Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[F:25][C:26]1([F:38])[O:30][C:29]2[CH:31]=[CH:32][C:33](B(O)O)=[CH:34][C:28]=2[O:27]1.O1CCOCC1>CO.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[F:38][C:26]1([F:25])[O:27][C:28]2[CH:34]=[CH:33][C:32]([C:2]3[N:7]4[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]4[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]4[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=4)[CH:3]=3)=[CH:31][C:29]=2[O:30]1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Reactant: OB(O)c1ccc2c(c1)OC(F)(F)O2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(-c3ccc4c(c3)OC(F)(F)O4)n2n1
Temperature: 110 °C
Yield: 38.7 %

Procedure:
A suspension of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 60 mg, 0.174 mmol), 2,2-difluorobenzo[d][1,3]dioxol-5-ylboronic acid (46 mg, 0.226 mmol), and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10 mg, 13.6 mmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (0.58 mL of 1,4-dioxane and 0.29 mL of saturated aqueous NaHCO3) was prepared in a 10 mL microwave reaction vessel and the sealed reaction vessel warmed to 110° C. for 10 minutes in a CEM microwave reactor. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC (60-75% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (31.4 mg, 39%). 1H NMR (DMSO-d6) δ: 11.21 (s, 1H), 8.62 (d, J=1.3 Hz, 1H), 8.26 (d, J=8.6 Hz, 1H), 8.05 (s, 1H), 7.99-8.04 (m, 3H), 7.93 (d, J=5.3 Hz, 1H), 7.67 (d, J=5.6 Hz, 1H), 7.61 (d, J=8.6 Hz, 2H), 6.41 (s, 1H), 5.20 (s, 1H), 2.41 (s, 3H), 1.46 (s, 6H); ESI-MS: m/z 467.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:13][C:5]2[CH2:6][N:7]([CH3:12])[CH2:8][CH2:9][CH:10]([OH:11])[C:4]=2[CH:3]=1.F[C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1>>[CH3:1][C:2]1[O:13][C:5]2[CH2:6][N:7]([CH3:12])[CH2:8][CH2:9][CH:10]([O:11][C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=3)[C:4]=2[CH:3]=1
Reactant: Cc1cc2c(o1)CN(C)CCC2O
Reactant: Fc1ccc2ccccc2c1
Product: Cc1cc2c(o1)CN(C)CCC2Oc1ccc2ccccc2c1

Procedure:
The same method as in Example 1 was conducted using 2,7-dimethyl-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepin-4-ol (Reference Example 20) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2-fluoronaphthalene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[CH:10]=[N:11][CH:12]=[N:13][CH:14]=2)=[CH:4][C:3]=1[C:15]12[CH2:24][CH2:23][O:22][CH2:21][CH:20]1[CH2:19][S:18][C:17]([NH:25]C(=O)OC(C)(C)C)=[N:16]2.C(O)(C(F)(F)F)=O.C(Cl)[Cl:41]>O.[OH-].[Na+]>[ClH:41].[ClH:41].[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[CH:10]=[N:11][CH:12]=[N:13][CH:14]=2)=[CH:4][C:3]=1[C@:15]12[CH2:24][CH2:23][O:22][CH2:21][CH:20]1[CH2:19][S:18][C:17]([NH2:25])=[N:16]2
Reactant: CC(C)(C)OC(=O)NC1=NC2(c3cc(-c4cncnc4)c(F)cc3F)CCOCC2CS1
Reactant: ClCCl
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cl
Product: NC1=N[C@@]2(c3cc(-c4cncnc4)c(F)cc3F)CCOCC2CS1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 8a-(2,4-difluoro-5-(pyrimidin-5-yl)phenyl)-4,4a,5,7,8,8a-hexahydropyrano[4,3-d][1,3]thiazin-2-ylcarbamate (0.258 g, 0.558 mmol) in CH2Cl2 (8 mL) is added TFA (4 mL) and the reaction is stirred at room temperature for 1 hour. The solvent is removed under reduced pressure to afford a residue that is diluted with water and 1 N NaOH to adjust the pH to 12. The aqueous layer is extracted three times with EtOAc. The organic layer is dried over Na2SO4 and the crude product is purified by silica gel chromatography eluting with a linear gradient of 1% to 10% 7 N NH3/MeOH in CH2Cl2 to afford the title compound as the freebase (0.165 g, 68%). The freebase (0.162 g, 0.448 mmol) is dissolved in CH2Cl2 and treated with of 1 M HCl in Et2O (0.94 mL, 0.940 mmol) and the solvent is removed under reduced pressure to afford the title compound (0.208 g, 86%). ES/MS m/e: 363 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:10][C:9]([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2Cl)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[NH:22]1[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.N12CCCN=C1CCCCC2.C(OCC)(=O)C>N1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[O:10][C:9]([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[N:22]2[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: C1CNCCNC1
Reactant: CCOC(=O)c1ccc(Cn2c(Cl)nc3ccccc32)o1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1ccc(Cn2c(N3CCCNCC3)nc3ccccc32)o1
Reaction time: 48 h

Procedure:
Combine 1-(5-(ethoxycarbonyl)fur-2-ylmethyl)-2-chloro-1H-benzimidazole (10 mmol), [1,4]diazepane (10 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.8 mL) in pyridine (20 mL). Heat to reflux. After 2 days, evaporate in vacuo to give a residue. Combine the residue and ethyl acetate. Extract with water and brine. Dry the the organic layer over Na2SO4, filter, and evaporate in vacuo to give 4-(1-(5-(ethoxycarbonyl)fur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepane.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16](C)[NH:15][N:14]=2)[N:3]=1.[CH2:19]([O:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1)[CH2:20][CH2:21][CH3:22]>>[CH2:19]([O:23][C:24]1[CH:25]=[CH:26][C:27]([NH:30][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[CH:16][NH:15][N:14]=3)[N:3]=2)=[CH:28][CH:29]=1)[CH2:20][CH2:21][CH3:22]
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: CCCCOc1ccc(N)cc1
Product: CCCCOc1ccc(Nc2nc(Nc3cc[nH]n3)cc3ccccc23)cc1

Procedure:
Similar procedure as described in example 273 was used, starting (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 4-butoxy-phenylamine to give N1-(4-butoxy-phenyl)-N3-(1H-pyrazol-3-yl)-isoquinoline-1,3-diamine. LC-MS m/e 374(MH+).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[C:18]([F:21])([F:20])[F:19])[C:4]([CH3:10])=[CH:5][C:6]=1[C:7](Cl)=[O:8].[S:22]([NH2:32])(=[O:31])([C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1)=[O:23].C(N(C(C)C)CC)(C)C>C1COCC1>[S:22]([C:24]1[CH:25]=[CH:26][C:27]([NH:30][C:7]([C:6]2[CH:5]=[C:4]([CH3:10])[N:3]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=3[C:18]([F:21])([F:20])[F:19])[C:2]=2[CH3:1])=[O:8])=[CH:28][CH:29]=1)(=[O:23])(=[O:31])[NH2:32]
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: Cc1cc(C(=O)Cl)c(C)n1-c1ccc(F)cc1C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2ccc(S(N)(=O)=O)cc2)c(C)n1-c1ccc(F)cc1C(F)(F)F
Temperature: 80 °C
Yield: 65.5 %

Procedure:
Into an oven-dried 1 dram vial was added 2,5-dimethyl-1-[4-fluoro-2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylic acid chloride (106 mg, 332 μmol), sulfanilamide (62.0 mg, 360 μmol), anhyd THF (2.0 mL) and diisopropylethylamine (50 μL). The vial was sealed and heated at 80° C. overnight. The resulting residue was purified by flash chromatography (SiO2), eluting with EtOAc/Hex (30:70 to 60:40) to afford the title compound as an off-white solid (99 mg, 66%); 1H NMR (CDCl3): δ 8.85 (s, 1H), 7.88 (d, J=7 Hz, 2H), 7.84 (d, J=7 Hz, 2H), 7.58 (dd, J=8, 3 Hz, 1H), 7.46 (m, 1H), 7.31 (dd, J=5, 8 Hz, 1H), 6.46 (s, 1H), 6.19 (s, 2H), 2.25 (s, 3H), 1.94 (s, 3H); MS (ESI) m/z 456 [M+H]+. D. In a manner similar to that described in Examples 1A-1C, but replacing 4-fluoro-2-(trifluoromethyl)aniline with 2-(trifluoromethyl)aniline, the following compound was prepared:
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([CH3:8])[CH2:5][CH2:4][C:3]1([C:12](=[O:16])[CH2:13][CH:14]=[CH2:15])[C:9]([CH3:11])=[CH2:10].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][CH:2]1[CH:7]=[C:6]([CH3:8])[CH2:5][CH2:4][C:3]1([C:12](=[O:16])[CH:13]=[CH:14][CH3:15])[C:9]([CH3:11])=[CH2:10]
Reactant: C=CCC(=O)C1(C(=C)C)CCC(C)=CC1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C1(C(=O)C=CC)CCC(C)=CC1C
Yield: 80 %

Procedure:
A solution of 1-(2,4-dimethyl-1-(prop-1-en-2-yl)cyclohex-3-enyl)but-3-en-1-one (2.5 g, 11.5 mmol) and triethylamine (2 g) in CH2Cl2 was stirred at room temperature over night. The solvent and excess of triethylamine were evaporated and the residue distilled bulb-to-bulb to yield the title compound (80%) as a slightly yellow oil.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[C:5]([C:16]2[C:21]([F:22])=[CH:20][C:19]([F:23])=[CH:18][C:17]=2[F:24])=[N:4][CH:3]=1.[CH2:25](B(O)O)[CH3:26].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>O.C(OCC)(=O)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>[CH2:25]([C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[C:5]([C:16]2[C:21]([F:22])=[CH:20][C:19]([F:23])=[CH:18][C:17]=2[F:24])=[N:4][CH:3]=1)[CH3:26]
Reactant: COC(=O)c1ccc2c(Br)cnc(-c3c(F)cc(F)cc3F)c2c1
Reactant: CCB(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1cnc(-c2c(F)cc(F)cc2F)c2cc(C(=O)OC)ccc12
Temperature: 100 °C
Reaction time: 24 h
Yield: 54.3 %

Procedure:
Under argon gas atmosphere, a mixture of methyl 4-bromo-1-(2,4,6-trifluorophenyl)isoquinoline-7-carboxylate (150 mg), ethylboronic acid (84 mg), tetrakis(triphenylphosphine)palladium (44 mg), tripotassium phosphate (241 mg), toluene (5 mL), and water (0.3 mL) was heated under stirring in an oil bath at 100° C. for one day. The reaction mixture was returned to room temperature, and diluted with water and ethyl acetate, and then the insoluble matter was separated by filtration. The filtrate was extracted with ethyl acetate, and the organic layer was concentrated under reduced pressure. The resulting residue was purified under silica gel column chromatography (hexane/ethyl acetate) to obtain methyl 4-ethyl-1-(2,4,6-trifluorophenyl)isoquinoline-7-carboxylate (71 mg).
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:20]1(=[O:27])[O:26][C:24](=[O:25])[CH2:23][CH2:22][CH2:21]1.[CH3:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].CS(O)(=O)=O>O>[C:24]([O:26][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:1]/[CH:2]=[CH:3]\[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])(=[O:25])[CH2:23][CH2:22][CH2:21][C:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:27]
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Reactant: O=C1CCCC(=O)O1
Reactant: CCCCCCC
Agent: CS(=O)(=O)O
Solvent: O
Product: CCCCCCCC/C=C\CCCCCCCCOC(=O)CCCC(=O)OCCCCCCCC/C=C\CCCCCCCC
Temperature: 25 °C

Procedure:
Dioleyl glutarate was synthesized by refluxing 421.2 grams (1.57 moles) oleyl alcohol, 85.6 grams (0.75 mole) glutaric anhydride, 204 grams (300 ml) heptane and 0.96 grams (0.01 mole) methane sulfonic acid under a nitrogen atmosphere for 5 hours in a 3-liter, 3-necked flask equipped with an air driven stirrer, thermometer, reflux condenser and heating mantle. Water produced in the reaction was removed in a Dean-Stark trap. The product solution was allowed to cool to 25° C. overnight with agitation and under a nitrogen atmosphere. Next, the product solution was diluted with 300 ml of hexane, washed with 2% aqueous sodium hydroxide and dried over molecular sieves. Most of the hydrocarbon solvent was removed by rotary evaporation using a water aspirator vacuum source. High vacuum stripping at a pressure of from 1.5 mm.Hg. to 2.0 mm.Hg. and a temperature of from 240° C. to 260° C. for 4 hours removed the last traces of solvent. Analysis indicates that the dioleyl glutarate produced contained 3.8% oleyl alcohol.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:18]=[C:17]([C:19]([NH:21][C@@H:22]([CH3:27])[C:23]([O:25][CH3:26])=[O:24])=[O:20])[CH:16]=C(C=C)[N:14]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.CC[C@H]1[C@H]2C[C@H]([C@H](OC3C4C(=CC=CC=4)C(O[C@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:53]C)C=C4)N(CC2)C1.[CH3:90][CH:91]([OH:93])[CH3:92]>O>[OH:93][C@@H:91]([C:92]1[N:14]=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([O:6][C:5]3[CH:30]=[CH:31][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:8][CH:9]=2)[N:18]=[C:17]([C:19]([NH:21][C@@H:22]([CH3:27])[C:23]([O:25][CH3:26])=[O:24])=[O:20])[CH:16]=1)[CH2:90][OH:53]
Reactant: CC[C@@H]1CN2CC[C@@H]1C[C@@H]2[C@H](Oc1nnc(O[C@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Reactant: C=Cc1cc(C(=O)N[C@@H](C)C(=O)OC)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Reactant: CC(C)O
Solvent: O
Product: COC(=O)[C@H](C)NC(=O)c1cc([C@H](O)CO)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Reaction time: 2.5 h
Yield: 54 %

Procedure:
To a warmed milky suspension of (S)-methyl 2-(2-(4-(4-fluorophenoxy)phenyl)-6-vinylpyrimidine-4-carboxamido)propanoate (0,407 g, 0.966 mmol) in iPrOH (5 mL) and water (5 mL) was added AD-Mix-α (1.328 g). After stirring 2.5 hours the reaction mixture was partitioned between 25 mL water and 50 mL EtOAc. The organic layers were isolated and the aqueous layer extracted once more with 25 mL EtOAc. The combined organic layers were dried over Na2SO4, filtered, and evaporated in vacuo. The residue was chromatographed over silica gel using 50-100% EtOAc in hexanes. The product fractions were evaporated in vacuo to give (S)-methyl 2-(6-((S)-1,2-dihydroxyethyl)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxamido)propanoate (Compound Example No. 14) as a cream-colored solid (0.236 g, 0.518 mmol, 54% yield). 1H NMR (400 MHz, DMSO-d6): 9.39 (1 H, d, J=7.9 Hz), 8.64 (2 H, d, J=9.0 Hz), 8.00 (1 H, s), 7.33-7.25 (2 H, m), 7.22-7.16 (2 H, m), 7.13 (2 H, d, J=9.0 Hz), 5.82 (1 H, d, J=5.3 Hz), 4.83 (1 H, t, J=6.1 Hz), 4.72-4.60 (2 H, m), 3.85-3.77 (1 H, m), 3.72-3.63 (4 H, m), 1.49 (3 H, d, J=7.2 Hz); LC/MS: m/z=456.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:13](Cl)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[CH:29]1[CH2:31][CH2:30]1)CCC>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:13]([CH:29]3[CH2:31][CH2:30]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(N3CCOCC3)cc2C1
Reactant: CCCC[Sn](CCCC)(CCCC)C1CC1
Product: CC(C)(C)OC(=O)N1Cc2cc(C3CC3)c(N3CCOCC3)cc2C1

Procedure:
Prepared in analogy to Example A54(a) from 5-chloro-6-morpholin-4-yl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A44(a)) and tributylcyclopropylstannane. Yellow solid. MS (m/e): 345.4 ([M+H]+, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:19][S:20]([NH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)Cc1cccc(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)Cc1cccc(NS(C)(=O)=O)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Methyl 3-aminophenylacetate (2.26 g, 13.7 mmol) was dissolved in dry methylene chloride (20 mL) and cooled to 0° C. Pyridine (2.2 mL, 27.2 mmol) was added followed by dropwise addition of methanesulfonyl chloride (1.3 mL, 16.8 mmol). The mixture was stirred at 0° C. for 1 hour and at room temperature for 3 hours, then poured into 100 mL of saturated sodium bicarbonate solution. The organic layer was washed with saturated sodium bicarbonate (100 mL), 1N HCl (2×100 mL) and brine. Dried over MgSO4. Solvent was evaporated to reveal methyl 3-(methanesulfonyl)phenylacetate. (3.36 g, 100%). 1H NMR (500 MHz, CDCl3) δ 7.32 (1H, dd), 7.2–7.1 (3H, m), 6.57 (1H, s), 3.72 (3H, s), 3.64 (2H, s), 3.02 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[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][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[C:29](Cl)(Cl)=[O:30].C(N(CC)CC)C.[CH3:40][O:41][C:42](=[O:51])[C:43]1[CH:48]=[CH:47][C:46]([CH2:49][NH2:50])=[CH:45][CH:44]=1>C(Cl)Cl>[CH3:40][O:41][C:42](=[O:51])[C:43]1[CH:48]=[CH:47][C:46]([CH2:49][NH:50][C:29]([N:9]2[CH2:10][C@@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[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:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:28])=[O:30])=[CH:45][CH:44]=1
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: COC(=O)c1ccc(CN)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CNC(=O)N2C[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1
Yield: 58.6 %

Procedure:
In a manner similar to the method described in Example 4, rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (126.9 mg, 0.30 mmol) was reacted with phosgene solution (Aldrich, 20% in toluene, 0.45 mL, 0.45 mmol), in the presence of triethylamine (TEA, 272.7 mg, 2.7 mmol) in CH2Cl2 (10 mL) followed by reacting with 4-aminomethyl-benzoic acid methyl ester (90.7 mg, 0.45 mmol) at rt for 30 min 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]amino}-methyl)-benzoic acid methyl ester (108.0 mg, 59.9%) as a white amorphous which was used in the next step without further purification.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O-]CC.[Na+].[C:23](#[N:26])[CH:24]=[CH2:25]>O1CCOCC1>[C:23]([CH2:24][CH2:25][C:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])#[N:26]
Reactant: C=CC#N
Reactant: CCOC(=O)C(c1ccccc1)c1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)C(CCC#N)(c1ccccc1)c1ccccc1
Temperature: 45 °C

Procedure:
The product of Example 68A (5.58 g) was dissolved in anhydrous dioxane (15 mL). Sodium ethoxide (1.58 g) was added and the mixture was heated to 40-50° C. for 30 minutes. Acrylonitrile (1.44 mL) was added dropwise with stirring. The mixture was heated at 60-70° C. for one hour. The dioxane was removed in vacuo, and the residue was taken up in diethyl ether, washed with water and brine, dried with magnesium sulfate, filtered, and concentrated. The crude material was purified by silica gel chromatography (3-10% ethyl acetate/hexane) to obtain the title compound. MS (DCI+) m/z 311 (M+NH4)+.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH2:5]([N:12]1[CH2:17][CH2:16][CH:15]([NH:18][CH2:19][CH2:20][NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1(C)C=CC=CC=1.[OH-].[K+]>[CH2:5]([N:12]1[CH2:13][CH2:14][CH:15]([N:18]2[CH2:19][CH2:20][N:21]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:1]2=[O:2])[CH2:16][CH2:17]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(Cl)Cl
Reactant: c1ccc(CN2CCC(NCCNc3ccccc3)CC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=C1N(c2ccccc2)CCN1C1CCN(Cc2ccccc2)CC1
Yield: 66.4 %

Procedure:
With stirring, 15 g of phosgene are introduced at 5° to 10° C in the course of 1 hour into a suspension of 10 g of 1-benzyl-4-(2-phenylamino-1-ethylamino)-piperidine in 100 ml of toluene and 48.5 ml of 3N potassium hydroxide solution. After stirring for 2 hours at 5° to 10° C, the reaction mixture is made alkaline with 43 ml of 6N potassium hydroxide solution and brought to room temperature. After it has been stirred for a further 15 hours at room temperature, the reaction mixture is filtered with suction and the residue is recrystallised from isopropanol-methanol to yield 7.2 g of 1-(1-benzyl-4-piperidinyl)-3-phenyl-2-imidazolidinone.
Reaction SMILES: [Na].C[O-].[CH3:4][C:5]1[N:10]=[CH:9][C:8]([CH2:11][C:12]#[N:13])=[CH:7][CH:6]=1.[CH3:14][C:15]1[CH:16]=[CH:17][C:18]([N+:23]([O-:25])=[O:24])=[C:19]([CH:22]=1)[CH:20]=O>CO.O>[CH3:14][C:15]1[CH:16]=[CH:17][C:18]([N+:23]([O-:25])=[O:24])=[C:19](/[CH:20]=[C:11](\[C:8]2[CH:9]=[N:10][C:5]([CH3:4])=[CH:6][CH:7]=2)/[C:12]#[N:13])[CH:22]=1
Reactant: Cc1ccc([N+](=O)[O-])c(C=O)c1
Reactant: Cc1ccc(CC#N)cn1
Agent: C[O-]
Agent: [Na]
Solvent: CO
Solvent: O
Product: Cc1ccc([N+](=O)[O-])c(/C=C(/C#N)c2ccc(C)nc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
Sodium metal (1.9 g, 0.0848 mol) was dissolved in MeOH (180 mL), and the resulting methoxide solution was cooled to 0° C. To this was added 2-(6-methylpyridin-3-yl)acetonitrile (11.19 g, 0.0848 mol), and the reaction mixture was stirred for 30 min. at 0° C. 5-Methyl-2-nitrobenzaldehyde (7.0 g, 0.0424 mol) was added at 0° C., and the mixture was further stirred for 1 h at 0° C. After completion of reaction (monitored by TLC), the mixture was diluted with water (100 mL), and extracted with EtOAc (3×150 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by column chromatography (20% EtOAc:hexane in silica 100-200 mesh, diameter of column—5.0 cm, height of silica—approx. 5 inch) to give the desired compound as a yellow colored solid (6.5 g, 59% yield).
Reaction SMILES: C1COCC1.C[Si](C)(C)[C:8]([F:11])([F:10])[F:9].[O:14]1[CH2:19][CH2:18][CH2:17][C:16](=[O:20])[CH2:15]1.Cl>O.CCOC(C)=O>[F:9][C:8]([F:11])([F:10])[C:16]1([OH:20])[CH2:17][CH2:18][CH2:19][O:14][CH2:15]1
Reactant: O=C1CCCOC1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: OC1(C(F)(F)F)CCCOC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 47.1 %

Procedure:
To a round-bottom flask equipped with a stir bar and placed under N2 atmosphere was added THF (50 mL), then trimethyl(trifluoromethyl)silane (1.03 mL, 6.99 mmol). The solution was cooled to 0° C. and to the solution was added dihydro-2H-pyran-3(4H)-one (500 mg, 4.99 mmol). The solution was stirred for 5 minutes at 0° C. and then was allowed to warm to room temperature with stirring for 30 minutes. The solution was cooled to 0° C. and to the solution was added aq 1M HCl (50 mL). The mixture was stirred at room temperature overnight. The mixture was diluted with water and EtOAc and was transferred to a separatory funnel. The organic phase was isolated; washed with brine; dried over MgSO4, filtered; then concentrated in vacuo to afford 3-(trifluoromethyl)tetrahydro-2H-pyran-3-ol as a colorless oil (0.40 g, 47%). 1H-NMR (400 MHz, CDCl3) δ 4.01-3.93 (m, 1H), 3.82 (dd, J=11.8, 2.5 Hz, 1H), 3.60 (d, J=12.0 Hz, 1H), 3.41 (td, J=11.8, 2.5 Hz, 1H), 2.10-2.08 (m, 2H), 1.97-1.90 (m, 1H), 1.82 (dd, J=12.9, 4.4 Hz, 1H), 1.65-1.55 (m, 1H).