Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]([CH2:20][O:21][C:22](=[O:25])[CH:23]=[CH2:24])([CH2:14][O:15]C(=O)C=C)[CH2:8][O:9]C(=O)C=C)(=[O:4])[CH:2]=[CH2:3].[CH3:26][NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(O)(=O)C>[CH3:26][N:27]([CH2:24][CH2:23][C:22]([OH:21])=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[CH3:26][N:27]([CH2:3][CH2:2][C:1]([OH:5])=[O:4])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[CH3:26][N:27]([CH2:24][CH2:23][C:22]([OH:21])=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[CH3:26][N:27]([CH2:24][CH2:23][C:22]([OH:21])=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[OH:5][CH2:6][C:7]([CH2:20][OH:21])([CH2:14][OH:15])[CH2:8][OH:9]
Reactant: CNc1ccccc1
Reactant: C=CC(=O)OCC(COC(=O)C=C)(COC(=O)C=C)COC(=O)C=C
Solvent: CC(=O)O
Product: CN(CCC(=O)O)c1ccccc1
Product: OCC(CO)(CO)CO
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Pentaerythritol tetraacrylate (4.4 g, 0.0125 moles) was added to N-methylaniline (5.4 g 0.050 moles), dissolved in glacial acetic acid (10 ml). The mixture was heated with stirring at 100° C. for 2 hours and then the acetic acid removed by vacuum distillation. An infrared spectrum of the residual oil revealed the presence of a little unreacted N-methylaniline but little sign of any unreacted acrylate groups. Absorptions due to the presence of a saturated ester (1730 cm−1) and an aromatic amine (1600 cm−) were found. 1H NMR δ 2.6 (CH2—CO, 8H t), 2.9 (CH3—N 12H s) 3.6 (CH2—N, 8H, t), 4.1 (CH2—O 8H s), 6.7 (aromatic protons 12H) 7.2 (aromatic protons 8H).
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]([CH3:5])([CH3:4])[CH3:3].CCOCC.[F:13][C:14]1[C:19](I)=[CH:18][CH:17]=[C:16]([F:21])[N:15]=1.[NH4+].[Cl-]>C1COCC1.[Cl-].[Zn+2].[Cl-]>[F:13][C:14]1[C:19]([CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])=[CH:18][CH:17]=[C:16]([F:21])[N:15]=1
Reactant: Fc1ccc(I)c(F)n1
Reactant: CC(C)(C)C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)Cc1ccc(F)nc1F
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
To a 500 mL RBF was added neopentylmagnesium chloride, 111.0M in ether (28.0 ml, 28 mmol) and an ice bath. After cooling, zinc(II) chloride, 0.5M in THF (56.0 ml, 28 mmol) was added dropwise. The cooling bath was removed and after stirring for 45 minutes, Reactant 1 (0.26 g, 0.32 mmol) was added followed by 2,6-difluoro-3-iodopyridine (2.74 g, 8.0 mmol) in THF (10 mL), which was added dropwise. The yellow solution was then heated to 60° C. After stirring overnight the reaction was allowed to cool and sat'd. NH4Cl was added cautiously. The reaction mixture was partitioned between EtOAc/Water. The aqueous layer was extracted with EtOAc (50 mL) and the combined organic layers washed with brine and concentrated in vacuo. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (40 g), eluting with 1% EtOAc in hexane, to provide 2,6-difluoro-3-neopentylpyridine as a colorless oil. MS m/z: 186 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=1[OH:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=1[O:19][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: Cc1cccc(C)c1O
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1Oc1ccc([N+](=O)[O-])cn1
Temperature: 110 °C
Yield: 72.3 %

Procedure:
In a 20 mL microwave vial 2-chloro-5-nitropyridine (500 mg, 3.15 mmol) was dissolved in N,N-dimethylformamide (10 mL) to give a pale yellow solution. 2,6-dimethylphenol (385 mg, 3.15 mmol) and potassium carbonate (1308 mg, 9.46 mmol) were added. The reaction vessel was sealed and heated under microwave irradiation (Biotage instrument) at 110° C. for 1 hour. The reaction mixture was quenched with 10 mL of water and diluted with 10 mL of Et2O. Phases were separated through a separating funnel. The organic phase was washed with 3 times 10 mL of water, 10 mL of brine, dried over sodium sulphate, filtered and evaporated under vacuum to afford the title compound as a pale orange oil (555.9 mg).
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[I:9][C:10]1[CH:11]=[N:12][NH:13][CH:14]=1.Cl[CH2:16][CH:17]1[O:21][C:20](=[O:22])[NH:19][CH2:18]1>O1CCOCC1.O.ClCCl>[I:9][C:10]1[CH:11]=[N:12][N:13]([CH2:16][CH:17]2[O:21][C:20](=[O:22])[NH:19][CH2:18]2)[CH:14]=1
Reactant: Ic1cn[nH]c1
Reactant: O=C1NCC(CCl)O1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C1NCC(Cn2cc(I)cn2)O1
Temperature: 110 °C

Procedure:
A mixture of potassium phosphate tribasic (6.57 g, 30.9 mmol), 4-iodo pyrazole (2.00 g, 10.3 mmol), and 5-(chloromethyl)-1,3-oxazolidin-2-one (2.80 g, 20.6 mmol) in 1,4-dioxane (103 mL) was sealed in a pressure vessel and heated for 72 hours at 110° C. Upon cooling to room temperature, the mixture was diluted with water and dichloromethane. The organic layer was separated, washed with water, and concentrated under reduced pressure. The residue was triturated with a mixture of methanol and hexanes for several hours at room temperature, and then the precipitate was collected by filtration to afford 5-[(4-iodo-1H-pyrazol-1-yl)methyl]-1,3-oxazolidin-2-one. MS ESI calc'd. for C2H8IN3O2 [M+H]+ 294. found 294. The enantiomers were separated by chiral SFC (supercritical fluid chromatography), IC column with 20% isopropyl alcohol in CO2 to give isomer 1 (faster eluting) and isomer 2 (slower eluting).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:24]([CH2:28][CH2:29][C:30]([F:33])([F:32])[F:31])[C:25]([NH2:27])=[O:26])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19](=[N:21][OH:22])[NH2:20])=[CH:15][C:14]=2[F:23])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:34](OCC)(OCC)OCC.B(F)(F)F.CCOCC.CCOC(C)=O>ClC(Cl)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:20]=[CH:34][O:22][N:21]=3)=[CH:15][C:14]=2[F:23])[C@H:24]([CH2:28][CH2:29][C:30]([F:32])([F:33])[F:31])[C:25]([NH2:27])=[O:26])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(OCC)OCC
Reactant: NC(=O)[C@@H](CCC(F)(F)F)N(Cc1ccc(C(N)=NO)cc1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: NC(=O)[C@@H](CCC(F)(F)F)N(Cc1ccc(-c2ncon2)cc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
To a solution of (R)-2-(4-chloro-N-(4-cyano-2-fluorobenzyl)phenylsulfonamido)-5,5,5-trifluoropentanamide (6.5 g, 13.6 mmol) in EtOH (70 mL) was added NH2OH (50% in H2O, 2.6 mL 40.8 mmol). The resulting mixture was stirred at 80° C. under nitrogen for 1 h and then cooled to rt. The solvents were evaporated under reduced pressure. The residue was dissolved in EtOAc and washed with water and dried over Na2SO4. Evaporation of the solvent gave a white solid which was recrystallized from EtOAc and hexanes to afford the intermediate amide oxime as a white solid (6.93 g, quantitative yield). To a mixture of the intermediate (R)-2-(4-chloro-N-(2-fluoro-4-(N′-hydroxycarbamimidoyl)benzyl)phenylsulfonamido)-5,5,5-trifluoropentanamide (6.93 g, 13.6 mmol) and triethyl orthoformate (6.77 mL, 40.8 mmol) in dichloroethane (30 mL) was added BF3.OEt2 (0.17 mL, 1.36 mmol). The resulting mixture was stirred at 70° C. for 1 h and then cooled to room temperature. Chromatography (silica gel, biotage, 40+M column, 3% to 80% EtOAc in hexanes, 651 mL) provided the title compound as a white solid. (4.9 g, 69.3% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([CH2:12][O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][N:15]=2)=[CH:10][O:9][N:8]=1.[CH:23]1([NH2:26])[CH2:25][CH2:24]1>>[CH:23]1([NH:26][C:18](=[O:20])[C:17]2[CH:21]=[CH:22][C:14]([O:13][CH2:12][C:11]3[C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[N:8][O:9][CH:10]=3)=[N:15][CH:16]=2)[CH2:25][CH2:24]1
Reactant: NC1CC1
Reactant: O=C(O)c1ccc(OCc2conc2-c2ccccn2)nc1
Product: O=C(NC1CC1)c1ccc(OCc2conc2-c2ccccn2)nc1
Yield: 82 %

Procedure:
As described for example 358 g, 6-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid (70 mg, 0.24 mmol) was converted using cyclopropylamine instead of 4-aminotetrahydropyran to the title compound (65 mg, 82%) which was obtained as a white solid. MS: m/e=337.3 [M+H]+.
Reaction SMILES: N#[C:2][Br:3].C(=O)([O-])[O-].[K+].[K+].CN(C)C[CH2:13][S:14][C:15]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[O:19][C:18]2[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=2[CH:16]=1>C(Cl)(Cl)Cl.CO>[Br:3][CH2:2][CH2:13][S:14][C:15]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[O:19][C:18]2[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=2[CH:16]=1
Reactant: N#CBr
Reactant: CN(C)CCSC1=Cc2ccccc2Oc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: BrCCSC1=Cc2ccccc2Oc2ccccc21

Procedure:
To a stirring solution of 0.36 g of cyanogen bromide, 2.28 g of potassium carbonate in 10 ml of chloroform is added dropwise a solution of 1.0 g of 10-[β-(dimethylamino)ethylthio]dibenz[b,f]oxepin, Example 8, in chloroform. After total addition the reaction mixture is refluxed for 2 hours and the solvent removed leaving an oil. The oil is dissolved in 10 ml of methanol and the methanolic solution refluxed for 10 minutes and again concentrated to recover the oil. The oil is chromatographed through a silica gel column with an eluant of ether. The top fraction is collected and concentrated leaving a white solid, mp 106°-107° C. of 10-[β-(bromo)ethylthio]dibenz[b,f]oxepin.
Reaction SMILES: ClCl.[CH3:3][S:4][CH3:5].[C:6]12([O:16][C:17]3[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=3)[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[CH2:7]1)[CH2:13]2.C(N(CC)CC)C>C(Cl)Cl>[C:6]12([O:16][C:17]3[CH:18]=[CH:19][C:20]([NH2:21])=[C:22]([CH2:3][S:4][CH3:5])[CH:23]=3)[CH2:13][CH:12]3[CH2:11][CH:10]([CH2:9][CH:8]([CH2:14]3)[CH2:7]1)[CH2:15]2
Reactant: Nc1ccc(OC23CC4CC(CC(C4)C2)C3)cc1
Reactant: CSC
Agent: ClCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSCc1cc(OC23CC4CC(CC(C4)C2)C3)ccc1N
Temperature: 25 °C

Procedure:
To 6.2 g. (0.088 mole) of chlorine in 240 ml. of CH2Cl2 in a one-liter 3-neck flask cooled to -70° to -73° was added dropwise with stirring a cold (~ -70°) solution of 5.7 g. (0.092 mole) of dimethyl sulfide in 20 ml. of CH2Cl2. The solution was stirred for several minutes, and then a solution of 21.4 g. (0.088 mole) of 4-(1-adamantyloxy)-aniline and 8.9 g. (0.088 mole) of triethylamine in 400 ml. of CH2Cl2 cooled either to -70° or to -40° to -50° was added dropwise rapidly. Then the mixture was either stirred at -70° and gradually allowed to warm to room temperature during four hours and then cooled again to -65° or it was stirred at -70° for 2 hours followed in either case by the addition of 51.8 g. of 25 % sodium methoxide in methanol solution, removal of the cold bath, and stirring at room temperature for 12 to 18 hours.
Reaction SMILES: C([C@@H:8]1[CH2:12]OC(=O)[N:9]1[C:14](=[O:35])[C@H:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:22][C:21]=1[Cl:34])CC=O)C1C=CC=CC=1.[NH:36]1[C:44]2[CH2:43][CH2:42][C@H:41](N)[CH2:40][C:39]=2[CH:38]=[N:37]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[Cl:34][C:21]1[CH:22]=[C:23]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH:24]=[C:25]([Cl:26])[C:20]=1[CH2:19][C@@H:15]1[CH2:12][CH2:8][N:9]([C@H:41]2[CH2:42][CH2:43][C:44]3[C:39](=[CH:38][NH:37][N:36]=3)[CH2:40]2)[C:14]1=[O:35]
Reactant: N[C@H]1CCc2[nH]ncc2C1
Reactant: O=CC[C@@H](Cc1c(Cl)cc(-c2ccc(F)cc2)cc1Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Product: O=C1[C@H](Cc2c(Cl)cc(-c3ccc(F)cc3)cc2Cl)CCN1[C@H]1CCc2n[nH]cc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.8 %

Procedure:
Add (R)-4-((R)-4-Benzyl-2-oxo-oxazolidin-3-yl)-3-(3,5-dichloro-4′-fluoro-biphenyl-4-ylmethyl)-4-oxo-butyraldehyde (Preparation 94) (1.13 mmoles; 580.00 mg) (dissolved in 5 ml dichloromethane) to (S)-(4,5,6,7-tetrahydro-1H-indazol-5-yl)amine 1.13 mmoles; 154.69 mg) dissolved in 5 ml Acetonitrile (5 mL). Cool the mixture in an ice water bath and add sodium triacetoxyborohydride (3.38 mmoles; 716.94 mg) portion wise. Remove the cooling bath and warm the mixture to ambient. Cool the mixture in an ice water bath and quench with 10 ml saturated sodium bicarbonate. Add 15 ml of ethyl acetate followed by 10 ml of brine. Charge the solution to a separatory funnel and separate the organic layer, dry over magnesium sulfate, filter, and concentrate to ⅓ volume. Add a seed crystal of (R)-3-(3,5-Dichloro-4′-fluoro-biphenyl-4-ylmethyl)-1-(S)-4,5,6,7-tetrahydro-2H-indazol-5-yl-pyrrolidin-2-one. Stir the solution at ambient temperature for 16 hours. Crystallization occurs and cool the mixture in an ice-water bath. Filter the cold mixture, collect the solid, and dry to give 284 mg of a white solid-crop A. LCMS=100% (M+1) at 458 amu. To the filtrate (now dry after evaporation), add 10 ml of MTBE to crystallize the rest of the product to obtain 89 mg white solid-crop B. LCMS=100% (M+1) at 458 amu 0.373/0.52=71.7%.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])[N:3]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][C:20]1=[O:25].C(N(CC)C(C)C)(C)C>C(O)CCC.C(OCC)(=O)C>[Cl:8][C:6]1[N:5]=[C:4]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])[N:3]=[C:2]([N:22]2[CH2:23][CH2:24][NH:19][C:20](=[O:25])[CH2:21]2)[CH:7]=1
Reactant: O=C1CNCCN1
Reactant: C[C@H](Nc1nc(Cl)cc(Cl)n1)c1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1nc(Cl)cc(N2CCNC(=O)C2)n1)c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 20 h
Yield: 106.9 %

Procedure:
To a solution of 150 mg of (S)-4,6-dichloro-N-[1-(4-fluorophenyl)ethyl]pyrimidine-2-amine and 58 mg of piperazin-2-one in 1.5 ml of 1-butanol was added 183 μl of N,N-diisopropylethylamine, and the mixture was stirred at 60° C. for 20 hours. The reaction solution was air-cooled to room temperature, and then diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 196 mg of the objective compound as white powder.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:19]2[NH:23][C:22]([C:24]3[S:28][C:27]([CH:29]=[O:30])=[N:26][N:25]=3)=[CH:21][CH:20]=2)[CH2:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:31][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([C:19]2[NH:23][C:22]([C:24]3[S:28][C:27]([CH:29]([OH:30])[CH3:31])=[N:26][N:25]=3)=[CH:21][CH:20]=2)[CH2:12][CH:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCOCC2)c2ccc(-c3nnc(C=O)s3)[nH]2)cc1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1nnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(C)(=O)=O)cc3)[nH]2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
To a solution of 5-(5-{1-[4-(methylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)-1,3,4-thiadiazole-2-carbaldehyde (700 mg) in tetrahydrofuran (10 mL) was added methylmagnesium bromide (1M tetrahydrofuran solution) (3.46 mL) and the mixture was stirred at room temperature for 10 min. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (460 mg, yield 63%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-methanol (9:1, volume ratio). MS: 462 (MH+).
Reaction SMILES: [CH3:1]/[CH:2]=[CH:3]/[CH:4]=O.[NH2:6][C:7]1[CH:8]=[C:9]([CH2:13][C:14]([OH:16])=[O:15])[CH:10]=[CH:11][CH:12]=1>Cl.C1(C)C=CC=CC=1>[CH3:4][C:3]1[CH:2]=[CH:1][C:12]2[C:7](=[CH:8][C:9]([CH2:13][C:14]([OH:16])=[O:15])=[CH:10][CH:11]=2)[N:6]=1
Reactant: Nc1cccc(CC(=O)O)c1
Reactant: C/C=C/C=O
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1ccc2ccc(CC(=O)O)cc2n1
Yield: 12 %

Procedure:
Crotonic aldehyde (33.0 mL, 0.40 mol) was added to 3-aminophenylacetic acid (30.0 g, 0.20 mmol) in concentrated hydrochloric acid (400 mL) and toluene (100 mL) at 110° C. The mixture was heated at 1100 for 90 minutes. The aqueous layer was separated, washed with diethyl ether (350 mL) then neutralised with aqueous ammonia. The aqueous solution was washed with chloroform (3×500 mL) and the organic phase was evaporated in vacuo. The solid residue was refluxed with chloroform (900 mL) and methanol (100 mL) then the solution was decanted and purified by column chromatography on silica gel (gradient of chloroform:MeOH 9:1 to 4:1) to afford a mixture of isomeric acids. This was purified by fractional crystallisation using isopropanol to afford the title compound as a white solid in 12% yield, 4.90 g.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]#[N:16].[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[C:25](O)(=O)C.C(O)=O>C(O)C>[CH2:17]([NH:24][C:15]1[N:16]=[CH:25][N:1]=[C:2]2[NH:6][N:5]=[C:4]([NH:7][C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=3)[C:3]=12)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(=O)O
Reactant: NCc1ccccc1
Reactant: N#Cc1c(Nc2cccc(Cl)c2)n[nH]c1N
Solvent: CCO
Solvent: O=CO
Product: Clc1cccc(Nc2n[nH]c3ncnc(NCc4ccccc4)c23)c1
Temperature: 200 °C
Reaction time: 0.33 h

Procedure:
A mixture of 1 g (4.28 mmol) of 5-amino-3-(3-chloro-phenylamino)-4-cyano-pyrazole (Step 49.1), 3.67 g (34.25 mmol) of benzylamine, 0.245 ml (4.28 mmol) of glacial acetic acid and 0.73 ml (19.35 mmol) of formic acid is heated at 200° C. for 20 hours. The reaction mixture is cooled to RT, 30 ml of ice-water and 5 ml of ethanol are added and stirring is carried out for a further 20 minutes. The reaction mixture is then filtered and the filter residue is washed with water. Recrystallization from isopropyl alcohol yields the title compound; m.p. 215-218° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:15]2([CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[O:14][CH2:13][C@H:12]1[C:21](=O)[NH:22][CH2:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][CH:27]=1)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:38]>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[C:15]2([CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[O:14][CH2:13][C@H:12]1[C:21]1[NH:22][CH:23]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][CH:27]=2)[N:38]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CNC(=O)[C@@H]1COC2(CCOCC2)N1C(=O)OCc1ccccc1)c1ccc(Br)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1[C@H](c2nc(-c3ccc(Br)cc3)c[nH]2)COC12CCOCC2
Temperature: 140 °C
Yield: 57.1 %

Procedure:
(S)-3-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-1,8-dioxa-4-aza-spiro[4.5]decane-4-carboxylic acid benzyl ester (1.13 gm, 2.18 mmol) was dissolved in xylenes (11 mL), ammonium acetate (0.84 gm, 10.94 mmol) was added as a solid and the mixture was heated at 140° C. for 24 h. The mixture was diluted with ethyl acetate (50 mL) and the organic layer was washed (aqueous NaHCO3, water, brine) and dried. This crude product was purified by silica gel chromatography (3:2 mixture of EtOAc:hexanes) to afford 0.62 gm (57%) of the title compound. LCMS 500.9 (M+2)
Reaction SMILES: [C@H:1]12[CH2:7][C@H:6]1[CH2:5][C@@H:4]([CH2:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=1)[NH:3][CH2:2]2.[CH2:20]([O:22][C:23]1[C:24]([C:30](O)=[O:31])=[N:25][C:26]([CH3:29])=[CH:27][CH:28]=1)[CH3:21]>>[CH2:20]([O:22][C:23]1[C:24]([C:30]([N:3]2[C@H:4]([CH2:8][NH:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:12][N:11]=3)[CH2:5][C@H:6]3[C@H:1]([CH2:7]3)[CH2:2]2)=[O:31])=[N:25][C:26]([CH3:29])=[CH:27][CH:28]=1)[CH3:21]
Reactant: FC(F)(F)c1ccc(NC[C@@H]2C[C@@H]3C[C@@H]3CN2)nc1
Reactant: CCOc1ccc(C)nc1C(=O)O
Product: CCOc1ccc(C)nc1C(=O)N1C[C@H]2C[C@H]2C[C@H]1CNc1ccc(C(F)(F)F)cn1
Yield: 92 %

Procedure:
Following a similar procedure to that described for Example 1, N-[(1S,4S,6S)-3-azabicyclo[4.1.0]hept-4-ylmethyl]-5-(trifluoromethyl)-2-pyridinamine D12 (0.030 g) and 3-(ethyloxy)-6-methyl-2-pyridinecarboxylic acid D15 (0.020 g) were reacted to give the free base of the title compound (0.044 g, 0.101 mmol, 92% yield). HPLC (walk-up): rt=4.14 min. MS: m/z (ES/+): 435 (M+1). C22H25F3N4O2 requires 434. 1H NMR [the SYN relative stereochemistry is derived from the stereochemistry of the previous intermediate D8. The product is present as a mixture of conformers. The assignment is provided for the major component] (400 MHz, DMSO-d6) δ ppm: 8.26 (m, 1 H), 7.72-7.56 (m, 1 H), 7.18-7.47 (m, 3H), 6.83-6.61 (m, 1 H), 4.24-4.10 (m, 1 H), 4.10-3.88 (m, 2 H), 3.67-3.34 (m, 3 H), 2.67-2.56 (m, 1 H), 2.43-2.37 (s, 3 H), 2.43-2.34 (m, 1 H), 1.23-1.19 (m, 3 H), 1.20-0.8 (m, 3 H), 0.72-0.58 (m, 1 H), 0.15-0.24 (m, 1 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]12[CH2:13][CH:12]1[CH2:11][N:10]([C:14]1[CH:15]=[N:16][C:17]([N+:20]([O-])=O)=[CH:18][CH:19]=1)[CH2:9]2)([CH3:4])([CH3:3])[CH3:2]>CO.C(Cl)Cl.C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]12[CH2:13][CH:12]1[CH2:11][N:10]([C:14]1[CH:15]=[N:16][C:17]([NH2:20])=[CH:18][CH:19]=1)[CH2:9]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC12CC1CN(c1ccc([N+](=O)[O-])nc1)C2
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC12CC1CN(c1ccc(N)nc1)C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.3 %

Procedure:
To a solution of [3-(6-Nitro-pyridin-3-yl)-3-aza-bicyclo[3.1.0]hex-1-yl]-carbamic acid tert-butyl ester (150 mg, 0.468 mmol) in MeOH—CH2Cl2 (3:1) was added Pd/C (24.92 mg, 0.234 mmol). The resulting mixture was stirred under H2 balloon (H2/vacuum exchange three times) at r.t. for 4 h. LCMS showed complete conversion. The reaction mixture was then filtered through a pad of Celite with DCM and concentrated to give a black precipitate. This precipitate was diluted in ethyl acetate followed by filtration. The filtrate was then evaporated to give 120 mg of [3-(6-Amino-pyridin-3-yl)-3-aza-bicyclo[3.1.0]hex-1-yl]-carbamic acid tert-butyl ester in 88% yield. MS (ESI) m/e (M+H+): 291.1
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[OH:13].[S:14]([O-:18])([O-])(=O)=[O:15]>N1C=CC=CC=1>[F:10][C:9]([F:12])([F:11])[S:14]([O:13][C:3]1[CH:4]=[CH:5][C:6]([O:8][C:9]([F:11])([F:12])[F:10])=[CH:7][C:2]=1[Br:1])(=[O:18])=[O:15]
Reactant: Oc1ccc(OC(F)(F)F)cc1Br
Reactant: O=S(=O)([O-])[O-]
Solvent: c1ccncc1
Product: O=S(=O)(Oc1ccc(OC(F)(F)F)cc1Br)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a cooled (0° C.) solution of 2-bromo-4-(trifluoromethoxy)phenol (Description 11, 10 g, 40 mmol) in pyridine (20 ml), was added trifluooromethanesulphonic anhydride (7.2 ml, 44 mmol), and the reaction was stirred at ambient temperature for 2 h. The reaction was diluted with saturated cooper (II) sulphate (80 ml) and extracted into ethyl acetate (3×60 ml). The combined organic fractions were washed with water (80 ml), brine (80 ml), dried (MgSO4) and evaporated in vacuo. Purification on silica, eluting with hexane gave the title compound as a clear oil (13.1 g, 85%). 1H NMR (250 MHz, CDCl3) δ7.28 (1H, m), 7.40 (1H, d, J 9.1 Hz), and 7.58 (1H, d, J 2.8 Hz).