Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:11][CH2:12][C:13]([OH:15])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].S(Cl)(Cl)=O.[NH2:20][C:21]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][C:22]=1[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[F:31])=[O:24]>O1CCCC1>[CH2:4]([O:3][C:1](=[O:2])[NH:11][CH2:12][C:13](=[O:15])[NH:20][C:21]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][C:22]=1[C:23](=[O:24])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[F:31])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1F
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: O=C(CNC(=O)OCc1ccccc1)Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1F
Reaction time: 1 h

Procedure:
45 g of carbobenzoxy-glycine dissolved in 1 liter of absolute tetrahydrofuran are treated dropwise while cooling with ice with 20 ml of thionyl chloride and stirred for 1 hour while cooling with ice. There is then rapidly added dropwise thereto a suspension of 50 g of 2-amino-5-nitro-2'-fluorobenzophenone in 200 ml of absolute tetrahydrofuran and the mixture is stirred at room temperature for 18 hours. The solution obtained is concentrated and the residue is treated with ice and 10% sodium bicarbonate solution and extracted with methylene chloride. The organic solution is dried over sodium sulphate, filtered and concentrated. The residue is dissolved in a small amount of hot ethyl acetate, concentrated partially and treated with ether. Benzyl{[[2-(o-fluorobenzoyl)-4-nitrophenyl]carbamoyl]methyl}-carbamate is obtained. The mother liquors are purified on a 100 g silica gel column using methylene chloride as the eluting agent, an additional amount of the aforementioned product being obtained.
Reaction SMILES: [C:1]1(=[C:8]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:30][C:31]#[N:32]>CC(C)=O>[C:1]1(=[C:8]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:30][C:31]#[N:32])=[CH:18][CH:17]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: N#CCBr
Reactant: Oc1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#CCOc1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1
Yield: 13.1 %

Procedure:
The O-alkylation procedure described for 190 was followed. To stirred mixture of 4,4′-(cycloheptylidenemethanediyl)diphenol (189) (1.18 g, 4 mmol), K2CO3 (0.691 g, 5 mmol) and acetone (50 mL) was added bromoacetonitrile (0.418 mL, 6.0 mmol). The reaction mixture was refluxed for 3.5 h. Standard work-up and purification by silica gel chromatography afforded 0.175 g (13%) of compound 216 as a white solid and 0.700 g (47%) of the bis-alkylated material 2,2′-[(cycloheptylidenemethanediyl) bis(benzene-4,1-diyloxy)]diacetonitrile as a white solid. IR (film): 3413, 2921, 1605, 1504, 1210, 1170, 828, 729 cm−1. 1H NMR (300 MHz, CDCl3): δ 7.14 (d, J=8.4 Hz, 2H), 7.02 (d, J=8.4 Hz, 2H), 6.91 (d, J=8.4 Hz, 2H), 6.76 (d, J=8.1 Hz, 2H), 5.0 (br, 1H), 4.74 (s, 2H), 2.33 (br s, 4H), 1.60 (s, 8H). LCMS (ESI): m/z 332 (M−H)−. Anal. Calcd for C22H23NO2, C, 79.25; H, 6.95; N, 4.20. Found: C, 79.14, H, 6.90; N, 4.21.
Reaction SMILES: C[O:2]/[CH:3]=[CH:4]/[CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:6]1.C1COCC1>CO>[O:2]=[CH:3][CH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:6]1
Reactant: CO/C=C/C1Cc2ccccc2N(C(=O)OC(C)(C)C)C1
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(CC=O)Cc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
To a solution of (E)-tert-butyl 3-(2-methoxyvinyl)-3,4-dihydroquinoline-1(2H)-carboxylate (225 mg, 0.778 mmol) in THF (5 mL) dilute HCl (0.2 ml, 6.58 mmol) was added. The reaction mixture was stirred overnight at RT. The progress of reaction was monitored by TLC. After completion of reaction methanol was evaporated under reduced pressure. Further it was purified by flash column chromatography (15% ethyl acetate in hexane) to get the title compound (160 mg, 30.4% yield); m/z-297.6 as Na+1.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[CH3:27]C([N-]C(C)C)C.CI>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:10][C:9]1([CH3:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C1(C)CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To ethyl 1,4-dibenzylpiperazine-2-carboxylate (35.4 g, 0.1 mol) in THF(200 mL) cooled to −78° C. was added dropwise LDA (64 mL, 1.8 M). The reaction was stirred at −78° C. for 1 h then MeI (7.2 mL, 0.11 mol) was added. The reaction was allowed to slowly warm to RT then quenched with sat'd NH4Cl. Water (200 mL) was added and the residue was extracted with EtOAc (200 mL). The EtOAc layer was washed twice with water then the solvent was removed in vacuo. Silica gel chromatography provided ethyl 1,4-dibenzyl-2-methylpiperazine-2-carboxylate (compound 10A) 14.91 g. HPLC RT: 2.42 min (Chromolith SpeedROD 4.6×50 mm, 10-90% aqueous MeOH over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm). (M+H)+:353.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([CH:18]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]2)=[O:17])[CH:10]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([CH:18]2[CH2:23][CH2:22][CH2:21][N:20]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:19]2)=[O:17])[CH:10]=1
Reactant: COc1ccccc1-c1cc(NC(=O)C2CCCNC2)ncn1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1-c1cc(NC(=O)C2CCCN(S(C)(=O)=O)C2)ncn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 65.5 %

Procedure:
Piperidine-3-carboxylic acid [6-(2-methoxy-phenyl)-pyrimidin-4-yl]-amide (compound #16A) (110 mg, 0.352 mmol) was dissolved in 5 mL of anhydrous dichloromethane, cooled to 0° C. and triethyl amine (13.0 g, 15.5 mmol) and methane sulfonyl chloride (60 mg, 0.53 mmol) were added simultaneously. The mixture was stirred for two hours at room temperature, treated with crushed ice and partitioned with between water and dichloromethane. The organic layer was separated, dried over sodium sulfate and concentrated to provide 1-methanesulfonyl-piperidine-3-carboxylic acid [6-(2-methoxy-phenyl)-pyrimidin-4-yl]-amide (compound #21A) (90 mg, 80.3%).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:29](O)=[O:30])[CH2:20][O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[NH2:57][CH2:58][CH2:59][CH2:60][CH2:61][N:62]([CH2:75][C:76]1[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=1)[CH2:63][CH2:64][C@H:65]([NH:67][C:68](=[O:74])[O:69][C:70]([CH3:73])([CH3:72])[CH3:71])[CH3:66]>ClCCl.C(OCC)(=O)C>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:20][O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:29](=[O:30])[NH:57][CH2:58][CH2:59][CH2:60][CH2:61][N:62]([CH2:75][C:76]3[CH:77]=[CH:78][CH:79]=[CH:80][CH:81]=3)[CH2:63][CH2:64][C@@H:65]([CH3:66])[NH:67][C:68]([O:69][C:70]([CH3:73])([CH3:71])[CH3:72])=[O:74])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](CCN(CCCCN)Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: O=C(N[C@@H](COCc1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@H](CCN(CCCCNC(=O)[C@H](COCc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21)Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
1.71 g (4.1.10-3 mol) of N-[(9H-fluoren-9-yl)methoxycarbonyl]-O-phenylmethyl-(L)-serine are dissolved in 60 ml of dichloromethane. The solution is cooled to 0° C. and a solution of 0.55 g (4.10-3 mol) of HOBT and 1.54 g (7.5.10-3 mol) of DCC in 20 ml of dichloromethane is added. The mixture is stirred for 0.5 hour, 1.30 g (3.72.10-3 mol) of N-[3-[(4-aminobutyl)(phenylmethyl)amino]-1-(R)-methylpropyl]carbamic acid, 1, 1-dimethylethyl ester are then added and the reaction mixture is stirred at room temperature for 16 hours. The solvent is removed under reduced pressure and the residue is purified by chromatography on silica gel using an ethyl acetate/methylcyclohexane mixture (1/1 v/v) and then pure ethyl acetate as the eluent to give 2.7 g of the expected product in the form of a white crystalline solid (yield=96%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]2[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)[CH3:3].[C:18]1([CH:24]=[CH:25][CH2:26][C:27](Cl)=[O:28])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>>[C:18]1([CH:24]=[CH:25][CH2:26][C:27]([O:17][C@H:14]2[CH2:15][CH2:16][C@@H:11]([C:8]3[CH:9]=[CH:10][C:5]([CH2:4][N:2]([CH3:1])[CH3:3])=[CH:6][CH:7]=3)[CH2:12][CH2:13]2)=[O:28])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)CC=Cc1ccccc1
Reactant: CN(C)Cc1ccc([C@H]2CC[C@@H](O)CC2)cc1
Solvent: CCN(CC)CC
Product: CN(C)Cc1ccc([C@H]2CC[C@@H](OC(=O)CC=Cc3ccccc3)CC2)cc1

Procedure:
from cis-4-(4-dimethylaminomethylphenyl)-cyclohexanol and 4-phenyl-3-butenoic acid chloride/triethylamine. White crystals.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH2:6][NH:7][C:8](=[O:14])OC(C)(C)C.C([O:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([CH2:37][N:38]2[C:46]3[C:41](=[CH:42][C:43](C(O)=O)=[CH:44][CH:45]=3)[C:40]([CH3:50])=[C:39]2[CH3:51])=[CH:33][CH:32]=1)=[O:24])(C)(C)C>>[NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH2:6][NH:7][C:8]([C:43]1[CH:42]=[C:41]2[C:46](=[CH:45][CH:44]=1)[N:38]([CH2:37][C:34]1[CH:33]=[CH:32][C:31]([C:26]3[C:25]([C:23]([OH:24])=[O:22])=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:36][CH:35]=1)[C:39]([CH3:51])=[C:40]2[CH3:50])=[O:14]
Reactant: CC(C)(C)OC(=O)NCc1cccc(CN)c1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NCc3cccc(CN)c3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using tert-butyl 3-(aminomethyl)benzylcarbamate and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. LC-MS 518 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](Cl)[C:7]=1[CH2:8][S:9][C:10]1[N:15]=[C:14]([OH:16])[CH:13]=[C:12]([C:17]([F:20])([F:19])[F:18])[N:11]=1.[CH3:22][O-:23].[Na+].O.Cl>CS(C)=O>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:23][CH3:22])[C:7]=1[CH2:8][S:9][C:10]1[N:15]=[C:14]([OH:16])[CH:13]=[C:12]([C:17]([F:20])([F:19])[F:18])[N:11]=1
Reactant: Oc1cc(C(F)(F)F)nc(SCc2c(Cl)cncc2Cl)n1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cncc(Cl)c1CSc1nc(O)cc(C(F)(F)F)n1
Yield: 93 %

Procedure:
A mixture of 2-{[(3,5-dichloropyridin-4-yl)methyl]sulfanyl}-6-(trifluoromethyl)-pyrimidin-4-ol (see, e.g., Example 120; 1.0 g, 2.8 mmol) and a sodium methoxide solution (25% wt., 2.6 mL) in dimethyl sulfoxide (10 mL) was stirred at 70° C. overnight. Water (100 mL) was added, and the pH of the mixture was adjusted to around 6 with 2N HCl. The mixture was extracted with EtOAc (3×75 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo to afford 2-{[(3-chloro-5-methoxypyridin-4-yl)methyl]sulfanyl}-6-(trifluoromethyl)pyrimidin-4-ol (912 mg. 93%); 1H NMR (500 MHz, DMSO-d6): δ 3.97 (s, 3H), 4.59 (s, 2H), 6.68 (s (br), 1H), 8.32 (s, 1H), 8.39 (s, 1H); M+352.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)(=O)=O)[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]([C:12]#[N:13])=[C:6]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[N:7]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccccc2)c1C#N
Reactant: C1CCNCC1
Solvent: COCCOC
Product: N#Cc1c(-c2ccccc2)nc(N)nc1N1CCCCC1

Procedure:
From 2-amino-4-methanesulfonyl-6-phenyl-pyrimidine-5-carbonitrile and piperidine in DME. EI-MS m/e (%): 279 (M+, 32), 278 ([M—H]+, 100).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][C:8]2=[O:9])[CH2:3][CH2:2]1.[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>ClCCl>[NH:24]([C:25]([N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][C:8]2=[O:9])[CH2:3][CH2:2]1)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1CCc2ccccc2N1C1CCNCC1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: O=C(Nc1ccccc1)N1CCC(N2C(=O)CCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-(4-Piperidinyl)-3,4-dihydrocarbostyril (0.8 g) is dissolved in dichloromethane (20 ml) and thereto is added phenylisocyanate (0.57 ml) and the mixture is stirred at room temperature for 4 hours. The solvent is concentrated and the residue is purified by silica gel column chromatography (solvent; n-hexane:ethyl acetate=5:1) and recrystallized from n-hexane/ethanol to give 1-(1-anilinocarbonyl-4-piperidinyl)-3,4-dihydrocarbostyril (0.8 g), as white powder, m.p. 194°-196° C.
Reaction SMILES: [OH:1][C:2]([CH3:11])([CH3:10])[CH2:3][CH2:4][CH2:5][C@H:6]([CH3:9])[CH:7]=[O:8].N1C(C)=CC=CC=1C.[Si:20](OS(C(F)(F)F)(=O)=O)([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22]>C(Cl)Cl>[CH3:9][C@@H:6]([CH2:5][CH2:4][CH2:3][C:2]([CH3:10])([O:1][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:11])[CH:7]=[O:8]
Reactant: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Reactant: C[C@H](C=O)CCCC(C)(C)O
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC[Si](CC)(CC)OC(C)(C)CCC[C@H](C)C=O
Temperature: 10 °C
Reaction time: 3 h
Yield: 79.5 %

Procedure:
To a solution of aldehyde 9 (93.4 mg, 0.6 mmol) and 2,6-lutidine (170 μL, 1.5 mmol) in anhydrous CH2Cl2 (3.7 mL) was added dropwise Et3SiOTf (161 μL, 0.72 mmol) at 0° C. under argon. The solution was stirred at 10° C. for 3 hours and then at room temperature for 30 minutes. The mixture was quenched with cold water and extracted with CH2Cl2. The solvent was removed under reduced pressure, and the residue was chromatographed on silica Sep-Pak cartridge using hexane/EtOAc (99.7:0.3) as an eluent to give an oily aldehyde 10 (130 mg, 81%).
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][CH2:5]CBr.[Mg].Cl[SiH:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=3)=[CH:18][CH:17]=2)[CH2:12][CH2:11]1>C1COCC1>[F:1][CH2:2][CH2:3][CH2:4][CH2:5][Si@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=3)=[CH:18][CH:17]=2)[CH2:12][CH2:11]1
Reactant: Fc1ccc(-c2ccc(C3CC[SiH](Cl)CC3)cc2)cc1F
Reactant: FCCCCCBr
Agent: [Mg]
Solvent: C1CCOC1
Product: FCCCC[Si@H]1CC[C@H](c2ccc(-c3ccc(F)c(F)c3)cc2)CC1

Procedure:
3.4 g (20 mmol) of fluoropentyl bromide was dripped into a mixture of 0.5 g of magnesium (21 mmol) and 50 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 50 ml THF solution of 6.5 g (20 mmol) of 4'-(4-chloro-4-silacyclohexyl)-3,4-difluorobiphenyl to obtain 4'-(trans-4-(4-fluorobutyl)-4-silacyclohexyl)-3,4-difluorobiphenyl. The silacyclohexane rings of this product were a mixture of trans isomers and cis isomers. They were separated by means of chromatography to obtain 6.3 g of the trans isomers (yield 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22](=[O:24])[CH3:23])=[C:18]([CH3:25])[CH:17]=2)=[C:12]([CH:26]([CH3:28])[CH3:27])[N:11]=[N:10]1.[BH4-].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]([OH:24])[CH3:23])=[C:18]([CH3:25])[CH:17]=2)=[C:12]([CH:26]([CH3:28])[CH3:27])[N:11]=[N:10]1
Reactant: CC(=O)c1ccc(OCc2c(C(C)C)nnn2-c2c(Cl)cccc2Cl)cc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(OCc2c(C(C)C)nnn2-c2c(Cl)cccc2Cl)ccc1C(C)O
Temperature: 25 °C
Yield: 94.4 %

Procedure:
To a 0° C. solution of 1-{4-[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-ethanone (314 mg, 0.751 mmol) in THF/MeOH (6 mL/1 mL) is added sodium borohydride (116 mg, 3.04 mmol). The reaction is warmed to room temperature overnight. The reaction is concentrated and the residue is partitioned between EtOAc (100 mL) and 1 N HCl (20 mL). The aqueous layer is extracted with EtOAc (100 mL) and the combined organic layers are washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The residue is purified via chromatography (40 g SiO2, 20% to 40% EtOAC/Hexanes) to yield the title compound (298 mg, 94%). LC-ES/MS m/e 419.7 (M+1).
Reaction SMILES: [C:1]([NH:20][CH:21]([CH2:40][OH:41])[CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[O:32][C:33]3[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=3[N:35]=2)=[CH:27][CH:26]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[K+].[C:44]1([CH2:50][CH2:51][CH2:52][CH2:53]I)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C1COCC1>[C:1]([NH:20][CH:21]([CH2:40][O:41][CH2:53][CH2:52][CH2:51][CH2:50][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH2:22][O:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]2[O:32][C:33]3[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=3[N:35]=2)=[CH:29][CH:30]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ICCCCc1ccccc1
Reactant: OCC(COCc1ccc(-c2nc3ccccc3o2)cc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: c1ccc(CCCCOCC(COCc2ccc(-c3nc4ccccc4o3)cc2)NC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
N-trityl-1-[4-(benzoxazol-2-yl)benzyloxy]-3-hydroxy-2-propanamine (0.4 g; 0.74 mmol) is added to a suspension of potassium hydride (0.12 g; 1. mmol; 35% suspension in oil) in dry THF (4 ml) at 0° C. The reaction is stirred for 15 minutes at 20° C. 4-Phenyl-1-butyl iodide (0.21 g; 0.81 mmol) is added and the reaction mixture stirred for 15 hours. The reaction is quenched with MeOH, diluted with CH2Cl2 and washed with water 2×. The organic phase is dried (Na2SO4), concentrated and purified by column chromatography with 80% CH2Cl2 /20% petroleum ether to yield N-trityl-1-[4-(benzoxazol-2-yl)benzyloxy]-3-(4-phenylbutoxy)-2-propanamine as an oil which is used directly in Step F.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:17]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:16][NH:15][N:14]=2)=[CH:4][CH:3]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:17]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:16][N:15]([C:35]([NH:34][C:31]3[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=3)=[O:36])[N:14]=2)=[CH:25][CH:26]=1
Reactant: Fc1ccc(Oc2ccccc2C2=NNCC2c2ccc(F)cc2)cc1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: ClCCl
Product: O=C(Nc1ccc(F)cc1)N1CC(c2ccc(F)cc2)C(c2ccccc2Oc2ccc(F)cc2)=N1
Temperature: 25 °C

Procedure:
3-[(4-Fluorophenoxy)phenyl]-4-(4-fluorophenyl)-4,5-dihydropyrazole (3 g; 8.6 mmol) was dissolved in dichloromethane (25 ml) and treated with 4-fluorophenyl isocyanate (1.04 g; 7.6 mmol), with stirring at room temperature. After an hour, the reaction mixture was filtered through silica gel, the filtrate was concentrated and treated with diisopropyl ether (50 ml). The precipitated crystals were separated and dried in vacuo (100 Torr).
Reaction SMILES: [F:1][C:2]([F:50])([F:49])[C:3]1[CH:4]=[C:5]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[N:34]([CH2:38][CH:39]1[CH2:41][CH2:40]1)[CH2:35][CH2:36][CH3:37])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:10][N:9]=1.[OH-].[Na+].C(OCC)(=O)C>C(O)C>[F:50][C:2]([F:1])([F:49])[C:3]1[CH:4]=[C:5]([CH:42]=[C:43]([C:45]([F:46])([F:47])[F:48])[CH:44]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[N:34]([CH2:38][CH:39]1[CH2:41][CH2:40]1)[CH2:35][CH2:36][CH3:37])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:12][N:13]=1
Reactant: CCCN(CC1CC1)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)OCC)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCN(CC1CC1)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
Ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (290 mg) is dissolved in ethanol (5 ml) and thereto is added a 2N-aqueous sodium hydroxide solution (604 μl) and the mixture is stirred at room temperature overnight. Thereto are added ethyl acetate and a 1N-hydrochloric acid, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid (277 mg). The resulting carboxylic acid is dissolved in ethanol (1 ml) and thereto is added 2N-aqueous sodium hydroxide solution (200 μl), and the reaction solution is concentrated under reduced pressure to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid sodium salt (278 mg). MS (m/z): 691 [M−Na]−
Reaction SMILES: [Cl:1][C:2]1[C:8]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:7][C:5]([NH2:6])=[C:4]([NH:18][CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:3]=1.Cl.[C:26](=N)(OC)[CH3:27].O>CO>[O:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:9]1[C:8]1[C:2]([Cl:1])=[CH:3][C:4]2[N:18]([CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:26]([CH3:27])=[N:6][C:5]=2[CH:7]=1
Reactant: Nc1cc(-c2nc3ccccc3o2)c(Cl)cc1NC1CCOCC1
Reactant: COC(C)=N
Agent: Cl
Solvent: CO
Solvent: O
Product: Cc1nc2cc(-c3nc4ccccc4o3)c(Cl)cc2n1C1CCOCC1
Yield: 40.8 %

Procedure:
To a solution of 2-(4-chloro-2-(tetrahydropyran-4-yl)aminoanilin-5-yl)benzoxazole (see Working Example 112-3) (0.04 g, 0.2 mmol) in methanol (1.2 mL) was added methyl acetimidate hydrochloride (0.06 g, 0.6 mmol), and this was heated to reflux for 3 hours. After the reaction solution was cooled, water was added, and the precipitated crystals were filtered, and after being washed with water were dried to yield the title compound (0.03 g, 79% yield) as a yellowish-brown solid.