Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:4][C@:5]1([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:30][CH:29]=2)[CH2:9][N:8]([C:10](=[O:24])[C@@H:11]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:12]([CH3:15])([CH3:14])[CH3:13])[C@H:7]([C:25]([OH:27])=O)[CH2:6]1)[CH:2]=[CH2:3].[NH2:40][C@:41]1([C:47]([NH:49][S:50]([C:53]2([CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH:61]=[CH2:62])[CH2:55][CH2:54]2)(=[O:52])=[O:51])=[O:48])[CH2:43][C@H:42]1[CH:44]([F:46])[F:45].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH2:1]([S:4][C@:5]1([C:28]2[CH:29]=[CH:30][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:32][CH:33]=2)[CH2:9][N:8]([C:10](=[O:24])[C@@H:11]([NH:16][C:17](=[O:18])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[C:12]([CH3:15])([CH3:14])[CH3:13])[C@H:7]([C:25](=[O:27])[NH:40][C@:41]2([C:47](=[O:48])[NH:49][S:50]([C:53]3([CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH:61]=[CH2:62])[CH2:54][CH2:55]3)(=[O:52])=[O:51])[CH2:43][C@H:42]2[CH:44]([F:46])[F:45])[CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCS[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@@H](C(=O)O)N(C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)C1
Reactant: C=CCCCCCC1(S(=O)(=O)NC(=O)[C@@]2(N)C[C@H]2C(F)F)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCCCCC1(S(=O)(=O)NC(=O)[C@@]2(NC(=O)[C@@H]3C[C@@](SCC=C)(c4ccc(-c5ccccc5)cc4)CN3C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)C[C@H]2C(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
To a slurry of (2S,4R)-4-(allylthio)-4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoyl)pyrrolidine-2-carboxylic acid (55.3 mg, 0.10 mmol), (1R,2R)-1-amino-2-(difluoromethyl)-N-(1-(hept-6-enyl)cyclopropylsulfonyl)cyclopropanecarboxamide (38.7 mg, 0.10 mmol) and HATU (57.0 mg, 0.150 mmol) in DCM (2 mL) was added N,N-Diisopropylethylamine (0.087 mL, 0.500 mmol). The formed solution was stirred at room temperature overnight. Diluted with DCM, washed with 1M HCl and brine, dried over MgSO4, filtered, and concentrated. The residue was purified by Biotage column, eluted with gradient 5%˜30% Acetone-Hexane to afford the desired product tert-butyl (S)-1-((2S,4R)-4-(allylthio)-4-(biphenyl-4-yl)-2-((1R,2R)-2-(difluoromethyl)-1-(1-(hept-6-enyl)cyclopropylsulfonylcarbamoyl)cyclopropylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (65 mg, 0.073 mmol, 73% yield) as a white foam. 1H NMR (400 MHz, MeOD) ppm 0.81-0.88 (m, 2 H) 1.07 (s, 9 H) 1.21-1.61 (m, 17 H) 1.64-1.80 (m, 1 H) 1.81-2.12 (m, 6 H) 2.37 (t, J=11.42 Hz, 1 H) 2.91-3.05 (m, 3 H) 3.91 (dd, J=10.29, 6.53 Hz, 1 H) 3.98 (d, J=11.04 Hz, 1 H) 4.48 (d, J=9.79 Hz, 1 H) 4.86-5.13 (m, 5 H) 5.66-6.14 (m, 3 H) 7.36 (t, J=7.28 Hz, 1 H) 7.45 (t, J=7.53 Hz, 2 H) 7.52-7.76 (m, 6 H). LC-MS (retention time: 3.39 min, Method B), MS m/z 885 (M+H).
Reaction SMILES: C([NH:8][C:9]1[C:18]([F:19])=[C:17]([Cl:20])[C:16]([F:21])=[C:15]2[C:10]=1[C:11](=[O:30])[C:12]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:13][N:14]2[CH:22]1[CH2:24][CH2:23]1)C1C=CC=CC=1.[H][H]>C(O)(=O)C.C(O)C.[Pd]>[NH2:8][C:9]1[C:18]([F:19])=[C:17]([Cl:20])[C:16]([F:21])=[C:15]2[C:10]=1[C:11](=[O:30])[C:12]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:13][N:14]2[CH:22]1[CH2:23][CH2:24]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(Cl)c(F)c(NCc3ccccc3)c2c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(Cl)c(F)c(N)c2c1=O
Reaction time: 3 h
Yield: 83.8 %

Procedure:
To a solution of 48.0 g of ethyl 5-benzylamino-1-cyclopropyl-7-chloro-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate (0.111 mol) dissolved in a mixture of 200 ml of acetic acid and ethanol was added 0.5 g of 5% Pd/C catalyst. Hydrogen gas was introduced at room temperature. The reaction was monitored with TLC and carried out for around 3 hours. Precipitates collected by filtration were dissolved in chloroform and filtered to remove the catalyst. After removing the solvent by evaporation, the residue was recrystallized from a mixture of chloroform and ethanol to give 32.0 g of ethyl 5-amino-1-cyclopropyl-7-chloro-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate (0.093 mol) in 83.9% yield.
Reaction SMILES: [CH3:1][C:2]([NH:45]C(=O)OC(C)(C)C)([CH2:36][O:37][Si](C)(C)C(C)(C)C)[C:3](=[O:35])[NH:4][C@@H:5]([C:15]([N:17]1[CH2:34][CH2:33][CH2:32][C:19]2([C:23](=[O:24])[N:22]([CH3:25])[CH2:21][CH:20]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:18]1)=[O:16])[CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.CCOCC.O>>[NH2:45][C@:2]([CH3:1])([CH2:36][OH:37])[C:3]([NH:4][C@H:5]([CH2:6][O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:15]([N:17]1[CH2:34][CH2:33][CH2:32][C:19]2([C:23](=[O:24])[N:22]([CH3:25])[CH2:21][CH:20]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:18]1)=[O:16])=[O:35]
Reactant: CN1CC(c2ccccc2)C2(CCCN(C(=O)[C@@H](COCc3ccccc3)NC(=O)C(C)(CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C)C2)C1=O
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: CN1CC(c2ccccc2)C2(CCCN(C(=O)[C@@H](COCc3ccccc3)NC(=O)[C@](C)(N)CO)C2)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture comprising tert-butyl (4R)-7,10,10,11,11-pentamethyl-4-(2-methyl-1-oxo-4-phenyl-2,7-diazaspiro[4.5]decane-7-carbonyl)-6-oxo-1-phenyl-2,9-dioxa-5-aza-10-siladodecan-7-ylcarbamate (Intermediate from step 4) (140 mg, 0.190 mmol) and 2M HCl in Et2O (2.9 mL, 5.70 mmol) was treated with water (300 mg, 16.65 mmol) dropwise and stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo. The resulting crude was dried in a vacuum oven for 24 hours at 50° C. to afford the title compound. No purification was performed on the title compound.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:21][C:22]([O:24]C)=O)[C:7]([NH:9][C@H:10]([C:18]([OH:20])=[O:19])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:17])[NH2:16])=[O:8])(=O)C.C(SCC(CC(OC)=O)C([N:34]1CCC[C@H]1C(O)=O)=O)(=O)C>>[SH:4][CH2:5][CH:6]([CH2:21][C:22](=[O:24])[NH2:34])[C:7]([NH:9][C@H:10]([C:18]([OH:20])=[O:19])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:17])[NH2:16])=[O:8]
Reactant: COC(=O)CC(CSC(C)=O)C(=O)N1CCC[C@H]1C(=O)O
Reactant: COC(=O)CC(CSC(C)=O)C(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Product: N=C(N)NCCC[C@H](NC(=O)C(CS)CC(N)=O)C(=O)O

Procedure:
By substituting Nα -[3-(acetylthio)-2-(methoxycarbonylmethyl)propanoyl]-L-arginine for the 1-[3-(acetylthio)-2-(methoxycarbonylmethyl)propanoyl]-L-proline in the procedure of Example 6A, and then isolating the product with Dowex 50 resin as described in the procedure of Example 17, Nα -[3-mercapto-2-(carbamoylmethyl)propanoyl]-L-arginine is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:9][N:8]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[C:5]2=[CH:6][N:7]=1.C([Sn]([C:36]1[C:37](=[O:41])[O:38][CH2:39][CH:40]=1)(CCCC)CCCC)CCC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[C:11]1([C:10]2[C:4]3[C:5](=[CH:6][N:7]=[C:2]([C:40]4[CH2:39][O:38][C:37](=[O:41])[CH:36]=4)[CH:3]=3)[N:8]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[N:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCOC1=O
Reactant: Brc1cc2c(-c3ccccc3)nn(C3CCCCO3)c2cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: O=C1C=C(c2cc3c(-c4ccccc4)nn(C4CCCCO4)c3cn2)CO1
Temperature: 110 °C
Reaction time: 72 h
Yield: 32.1 %

Procedure:
A high-pressure reaction vessel was charged with 5-bromo-3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine (400.0 mg, 1.12 mmol), bis(triphenylphosphine)palladium(II) chloride (79.0 mg, 0.11 mmol), and anhydrous toluene (8.0 mL). Tributylstannanyl-5H-furan-2-one (437.5 mg, 1.17 mmol) was added, and the reaction mixture was vacuum-purged and back filled with nitrogen (3×). The vessel was sealed, and the reaction mixture was stirred at 110° C. for 3 days. The reaction was cooled to RT and slowly poured into saturated aqueous sodium bicarbonate solution (30 mL). The resultant mixture was extracted with ethyl acetate (3×75 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified using flash column chromatography (Si-PPC gradient elution, solvent: 0-100% ethyl acetate in heptanes) to give 4-(3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)furan-2(5H)-one as white solid (130.0 mg, 32.2%). LC/MS: m/z 362.3 [M+1].
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4](S(C)(=O)=O)[N:3]=1.[NH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4]([NH:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[N:3]=1
Reactant: NCCN1CCOCC1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccc3c(c2)OCO3)c1C#N
Solvent: COCCOC
Product: N#Cc1c(NCCN2CCOCC2)nc(N)nc1-c1ccc2c(c1)OCO2

Procedure:
From 2-amino-4-benzo[1,3]dioxol-5-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile and 4-(2-aminoethyl)morpholine in DME. ES-MS m/e (%): 369 (M+H+, 100), 282 ([M+H—C4H9NO]+, 75).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[F:7][C:8]1[CH:9]=[C:10]([CH:15]2[CH2:20][C:19](=O)[CH2:18][CH2:17][N:16]2[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH:11]=[CH:12][C:13]=1[F:14]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.CCCCCC>[F:7][C:8]1[CH:9]=[C:10]([CH:15]2[CH2:20][C:19](=[CH2:1])[CH2:18][CH2:17][N:16]2[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH:11]=[CH:12][C:13]=1[F:14]
Reactant: CC(C)(C)[O-]
Reactant: O=C1CCN(C(=O)OCc2ccccc2)C(c2ccc(F)c(F)c2)C1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=C1CCN(C(=O)OCc2ccccc2)C(c2ccc(F)c(F)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
Potassium tert-butoxide (0.81 g, 7.2 mmol) was added to a suspension of methyltriphenylphosphonium bromide (2.58 g, 7.2 mmol) in tetrahydrofuran (20 mL) and the resulting mixture was stirred at room temperature for one hour. A solution of phenylmethyl 2-(3,4-difluorophenyl)-4-oxopiperidine-1-carboxylate (1.00 g, 2.9 mmol) (reagent preparation 20) in tetrahydrofuran (5 mL) was added and the resulting mixture was stirred at 35° C. for two hours. The mixture was cooled, diluted with hexane (100 mL), filtered, and the filtrate washed with water then brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (20% ethyl acetate in hexanes) to give phenylmethyl 2-(3,4-difluorophenyl)-4-methylidenepiperidine-1-carboxylate (0.79 g, 79% yield), MS (EI) for C20H19F2NO2: 344 (MH+).
Reaction SMILES: [CH:1](/[N:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:2]\[CH3:3].CO>ClCCl>[CH:1]([N:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:2][CH3:3]
Reactant: C/C=C/n1c2ccccc2c2ccccc21
Solvent: ClCCl
Solvent: CO
Product: CC=Cn1c2ccccc2c2ccccc21

Procedure:
In a vial, 0.5 g of trans-9-(1-propenyl)carbazole and 0.013 g of IOC10 (2 mole % based on 9-(1-propenyl)carbazole) were dissolved in 1 mL of dichloromethane. The solution was exposed to UV light using a GE H3T-7 200 W medium pressure mercury arc lamp for 3 minutes and then poured into methanol. After filtering and drying the resulting precipitated oligomer in a vacuum oven, a yield of 0.25 g (50%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26])[N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH2:17][C:18]#[N:19])[CH2:11][CH2:10]1.[H][H]>O1CCOCC1.C(O)C.[Ni]>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])[CH2:11][CH2:10]1
Reactant: N#CCCCC1CCN(C(c2ccccc2Cl)c2ccccc2Cl)CC1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Solvent: C1COCCO1
Product: NCCCCC1CCN(C(c2ccccc2Cl)c2ccccc2Cl)CC1

Procedure:
8.0 g (20.6 mmol) 4-{1-[bis(2-chlorophenyl)-methyl]-piperidin-4-yl}-butyronitrile are dissolved in 240 ml dioxane/ethanol (1/5) and added to 1.5 g Raney-nickel. The mixture is stirred at RT under hydrogen atmosphere until uptake of the theoretical amount of hydrogen. The reaction solution is filtered from the catalyst and the solvent is removed under vacuum. The residue is dispersed between 100 ml 10% sodium hydroxide solution and 300 ml acetic acid ethyl ester. The organic phase is dried with sodium sulfate and the solvent is removed under vacuum. The resin is processed further without additional purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.ClC1C=CC=C2C=1N([CH2:21][CH2:22][C:23]#[C:24][Si:25]([CH3:28])([CH3:27])[CH3:26])N=C2>>[Cl:1][C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH2:21][CH2:22][C:23]#[C:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C#CCCn1ncc2cccc(Cl)c21
Reactant: Clc1cccc2cn[nH]c12
Product: C[Si](C)(C)C#CCCn1cc2cccc(Cl)c2n1
Yield: 63 %

Procedure:
The title compounds were prepared in accordance with the general method of Example 108(A), from 7-chloro-1H-indazole (220 mg, 1.44 mmol) to yield 250 mg (0.90 mmol, 63%) of 7-chloro-2-(4-trimethylsilanyl-but-3-ynyl)-2H-indazole and 7-chloro-1-(4-trimethylsilanyl-but-3-ynyl)-1H-indazole.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:8])=[CH:3]\[C:4]([O:6][CH3:7])=[O:5].[CH3:9][S:10]([OH:13])(=[O:12])=[O:11].[H][H]>CO>[CH3:9][S:10]([OH:13])(=[O:12])=[O:11].[NH2:1][C@H:2]([CH3:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)/C=C(/C)N
Reactant: [H][H]
Agent: CS(=O)(=O)O
Solvent: CO
Product: COC(=O)C[C@@H](C)N
Yield: 61.2 %

Procedure:
Under a nitrogen atmosphere, 78.0 mg (0.0869 mmol) of Ru(OCOCH3)2((R)-tol-binap), 1.00 g (8.69 mmol) of methyl 3-aminocrotonate, 0.83 g (8.69 mmol) of methanesulfonic acid and 5 ml of methanol were placed in a stainless steel autoclave, and the mixture was kept at 50° C. under 3MPa pressure of hydrogen for 15 hours with stirring. After completion of the reaction, the solvent was distilled off, and the residue was recrystallized from methanol/ethyl acetate to give the objective methyl (R)-3-aminobutanoate methanesulfonate (1.135 g, white crystals). The yield was 61.3%.
Reaction SMILES: [CH:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:10]([Mg]Br)[CH:11]=[CH2:12]>CCOCC>[CH2:10]=[CH:11][CH2:12][CH:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC=O
Reactant: C=CC[Mg]Br
Solvent: CCOCC
Product: C=CCC(O)CCCCCCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
To a solution of 1.2 mL (7.8 mmol) of octanal in 30 mL of ether was added 15.6 mL of a 1.0 M solution of allylmagnesium bromide in ether. The reaction was allowed to stir at room temperature for 18 h and then quenched with saturated NH4Cl. The product was extracted with ether (2×20 mL), dried over Na2SO4 and filtered. The solvent was removed under reduced pressure and the remaining residue was purified by flash chromatography to give 0.79 g (60%) of the allylic alcohol. 1H NMR (400 MHz, CDCl3) δ 5.80-5.70 (m, 1H), 5.04-4.99 (m, 2H), 3.53 (m, 1H), 2.52 (br s, 1H), 2.20-2.05 (m, 2H), 1.381-34 (m, 2H), 1.25-1.15 (m, 10H), 0.80 (t, J=7.1 Hz, 3H); 13C NMR (400 MHz, CDCl3) δ 133.6, 116.3, 70.6, 42.5, 37.5, 32.7, 30.6, 30.2, 26.7, 23.7, 15.2.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([Si](C(C)C)(C(C)C)C(C)C)[CH:3]=1.C([Mg]Cl)(C)C.Cl[C:27]1[N:28]=[C:29]([N:34]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=2)[CH3:35])[S:30][C:31]=1[CH:32]=[O:33]>O1CCCC1>[Cl:43][C:40]1[CH:41]=[CH:42][C:37]([CH2:36][N:34]([CH3:35])[C:29]2[S:30][C:31]([C:32]([C:2]3[C:10]4[C:5](=[N:6][CH:7]=[CH:8][CH:9]=4)[NH:4][CH:3]=3)=[O:33])=[CH:27][N:28]=2)=[CH:38][CH:39]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cccnc21
Reactant: CN(Cc1ccc(Cl)cc1)c1nc(Cl)c(C=O)s1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CN(Cc1ccc(Cl)cc1)c1ncc(C(=O)c2c[nH]c3ncccc23)s1
Temperature: 0 °C
Yield: 93.3 %

Procedure:
To a solution of 3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (96, 0.82 g, 2.0 mmol) in tetrahydrofuran (5 mL) at −20° C., isopropylmagnesium chloride (2 M in tetrahydrofuran, 1.1 mL, 2.2 mmol) was added dropwise. The reaction mixture was allowed to warm to 0° C. in 10 minutes. The reaction mixture was then cooled to −40° C. To the reaction mixture was added a solution of 4-chloro-2-[(4-chloro-benzyl)-methyl-amino]-thiazole-5-carbaldehyde (551, 0.41 g, 1.4 mmol) in tetrahydrofuran (10 mL). The reaction mixture was allowed to warm to −10° C. in 30 minutes. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexanes to provide the desired compound as a yellow solid (552, 0.5 g, 60%). MS (ESI) [M+H+]+=575.29.
Reaction SMILES: [Li]CCCC.[Cl:6][C:7]1[CH:8]=[C:9]([CH3:14])[CH:10]=[C:11]([F:13])[CH:12]=1.[CH:15](N1CCOCC1)=[O:16]>C1COCC1>[Cl:6][C:7]1[CH:8]=[C:9]([CH3:14])[CH:10]=[C:11]([F:13])[C:12]=1[CH:15]=[O:16]
Reactant: O=CN1CCOCC1
Reactant: Cc1cc(F)cc(Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(F)c(C=O)c(Cl)c1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
Under Ar, a 2.5M solution of n-BuLi (6.0 mL, 15.0 mmol) was added slowly to a solution of 3-chloro-5-fluorotoluene (2.0, 13.8 mmol) in THF (20 mL) cooled in a dry ice/acetone bath at approximately −70° C. After the addition was complete, the reaction was stirred for 1 h at approximately −70° C. and a solution of N-formylmorpholine (2.3 g, 2.0 mmol) in THF (10 mL) was added dropwise. After stirring for 10 min, the reaction was allowed to warm to rt with stirring over 1 h, then cooled to −30° C. and quenched by the addition of H2O then 1M citric acid. The mixture was allowed to warm to rt with stirring and the phases were separated. The aqueous phase was extracted with EtOAc and the combined organic phases were washed with H2O, dried with MgSO4 and concentrated to yield the title compound as an oil which solidified on standing (2.2 g, 12.8 mmol).
Reaction SMILES: [C:1]([S:4][CH:5]1[CH2:10][CH2:9][N:8](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:7]/[C:6]/1=[CH:30]\[C:31]1[N:35]([CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[N:34]=[N:33][CH:32]=1)(=[O:3])[CH3:2].[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>ClCCl>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[C:1]([S:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7]/[C:6]/1=[CH:30]\[C:31]1[N:35]([CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[N:34]=[N:33][CH:32]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)CCn1nncc1/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1SC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CCn1nncc1/C=C1\CNCCC1SC(C)=O
Temperature: 0 °C
Yield: 61 %

Procedure:
To a solution of (E)-4-(acetylsulfanyl)-3-({1-[2-(methoxycarbonyl)ethyl]-1H-1,2,3-triazol-5-yl}methylidene)-1-(triphenylmethyl)piperidine (4.27 g) in dichloromethane (100 ml) was added trifluoroacetic acid (1.2 ml) with stirring at 0° C. The resulting mixture was stirred at 0° C. for 15 minutes and the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography using dichloromethane and methanol (10:1) as the eluent to afford the title compound (2.0 mg, yield: 61%) as a yellow amorphous solid.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[C:4]([NH2:14])=[C:5]([NH2:13])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[N:17]([CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][CH2:21]1)=[C:18]=S>>[F:10][C:9]([F:12])([F:11])[C:7]1[CH:8]=[C:3]([C:2]([F:15])([F:16])[F:1])[C:4]2[N:14]=[C:18]([NH:17][CH:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:23][CH2:22][CH2:21]3)[NH:13][C:5]=2[CH:6]=1
Reactant: S=C=NC1CCCc2ccccc21
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1N
Product: FC(F)(F)c1cc(C(F)(F)F)c2nc(NC3CCCc4ccccc43)[nH]c2c1

Procedure:
The title compound was prepared from 3,5-bis(trifluoromethyl)-1,2-diaminobenzene and 1-isothiocyanato-1,2,3,4-tetrahydronaphthalene by Procedure D. The title compound was isolated by column chromatography as the free base and as a mixture of enantiomers (solid, dec. >240° C.). MS(ES+) m/z 400 ([M+1]+, 100).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[C:13]([C:16]([OH:18])=[O:17])[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:19]=1.[CH3:20]N(C)C=O.C(=O)([O-])[O-].[K+].[K+].CI>O>[CH3:20][O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[C:13]([C:16]([OH:18])=[O:17])[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:19]=1
Reactant: CN(C)C=O
Reactant: O=C(O)c1ccc2c(c1)Sc1ccc(O)cc1C=C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: COc1ccc2c(c1)C=Cc1ccc(C(=O)O)cc1S2

Procedure:
1 G. 8-hydroxydibenzo[b,f]thiepin-3-carboxylic acid is stirred in 50 cc. dimethylformamide with 1.5 g. potassium carbonate and 3 cc. methyl iodide. 100 cc. water is added to the reaction mixture, heated for three hours and then extracted with ethyl acetate, and the aqueous layer acidified. The precipitated solid is filtered, washed with water and a small volume of cold methanol, and dried. Yield of the desired material 700 mg.
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]([CH2:7][C@@:8]2([CH3:29])[N:12]3[C:13]([C:16](O)=[O:17])=[CH:14][N:15]=[C:11]3[N:10]([C:19]3[CH:24]=[C:23]([Cl:25])[C:22]([F:26])=[C:21]([Cl:27])[CH:20]=3)[C:9]2=[O:28])=[CH:5][CH:4]=1)#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.Cl.[CH2:66]([O:69][C:70]([C:72]1([NH2:75])[CH2:74][CH2:73]1)=[O:71])[CH:67]=[CH2:68]>C1COCC1>[CH2:66]([O:69][C:70]([C:72]1([NH:75][C:16]([C:13]2[N:12]3[C@@:8]([CH2:7][C:6]4[CH:30]=[CH:31][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)([CH3:29])[C:9](=[O:28])[N:10]([C:19]4[CH:20]=[C:21]([Cl:27])[C:22]([F:26])=[C:23]([Cl:25])[CH:24]=4)[C:11]3=[N:15][CH:14]=2)=[O:17])[CH2:74][CH2:73]1)=[O:71])[CH:67]=[CH2:68]
Reactant: C=CCOC(=O)C1(N)CC1
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)c(F)c(Cl)c2)c2ncc(C(=O)O)n21
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
Product: C=CCOC(=O)C1(NC(=O)c2cnc3n2[C@](C)(Cc2ccc(C#N)cc2)C(=O)N3c2cc(Cl)c(F)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
(R)-5-(4-Cyano-benzyl)-7-(3,5-dichloro-4-fluoro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid (10 g, 22 mmol), was added to a 500 mL round bottomed flask containing THF (100 mL). To this solution was added HATU (9.1 g, 24 mmol), diisopropylethylamine (11 mL, 65 mmol) and 1-amino-cyclopropane-carboxylic acid allyl ester hydrochloride (4.3 g, 24 mmol). The reaction was allowed to stir at room temperature for 18 h. The organics were washed with water (2×30 mL) and brine (1×30 mL) then dried (MgSO4) and concentrated to afford crude 1-{[(R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-4-fluoro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazol[1,2-a]imidazole-3-carbonyl]-amino}-cyclopropanecarboxylic acid allyl ester (12.6 g, 22 mmol) which was taken onward without further purification.