Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[CH:19][C:20]3[NH:27][CH2:26][CH2:25][CH2:24][C:23]([C:28]([O:30][CH3:31])=[O:29])=[CH:22][C:21]=3[CH:32]=2)=[CH:13][CH:12]=1)[CH2:4][CH2:5][CH3:6].Br[CH2:34][C:35]([CH3:37])=[CH2:36].[I-].[Na+]>CN(C=O)C.[Cl-].[Na+].O.O>[CH2:3]([O:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:18]=[CH:19][C:20]3[N:27]([CH2:36][C:35]([CH3:37])=[CH2:34])[CH2:26][CH2:25][CH2:24][C:23]([C:28]([O:30][CH3:31])=[O:29])=[CH:22][C:21]=3[CH:32]=2)=[CH:15][CH:16]=1)[CH2:4][CH2:5][CH3:6]
Reactant: C=C(C)CBr
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCCN3)cc1
Agent: [Cl-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)CN1CCCC(C(=O)OC)=Cc2cc(-c3ccc(OCCOCCCC)cc3)ccc21
Reaction time: 1 h

Procedure:
To a solution of sodium hydroxide (530 mg) in DMF (10 ml) was added dropwise a solution of methyl 8-(4-(2-butoxyethoxy)phenyl)-1,2,3,4-terahydro-1-benzoazocine-5-carboxylate (1.8 g) in DMF (20 ml) at 0° C. under nitrogen atmosphere. After returning to room temperature and stirring for 1 hour, 3-bromo-2-methylpropene (1.33 ml) and sodium iodide (1.98 g) were added, and the mixture was stirred at 100° C. overnight. After returning to room temperature, water and saturated brine were added and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water twice and with saturated brine once, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=12:1→hexane:ethyl acetate=9:1). The resulting residue was recrystallized from hexane-ethyl acetate to give methyl 8-(4-(2-butoxyethoxy)phenyl)-1-(2-methyl-2-propen-1-yl)-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxylate (1.64 g) as yellow crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH:20]1[O:41][CH:21]1[CH:22]([NH:30][C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].FC(F)(F)C(O)=O>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C@@H:20]([OH:41])[CH2:21][C@@H:22]([NH:30][C:31]([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:32])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC(Cc1ccccc1)C1OC1C(Cc1ccccc1)NC(=O)OCc1ccccc1)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 58 %

Procedure:
A mixture of 39.2 g (71.2 mmol) of 2S,3R,4R,5S)-2,5-bis-(N-(((benzyl)oxy)carbonyl)amino)-3,4-epoxy-1,6-diphenylhexane in 600 ml of THF was treated under N2 atmosphere with 13 g (0.36 mol) of sodium borohydride. The resulting mixture was treated dropwise with 27.7 ml (0.36 mol) of trifluoroacetic acid. After being stirred for 3.5 h at ambient temperature, the resulting mixture was quenched with 1N aqueous HCl, diluted with water, and stirred for 16 h. The resulting mixture was filtered. washed with water, and dried to provide 22.85 g (58%) of the desired compound as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([OH:10])=O.[CH2:11]([C@@H:18]1[NH:23][CH2:22][CH2:21][N:20]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH:33]([CH3:35])[CH3:34])[CH:25]=2)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([C@H:18]1[CH2:19][N:20]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH:33]([CH3:35])[CH3:34])[CH:25]=2)[CH2:21][CH2:22][N:23]1[C:8](=[O:10])[CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC(C)C
Reactant: O=C(O)Cc1ccccn1
Product: COc1ccc(N2CCN(C(=O)Cc3ccccn3)[C@@H](Cc3ccccc3)C2)cc1OC(C)C

Procedure:
Prepared by the method outlined for Example 189 using pyridine-2-yl-acetic acid and 3(S)-benzyl-1-(3-(1-methylethoxy)-4-methoxy-phenyl)-piperazine (Example 9, Compound 97) as starting materials. Product as an oil (30 mg, 68%). LC/MS (Method B) 2.45 min, [M+1]+ 460. Potency class B.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[C:4]#[C:5][CH2:6][CH3:7].Cl[C:10]1[CH:15]=[C:14](Cl)[N:13]=[CH:12][N:11]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:8][C:10]1[CH:15]=[C:14]([O:8][CH2:3][C:4]#[C:5][CH2:6][CH3:7])[N:13]=[CH:12][N:11]=1)[C:4]#[C:5][CH2:6][CH3:7]
Reactant: CCC#CCO
Reactant: Clc1cc(Cl)ncn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC#CCOc1cc(OCC#CCC)ncn1
Temperature: 25 °C
Yield: 98.8 %

Procedure:
In 5 ml of tetrahydrofuran was suspended 0.34 g of sodium hydride (60% in oil), to which 0.9 ml of a tetrahydrofuran solution containing 0.62 g of 2-pentyn-1-ol was slowly added dropwise with stirring at room temperature. The mixture was then stirred at room temperature for 20 minutes, to which 0.9 ml of a tetrahydrofuran solution containing 0.5 g of 4,6-dichloropyrimidine was slowly added dropwise. After completion of the dropwise addition, the mixture was stirred at room temperature for 40 minutes. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with chloroform. The chloroform layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.81 g of 4,6-bis(2-pentynyloxy)pyrimidine (the present compound (3)).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])N=1.B(F)(F)F.CC[O:18]CC>CC(C)=O>[CH3:10][C:4]1([CH3:11])[NH:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2](=[O:18])[CH2:1]1
Reactant: CCOCC
Reactant: CC1=NC(C)(C)NC(C)(C)C1
Agent: FB(F)F
Solvent: CC(C)=O
Product: CC1(C)CC(=O)CC(C)(C)N1
Yield: 116 %

Procedure:
A solution of 15.4 g. of acetonine in 60 g. of acetone was added dropwise with 6.5 g. of boron trifluoride etherate at room temperature. After completion of the addition, the mixture was heated at 48°-50°C. for 3 hours to effect the reaction. After completion of the reaction, the reaction mixture was purified in the same manner as in Example 1 to obtain triacetonamine in a yield of 116%.
Reaction SMILES: [C:1]([O:10][CH2:11]C=C)(=[O:9])[CH2:2][C:3]([O:5][CH2:6]C=C)=[O:4].C(O)C=C>>[C:1]([O:10][CH3:11])(=[O:9])[CH2:2][C:3]([O:5][CH3:6])=[O:4]
Reactant: C=CCOC(=O)CC(=O)OCC=C
Solvent: C=CCO
Product: COC(=O)CC(=O)OC

Procedure:
in place of the diallyl malonate and in place of the allyl alcohol
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.[Br:19]N1C(=O)CCC1=O>C1(C(F)(F)F)C=CC=CC=1.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:19][CH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(Oc2cccc3ccccc23)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: FC(F)(F)c1ccccc1
Product: BrCc1cccc(Oc2cccc3ccccc23)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 73.1 %

Procedure:
1-(3-Methylphenoxy)naphthalene (500 mg, 2.1 mmol) was dissolved in benzotrifluoride (30 mL), N-bromosuccinimide (417 mg, 2.3 mmol) and 2,2′-azobis(isobutyronitrile) (10 mg, 0.06 mmol) were added thereto, and then the mixture was stirred at 100° C. for 4 hours. The reaction solution was filtered, and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=100:0 to 90:10) to give the title compound (481 mg, yield 73%).
Reaction SMILES: [O:1]=[S:2]1(=[O:34])[C:8]2[CH:9]=[C:10]([O:15][CH2:16][C:17]([O:19]CC)=[O:18])[C:11]([O:13][CH3:14])=[CH:12][C:7]=2[N:6]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:5][C:4]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:28][CH3:29])[CH2:3]1.[OH-].[Na+].CC(O)=O>C(O)C.O>[O:34]=[S:2]1(=[O:1])[C:8]2[CH:9]=[C:10]([O:15][CH2:16][C:17]([OH:19])=[O:18])[C:11]([O:13][CH3:14])=[CH:12][C:7]=2[N:6]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:5][C:4]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:28][CH3:29])[CH2:3]1
Reactant: CCCCC1(CC)CN(c2ccccc2)c2cc(OC)c(OCC(=O)OCC)cc2S(=O)(=O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CCCCC1(CC)CN(c2ccccc2)c2cc(OC)c(OCC(=O)O)cc2S(=O)(=O)C1
Temperature: 40 °C
Yield: 97.2 %

Procedure:
1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methoxy-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 47; 1.2 g) was dissolved in ethanol (20 ml). Sodium hydroxide (0.5) dissolved in H2O (1 ml) was added and the reaction mixture was warmed to 40° C. for 30 min. AcOH (1 ml) was added and the solvent was removed at reduced pressure. The residue was partitioned between DCM/H2O and the organic layer was separated and dried. Trituration of the residue with n-hexane gave the title compound 1.1 g (97%) as a solid. NMR (400 MHz; CDCl3): 0.75-0.85 (m, 3H), 0.9 (t, 3H), 1.0-1.7 (m, 8H), 3.2 (q, 2H), 3.65 (s, 3H), 3.65-3.85 (m, 2H), 4.7 (s, 2H), 6.4 (s, 1H), 7.0 (t, 1H), 7.1 (d, 2H), 7.3 (t, 2H), 7.5 (s, 1H).
Reaction SMILES: [C:1]([N:3]=[C:4]([NH:9][CH3:10])[NH:5][CH2:6][CH2:7][SH:8])#[N:2].[H-].[Na+].Cl[CH2:14][C:15]1[O:19][C:18]([CH2:20][N:21]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:31])=[CH:17][CH:16]=1>CN(C)C=O>[C:1]([N:3]=[C:4]([NH:9][CH3:10])[NH:5][CH2:6][CH2:7][S:8][CH2:14][C:15]1[O:19][C:18]([CH2:20][N:21]2[C:22](=[O:31])[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:29]2=[O:30])=[CH:17][CH:16]=1)#[N:2]
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(CCl)o1
Reactant: CNC(=NC#N)NCCS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=NC#N)NCCSCc1ccc(CN2C(=O)c3ccccc3C2=O)o1
Reaction time: 2 h
Yield: 55.8 %

Procedure:
To a stirred solution of N"-cyano-N-(2-mercaptoethyl)-N'-methylguanidine (1.0 g) and sodium hydride (0.152 g) in dry dimethylformamide (4 ml) at room temperature was added slowly a solution of 2-(5-chloromethyl-2-furanylmethyl)-1H-isoindole-1,3(2H)-dione (1.74 g) in dry dimethylformamide (8 ml). After stirring for 2 hr in the solution was evaporated to dryness and the oily residue suspended in an ethyl acetate (25 ml)-water (20 ml) mixture. The solid residue was filtered and crystallised from methanol to give the title compound (1.4 g) m.p. 179°-182°.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.CC(N)(C)C[C:22]1[CH:27]=[CH:26][C:25]([NH:28][S:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)(=[O:31])=[O:30])=[CH:24][CH:23]=1>C(O)C>[OH:1][C@@H:2]([CH2:3][N:11]([C:22]1[CH:23]=[CH:24][C:25]([NH:28][S:29]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)(=[O:30])=[O:31])=[CH:26][CH:27]=1)[CH2:10][CH:18]([CH3:6])[CH3:17])[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(N)Cc1ccc(NS(=O)(=O)c2ccccc2)cc1
Reactant: c1ccc2c(c1)[nH]c1cccc(OC[C@@H]3CO3)c12
Solvent: CCO
Product: CC(C)CN(C[C@H](O)COc1cccc2[nH]c3ccccc3c12)c1ccc(NS(=O)(=O)c2ccccc2)cc1
Yield: 134.6 %

Procedure:
A solution of (S)-4-(oxiranylmethoxy)-9H-carbazole (1.0 g, 4.18 mmol) and N-(4-[2-methyl-2-aminopropyl]phenyl)benzenesulfonamide (1.9 g, 6.24 mmol) in absolute ethanol (100 mL) was refluxed for 18 h. The solvent was removed under vacuum and the residue was purified by column chromatography eluting with chloroform:methanol (95:5). Concentration of the appropriate fractions provided 1.53 g (69%) of the desired product. MS (FD) m/e 544.3 (MH+); Anal. Calcd. for C31H33N3O4S: C, 68.48; H, 6.12; N, 7.73. Found: C, 68.49; H, 6.02; N, 7.53.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[C:20](=[O:21])[NH:19][CH2:18][CH2:17][N:16]3[CH3:22])=[CH:11][CH:10]=2)[C:5](=[O:23])[N:4]([CH3:24])[CH:3]=1.[C:25]([C:29]1[S:36][C:35]2[C:34](=[O:37])[N:33]([C:38]3[CH:43]=[CH:42][CH:41]=[C:40](B4OC(C)(C)C(C)(C)O4)[C:39]=3[CH3:53])[CH2:32][C:31]=2[CH:30]=1)([CH3:28])([CH3:27])[CH3:26].C(=O)([O-])[O-].[Na+].[Na+]>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.O>[C:25]([C:29]1[S:36][C:35]2[C:34](=[O:37])[N:33]([C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([C:2]4[N:7]=[C:6]([NH:8][C:9]5[CH:14]=[CH:13][C:12]([CH:15]6[C:20](=[O:21])[NH:19][CH2:18][CH2:17][N:16]6[CH3:22])=[CH:11][CH:10]=5)[C:5](=[O:23])[N:4]([CH3:24])[CH:3]=4)[C:39]=3[CH3:53])[CH2:32][C:31]=2[CH:30]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CN1CCNC(=O)C1c1ccc(Nc2nc(Br)cn(C)c2=O)cc1
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1Cc2cc(C(C)(C)C)sc2C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1c(-c2cn(C)c(=O)c(Nc3ccc(C4C(=O)NCCN4C)cc3)n2)cccc1N1Cc2cc(C(C)(C)C)sc2C1=O
Temperature: 110 °C
Yield: 12.6 %

Procedure:
A 5-mL reaction tube equipped with a magnetic stirrer was charged with 104d (65 mg, 0.166 mmol), 102g (68 mg, 0.166 mmol), sodium carbonate (53 mg, 0.498 mmol) dioxane (1.0 mL) and water (0.2 mL). This mixture was degassed with nitrogen for 30 min. Tetrakis(triphenylphosphine)palladium (19 mg, 0.017 mmol) was added, and the tube was sealed. After heating at 110° C. (bath temperature) for 16 h, the reaction mixture was cooled to room temperature and concentrated to a residue. The resulting residue was purified by flash chromatography on silica gel. This material was further purified using a preparative HPLC to afford a 13% yield (12.5 mg) of 104 as a yellow solid: mp 174-176° C. dec; 1H NMR (500 MHz, DMSO-d6) δ 9.19 (s, 1H), 7.91 (d, 2H, J=8.5 Hz), 7.82 (d, 1H, J=4.5 Hz), 7.43 (t, 2H, J=8.0 Hz), 7.34 (t, 1H, J=7.8 Hz), 7.22 (s, 1H), 7.19 (d, 2H, J=8.5 Hz), 7.14 (s, 1H), 4.78 (s, 2H), 3.55 (s, 3H), 3.52 (s, 1H), 3.40 (td, 1H, J=11.0, 3.5 Hz), 3.13 (m, 1H), 2.90 (dd, 1H, J=6.0, 3.0 Hz), 2.47 (m, 1H), 2.24 (s, 3H), 2.05 (s, 3H), 1.42 (s, 9H); MS (ESI+) m/z 597.7 (M+H).
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:40]=[CH:39][C:7]2[CH2:8][CH2:9][CH2:10][CH:11]([N:13]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:14][C@H:15]([O:24][Si:25]([CH2:30][CH3:31])([CH2:28][CH3:29])[CH2:26][CH3:27])[CH2:16][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:12][C:6]=2[CH:5]=1.[CH:41](Br)([CH3:43])[CH3:42].C(=O)([O-])O.[Na+]>CS(C)=O>[CH:41]([O:3][C:4]1[CH:40]=[CH:39][C:7]2[CH2:8][CH2:9][CH2:10][CH:11]([N:13]([C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[CH2:14][C@H:15]([O:24][Si:25]([CH2:28][CH3:29])([CH2:26][CH3:27])[CH2:30][CH3:31])[CH2:16][O:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:12][C:6]=2[CH:5]=1)([CH3:43])[CH3:42]
Reactant: CC[Si](CC)(CC)O[C@H](COc1ccccc1)CN(C(=O)OC(C)(C)C)C1CCCc2ccc(O)cc2C1
Reactant: CC(C)Br
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC[Si](CC)(CC)O[C@H](COc1ccccc1)CN(C(=O)OC(C)(C)C)C1CCCc2ccc(OC(C)C)cc2C1
Reaction time: 1 h

Procedure:
Under nitrogen, to dimethylsulfoxide (3 ml) was added potassium hydroxide (31 mg) at room temperature, and the suspension was stirred at the same temperature for 1 hour. To this one were added N-(3-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]-tert-butoxycarbonylamine (150 mg) and isopropyl bromide (78 μl), and the mixture was stirred at room temperature for 3 hours. The resulting mixture was poured into aqueous 10% sodium hydrogencarbonate, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=20:1) to give N-(3-isopropoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]-tert-butoxycarbonylamine (96 mg).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:40])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:36])([CH3:35])[CH:32]([CH3:34])[CH3:33])[NH:17][CH:16]2[C:37]([OH:39])=O)[CH:12]=[CH:13][CH:14]=1.CC1(C)[O:46][C@@H:45]([CH2:47][CH2:48][NH2:49])[CH2:44][O:43]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O1CCCC1>[OH:46][C@H:45]([CH2:44][OH:43])[CH2:47][CH2:48][NH:49][C:37]([CH:16]1[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=2[F:40])[C:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:35])([CH3:36])[CH:32]([CH3:34])[CH3:33])[NH:17]1)=[O:39]
Reactant: CC(C)C(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CC1(C)OC[C@H](CCN)O1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)C(C)(C)CC1NC(C(=O)NCC[C@H](O)CO)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 61 %

Procedure:
In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2,3-trimethyl-butyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 78c (0.55 g, 0.9 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.39 g, 2.7 mmol), HATU (0.62 g, 1.6 mmol) and iPr2NEt (0.78 mL, 4.5 mmol) in CH2Cl2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2,3-trimethyl-butyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.32 g, 62%).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[CH2:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][NH:19]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][N:19]1[C:7]([C:6]1[CH:10]=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:12]=[CH:13][C:5]=1[O:4][CH:1]([CH3:2])[CH3:3])=[O:9]
Reactant: c1ccc2c(c1)CNC2
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A mixture of 0.387 mmol 2-isopropoxy-5-methanesulfonyl-benzoic acid (example BI), 0.464 mmol 2,3-Dihydro-1H-isoindole (commercial), 0.426 mmol TBTU and 1.935 mmol DIPEA in 1.4 ml DMF was stirred at RT for 2 h. The reaction mixture was evaporated in vacuo. The residue was taken in water and extracted with ethylacetate. The combined organic phases were washed with saturated sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (SiO2, heptane/ethyl acetate) to yield the title compound as a light brown solid (88% yield). MS (m/e): 360.2 [M+H]+, 100%)
Reaction SMILES: Br[CH2:2][CH2:3][C@H:4]1[CH2:9][CH2:8][Si@H:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:6][CH2:5]1.[Mg].P(OCC)(OCC)(OCC)=O.Br[CH:28]1[CH2:33][CH2:32][CH:31]([C:34]2[CH:39]=[CH:38][C:37]([C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=3)=[C:36]([F:47])[CH:35]=2)[CH2:30][CH2:29]1>[Cu]I.C1COCC1>[CH2:10]([Si@H:7]1[CH2:8][CH2:9][C@H:4]([CH2:3][CH2:2][C@H:28]2[CH2:29][CH2:30][C@H:31]([C:34]3[CH:39]=[CH:38][C:37]([C:40]4[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=4)=[C:36]([F:47])[CH:35]=3)[CH2:32][CH2:33]2)[CH2:5][CH2:6]1)[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: Fc1ccc(-c2ccc(C3CCC(Br)CC3)cc2F)cc1
Reactant: CCCCC[Si@H]1CC[C@H](CCBr)CC1
Agent: [Cu]I
Agent: [Mg]
Solvent: CCOP(=O)(OCC)OCC
Solvent: C1CCOC1
Product: CCCCC[Si@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccc(-c4ccc(F)cc4)c(F)c3)CC2)CC1

Procedure:
27.7 g (0.1 mol) of trans-1-(2-bromoethyl)-4-n-pentyl-4-silacyclohexane was dripped into a mixture of 2.5 g (0.11 mol) of magnesium and 300 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 500 ml THF solution of 0.5 g of triethyl phosphate, 0.1 g of copper (I) iodide and 35.1 g (0.1 mol) of 4-(4-bromocyclohexyl)-2,4'-difluorobiphenyl. After a conventional after treatment, 4-(trans-4-(2-(trans-4-n-pentyl-4-silacyclohexyl)ethyl)cyclohexyl)-2,4'-difluorobiphenyl was obtained. The silacyclohexane rings of the product were a mixture of trans isomers and cis isomers. They were separated by means of chromatography to obtain 13.1 g (yield 29.2%) of the trans isomer.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([OH:28])=O)[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:74][C@@H:75]1[CH2:79][CH2:78][N:77]([C:80]([O:82][C:83]([CH3:86])([CH3:85])[CH3:84])=[O:81])[CH2:76]1>C(Cl)Cl.CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([NH:74][C@@H:75]4[CH2:79][CH2:78][N:77]([C:80]([O:82][C:83]([CH3:86])([CH3:85])[CH3:84])=[O:81])[CH2:76]4)=[O:28])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: O=C(O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)COc2cccc(-c3nc(Nc4ccc5[nH]ncc5c4)c4ccccc4n3)c2)C1
Reaction time: 0.5 h

Procedure:
A suspension of 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (67 mg, 0.13 mmol), PyBOP® (37 mg, 0.072 mmol), DIEA (23 μL, 0.13 mmol) in dry CH2Cl2:DMF (2:0.1 mL) was stirred at RT for 15 minutes. To this solution of activated acid was added (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate (16 mg, 0.084 mmol). After 30 minutes, 1.0 equivalent of DIEA and 0.55 equivalent of PyBOP® were added. After stirring the solution for 15 minutes, 0.65 equivalent of (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate were added and the mixture was stirred for an additional 30 minutes. The solvent was removed in vacuo to afford the crude (3R)-tert-butyl 3-(2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetamido)pyrrolidine-1-carboxylate.