Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[N:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)[CH:9]=[CH:10][CH:11]=1)=[C:2]=[O:3].[CH:28]([C:31]1[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:32]=1[NH:38][C:39]([NH2:41])=[S:40])([CH3:30])[CH3:29]>>[CH:28]([C:31]1[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:32]=1[NH:38][C:39]([NH:41][C:2]([NH:1][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[N:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:26])([F:25])[F:27])=[CH:19][CH:18]=3)[N:13]=2)[CH:7]=1)=[O:3])=[S:40])([CH3:30])[CH3:29]
Reactant: Cc1ccc(NC(N)=S)c(C(C)C)c1
Reactant: O=C=NCCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1
Product: Cc1ccc(NC(=S)NC(=O)NCCc2cccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)c2)c(C(C)C)c1

Procedure:
The title compound was prepared as described in Example 75 using 3-(3-(2-isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (CA44) and 1-(2-isopropyl-4-methylphenyl)thiourea isolated as a white solid (0.077 g, 25%): 1H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 10.10 (s, 1H), 9.42 (s, 1H), 8.15-8.05 (m, 2H), 8.04-7.96 (m, 2H), 7.61 (ddd, J=7.9, 2.0, 1.0 Hz, 2H), 7.49 (t, J=7.6 Hz, 1H), 7.39 (dt, J=7.7, 1.4 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.16-7.11 (m, 1H), 7.05-6.96 (m, 2H), 3.46 (q, J=6.7 Hz, 2H), 2.91 (dt, J=17.9, 6.9 Hz, 3H), 2.30 (s, 3H), 1.14 (d, J=6.8 Hz, 6H); 19F NMR (376 MHz, DMSO-d6) δ −56.97; ESIMS m/z 583 ([M+H]+), 581 ([M−H]−).
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6]([CH3:9])=[N:5]1)([CH3:3])[CH3:2].[B-:10]([F:14])([F:13])([F:12])[F:11].[CH3:15]C[O+](CC)CC>ClCCl>[F:11][B-:10]([F:14])([F:13])[F:12].[CH:1]([C@H:4]1[CH2:8][O:7][C:6]([CH3:9])=[N+:5]1[CH3:15])([CH3:3])[CH3:2]
Reactant: CC[O+](CC)CC
Reactant: CC1=N[C@@H](C(C)C)CO1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CC1=[N+](C)[C@@H](C(C)C)CO1
Temperature: -20 °C
Reaction time: 2 h

Procedure:
15 g (0.12 mol) 4-(S)-isopropyl-2-methyloxazoline are dissolved in 50 ml dichloromethane and cooled to −20° C. 18 g (0.122 mol) Meerwein's reagent are added portionwise. The reaction mixture is stirred for 2 h at room temperature after addition is completed. The solvent is removed under vacuum and the residue is washed with diethyl ether. The yield of 4-(S)-isopropyl-2,3-dimethyl-oxazoliniumtetrafluoroborate is 27 g. The enantiomer excess in the product is >95%.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>O>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: C1COCCN1
Solvent: O
Product: Clc1cc(N2CCOCC2)ncn1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
45.0 g (302.1 mmol) 4,6-dichloropyrimidine are initially introduced into 450 ml water. 26.3 g (302.1 mmol) morpholine are added and the mixture is stirred at 90° C. for 16 h. Thereafter, it is cooled to 0° C. and the precipitate formed is filtered off. The precipitate is washed once with 50 ml water and dried in air.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25](O)=[O:26])[CH:4]=[N:3]1.Cl.[O:29]1[CH2:32][CH:31]([NH2:33])[CH2:30]1.C(N(C(C)C)CC)(C)C.CCCP(=O)=O>O1CCCC1>[CH3:1][N:2]1[C:6]([C:7]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=[C:11]3[CH:10]=2)=[O:24])=[C:5]([C:25]([NH:33][CH:31]2[CH2:32][O:29][CH2:30]2)=[O:26])[CH:4]=[N:3]1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Reactant: NC1COC1
Agent: CCCP(=O)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(C(=O)NC2COC2)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Reaction time: 20 h
Yield: 38.2 %

Procedure:
A mixture of 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (100 mg, 276 μmol), oxetan-3-amine hydrochloride (60.5 mg, 552 μmol), diisopropylethylamine (241 μl, 1.38 mmol) and propylphosphonic anhydride (50% in ethyl acetate, 407 μl, 690 μmol) in tetrahydrofurane (7 ml) is stirred for 20 hours at reflux under nitrogen atmosphere. The solvent is evaporated and to the residue is added sat. aqueous sodium hydrogencarbonate solution. The mixture is stirred for 20 minutes while a white solid precipitates. The solid is collected by filtration, washed with diethylether and dried. The residue (94 mg white solid) is triturated with ethyl acetate, filtered and the filtrate is evaporated affording 1-methyl-N4-(oxetan-3-yl)-N5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-4,5-dicarboxamide (44 mg, 38.2%) as a white solid. mp.: >250° C. MS: m/z=418.3 (M+H+).
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH:4]([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:3][CH2:2]1.[NH2:16][NH2:17]>>[CH:10]1([NH:9][C:8]([NH:16][NH:17][C:8](=[N:7][CH:4]2[CH2:5][CH2:6][CH2:1][CH2:2][CH2:3]2)[NH:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:7][CH:4]2[CH2:3][CH2:2][CH2:1][CH2:6][CH2:5]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: NN
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Product: C1CCC(N=C(NNC(=NC2CCCCC2)NC2CCCCC2)NC2CCCCC2)CC1

Procedure:
DCC (1.03 g, 4.97 mmol) was dissolved in tetrahydrofuran (15 mL). Hydrazine (135 mg, 4.22 mmol) was added via syringe. Stirring 30 hours at room temperature produced a clear yellow mixture which was evaporated to a white powder (922 mg). Solution of this powder in diethyl ether, filtration and acidification with HCl (60 mL of saturated Et2O) gave a yellow white precipitate (856 mg). Two recrystallizations (EtOH in an Et2O chamber) gave white prisms (133 mg, 18%, M.P. 288°-290° C.). The low percentage of nitrogen in the elemental analysis of this compound indicates that two equivalents of DCC have reacted to hydrazine, forming the title compound. 1H NMR ([2H]--CH3OH) δ 3.21 (s, 4, N-bearing cyclohexyl), 2.0-1.5 (m, 44, cyclohexyls). 13C NMR ([2H]--CH3OH) δ 154.1 (guanidine), 51.7 (N-bearing cyclohexyl), 32.4 and 24.8 (cyclohexyls). IR shows peaks at 1639 and 1589 cm-1. Elem. Analysis (C26N6H50Cl2 : 1/2 H2O). Theor. C 59.30, H 9.76, N 15.96, Found C 58.94, H 9.76, N 16.01.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([NH:7][NH2:8])=[O:6].[OH:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH:24]=O)=[CH:16][CH:15]=1>CS(C)=O.C(O)(=O)C.C(OCC)(=O)C>[OH:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH:24]=[N:8][NH:7][C:5](=[O:6])[C:4]2[CH:9]=[CH:10][C:11]([OH:12])=[C:2]([Cl:1])[CH:3]=2)=[CH:16][CH:15]=1
Reactant: NNC(=O)c1ccc(O)c(Cl)c1
Reactant: O=Cc1ccc(O)c2ccccc12
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: O=C(NN=Cc1ccc(O)c2ccccc12)c1ccc(O)c(Cl)c1
Reaction time: 8 h

Procedure:
To a solution of 3-chloro-4-hydroxybenzoic acid hydrazide (200 mg, 1.1 mmol) in DMSO (2 ml) was added 4-hydroxynaphthaldehyde and a catalytic amount of glacial acetic acid (5 drops). The reaction was stirred overnight under nitrogen and diluted with ethyl acetate. The solution was washed with saturated sodium bicarbonate, water, brine, and dried over MgSO4. The organic volume was concentrated in vacuo to give the crude product. The product was purified by silica gel column chromatography using CH2Cl2/MeOH as the mobile phase.
Reaction SMILES: [CH2:1]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])[CH2:2][CH2:3][CH3:4].[N+:22]([C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)([O-:24])=[O:23].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([O:20][C:19](=[O:21])/[CH:18]=[CH:17]/[C:6]2[CH:7]=[CH:8][C:9]3[C:14](=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=3)[C:5]=2[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCCCc1c(/C=C/C(=O)O)ccc2cc(OC)ccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCc1c(/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)ccc2cc(OC)ccc12
Temperature: 25 °C
Yield: 93.5 %

Procedure:
A stirred mixture of (E)-3-(1-butyl-6-methoxy-2-naphthalenyl)-2-propenoic acid (1.5 g) and 4-nitrophenol (0.81 g) in dichloromethane, was cooled in an ice bath, during the addition of a solution of 1,3-dicyclohexyl- carbodiimide (1.1 g) in dichloromethane (5 mL) then the reaction was stirred at room temperature over the weekend. After the precipitated dicyclohexylurea was removed by filtration, the filtrate was concentrated and applied to a column of silica gel (25 g) made up in dichloromethane-hexane (2:1). Elution with the same solvent mixture and concentration of the appropriate fractions yielded 2 g of (E)-3-(1-butyl-6-methoxy-2-naphthalenyl)-2-propenoic acid 4-nitrophenyl ester. Crystallization of the material from 2-propanol gave 1.85 g of the active ester, mp 140°-141° C. Anal. Calcd for C24H23NO5 : C, 71.10; H, 5.72; N, 3.45 Found: C, 70.98; H, 5.50; N, 3.33
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C:3]1=[CH:15]N(C)C.C(O)(=O)C.[C:23]([NH2:26])(=[NH:25])[CH3:24]>>[C:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][C:2]2[N:25]=[C:23]([CH3:24])[N:26]=[CH:15][C:3]=2[CH2:4]1)=[O:9])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(=N)N
Reactant: CN(C)C=C1CN(C(=O)OC(C)(C)C)CCC1=O
Solvent: CC(=O)O
Product: Cc1ncc2c(n1)CCN(C(=O)OC(C)(C)C)C2

Procedure:
Reaction of tert-butyl 4-oxo-3-(dimethylaminomethylidene)-1-piperidinecarboxylate (1.15 g) from Intermediate 28, Step A with acetamidine acetate (0.54 g) according to the procedure described for Intermediate 28, Step B, and purification by flash chromatography (silica gel; 2% methanol/dichloromethane as eluant) afforded the title compound as a viscous orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:3]=12.[CH2:19]([Li])CCC.IC>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:9]([CH3:19])=[CH:10][C:3]=12
Reactant: [Li]CCCC
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)ccnc21
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc2c(Cl)ccnc2n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 95.3 %

Procedure:
To a solution of 4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (150 mg, 0.53 mmol) in THF (1 mL) at −78° C. under argon was added butyllithium (0.4 mL, 1.6 M in hexanes, 6.4 mmol) dropwise. The mixture was stirred at the same temperature for 5 min, and treated with iodomethane (0.1 mL). The mixture was warmed up to room temperature, quenched by the addition of saturated ammonium chloride solution, and extracted with ethyl acetate (3×10 mL). The combined extracts were washed with brine, dried (MgSO4) and concentrated in vacuo to give the crude product (150 mg, 95%), which was used for the next reaction. 1H NMR (CDCl3) δ 8.19 (d, 1H, J=5.5 Hz), 7.14 (d, 1H, J=5.5 Hz), 6.42 (s, 1H), 5.74 (s, 2H), 3.60 (t, 2H, J=6.8 Hz), 2.61 (s, 3H), 0.96 (t, 2H, J=6.8 Hz), 0.07 (s, 9H); MS(ESI+) m/z 297 and 299 (M+H, 1 Cl)+.
Reaction SMILES: C(N(CC)CC)C.[CH:8]([NH:10][CH:11]([C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)[CH2:12][CH3:13])=O.P(Cl)(Cl)(Cl)=O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[S:15]1[CH:16]=[CH:17][CH:18]=[C:14]1[CH:11]([N+:10]#[C-:8])[CH2:12][CH3:13]
Reactant: CCC(NC=O)c1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [C-]#[N+]C(CC)c1cccs1
Reaction time: 1 h
Yield: 86.4 %

Procedure:
231 g of triethylamine are added to a solution of 96.5 g of 2-(1-formylaminopropyl) thiophene in 500 ml of methylene chloride and the mixture is cooled at below -30° C. 105 g of phosphorus oxychloride are added dropwise to the mixture at below -30° to -20° C. and and the mixture is stirred at the same temperature for 1 hour. After the reaction, the mixture is poured into 1 litter of an aqueous 10% potassium carbonate solution. The aqueous mixture is stirred at room temperature for 1 hour and the methylene chloride layer is separated therefrom. Said methylene chloride layer is washed with water, dried and evaporated to remove solvent. The residue is distilled under reduced pressure to give 74.5 g of 1-(2-thienyl)propyl isocyanide as a colorless oil.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([F:19])[CH:8]=1.[CH3:20]O>>[NH2:6][C:7]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:10]([C:11]([O:13][CH3:20])=[O:12])=[C:9]([F:19])[CH:8]=1
Reactant: Nc1cc(F)c(C(=O)O)cc1[N+](=O)[O-]
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])c(N)cc1F
Temperature: 25 °C
Yield: 69 %

Procedure:
Sulfuric acid (10 mL) was added to a solution of 4-amino-2-fluoro-5-nitrobenzoic acid ammoniate (10 g, 46 mmol) in methanol (100 mL) and refluxed for 30 h. The solution was cooled to ambient temperature and the solid thus obtained was collected by filtration, washed with hexanes, and dried in vacuo at 40° C. for 14 h to afford the desired methyl 4-amino-2-fluoro-5-nitrobenzoate as a yellow solid (6.84 g, 31.9 mmol, 69%). 1H NMR (MeOD) δ 8.62-8.58 (m, 1H), 6.63-6.59 (m, 1H).
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:12][S:11][CH2:10][C@H:2]1[C:3]([NH:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].CS(O)(=O)=O.ClCCl.[OH-].[Na+]>C(#N)C.ClCCl>[NH:1]1[CH2:12][S:11][CH2:10][C@H:2]1[C:3]([NH:5][C:6]([CH3:9])([CH3:7])[CH3:8])=[O:4]
Reactant: CC(C)(C)NC(=O)[C@@H]1CSCN1C(=O)OC(C)(C)C
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(C)NC(=O)[C@@H]1CSCN1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.3 %

Procedure:
To a solution of 5.00 g (17.4 mmol) of Boc-Thz-NH-tBu in 23.7 ml of acetonitrile-dichloromethane (1:6), 3.39 ml (52.1 mmol) of methanesulfonic acid was added. After stirring at room temperature for 1.5 h, 30 ml of dichloromethane and 26 ml (52 mmol) of 2N NaOH aqueous solution were added under ice cooling to extract the product. The organic layer was washed with 5% NaHCO3 aqueous solution and saturated NaCl aqueous solution successively, dried over Na2SO4, and evaporated under reduced pressure. The residue was triturated in 50 ml of hexane to give 2.86 g (Y. 88%) of H-Thz-NH-tBu which was converted to Qoa-Mta-AHPBA-Thz-NH-tBu by a similar method with processes 3-5 of Example 3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH:13]([CH2:19][NH2:20])[CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[N:12]=2)=[CH:4][CH:3]=1.[F:21][C:22]([F:38])([F:37])[C:23]1[O:27][N:26]=[C:25]([C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31](O)=[O:32])[N:24]=1>>[CH3:17][N:16]([CH3:18])[CH2:15][CH2:14][CH:13]([C:11]1[N:12]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[O:9][CH:10]=1)[CH2:19][NH:20][C:31](=[O:32])[C:30]1[CH:34]=[CH:35][CH:36]=[C:28]([C:25]2[N:24]=[C:23]([C:22]([F:38])([F:37])[F:21])[O:27][N:26]=2)[CH:29]=1
Reactant: CN(C)CCC(CN)c1coc(-c2ccc(F)cc2)n1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: CN(C)CCC(CNC(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1)c1coc(-c2ccc(F)cc2)n1
Yield: 10 %

Procedure:
This compound was synthesized from 3-(2-(4-fluorophenyl)oxazol-4-yl)-N1,N1-dimethylbutane-1,4-diamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (17 mg, yield 10%). 1H NMR (400 MHz, MeOD) δ 8.55-8.54 (t, J=1.5 Hz, 1H), 8.30-8.27 (m, 1H), 8.08-8.02 (m, 3H), 7.82 (s, 1H), 7.71-7.67 (t, J=7.8 Hz, 1H), 7.26-7.21 (t, J=8.9 Hz, 2H), 3.76-3.65 (m, 2H), 3.16-3.10 (m, 1H), 2.53-2.40 (m, 2H), 2.30 (m, 6H), 2.04-1.98 (m, 2H). MS (ESI) m/z: Calculated for C24H22F4N6O3: 518.17. found: 519.2 (M+H)+.
Reaction SMILES: [C:1]([Cl:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].ClCl.[Cl:23]S(O)(=O)=O.C1C(=C(C#N)C#N)C=CC(=C(C#N)C#N)C=1>>[Cl:23][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:1]([Cl:20])=[O:19]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: O=S(=O)(O)Cl
Agent: ClCl
Agent: N#CC(C#N)=c1ccc(=C(C#N)C#N)cc1
Product: CCCCCCCCCCCCCCCCC(Cl)C(=O)Cl

Procedure:
Following the procedure of Example I, stearoyl chloride is reacted with chlorine in the presence of ClSO3H and TCNQ. The product is distilled to provide substantially pure 2-chlorostearoyl chloride.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][C:10]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=2)([C:13]([F:16])([F:15])[F:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)=O.[H][H]>CO.[Pt].C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([C:17]2[CH:18]=[C:19]([Cl:24])[CH:20]=[C:21]([Cl:23])[CH:22]=2)([C:13]([F:16])([F:15])[F:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)C=CN(Cc2ccccc2)C1
Reactant: [H][H]
Agent: [Pt]
Solvent: O=CO
Solvent: CO
Solvent: CCOC(C)=O
Product: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 96 %

Procedure:
1-Benzyl-3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-2,3-dihydro-1H-pyrrole (200 mg, 82% purity, 440 μmol) was dissolved in methanol (5 mL) under an argon atmosphere. Formic acid (200 μL, 5.30 mmol) and platinum on charcoal (5 w/w % Pt/C, ˜60% H2O, 42.9 mg, 4.4 μmol) was added and the flask was charged with hydrogen (balloon). The reaction was stirred for six hours at room temperature and then left standing over night. After the addition of platinum on charcoal (0.5 mol %) and formic acid (1 mL) the reaction mixture was warmed to 40-50° C. for six hours and then left standing at room temperature. Refluxing the mixture for three more hours and addition of more platinum on charcoal (1.0 mol %) after one hour led to complete conversion. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (5 mL), filtered over celite, washed with saturated sodium bicarbonate and brine solution. The organic phase was dried over sodium sulfate, filtered and the solvents evaporated. 1-benzyl-3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidine was obtained (163 mg, 97% purity, 96% yield).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])[C:3]=1[C:13]([NH:16][CH2:17][CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2([C:31]([O:33][CH3:34])=[O:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH2:20][CH2:19]1)=[N:14][OH:15].CC(C)([O-])C.[K+]>CN1CCCC1=O.O>[CH2:9]([O:8][C:4]1[C:3]2[C:13]([NH:16][CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([CH2:24][C:25]4([C:31]([O:33][CH3:34])=[O:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH2:20][CH2:19]3)=[N:14][O:15][C:2]=2[CH:7]=[CH:6][CH:5]=1)[CH:10]([CH3:12])[CH3:11]
Reactant: COC(=O)C1(CN2CCC(CNC(=NO)c3c(F)cccc3OCC(C)C)CC2)CCOCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)C1(CN2CCC(CNc3noc4cccc(OCC(C)C)c34)CC2)CCOCC1
Temperature: 100 °C
Yield: 36.3 %

Procedure:
To a solution of methyl 4-{[4-({[(2-fluoro-6-isobutoxyphenyl)(hydroxyimino)methyl]amino}methyl)-piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-carboxylate (0.84 g, 1.8 mmol, EXAMPLE 16, Step 8) in N-methylpyrrolidone (9.0 mL) was added potassium tert-butoxide (0.22 g, 2.0 mmol) at room temperature. The mixture was heated at 100° C. for 5 h and cooled to room temperature. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL×2) and washed with water (50 mL). The combined extracts were dried over magnesium sulfate and concentrated in vacuo to give an oil. The residual oil was purified by silica gel column chromatography (hexane/ethyl acetate 1:1 to 1:2) to give 0.30 g (36%) of the title compound as a colorless viscous oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:36])=[C:23]([N:25]4[CH2:34][CH2:33][C:32]5[C:27](=[CH:28][CH:29]=[CH:30][C:31]=5[F:35])[CH2:26]4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CO.CCOCC>[F:35][C:31]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:32]=1[CH2:33][CH2:34][N:25]([C:23]1[C:22]([NH2:36])=[N:21][CH:20]=[C:19]([C:17]3[CH:16]=[N:15][N:14]([CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH:18]=3)[CH:24]=1)[CH2:26]2
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(N4CCc5c(F)cccc5C4)c3)cn2)CC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1N1CCc2c(F)cccc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-{4-[6-Amino-5-(5-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (34 mg) was dissolved in MeOH (20 mL), 1.0 M of HCl in Et2O (20 mL) was added, and the mixture was stirred at rt overnight. The solvent was removed in vacuo to give a brown oil. It was purified by Gilson HPLC eluting with H2O/CH3CN/0.1% formic acid mixtures to give the title compound contaminated with the corresponding formamide. This material was dissolved in MeOH (2 ml), aqueous NaOH (10 N, 2 ml) was added, and the solution was stirred at rt overnight. It was then treated with water (5 ml) and extracted with DCM (3×20 ml). The extracts were washed with water (2×20 ml), brine (20 ml), dried over MgSO4, filtered, and concentrated in vacuo, to give the title compound as a beige solid. 1H NMR (400 MHz, CD3OD): δ=1.79-1.92 (m, 2H), 1.98-2.06 (m, 2H), 2.63-2.70 (m, 2H), 2.90 (t, J=6.0 Hz, 2H), 3.06-3.14 (m, 2H), 3.18-3.24 (m, 2H), 4.06 (s, 2H), 4.15-4.23 (m, 1H), 6.82 (d, J=8.8 Hz, 1H), 6.85-6.88 (m, 1H), 7.05-7.12 (m, 1H), 7.44 (d, J=2.4 Hz, 1H), 7.66 (d, J=0.8 Hz, 1H), 7.83 (d, J=2.0 Hz, 1H), 7.91 (d, J=0.4 Hz, 1H). MS(ES+): m/z=394.14 (45) [MH+]. HPLC: tR=2.21 min (ZQ2, polar—5 min).
Reaction SMILES: COC(=O)C(O)=CC(=O)N(CC1C=CC(F)=CC=1)C.C=O.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][NH2:31])=[CH:25][CH:24]=1.[F:32][C:33]1[CH:51]=[CH:50][C:36]([CH2:37][N:38]([CH3:49])[C:39]([C:41]2[CH2:42]N(C)[C:44](=[O:47])[C:45]=2[OH:46])=[O:40])=[CH:35][CH:34]=1>>[F:32][C:33]1[CH:51]=[CH:50][C:36]([CH2:37][N:38]([CH3:49])[C:39]([C:41]2[CH2:42][N:31]([CH2:30][CH2:29][C:26]3[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=3)[C:44](=[O:47])[C:45]=2[OH:46])=[O:40])=[CH:35][CH:34]=1
Reactant: CN1CC(C(=O)N(C)Cc2ccc(F)cc2)=C(O)C1=O
Reactant: NCCc1ccc(F)cc1
Agent: C=O
Agent: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(F)cc1
Product: CN(Cc1ccc(F)cc1)C(=O)C1=C(O)C(=O)N(CCc2ccc(F)cc2)C1

Procedure:
3-[(4-Fluoro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 1-D) was treated with paraformaldehyde and 2-(4-fluoro-phenyl)-ethylamine as described in the preparation of Compound 1. (HRMS (M−H) calcd for C21H19F2N2O3: 385.1364. found: 385.1377. 1H NMR (500 MHz, CDCl3) δ: 2.90 (t, 2, J=7), 2.95 (s, 3), 3.71 (t, 2, J=7), 3.95 (s, 2), 4.57 (s, 2), 6.95–7.26 (overlapping m, 8). 13C NMR (125 MHz, CDCl3) δ: 33.74, 34.48, 44.70, 49.41, 51.47, 108.82, 115.49, 115.66, 115.71, 115.77, 115.89, 129.22, 129.27, 130.04, 130.10, 131.97, 133.72, 153.60, 160.81, 161.42, 162.76, 163.38, 164.71, 166.21.