Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1.[CH2:40]1[O:51][C:50]2[CH:49]=[CH:48][C:44]([C:45](Cl)=[O:46])=[CH:43][C:42]=2[O:41]1>>[CH2:40]1[O:51][C:50]2[CH:49]=[CH:48][C:44]([C:45]([O:1][CH:2]3[CH2:20][CH:19]4[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]5[C:16]([C:22]([NH:24][S:25]([CH:28]6[CH2:30][CH2:29]6)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]4=[O:21])[CH2:15]5)[CH2:3]3)=[O:46])=[CH:43][C:42]=2[O:41]1
Reactant: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Product: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(OC(=O)c3ccc4c(c3)OCO4)CN2C1=O
Yield: 35.1 %

Procedure:
Prepared by way of method I using 18-hydroxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]-nonadec-7-ene (100 mg, 0.175 mmol) and 3,4-methylenedioxybenzoyl chloride (65 μL, 0.35 mmol). The final trituration (diethyl ether/hexane) and filtration gave 44 mg (35%) of 18-(3,4-methylenedioxybenzoyloxy)-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo-[14.3.0.04,6]-nonadec-7-ene as a white powder: 98.6% pure (HPLC), MS m/z 717 (M+H)+, HRMS: calcd. 717.2806 and found 717.2789 (M+H)+, mp 153-155° C.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([F:25])[C:22](OC)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>[Cl-].[Na+].O>[CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([F:25])[C:22]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: COc1c(F)cc2c3c(cccc13)C(=O)N(OCc1ccccc1)C2=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=C1c2cccc3c(N4CCCC4)c(F)cc(c23)C(=O)N1OCc1ccccc1

Procedure:
A solution of 48 mg (0.14 mmol) of 2-benzyloxy-5-fluoro-6-methoxy-benzo[de]isoquinoline-1,3-dione (from Example Y3) in 1 mL of pyrrolidine was refluxed for 1 hour and poured into 15 mL of brine. The precipitate was isolated and washed with water until washings were colorless. The solid was dried to yield 32 mg of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:12]3[CH:13]=[C:14]([NH:17][CH:18]4[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]4)[CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[O:25]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26]1.C([O-])([O-])=O.[Na+].[Na+]>C(O)C.O>[O:25]1[CH:29]=[CH:28][C:27]([C:2]2[CH:7]=[C:6]([C:8]3[N:12]4[CH:13]=[C:14]([NH:17][CH:18]5[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]5)[CH:15]=[CH:16][C:11]4=[N:10][CH:9]=3)[CH:5]=[CH:4][N:3]=2)=[CH:26]1
Reactant: OC1CCC(Nc2ccc3ncc(-c4ccnc(Cl)c4)n3c2)CC1
Reactant: OB(O)c1ccoc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OC1CCC(Nc2ccc3ncc(-c4ccnc(-c5ccoc5)c4)n3c2)CC1

Procedure:
To [4-[3-(2-chloro-pyridin-4-yl)-imidazo[1,2-a]pyridin-6-ylamino]-cyclohexanol (Example 2.1) (1 eq, 100 mg, 0.29 mmol), 3-furyl boronic acid (1.05 eq, 0.3 mmol, 34 mg), Na2CO3 (2 eq, 0.58 mmol, 62 mg) in ethanol (2 ml) and H2O (0.7 ml), under inert atmosphere is added tetakis(triphenylphosphine)palladium (0.1 eq, 0.029 mmol, 21 mg). The reaction is heated in using microwave radiation at 80° C. for 2 hours. The mixture is diluted with H2O (5 ml) and extracted with EtOAc. The combined organic portions are washed with brine, dried (MgSO4) and concentrated in vacuo. The residue is purified by flash chromatography on silica eluting with 0-2.5% methanol in EtOAc to afford the title compound; [M+H]+375
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C:15]1[O:19][N:18]=[C:17]([C:20]([CH3:28])([CH3:27])[CH2:21][N:22]([C:24](=[O:26])[CH3:25])[CH3:23])[CH:16]=1)(C)(C)C>C(Cl)Cl>[NH2:14][C:15]1[O:19][N:18]=[C:17]([C:20]([CH3:28])([CH3:27])[CH2:21][N:22]([CH3:23])[C:24](=[O:26])[CH3:25])[CH:16]=1
Reactant: CC(=O)N(C)CC(C)(C)c1cc(NC(=O)OC(C)(C)C)on1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N(C)CC(C)(C)c1cc(N)on1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.3 %

Procedure:
Trifluoroacetic acid (0.108 mL, 1.4 mmol) is added to a solution of {3-[2-(acetyl-methyl-amino)-1,1-dimethyl-ethyl]isoxazol-5-yl}-carbamic acid tert-butyl ester (87.0 mg, 0.28 mmol) in DCM (1 mL). The reaction mixture is stirred at room temperature for 1 h. More trifluoroacetic acid (0.20 mL, 2.59 mmol) is added to the reaction mixture and the reaction mixture is stirred for another hour. After this time, the reaction mixture is diluted with DCM and quenched with saturated aqueous NaHCO3 solution. The layers are separated and the aqueous layer is extracted with DCM twice. The organics are combined and washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to provide 28.0 mg of the title compound. Yield: 47%. LC-MS Retention time: 0.94 mins. ESI+ion mode. Zorbax SB-C18 column (3.5 μm, 4.6×30 mm). Gradient: 5% B to 80% B (0 min to 1.7 mins), 80% B to 95% B (1.7 mins to 2 mins), 95% B to 95% B (2 mins to 2.1 mins). Flow rate: 2.5 mL/min. A=(Water+0.1% Formic Acid) B=(Acetonitrile+0.1% Formic Acid). Diode Array Detector; m/z 212 [M+H].
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].[NH2:31][C:32]1[CH:47]=[CH:46][C:35]([O:36][CH2:37][CH:38]([OH:45])[CH2:39][N:40]([CH2:43][CH3:44])[CH2:41][CH3:42])=[CH:34][CH:33]=1>C1COCC1>[CH2:43]([N:40]([CH2:41][CH3:42])[CH2:39][CH:38]([OH:45])[CH2:37][O:36][C:35]1[CH:34]=[CH:33][C:32]([NH:31][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[C:16]([NH:20][C:21]([C:23]5[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=5)=[O:22])[CH:17]=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:30])=[CH:47][CH:46]=1)[CH3:44]
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Reactant: CCN(CC)CC(O)COc1ccc(N)cc1
Solvent: C1CCOC1
Product: CCN(CC)CC(O)COc1ccc(NC=C2C(=O)Nc3cc(C(=O)c4cccc(NC(=O)c5cc(C)nn5C)c4)ccc32)cc1
Temperature: 65 °C
Reaction time: 24 h
Yield: 35 %

Procedure:
A small screw cap test tube was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 60, 132.3 mg, 0.3288 mmol) and THF (2 mL). To the resulting solution was added 1-(4-Amino-phenoxy)-3-diethylamino-propan-2-ol (prepared below; 95.7 mg, 0.4015 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. The room temperature reaction mixture was concentrated in vacuo. The solid residue was recrystallized from EtOAc (5 mL) and Hexanes (2 mL) yielding the title compound in 35% yield (0.072 g, 0.1156 mmol).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:11]2[C:20]([CH3:22])([CH3:21])[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:23]([O:25]C)=[O:24])[CH:17]=3)[NH:12]2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[OH-].[Na+]>CO.O>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:11]2[C:20]([CH3:22])([CH3:21])[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:23]([OH:25])=[O:24])[CH:17]=3)[NH:12]2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(C)=O)c1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=O)Nc1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Yield: 33.1 %

Procedure:
To a mixture of methyl 2-(3-acetamidophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (129 mg, 0.37 mmol) in methanol (10 mL) and water (5 mL) was added with a solution of sodium hydroxide (249 mg, 6.22 mmol) in water (5 mL). The resultant mixture was heated to reflux for 1.5 hours. The methanol was removed under vacuum. The residue was acidified with 2 M hydrochloric acid to pH=5-6. The precipitates were collected by filtration, purified by preparative Thin layer chromatography (silica gel, petroleum ether/ethyl acetate=3:1) to afford 2-(3-acetamidophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a solid. (41 mg, yield: 33.1%). MS (ES+APCI) M+1=339.1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:38])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][N:9]2[C:28](=[O:37])[C:29]2[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=2)[CH:5]=[CH:6][CH:7]=1.OO.C([O-])([O-])=[O:42].[K+].[K+]>CS(C)=O>[Cl:1][C:2]1[C:3]([F:38])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][N:9]2[C:28]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([NH2:36])=[O:42])=[CH:31][CH:30]=2)=[O:37])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)CC1CN(C(=O)c2ccc(C#N)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)C[C@@H]1CN(C(=O)c2ccc(C(N)=O)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Yield: 56.7 %

Procedure:
In a manner similar to the method described in Example 19, rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-1-(4-cyano-benzoyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (27.6 mg, 0.05 mmol) was reacted with 30% H2O2 (1.0 mL, excess), K2CO3 (excess) in DMSO (2 mL) at rt overnight to give rac-4-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-benzamide (15.3 mg, 56.7%). HRMS (ES+) m/z Calcd for C30H27Cl2F2N3O2+H [(M+H)+]: 570.1521, found: 570.1523.
Reaction SMILES: [F:1][C:2]1([F:40])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:18]=[C:19]5[C:23](=[CH:24][C:25]=4[F:26])[N:22]([CH2:27][C@@H:28]4[CH2:32][O:31]C(C)(C)[O:29]4)[C:21]([C:35]([CH3:39])([CH3:38])[CH2:36][OH:37])=[CH:20]5)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.O.CC1C=CC(S(O)(=O)=O)=CC=1.O>CO>[F:40][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:18]=[C:19]5[C:23](=[CH:24][C:25]=4[F:26])[N:22]([CH2:27][C@@H:28]([OH:29])[CH2:32][OH:31])[C:21]([C:35]([CH3:38])([CH3:39])[CH2:36][OH:37])=[CH:20]5)=[O:15])[CH2:12][CH2:13]3)=[CH:10][C:4]=2[O:3]1
Reactant: CC1(C)OC[C@@H](Cn2c(C(C)(C)CO)cc3cc(NC(=O)C4(c5ccc6c(c5)OC(F)(F)O6)CC4)c(F)cc32)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CC(C)(CO)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)c(F)cc2n1C[C@@H](O)CO
Temperature: 80 °C

Procedure:
(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (3.0 g, 5.4 mmol) was dissolved in methanol (52 mL). Water (5.2 mL) was added followed by p-TsOH.H2O (204 mg, 1.1 mmol). The reaction was heated at 80° C. for 45 minutes. The solution was concentrated and then partitioned between ethyl acetate and saturated NaHCO3 solution. The ethyl acetate layer was dried over MgSO4 and concentrated. The residue was purified by column chromatography (50-100% ethyl acetate-hexanes) to yield the product as a cream colored foamy solid. (1.3 g, 47%, ee>98% by SFC). ESI-MS m/z calc. 520.5. found 521.7 (M+1)+. Retention time 1.69 minutes. 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.53 (s, 1H), 7.42-7.38 (m, 2H), 7.33-7.30 (m, 2H), 6.22 (s, 1H), 5.01 (d, J=5.2 Hz, 1H), 4.90 (t, J=5.5 Hz, 1H), 4.75 (t, J=5.8 Hz, 1H), 4.40 (dd, J=2.6, 15.1 Hz, 1H), 4.10 (dd, J=8.7, 15.1 Hz, 1H), 3.90 (s, 1H), 3.65-3.54 (m, 2H), 3.48-3.33 (m, 2H), 1.48-1.45 (m, 2H), 1.35 (s, 3H), 1.32 (s, 3H) and 1.14-1.11 (m, 2H) ppm.
Reaction SMILES: Cl[C:2]1[N:17]=[CH:16][C:15]([F:18])=[CH:14][C:3]=1[C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]1)=[O:5].[CH3:19][S:20][C:21]1[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:18][C:15]1[CH:16]=[N:17][C:2]([O:27][C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([S:20][CH3:19])[CH:22]=2)=[C:3]([CH:14]=1)[C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]1)=[O:5]
Reactant: O=C(N[C@H]1CC[C@H](O)CC1)c1cc(F)cnc1Cl
Reactant: CSc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@H](O)CC2)c1
Temperature: 55 °C
Reaction time: 18 h

Procedure:
2-Chloro-5-fluoro-N-(trans-4-hydroxy-cyclohexyl)-nicotinamide (150 mg, 0.55 mmol), 3-methylsulfanyl-phenol (77 mg, 0.55 mmol) and caesium carbonate (358 mg, 1.10 mmol) were suspended in DMF (2 ml) and the reaction was heated to 55° C. and stirred at this temperature under nitrogen for 18 h. The reaction was quenched with sat. ammonium chloride solution (1.5 ml) and water (1.5 ml) and the organic phase was collected by passing the mixture through a chemelute cartridge, washing with ethyl acetate. The solvent was removed on a Genevac™ and the residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol (100:0 changing to 96:4, by volume) to give 5-fluoro-N-(trans-4-hydroxy-cyclohexyl)-2-(3-methylsulfanyl-phenoxy)-nicotinamide (50 mg) as pale green solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:9]=[C:10]([CH2:15][C:16](O)=[O:17])[CH:11]=[CH:12][C:13]=1[Cl:14]>C(OCC)C>[Cl:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][C:13]=1[Cl:14])[CH2:15][CH2:16][OH:17]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCCc1ccc(Cl)c(Cl)c1
Yield: 101 %

Procedure:
To a solution of lithium aluminum hydride (7.79 g, 195 mmol) in anhydrous diethyl ether (435 mL) was added slowly as a powder, via a solid dropping funnel, 3,4-dichlorophenyl acetic acid (27.20 g, 130 mmol). When the addition was completed, the reaction mixture was refluxed for 12 hours. The reaction was quenched by cautious addition of saturated sodium sulfate aqueous solution (20 mL), the resulting insoluble was then filtered off and the filtrate was concentrated in vacuo to yield 25.09 g of the desired alcohol.
Reaction SMILES: [Na].[CH2:2]([C:9]1[CH:18]=[CH:17][C:12]2[NH:13][C:14](=[S:16])[NH:15][C:11]=2[CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:19]([O:21][C:22](=O)[CH2:23]Br)[CH3:20]>C(O)C>[CH2:19]([O:21][C:22](=[SH:16][C:14]1[NH:15][C:11]2[CH:10]=[C:9]([CH2:2][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:18]=[CH:17][C:12]=2[N:13]=1)[CH3:23])[CH3:20]
Reactant: S=c1[nH]c2ccc(Cc3ccccc3)cc2[nH]1
Reactant: CCOC(=O)CBr
Agent: [Na]
Solvent: CCO
Product: CCOC(C)=[SH]c1nc2ccc(Cc3ccccc3)cc2[nH]1
Reaction time: 4 h
Yield: 97.1 %

Procedure:
0.46 g (20 mmoles) of metal sodium are dissolved in 40 ml of ethanol. To the ethylate 4.8 g (20 mmoles) of 5-benzyl-benzimidazoline-2-thione are added and 2.4 ml of bromoacetic acid ethyl ester are added dropwise at room temperature. After 4 hours boiling the salt is filtered off, the mother liquor is evaporated and 60 ml of petrol-ether are added to the distillation residue. Thus 7.23 g of crude title product are isolated. This is purified by suspending in water. Thus 6.33 g (97.1%) of title compound melting at a temperature of 103° C. are obtained, which can be crystallized from methanol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[O:14][C:15]([CH3:20])([CH3:19])[CH2:16][CH:17]([NH2:18])[C:11]3=[CH:10][C:9]=2[C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[C:4]([Cl:28])[CH:3]=1.[C:29](Cl)(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31].CCN(CC)CC>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[O:14][C:15]([CH3:20])([CH3:19])[CH2:16][CH:17]([NH:18][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[C:11]3=[CH:10][C:9]=2[C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)=[C:4]([Cl:28])[CH:3]=1
Reactant: CC1(C)CC(N)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Br)cc3Cl)nc2O1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)CC(NC(=O)C(C)(C)C)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Br)cc3Cl)nc2O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the 7-(4-bromo-2-chlorophenyl)-6-(4-chlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-amine (536.2 mg, 1.12 mmol) in 10 mL of CH2Cl2 at 0° C. was added pivaloyl chloride (166 μL, 1.34 mmol) and NEt3 (313 μL, 2.24 mmol). After stirring at rt for 1 h, the reaction mixture was concentrated. Chromatography on a Biotage 40+M cartridge using 1:3 v/v EtOAc/hexanes as the eluant afforded the product: 1H NMR δ 1.26 (s, 9H), 1.47 (s, 3H), 1.55 (s, 3H), 1.82 (t, J=12.3, 1H), 2.26 (dd, J=6.2, 13.3, 1H), 5.48 (m, 1H), 5.81 (br. s, 1H), 6.97 (d, J=8.5, 2H), 7.16-7.20 (m, 3H), 7.33-7.42 (m, 2H), 7.55 (s, 1H).
Reaction SMILES: [NH2:1]/[C:2](/[CH3:9])=[C:3](\[C:7]#[N:8])/[C:4](=[S:6])[NH2:5].OO>CO>[NH2:5][C:4]1[S:6][N:1]=[C:2]([CH3:9])[C:3]=1[C:7]#[N:8]
Reactant: C/C(N)=C(/C#N)C(N)=S
Agent: OO
Solvent: CO
Product: Cc1nsc(N)c1C#N
Temperature: 60 °C
Reaction time: 3 h
Yield: 97.3 %

Procedure:
To a stirred solution of (2E)-3-amino-2-cyanobut-2-enethioamide (method 3) (111 g, 0.78 mol) in methanol (2 L) was added dropwise 200 ml of 35% hydrogen peroxide over a period of 30 min. After the completion of the addition the mixture was stirred at 60° C. for 3 h after which the TLC showed the completion of the reaction. The reaction mixture was evaporated to 300 ml in a rotary evaporator and cooled in an ice-bath. The crystallized product was filtered off and washed with isopropyl alcohol (100 ml) and dried in vacuum at 50° C. overnight to provide 5-amino-3-methylisothiazole-4-carbonitrile (105.63 g, 96%) as a light yellow crystalline solid. 1H NMR (300 MHz, DMSO-d6) δ 2.24 (s, 3H), 8.00 (bs, 2H).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:22]=[CH:21][C:6]([O:7][CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:22]=[CH:21][C:6]([O:7][CH:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(F)(F)F)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1ccc(OC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.7 %

Procedure:
Tert-butyl 4-(4-trifluoromethylphenoxy)piperidine-1-carboxylate (1.13 g, 3.27 mmol) prepared in Reference Example 37 was dissolved in methylene chloride (10 ml). To which trifluoroacetic acid (10 ml) was added dropwise and the mixture was stirred at room temperature for 5 hours. After the reaction mixture was concentrated under reduced pressure, the residue was again dissolved in methylene chloride. The solution was neutralized with a sodium hydroxide aqueous solution, and the mixture was extracted with methylene chloride. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to afford 4-(4-trifluoromethylphenoxy)piperidine (727 mg, yield 91%) as a white powder.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([OH:22])=O)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[NH:26]1[CH2:29][CH:28]([C:30]#[N:31])[CH2:27]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:26]3[CH2:29][CH:28]([C:30]#[N:31])[CH2:27]3)=[O:22])[N:14]=2)[CH:4]=[C:3]([C:2]([F:24])([F:23])[F:1])[CH:8]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: N#CC1CNC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#CC1CN(C(=O)/C=C\n2cnc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C1
Temperature: -60 °C
Reaction time: 0.75 h
Yield: 59.2 %

Procedure:
(Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.2 g, 1.0 eq.) was dissolved in DCM (20 mL). The reaction mixture was cooled to −60° C. where azetidine-3-carbonitrile hydrochloride (0.08 g, 1.2 eq), T3P (50% in EtOAc) (0.4 mL, 1.2 eq) followed by DIPEA (0.2 mL, 2 eq) were added dropwise. The clear reaction mixture was stirred at −60° C. for 45 min. The reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product, which was purified by chromatography (3-5% Methanol in DCM). to obtain (Z)-1-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)azetidine-3-carbonitrile (0.14 g, 60% yield). 1H NMR (400 MHz, DMSO) δ=9.36 (s, 1H), 8.54 (s, 2H), 8.30 (s, 1H), 7.45-7.43 (d, J=10 Hz, 1H), 5.95-5.92 (d, J=10 Hz, 1H), 4.39-4.37 (t, 1H), 4.29-4.11 (m, 3H), 3.84-3.82 (m, 1H); LCMS calcd. for C17H12F6N5O [M+H]+ 416.29. found 416.14, at 2.64 min retention time
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([OH:11])=O)[CH:4]=1)[CH3:2].[NH2:12][C:13]1[NH:17][N:16]=[N:15][N:14]=1>>[NH:14]1[C:13]([NH:12][C:9]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[CH:8]=[CH:7][N:6]=2)=[O:11])=[N:17][N:16]=[N:15]1
Reactant: CCc1ccnc(C(=O)O)c1
Reactant: Nc1nnn[nH]1
Product: CCc1ccnc(C(=O)Nc2nnn[nH]2)c1
Yield: 24.1 %

Procedure:
0.46 g of 4-ethyl-2-pyridinecarboxylic acid, 0.5 g of N,N'-carbonyldiimidazole and 0.28 g of 5-aminotetrazole are treated in the same manner as described in Example 2. The crude product thus obtained is recrystallized from a mixture of dimethylformamide and water, whereby 0.16 g of N-(5-tetrazolyl)-4-ethyl-2-pyridinecarboxamide is obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:9][C:10]1[S:11][CH:12]=[C:13]([C:15]#[CH:16])[N:14]=1.C(N(CC)CC)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:16]#[C:15][C:13]2[N:14]=[C:10]([CH3:9])[S:11][CH:12]=2)=[CH:4][N:3]=1
Reactant: Clc1ncc(Br)cn1
Reactant: C#Cc1csc(C)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: Cc1nc(C#Cc2cnc(Cl)nc2)cs1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
2-Chloro-5-bromopyrimidine (5.0 g, 26 mmol), 2-methyl-4-ethynyl-1,3-thiazole (3.2 g, 26 mmol), tetrakis(triphenylphosphine)palladium(0) (0.6 g, 0.5 mmol), copper(I) iodide (0.1 g, 0.5 mmol) and triethylamine (13 g, 130 mmol) were added to deoxygenated toluene (50 mL) at room temperature. The reaction was then warmed to 60° C. Stirring continued for 2.5 hrs and the reaction contents were then poured in to a separatory funnel and partitioned with EtOAc (100 mL) and water (100 mL). The organic layer was then washed with water twice (250 mL each). The organic layer were dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was chromatographed on SiO2, eluting with 1:1 EtOAc:hexanes to afford 2-chloro-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyrimidine as a tan solid. 1H-NMR (CDCl3, 300 MHz) δ 8.78 (s, 2H), 7.52 (s, 1H), 2.78 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([C:16]([F:19])([F:18])[F:17])[CH:10]=2)[CH:5]=[C:4](Cl)[N:3]=1.O.[NH2:22][NH2:23]>O1CCOCC1.O>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([C:16]([F:19])([F:18])[F:17])[CH:10]=2)[CH:5]=[C:4]([NH:22][NH2:23])[N:3]=1
Reactant: Fc1ccc(Nc2cc(Cl)nc(Cl)n2)cc1C(F)(F)F
Reactant: NN
Solvent: C1COCCO1
Solvent: O
Product: NNc1cc(Nc2ccc(F)c(C(F)(F)F)c2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
To a stirred solution of (2,6-dichloropyrimidin-4-yl)-(4-fluoro-3-trifluoro-methylphenyl)amine (XXII) (2.5 g, 7.66 mmol) in dioxane (15 mL) was added hydrazine monohydrate (1 mL) and the mixture stirred at ambient temperature for 24 h. The mixture was diluted with water and the resulting slurry was stirred for 10 min then filtered under vacuum. The white precipitate was rinsed with water and dried under vacuum to give (2-chloro-6-hydrazinopyrimidin-4-yl)-(4-fluoro-3-trifluoromethylphenyl)amine (XXIV) as a white solid (2.1 g, 85% yield): m.p. 102-103° C., 1H NMR (CDCl3) δ 7.7 (m. 1H), 7.59 (m, 1H), 7.21 (m, 1H), 5.95 (s, 1H), 3.77 (s, 3H); ESI/MS 325 (M−H).