compound (0.060 g, 65% yield) which was isolated by filtration: 1H NMR (DMSO-d6) δ 10.41 (s, 1H), 8.74 (s, 1H), 8.46 (s, 1H), 8.33 (s, 1H), 8.10 (d, 1H), 7.94 (d, 3H), 7.72 (m, 2H), 7.54 (t, 1H), 7.36 (d, 2H), 2.40 (s, 3H); ES-MS (m/z) 395 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:3]=1[C:4](OC)=[O:5].[CH:13]([NH2:15])=O>>[I:12][C:9]1[CH:8]=[C:3]2[C:2](=[CH:11][CH:10]=1)[N:1]=[CH:13][NH:15][C:4]2=[O:5]
Reactant: COC(=O)c1cc(I)ccc1N
Reactant: NC=O
Product: O=c1[nH]cnc2ccc(I)cc12
Temperature: 25 °C

Procedure:
Methyl 2-amino-5-iodobenzoate (17.8 g, 64 mmol) was heated in 300 mL of formamide at 190° C. for 2 hours. The mixture was cooled to room temperature and the solid product was filtrated and dried in vacuum. The formed product 1403-174 was used without further purification. (10 g, 56.1%): LC-MS: 273 [M+1]+, 1H NMR (DMSO-d6): δ 7.46 (d, J=9.0 Hz, 1H), 8.10 (m, 2H), 8.36 (d, J=2.1 Hz, 1 H), 12.40 (s, 1H).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[I:13]N1C(=O)CCC1=O>C(O)(=O)C>[F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH:6]=[C:7]([I:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2cccnc2c1F
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: Fc1ccc2cc(I)cnc2c1F
Temperature: 90 °C
Reaction time: 30 h

Procedure:
185.5 g (1.12 mol) of 7,8-difluoroquinoline, 505.4 g (2.25 mol) of N-iodosuccinimide and 927 mL of acetic acid were placed in a 3 L eggplant flask containing a stirrer, followed by stirring the mixture for 30 hours at 90° C. After cooling the resultant, the precipitated crystals were filtered and dried.