Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24](O)=[O:25])[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.[N:50]1[CH:55]=[CH:54][CH:53]=[C:52]([CH2:56][N:57]2[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]2)[CH:51]=1>C(Cl)Cl.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:19][CH2:20][CH:21]([C:24]([N:60]3[CH2:61][CH2:62][N:57]([CH2:56][C:52]4[CH:51]=[N:50][CH:55]=[CH:54][CH:53]=4)[CH2:58][CH2:59]3)=[O:25])[CH2:22][CH2:23]2)=[O:17])=[CH:4][CH:3]=1
Reactant: c1cncc(CN2CCNCC2)c1
Reactant: O=C(O)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: O=C(c1cc2ccccc2n1Cc1ccc(Cl)cc1)N1CCC(C(=O)N2CCN(Cc3cccnc3)CC2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-(1-(4-chlorobenzyl)-1H-indole-2-carbonyl)piperidine-4-carboxylic acid (100 mg, 0.252 mmol), 1-hydroxybenzotriazole (68.1 mg, 0.504 mmol) and EDCI (97 mg, 0.504 mmol) were dissolved in DCM (Volume: 4.0 ml). The suspension was stirred at room temperature for 10 minutes where it turned clear. Hunig'sBase (0.088 ml, 0.504 mmol) and 1-(pyridin-3-ylmethyl)piperazine (100 mg, 0.564 mmol) were added. The reaction was stirred at room temperature overnight. It was diluted with water and ethyl acetate. The water layer was washed with another portion of ethyl acetate. The combined organic layer was washed with saturated sodium bicarbonate and saturated sodium chloride. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The dark brown oil crude material was purified using 5% Methanolic ammonia/DCM resulting in a white solid as a product. (Yield: 105 mg, white solid) 1H-NMR (400 MHz, DMSO-d6) 8.51-8.45, 7.74-7.68, 7.62, 7.53, 7.39-7.30, 7.24-7.18, 7.13-7.07, 6.73, 5.49, 4.58-3.85, 3.55-3.42, 3.13-2.80, 2.40-2.27, 1.60, 1.36
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:10]=[C:11]([CH2:21][C:22]([OH:24])=O)[C:12](=[O:20])[N:13]([CH2:15][C:16]([F:19])([F:18])[F:17])[CH:14]=1.Cl.Cl.[O:27]=[C:28]1[NH:36][C:31]2=[N:32][CH:33]=[CH:34][CH:35]=[C:30]2[N:29]1[CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[Br:8][C:9]1[CH:10]=[C:11]([CH2:21][C:22]([N:40]2[CH2:39][CH2:38][CH:37]([N:29]3[C:30]4[C:31](=[N:32][CH:33]=[CH:34][CH:35]=4)[NH:36][C:28]3=[O:27])[CH2:42][CH2:41]2)=[O:24])[C:12](=[O:20])[N:13]([CH2:15][C:16]([F:17])([F:18])[F:19])[CH:14]=1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: O=C(O)Cc1cc(Br)cn(CC(F)(F)F)c1=O
Agent: Cl
Agent: O=C([O-])O
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Cc1cc(Br)cn(CC(F)(F)F)c1=O)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Reaction time: 24 h
Yield: 50.7 %

Procedure:
Triethylamine (410 μL, 2.94 mmol) was added to a solution of [5-bromo-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridin-3-yl]acetic acid (231 mg, 0.736 mmol), 2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine dihydrochloride (236 mg, 0.809 mmol), EDC (212 mg, 1.10 mmol), and HOAt (100 mg, 0.736 mmol) in DMF (13 mL). After 24 h, saturated aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate (3×). The organic layers were dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography [100% dichloromethane→90% dichloromethane/methanol] gave the title compound (0.192 g). MS 516.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2[O:8][C:9]3[CH:15]=[CH:14][C:13]([CH2:16]O)=[CH:12][C:10]=3[CH:11]=2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:39]1(=[O:49])[NH:43][C:42](=[O:44])[C:41]2=[CH:45][CH:46]=[CH:47][CH:48]=[C:40]12.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2[O:8][C:9]3[CH:15]=[CH:14][C:13]([CH2:16][N:43]4[C:39](=[O:49])[C:40]5[C:41](=[CH:45][CH:46]=[CH:47][CH:48]=5)[C:42]4=[O:44])=[CH:12][C:10]=3[CH:11]=2)=[CH:4][CH:3]=1
Reactant: OCc1ccc2oc(Cc3ccc(F)cc3)cc2c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1ccc2oc(Cc3ccc(F)cc3)cc2c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 64.9 %

Procedure:
To a tetrahydrofuran (5 mL) solution of (2-(4-fluoro-benzyl)-benzofuran-5-yl)-methanol (83 mg, 0.324 mmol) described in Production Example 76-1-2 were added triphenylphosphine (93.5 mg, 0.356 mmol), phthalimide (52.4 mg, 0.356 mmol) and diethylazodicarboxylate (62.1 mg, 0.356 mmol). This mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to obtain the title compound (81 mg, 65%).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:14]#[N:15])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1.CO.ClCCl>C1COCC1.[Ni]>[CH2:16]([C:5]1([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=2)[CH2:14][NH:15][C:3](=[O:2])[CH2:4]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)CC(C#N)(Cc1ccccc1)c1cccc(OC)c1
Agent: [Ni]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: COc1cccc(C2(Cc3ccccc3)CNC(=O)C2)c1
Reaction time: 13 h
Yield: 90.6 %

Procedure:
To a solution of 3-benzyl-3-cyano-3-(3-methoxy-phenyl)-propionic acid methyl ester (200 mg, 0.6 mmol) in THF (20 ml) was added Raney-Nickel (3×300 mg at 0/5/10 h). Hydrogenation occurred at 50° C. over 13 h. Methanol (15 ml) and dichloromethane (15 ml) was added, stirred for 15 min, then the mixture was filtered and the solvent evaporated. The oil was dissolved in dichloromethane, washed with HCl (1M) and brine. The organic layer was dried, filtered and the solvent evaporated. The residue was suspended in pentane, stirred over night, filtered and dried to obtain 153 mg of product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Li]CCCC.Br[CH2:14][CH2:15][CH2:16][Cl:17].O>C1COCC1>[Cl:17][CH2:16][CH2:15][CH2:14][CH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: Cc1ccncc1
Reactant: ClCCCBr
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: ClCCCCc1ccncc1
Temperature: 45 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
4-Methylpyridine (8.4 g, 90 mmol) and THF (40 mL) were mixed in dry glassware, flushed with nitrogen and cooled to −60° C. n-BuLi (1.6 M solution, 61.9 mL, 99 mmol) was added dropwise over 1.5 h. The temperature was not allowed to exceed −50° C. The mixture was then allowed to reach rt, THF (20 mL) was added and the mixture was then stirred at 45° C. for 2 h. Additional THF (20 mL) was added. This mixture was cooled to 0° C. and added dropwise through a cooled dropping funnel to a 65° C. solution of 3-bromo-1-chloropropane (14.9 g, 94.5 mmol) in THF (15 mL). The reaction mixture was slowly allowed to reach 0° C. overnight. Water (90 mL) was added, and the mixture was stirred for 10 min. The organic layer was separated and dried (Na2SO4) to give the sub-title compound in 97.6% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N:15]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][C:10]=1[CH:24]=[CH:25][C:26]1[S:30][C:29]([CH:31]=O)=[CH:28][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]([C:35]1[C:36](=[C:51]([C:54]#[N:55])[C:52]#[N:53])[O:37][C:38]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([C:41]([F:44])([F:43])[F:42])[C:39]=1[CH3:40])#[N:34]>C(O)C.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N:15]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][C:10]=1[CH:24]=[CH:25][C:26]1[S:30][C:29]([CH:31]=[CH:40][C:39]2[C:38]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:41]([F:44])([F:42])[F:43])[O:37][C:36](=[C:51]([C:54]#[N:55])[C:52]#[N:53])[C:35]=2[C:33]#[N:34])=[CH:28][CH:27]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)s2)c(OCc2ccccc2)c1
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(c1ccccc1)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(c3ccccc3)C(F)(F)F)s2)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 21 h
Yield: 94.7 %

Procedure:
In 15 ml of ethanol and 5 ml of tetrahydrofuran were dissolved 730 mg (1.63 mmol) of 5-[2-(2-benzyloxy-4-dibutylaminophenyl)vinyl]thiophene-2-carboaldehyde and 573 mg (1.82 mmol) of 2-(3-cyano-4-methyl-5-phenyl-5-trifluoromethyl-2(5H)-furanylidene)propanedinitrile. The mixture was stirred at room temperature for 21 hours and further stirred with heating at 50° C. for 3 hours. The solvent was evaporated off and the residue was washed with ethanol to give 1.15 g of a dark reddish brown crystal (yield: 94.7%; mp: 196-197° C.)
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[CH:13]2[CH2:16][CH2:17][CH2:18][C:12]2=[N:11][C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].Cl.C(O)C.C(=O)([O-])O.[Na+]>C(O)C.O1CCCC1.CC1C(Br)=C(O)C(Br)=CC=1C1(C2C=C(Br)C(O)=C(Br)C=2C)OS(=O)(=O)C2C=CC=CC1=2.O>[CH2:1]([N:8]1[C:14](=[O:15])[CH:13]2[CH2:16][CH2:17][CH2:18][CH:12]2[NH:11][C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C2CCCC2=Nc2ccccc2N1Cc1ccccc1
Agent: Cc1c(C2(c3cc(Br)c(O)c(Br)c3C)OS(=O)(=O)c3ccccc32)cc(Br)c(O)c1Br
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: O=C1C2CCCC2Nc2ccccc2N1Cc1ccccc1
Temperature: 0 °C
Yield: 83.5 %

Procedure:
A suspension of 9-benzyl-2,3,9,10a-tetrahydrobenzo [b]cyclopenta[e][1,4]diazepin-10(1H)-one (87.5 g, 0.30 mol) and bromocresol green (20 mg) in ethanol (300 mL) in a mixture of ethanol (300 mL) and tetrahydrofuran (300 mL) was cooled to 0° C., to which was added sodium cyanoborohydride (20.8 g, 0.33 mol). To the mixture was added dropwise slowly a 2.43N HCl-ethanol solution until the color of the solution does not change any more. To the reaction mixture was added water (800 mL), to which was added a saturated aqueous solution of sodium hydrogencarbonate to make the pH of the solution alkaline. Resulting crystalline precipitate was collected by filtratin, washed with water, and dried at 60° C. over diphosphorus pentoxide under reduced pressure to give 73.2 g (yield 83%) of the titled compound. The filtrate was concentrated under reduced pressure to distill off the organic solvent. The aqueous layer was subjected to extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, followed by filtration and concentration under reduced pressure. The concentrate was recrystallized from ethyl acetate-hexane to give additional 7.0 g (7%) of the titled compound, m.p. 172°-173° C.
Reaction SMILES: [C:1]([O:6][CH:7]([CH2:14][CH3:15])[C:8]([C:11]([OH:13])=[O:12])([F:10])[F:9])(=[O:5])[C:2]([CH3:4])=[CH2:3].[OH-].[Na+].[Br-].[C:19]1([S+:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)(Cl)Cl>[F:9][C:8]([F:10])([CH:7]([O:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])[CH2:14][CH3:15])[C:11]([O-:13])=[O:12].[C:32]1([S+:25]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: C=C(C)C(=O)OC(CC)C(F)(F)C(=O)O
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: C=C(C)C(=O)OC(CC)C(F)(F)C(=O)[O-]
Temperature: 0 °C
Yield: 101.1 %

Procedure:
A 1-L glass flask equipped with a dropping funnel was charged with 108 g (0.486 mol) of 1-hydroxycarbonyl-1,1-difluoro-2-butyl methacrylate and 108 g of chloroform, which were stirred and cooled at 0° C. Then 224 g (0.560 mol/1.15 equivalent) of a 10 wt % sodium hydroxide aqueous solution was added dropwise to the solution, which was stirred at room temperature for 1 hour. Then 169 g (0.492 mol/1.01 equivalent) of triphenylsulfonium bromide in 432 g of chloroform was added to the solution, which was stirred at room temperature for 1 hour. After the completion of reaction was confirmed by 1H-NMR spectroscopy, an organic layer was separated from the reaction liquid and washed 3 times with 300 g of water. The organic layer was concentrated in vacuum, obtaining 238 g (yield 81%, purity 80%) of triphenylsulfonium 2,2-difluoro-3-methacryloyloxypentanoate, designated Monomer Z-1, having the following structure.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2]O.C1C=CC=CC=1.[CH3:11][C:12]1[CH:13]=[C:14]([CH:29]=[CH:30][CH:31]=1)[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23](=[N:26][O:27][CH3:28])[C:24]#[N:25].NCCO>O.O.C([O-])(=O)C.[Zn+2].C([O-])(=O)C.C(OCC)(=O)C>[CH3:28][O:27][N:26]=[C:23]([C:24]1[O:4][CH2:1][CH2:2][N:25]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][O:15][C:14]1[CH:29]=[CH:30][CH:31]=[C:12]([CH3:11])[CH:13]=1
Reactant: OCCO
Reactant: CON=C(C#N)c1ccccc1COc1cccc(C)c1
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: NCCO
Solvent: O
Solvent: c1ccccc1
Product: CON=C(C1=NCCO1)c1ccccc1COc1cccc(C)c1
Temperature: 100 °C
Reaction time: 20 h
Yield: 24 %

Procedure:
Ethylene glycol (2 ml) and benzene (10 ml) were added to 2-(3-methylphenoxymethyl)-α-methoxyiminophenylacetonitrile (1.0 g, 3.6 mmol), 2-aminoethanol (400 mg, 6.6 mmol) and zinc acetate dihydrate (100 mg, 0.46 mmol), and the mixture was subjected to azeotropic dehydration and stirred at 100° C. for 20 hours. After allowing the mixture to stand for cooling, ethyl acetate was added to the reaction mixture. The mixture was washed successively with water and saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane) to give 2-(3-methylphenoxymethyl)phenyl 2-oxazolin-2-yl ketone O-methyloxime (280 mg,24%) as an oil.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:18]=[C:17]([Sn](C)(C)C)[CH:16]=[C:15]3[C:11]=2[CH:12]=[N:13][N:14]3S(C2C=CC=CC=2)(=O)=O)=[O:8])[N:6]=1.[F:32][C:33]1[C:34](I)=[C:35]2[CH:41]=[CH:40][N:39](S(C3C=CC([N+]([O-])=O)=CC=3)(=O)=O)[C:36]2=[N:37][CH:38]=1.C(O)(C(F)(F)F)=O>CN(C=O)C.CC#N>[F:32][C:33]1[C:34]([C:17]2[CH:16]=[C:15]3[C:11]([CH:12]=[N:13][NH:14]3)=[C:10]([NH:9][C:7]([C:5]3[N:6]=[C:2]([CH3:1])[S:3][CH:4]=3)=[O:8])[CH:18]=2)=[C:35]2[CH:41]=[CH:40][NH:39][C:36]2=[N:37][CH:38]=1
Reactant: Cc1nc(C(=O)Nc2cc([Sn](C)(C)C)cc3c2cnn3S(=O)(=O)c2ccccc2)cs1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)n2ccc3c(I)c(F)cnc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)Nc2cc(-c3c(F)cnc4[nH]ccc34)cc3[nH]ncc23)cs1
Reaction time: 8 h

Procedure:
2-Methyl-N-[1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-yl]-1,3-thiazole-4-carboxamide (1 g) was dissolved in DMF (4 ml) and 400 μl of the resultant solution was dispensed to 5-fluoro-4-iodo-1-[(4-nitrophenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridine (0.18 mmol) in DMF (400 μl) in a microwave vessel. Solvias catalyst (4 mg) was added and the reaction was heated in the microwave using initial 700 W to 135° C. for 20 min. The solution was loaded onto C18 SPE (pre-conditioned with 0.1% TFA in MeCN) and flushed through with 0.1% TFA in MeCN (3 ml). The solvent was removed under nitrogen blowdown. The sample was dissolved in DMSO (0.5 ml) and purified by MDAP (method D). The solvent was evaporated in vacuo using the Genevac. The sample was dissolved in IPA (300 μl) and 2M NaOH (aq) (300 μl) was added. The reaction was left overnight. The sample was dissolved in DMSO (0.6 ml) and purified by MDAP (method M). The solvent was evaporated in vacuo using the Genevac to give title compound, 2 mg.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][C:13]([C:36]#[N:37])([NH:16][C:17](=[O:35])[CH:18]([NH:26][C:27]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:28])[CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:12]1)=O)C1C=CC=CC=1.CO>CCO.C(Cl)Cl.[Pd]>[C:36]([C:13]1([NH:16][C:17]([CH:18]([NH:26][C:27]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:28])[CH2:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[O:35])[CH2:14][CH2:15][NH:11][CH2:12]1)#[N:37]
Reactant: N#CC1(NC(=O)C(CC2CCCCC2)NC(=O)N2CCOCC2)CCN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Solvent: CO
Product: N#CC1(NC(=O)C(CC2CCCCC2)NC(=O)N2CCOCC2)CCNC1

Procedure:
3-Cyano-3-{3-cyclohexyl-2-[(morpholine-4-carbonyl)-amino]-propionylamino}-pyrrolidine-1-carboxylic acid benzyl ester (0.1 g, 0.20 mmol, 1.0 equiv) was dissolved in 15 mL of absolute EtOH. 10% Pd on carbon (20 mg) was added and the mixture was stirred under 1 atm of H2 until the starting material disappeared by TLC (5% MeOH in CH2Cl2. The crude mixture was filtered on diatomaceous earth and the filtrate was concentrated. The crude material was purified by reverse-phase HPLC to give two diastereomers; MS, m/z 378=M+1.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:32]=[CH:31][C:8]([CH2:9][N:10]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C@@H:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]([CH3:15])([OH:14])[CH3:13])=[CH:7][CH:6]=1.[CH3:33]I>C1COCC1>[CH3:33][O:14][C:12]([CH3:15])([CH3:13])[C@H:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[N:10]([CH2:9][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:32][CH:31]=1)[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1
Reactant: CI
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)[C@@H](c2ccccc2)C(C)(C)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)[C@@H](c2ccccc2)C(C)(C)OC)cc1
Reaction time: 0.25 h

Procedure:
At 0° C., to a suspension of NaH (0.13 g, 2.96 mmol) in anhydrous THF (5 mL), was added a solution of (S)-1-(bis(4-methoxybenzyl)amino)-2-methyl-1-phenylpropan-2-ol 4 (1.0 g, 2.47 mmol) in anhydrous THF (10 mL). After 15 min, MeI (0.55 g, 3.71 mmol) was added and the contents were heated to reflux. After 8 h, the reaction was brought back to ambient temperature, quenched carefully with ice cold H2O (10 mL), and the organic contents were extracted with EtOAc (3×25 mL). The combined organic extracts were washed with brine (1×20 mL), dried over Na2SO4, concentrated to afford (S)-2-methoxy-N,N-bis(4-methoxybenzyl)-2-methyl-1-phenylpropan-1-amine. H1NMR (CD3OD, 400 MHz) δ 7.45-7.44 (m, 2H), 7.37-7.34 (m, 2H), 7.33-7.28 (m, 5H), 6.88-6.86 (m, 4H), 4.20 (s, 1H), 3.78 (s, 6H), 3.25 (s, 4H), 2.81 (s, 3H), 1.4 (s, 3H), 0.81 (s, 3H). MS: [M+H]+ m/z 420.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:11][CH:10]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[O:13])[CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.C1CC=CCC=1>[Pd]>[N:7]1[CH:2]=[CH:3][CH:4]=[C:5]([N:8]2[CH2:11][CH:10]([C:12]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([CH:21]4[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]4)=[CH:19][CH:20]=3)=[O:13])[CH2:9]2)[N:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)C3CN(c4ccc(Cl)nn4)C3)cc2)CC1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1=CCC=CC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)C3CN(c4cccnn4)C3)cc2)CC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a 50 mL round-bottomed flask was added tert-butyl 4-(4-(1-(6-chloropyridazin-3-yl)azetidine-3-carboxamido)phenyl)piperidine-1-carboxylate (550 mg, 1.165 mmol) and Pd/C (93 mg, 0.087 mmol). The flask was flushed with nitrogen for 10 minutes and ethanol (11.7 ml) was added. Triethylamine (0.162 ml, 1.165 mmol) and cyclohexa-1,4-diene (654 mg, 8.16 mmol) were added and the reaction was stirred at 80° C. for 1 hour, cooled and filtered through diatomaceous earth. The filtrate was concentrated in vacuo and the residue was purified by regular phase flash column chromatography to give the title compound.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[CH2:13]([N:20]1[C:24]2([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[NH:23][CH:22]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:21]1=[O:37])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH2:13]([N:20]1[C:24]2([CH2:25][CH2:26][N:27]([S:9]([CH3:8])(=[O:11])=[O:10])[CH2:28][CH2:29]2)[NH:23][CH:22]([CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:21]1=[O:37])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C1C(Cc2ccccc2)NC2(CCNCC2)N1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC2(CC1)NC(Cc1ccccc1)C(=O)N2Cc1ccccc1

Procedure:
Triethylamine (0.15 ml, 1.78 mmol) and subsequently methanesulfonyl chloride (0.14 ml, 1.78 mmol) were added to a solution of 1,3-dibenzyl-1,4,8-triazaspiro-[4,5]decan-2-one (300 mg, 0.89 mmol) in CH2Cl2 (8.1 ml) with stirring using nitrogen as an inert gas at RT. The reaction mixture was stirred overnight. The organic phase was rendered alkaline using aqueous sodium carbonate solution (20 ml) and the aqueous phase was extracted with CH2Cl2 (15 ml). The combined organic phases were dried over Na2SO4. After filtration, removal of the solvent, and column chromatography, the desired product 1,3-dibenzyl-8-methanesulfonyl-1,4,8-triazaspiro[4,5]decan-2-one was obtained in a yield of 287 mg (77% of theory).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([Si:15]([C:44]2[CH:49]=[CH:48][C:47]([O:50]CC3C=CC=CC=3)=[CH:46][CH:45]=2)([C:30]2[CH:35]=[CH:34][C:33]([O:36]CC3C=CC=CC=3)=[CH:32][CH:31]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22]CC3C=CC=CC=3)=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>[Pd].C1COCC1>[OH:22][C:19]1[CH:18]=[CH:17][C:16]([Si:15]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)[C:44]2[CH:45]=[CH:46][C:47]([OH:50])=[CH:48][CH:49]=2)=[CH:21][CH:20]=1
Reactant: [H][H]
Reactant: c1ccc(COc2ccc([Si](c3ccc(OCc4ccccc4)cc3)(c3ccc(OCc4ccccc4)cc3)c3ccc(OCc4ccccc4)cc3)cc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: Oc1ccc([Si](c2ccc(O)cc2)(c2ccc(O)cc2)c2ccc(O)cc2)cc1
Reaction time: 48 h
Yield: 91.1 %

Procedure:
A THF (200 mL) solution containing tetrakis(4-benzyloxyphenyl)silane 40 (10.00 g, 13.15 mmol) and 10 wt % palladium on carbon (400 mg) (e.g., catalyst), was placed in the 1000 mL pressure safe vessel equipped with viton seals and, in turn, connected to the hydrogenator, as provided above. The vessel was pressurized with hydrogen (35 psi) and the solution was allowed to react with stirring for 48 hr. The catalyst was removed by filtration through celite, and the solvent was removed under reduced pressure to afford 4.80 g (91% yield) of tetrakis(4-hydroxyphenyl)silane 42 (FIG. 8) as an off-white solid. For purification, tetrakis(4-hydroxyphenyl)silane 42 was dissolved in THF and precipitated out in hexane. The white product was filtered, washed with ether, and dried under dynamic vacuum. NMR assignments of the molecule shown in FIG. 8, include: 1H NMR (acetone-d6) δ: 8.63 (s, 4H), 7.38 (d, J=6 Hz, 8H), 6.81 (d, J=6 Hz, 8H). 13C NMR (acetone-d6) δ: 159.54 (C4), 138.59 (C2), 125.98 (C1), 115.92 (C3). 29Si NMR (acetone-d6) δ: −14.64 (s).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[S:13][CH3:14].CC(C[AlH]CC(C)C)C.CO>C1(C)C=CC=CC=1.CC(=O)OCC>[F:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][CH:3]=[O:2])=[C:7]([S:13][CH3:14])[CH:8]=1
Reactant: COC(=O)CCc1ccc(F)cc1SC
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCOC(C)=O
Solvent: CO
Solvent: Cc1ccccc1
Product: CSc1cc(F)ccc1CCC=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.3 %

Procedure:
To a solution of 3-(4-fluoro-2-methylsulfanyl-phenyl)-propionic acid methyl ester (1 g, 4.3 mmol) in dry toluene was added DIBAL-H (5.2 ml in toluene, 1N) drop-wise at −78° C. After stirring at this temperature for 1 h, methanol (5 ml) was added dropwise to quench the reaction. The mixture was warmed to room temperature and diluted with EA. The mixture was washed with brine, dried and concentrated. The residue was purified by column chromatography to give the titled compound (804 mg, yield 92%)