Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[S:3])=S.[CH2:4]([O:6][CH2:7][CH2:8][N:9]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[N:11]=[C:10]1[CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH2:27])[CH2:21][CH2:20]1)[CH3:5]>O1CCCC1>[CH2:4]([O:6][CH2:7][CH2:8][N:9]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[N:11]=[C:10]1[CH2:18][CH:19]1[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][N:27]=[C:1]=[S:3])[CH2:23][CH2:24]1)[CH3:5]
Reactant: S=C=S
Reactant: CCOCCn1c(CC2CCN(CCN)CC2)nc2cccnc21
Solvent: C1CCOC1
Product: CCOCCn1c(CC2CCN(CCN=C=S)CC2)nc2cccnc21
Yield: 100 %

Procedure:
To a stirred and cooled (-10° C.) mixture of 15 parts of carbon disulfide, 6.2 parts of N,N-methanetetraylbis[cyclohexanamine] and 90 parts of tetrahydrofuran was added dropwise a solution of 8.6 parts of 4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl]-1-piperidineethanamine in tetrahydrofuran. Upon complete addition, the reaction mixture was stirred for 1 hour at room temperature. The whole was evaporated, yielding 11.2 parts (100%) of 3-(2-ethoxyethyl)-2-[[1-(2-isothiocyanatoethyl)-4-piperidinyl]methyl]-3H-imidazo[4,5-b]pyridine as a residue (compound 136).
Reaction SMILES: [CH2:1]([N:8]1[C@H:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][C:11](=[O:21])[CH:10](C(OC)=O)[C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[C@H:13]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:12][C:11](=[O:21])[CH2:10][C:9]1=[O:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1C(=O)C[C@@H](Cc2ccccc2)N(Cc2ccccc2)C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: O=C1CC(=O)N(Cc2ccccc2)[C@H](Cc2ccccc2)C1
Temperature: 25 °C

Procedure:
A solution of 106.1 g (0.301 mol) of methyl (6R)-1,6-dibenzyl-2,4-dioxo3-piperidine carboxylate in 298 ml of toluene and 445 ml of 10% strength (vol/vol) acetic acid is heated at 80° for 21/2 hours. The reaction mixture is cooled to room temperature, neutralised by adding 48 g of solid sodium carbonate while cooling in ice-water, the phases are separated, and the aqueous phase is extracted once more with 300 ml of ethyl acetate. The combined organic phases are washed with water, then with brine dried over sodium sulfate and evaporated to dryness. The resulting oil is crystallised from ether, resulting in the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH:12]=1.[H][H]>C(O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: [H][H]
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Agent: [Pd]
Solvent: CCO
Product: Fc1ccc2[nH]cc(C3CCNCC3)c2c1
Yield: 76.1 %

Procedure:
To a solution of 10.75 gm (50 mMol) 5-fluoro-3-[1,2,5,6-tetrahydro-4-pyridyl]-1H-indole in 500 mL ethanol were added 2.0 gm 5% palladium on carbon and the reaction mixture hydrogenated at ambient temperature for 18 hours at an initial hydrogen pressure of 60 p.s.i. The reaction mixture was then filtered through a pad of celite and the filtrate concentrated under reduced pressure to give an off-white solid. The solid was recrystallized from methanol to give 8.31 gm (76.2%) of the title compound as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:27])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23]Br)=[C:17]([O:25][CH3:26])[CH:16]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+].[CH2:34]([NH2:37])[CH2:35][NH2:36]>CS(C)=O.ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:27])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][NH:36][CH2:35][CH2:34][NH2:37])=[C:17]([O:25][CH3:26])[CH:16]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: COc1cc(CC(=O)NCCCc2ccc(C)c(C)c2)ccc1OCCBr
Reactant: NCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1cc(CC(=O)NCCCc2ccc(C)c(C)c2)ccc1OCCNCCN
Temperature: 25 °C
Reaction time: 4 h
Yield: 29.9 %

Procedure:
0.35 g (0.81 mmol) of N-{3-(3,4-dimethylphenyl)propyl}-4-(2-bromoethoxy)-3-methoxyphenylacetamide obtained in step 1 of Example 2 was dissolved in 3 ml of dimethylsulfoxide and 0.56 g (4.02 mmol) of potassium carbonate was added thereto. To this mixture, 0.48 g (8.06 mmol) of ethylenediamine was slowly added at room temperature, followed by stirring at room temperature for 4 hours. The reaction mixture was diluted with 40 ml of dichloromethane, washed with water and acidified with 1N HCl and the aqueous layer was separated. The aqueous layer was basified with hydrogen peroxide, extracted with 40 ml of dichloromethane, dried and the solvent was removed under a reduced pressure. The residue was triturated with a mixture of dichloromethane and hexane(1:2) to obtain 0.10 g of the title compound as a white solid(yield: 30%).
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([NH:7][CH2:8][C:9]2[CH:10]=[C:11]([C:15](O)=[O:16])[O:12][C:13]=2[CH3:14])=[CH:3][CH:2]=1.[C:24]1([S:30]([NH2:33])(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>CN(C1C=CN=CC=1)C.O1CCCC1.C(#N)C>[C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:2]=[CH:3][C:4]([NH:7][CH2:8][C:9]2[CH:10]=[C:11]([C:15]([NH:33][S:30]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:32])=[O:31])=[O:16])[O:12][C:13]=2[CH3:14])=[CH:5][CH:6]=1
Reactant: Cc1oc(C(=O)O)cc1CNc1ccc(-c2ccccc2)cc1
Reactant: NS(=O)(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: C1CCOC1
Product: Cc1oc(C(=O)NS(=O)(=O)c2ccccc2)cc1CNc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 49.8 %

Procedure:
A stirred solution of 4-(biphenyl-4-ylaminomethyl)-5-methyl-furan-2-carboxylic acid (160) (15 mg, 0.036 mmoles), benzenesulphonamide (17 mg, 0.107 mmoles) and 4-(N,N-dimethylamino)-pyridine (1 mg) in a mixture of tetrahydrofuran (3 ml) and acetonitrile (0.5 ml) was treated with triethylamine (5.5 μl, 0.039 mmoles) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (10.5 mg, 0.053 mmoles). The mixture was stirred at room temperature for 19 hours under an argon atmosphere. The reaction mixture was concentrated in vacuo and the residue was purified by HPLC to afford compound 161 (8 mg) as a white solid. LC/MS System D; Rt=8.84 mins, m/z (ES+)=447 (M+H for C25H22N2O4S).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH2:5][S:4][C:3]1=[S:8].[C:9]([O:12][C:13](=O)C)(=O)[CH3:10]>C([O-])([O-])OCC>[CH2:9]([O:12][CH:13]=[C:5]1[S:4][C:3](=[S:8])[N:2]([CH3:1])[C:6]1=[O:7])[CH3:10]
Reactant: CN1C(=O)CSC1=S
Reactant: CC(=O)OC(C)=O
Agent: CCOC([O-])[O-]
Product: CCOC=C1SC(=S)N(C)C1=O

Procedure:
3-Methyl-4-oxo-thiazolidine-2-thione (403 g) and ethyl orthoformate (1370 ml) were added to acetic anhydride (775 ml), and the mixture was refluxed for 6 hours. The mixture was allowed to stand, and the resulting crystals were collected by filtration and washed with diisopropyl ether to give 342 g of 5-ethoxymethylene-3-methyl-4-oxo-thiazolidine-2-thione.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]([CH2:23][CH2:24][C:25]([NH:27][NH2:28])=[O:26])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:29](OCC)(OCC)(OCC)[CH3:30]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:14])=[O:15])[CH:11]([CH2:23][CH2:24][C:25]3[O:26][C:29]([CH3:30])=[N:28][N:27]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N2C(CCC(=O)NN)CCC2c2ccc(F)cc2)cc1
Reactant: CCOC(C)(OCC)OCC
Product: Cc1ccc(S(=O)(=O)N2C(CCc3nnc(C)o3)CCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, light yellow oil, MS: m/e=430.2 (M+H+), was prepared in accordance with the general method of example 127 from (2RS,5SR)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionic acid hydrazide and triethyl orthoacetate.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:6][C:5]1([C:11]([O-:13])=O)[C:7]([O:9][CH3:10])=[O:8])[CH2:2][CH3:3].ClC(OCC)=O.[Br:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[C:23]([CH3:28])[CH:22]=1.C(N(CC)CC)C>>[Br:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:11]([C:5]2([C:7]([O:9][CH3:10])=[O:8])[CH2:6][CH:4]2[CH2:1][CH2:2][CH3:3])=[O:13])=[C:23]([CH3:28])[CH:22]=1
Reactant: CCCC1CC1(C(=O)[O-])C(=O)OC
Reactant: Cc1cc(Br)ccc1N
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Product: CCCC1CC1(C(=O)Nc1ccc(Br)cc1C)C(=O)OC
Yield: 53.8 %

Procedure:
Monomethyl 2-(n-propyl)cyclopropane-1,1-dicarboxylate (2.47 grams, 0.013 mole) from Part B, above, ethyl chloroformate (1.44 grams, 0.013 mole) and 4-bromo-2-methylaniline (2.48 grams, 0.013 mole) were reacted sequentially in the presence of triethylamine (1.35 grams, 0.013 mole) in a manner similar to that described In Example XXXIII to give 2.43 grams (0.007 mole) of methyl 1-(4-bromo-2-methyl-phenylaminocarbonyl)-2-n-propylcyclopropanecarboxylate having a melting point of 60° C.-66° C. Elemental analysis of the product indicated the following:
Reaction SMILES: Br[CH:2]1[CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([C:12]#[N:13])[CH:6]=[CH:5][C:4]=2[C:3]1=[O:14].[N-:15]=[N+:16]=[N-:17].[Na+]>CN(C=O)C.C(O)(=O)C.O>[N:15]([CH:2]1[CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([C:12]#[N:13])[CH:6]=[CH:5][C:4]=2[C:3]1=[O:14])=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc2c(c1)CCC(Br)C2=O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: N#Cc1ccc2c(c1)CCC(N=[N+]=[N-])C2=O
Reaction time: 1 h
Yield: 40 %

Procedure:
To a solution of racemic 6-bromo-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (100 mg, 0.4 mmol) in DMF (2611 mL) and acetic acid (65.3 mL) was added a solution of sodium azide (52.0 mg, 0.8 mmol) in water (522 mL) dropwise at 0° C. After 1 hour, the reaction was complete. The mixture was directly loaded to a 24 g ISCO column and purified by ISCO Combiflash Companion (0% ethyl acetate-hexane for 3 min then ramped to 20% ethyl acetate-hexane over 7 min then 20% ethyl acetate-hexane for 5 more minutes. The product came out 8-10 min) to afford racemic 6-azido-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (35 mg, 0.16 mmol, 41.2%) as a white solid: LCMS=213.22 [M+H]+.
Reaction SMILES: [CH2:1]([O:4][C:5]([O:7][CH2:8][C:9]1[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][C:10]=1[C:11]([O:13]CC1C=CC(OC)=CC=1)=[O:12])=[O:6])[CH:2]=[CH2:3].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[CH2:1]([O:4][C:5]([O:7][CH2:8][C:9]1[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][C:10]=1[C:11]([OH:13])=[O:12])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)OCc1ccc(C#N)cc1C(=O)OCc1ccc(OC)cc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: C=CCOC(=O)OCc1ccc(C#N)cc1C(=O)O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 94.5 %

Procedure:
A mixture of 4-methoxybenzyl 2-[(allyloxycarbonyl)oxymethyl]-5-cyanobenzoate (3 g, 7.9 mmol) and anisole (3.5 g) was cooled to 0° C., and trifluoroacetic acid (10 ml) was added thereto. The mixture was stirred at room temperature for 15 minutes, diluted with toluene, and the solvent was distilled off under reduced pressure. The residue was subjected to chromatography on a silica gel (35 g) column (eluent; dichloromethane:ethyl acetate=1:1) to afford the title compound (1.95 g, 95% yield) as a colorless solid (mp. 81-83° C.)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].Br[CH2:14][CH:15]1[CH2:17][CH2:16]1>>[CH:15]1([CH2:14][N:9]2[C:10]3[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=3)[CH:7]=[N:8]2)[CH2:17][CH2:16]1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Reactant: BrCC1CC1
Product: O=[N+]([O-])c1ccc2c(cnn2CC2CC2)c1

Procedure:
Synthesized as described in Example 4 using 5-nitro-1H-indazole and (bromomethyl)cyclopropane to afford a mixture of regioisomers. The following data are for the title regioisomer: 1H NMR (400 MHz, CDCl3) δ 8.73 (d, J=2.0 Hz, 1H), 8.26 (dd, J=9.3 and 2 Hz, 1H), 8.20 (s, 1H), 7.48 (d, J=9.3 Hz, 1H), 4.31 (d, J=6.8 Hz, 2H), 1.35 (m, 1H), 0.62 (m, 2H), 0.44 (m, 2H); MS (ES) m/z 218(M+1).
Reaction SMILES: [CH:1]1[CH2:7][CH2:6][CH2:5][CH:4]=[CH:3][CH:2]=1.[Cl:8][SiH:9]([Cl:11])[Cl:10]>[Cl-].C([P+](CCCC)(CCCC)CCCC)CCC>[Cl:8][Si:9]([Cl:11])([Cl:10])[C:2]([CH2:3][CH2:4][CH2:5][CH:6]([Si:9]([Cl:11])([Cl:10])[Cl:8])[CH3:7])=[CH2:1]
Reactant: Cl[SiH](Cl)Cl
Reactant: C1=CCCCC=C1
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Product: C=C(CCCC(C)[Si](Cl)(Cl)Cl)[Si](Cl)(Cl)Cl
Temperature: 180 °C
Yield: 24.8 %

Procedure:
As in Example 1, 1,3-cycloheptadiene (1.00 g, 10.62 mmol), trichlorosilane (5.76 g, 42.52 mmol) and tetrabutylphosphonium chloride (0.31 g, 1.05 mmol) were added in a 25 mL stainless steel tube under nitrogen atmosphere. After sealing the cylinder with a cap, the reactor was maintained at 180° C. for 18 hours. The resulting mixture was distilled to yield 0.96 g (yield: 25%) of 2,6-bis(trichlorosilyl)-1-heptene.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[C:14]([O:15][CH:16]2[CH2:20][CH2:19][N:18]([CH:21]3[CH2:24][O:23][CH2:22]3)[CH2:17]2)=[CH:13][C:12]([C:25]#[N:26])=[CH:11][C:10]=1[NH:27][C:28]1[N:33]=[C:32]([N:34]([CH:44]2[CH2:46][CH2:45]2)CC2C=CC(OC)=CC=2)[C:31]2=[N:47][CH:48]=[C:49]([C:50]#[N:51])[N:30]2[N:29]=1.C1(OC)C=CC=CC=1>ClCCCl>[Cl:8][C:9]1[C:14]([O:15][CH:16]2[CH2:20][CH2:19][N:18]([CH:21]3[CH2:22][O:23][CH2:24]3)[CH2:17]2)=[CH:13][C:12]([C:25]#[N:26])=[CH:11][C:10]=1[NH:27][C:28]1[N:33]=[C:32]([NH:34][CH:44]2[CH2:45][CH2:46]2)[C:31]2=[N:47][CH:48]=[C:49]([C:50]#[N:51])[N:30]2[N:29]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(OC4CCN(C5COC5)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCCl
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(OC2CCN(C3COC3)C2)c1
Temperature: 60 °C
Yield: 72.1 %

Procedure:
TFA (25% in DCE, 2 ml, 26.0 mmol) was added to a solution of (+/−)-2-((2-chloro-5-cyano-3-((1-(oxetan-3-yl)pyrrolidin-3-yl)oxy)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (38 mg, 0.062 mmol) and anisole (0.027 ml, 0.248 mmol) in DCE (1 mL) and the reaction mixture was heated at 60° C. for 2 hours. Solvent was evaporated in vacuo and the residue was dried under vacuum overnight. The crude was trituated with hexane 3×1 ml, dissolved in acetonitrile and neutralized with 2N ammonia in methanol. Solvent was evaporated to give a solid which was purified by flash chromatography on silica gel using an automated ISCO system (24 g gold column, eluting with 1-4% 2 N ammonia in methanol/dichloromethane). (+/−)-2-((2-chloro-5-cyano-3-((1-(oxetan-3-yl)pyrrolidin-3-yl)oxy)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (22 mg) was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C@@H:9]([NH2:15])[CH2:10][CH2:11][S:12]2)=[CH:7][C:6]=1[Cl:16])=[O:4].[CH2:17]([O:24][C:25](Cl)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C@@H:9]([NH:15][C:25]([O:24][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:26])[CH2:10][CH2:11][S:12]2)=[CH:7][C:6]=1[Cl:16])=[O:4]
Reactant: COC(=O)c1cc2c(cc1Cl)[C@@H](N)CCS2
Reactant: O=C(Cl)OCc1ccccc1
Product: COC(=O)c1cc2c(cc1Cl)[C@@H](NC(=O)OCc1ccccc1)CCS2

Procedure:
By a similar reaction operation as in Starting Material Synthetic Example 4 using (S)-4-amino-6-chlorothiochromane-7-carboxylic acid methyl ester (450 mg) and benzyloxycarbonyl chloride (0.31 ml), the objective (S)-4-(benzyloxycarbonylamino)-6-chlorothiochromane-7-carboxylic acid methyl ester (478 mg) was obtained as colorless crystals.
Reaction SMILES: CC(N)CC.O[CH2:7][CH2:8][NH:9][CH:10]([CH2:12][CH3:13])[CH3:11].O=S(Cl)[Cl:16]>>[Cl-:16].[Cl:16][CH2:7][CH2:8][NH2+:9][CH:10]([CH2:12][CH3:13])[CH3:11]
Reactant: O=S(Cl)Cl
Reactant: CCC(C)NCCO
Agent: CCC(C)N
Product: CCC(C)[NH2+]CCCl
Product: [Cl-]

Procedure:
2-Butylamine was converted to N-(2-hydroxyethyl)-N-(2-butyl)amine according to Method B5a. The amine was reacted with SOCl2 according to Method B7a to give N-(2-chloroethyl)-N-(2-butyl)ammonium chloride. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to give to give 2-(2-methyl-4-nitrophenylimino)-3-(2-butyl)-1,3-thiazolidine.
Reaction SMILES: [CH2:1]([C:3]1([OH:11])[CH2:8][CH2:7][C:6]([F:10])([F:9])[CH2:5][CH2:4]1)[CH3:2].C(N(CC)CC)C.[C:19](Cl)(=[O:23])[C:20]([CH3:22])=[CH2:21]>CN(C)C1C=CN=CC=1.CC(C)=O>[C:19]([O:11][C:3]1([CH2:1][CH3:2])[CH2:4][CH2:5][C:6]([F:10])([F:9])[CH2:7][CH2:8]1)(=[O:23])[C:20]([CH3:22])=[CH2:21]
Reactant: C=C(C)C(=O)Cl
Reactant: CCC1(O)CCC(F)(F)CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: C=C(C)C(=O)OC1(CC)CCC(F)(F)CC1
Yield: 79.9 %

Procedure:
A four-necked flask equipped with a stirrer, a thermometer, and a dropping funnel was charged with 6.6 g (0.04 mol) of 1-ethyl-4,4-difluorocyclohexanol, 0.2 g of 4-dimethylaminopyridine, 4.9 g of triethylamine, and 20 g of acetone. The mixture was stirred to obtain a solution. A solution prepared by dissolving 4.6 g (0.044 mol) of methacrylic acid chloride in 5 g of acetone was added to the solution at 4° C. over 30 minutes. The mixture was stirred at 4° C. for 3 hours to obtain a reaction mixture. The reaction mixture was washed with water to obtain 7.42 g of 1-ethyl-4,4-difluorocyclohexyl methacrylate (hereinafter may be referred to as “compound (M-8)” ((M-8) in Table 1)). The yield of 1-ethyl-4,4-difluorocyclohexyl methacrylate with respect to 1-ethyl-4,4-difluorocyclohexanol was 78%.
Reaction SMILES: Cl[S:2]([NH:5][C:6](=[O:9])[O:7][CH3:8])(=[O:4])=[O:3].[Cl:10][C:11]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([Cl:22])[C:12]=1[NH2:13].C(N(CC)CC)C.O>C(Cl)Cl>[Cl:10][C:11]1[CH:17]=[C:16]([C:18]([F:21])([F:19])[F:20])[CH:15]=[C:14]([Cl:22])[C:12]=1[NH:13][S:2]([NH:5][C:6](=[O:9])[O:7][CH3:8])(=[O:4])=[O:3]
Reactant: COC(=O)NS(=O)(=O)Cl
Reactant: Nc1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NS(=O)(=O)Nc1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: -20 °C
Reaction time: 12 h

Procedure:
Methyl chlorosulfonylcarbamate (27.90 g, 0.16 mol) was dissolved in CH2Cl2 (100 mL) and cooled to −20° C. To the solution of methyl chlorosulfonylcarbamate, was dropwisely added 2,6-dichloro-4-(trifluoromethyl)aniline (2.50 g, 10.7 mmol) and triethylamine (2.53 g, 32.1 mmol) in CH2Cl2 (70 mL) and agitated for 12 hr at room temperature. The reaction mixture was added with water (100 mL) for extraction to obtain the organic layer. The resultant was dried over MgSO4, concentrated under reduced pressure, and purified by column chromatography (hexane:ethyl acetate=7:3), giving the compound of interest (2.11 g, 6%, yellow solid). 1H NMR (300 MHz, CDCl3): δ 7.57 (s, 2H), 3.84 (s, 3H).
Reaction SMILES: N12CCCN=C1CCCCC2.[F:12][C:13]([F:27])([F:26])[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[NH:21][O:22][C:23](=[O:25])[N:24]=2)[CH:15]=1.[CH:28]([N:31]([CH:35]([CH3:37])[CH3:36])[C:32](Cl)=[O:33])([CH3:30])[CH3:29]>N1C=CC=CC=1>[F:27][C:13]([F:12])([F:26])[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[N:24]([C:32]([N:31]([CH:35]([CH3:37])[CH3:36])[CH:28]([CH3:30])[CH3:29])=[O:33])[C:23](=[O:25])[O:22][N:21]=2)[CH:15]=1
Reactant: CC(C)N(C(=O)Cl)C(C)C
Reactant: O=c1nc(-c2cc(C(F)(F)F)ccn2)[nH]o1
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)N(C(=O)n1c(-c2cc(C(F)(F)F)ccn2)noc1=O)C(C)C
Reaction time: 8 h
Yield: 19.4 %

Procedure:
To 1 ml of pyridine were added 0.28 g of 1,8-diazabicyclo[5,4,0]undec-7-ene, and 0.3 g of 3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one, and 0.3 g of N,N-diisopropylcarbamoyl chloride was added at room temperature. After stirring for 8 hours, the resultant solution was concentrated, and the residue was subjected to silica gel column chromatography to obtain 0.09 g of 3-(4-trifluoromethylpyridin-2-yl)-N,N-diisopropyl-1,2,4-oxadiazol-5-one-4-carboxamide (present compound (18)).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2Cl.Cl.Cl.[CH3:18][N:19]([CH2:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([NH2:28])[CH2:24][CH2:23]1)[CH3:20]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:28][C@H:25]1[CH2:26][CH2:27][C@H:22]([CH2:21][N:19]([CH3:20])[CH3:18])[CH2:23][CH2:24]1
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Cl
Reactant: CN(C)C[C@H]1CC[C@H](N)CC1
Agent: Cl
Product: CC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](CN(C)C)CC1

Procedure:
Following general procedure C, 1-(6-bromo-4-chloroquinolin-3-yl)ethanone (256 mg, 0.90 mmol) was reacted with trans-4-((dimethylamino)methyl)cyclohexanamine dihydrochloride (320 mg, 1.40 mmol) to afford the desired product (149 mg, 70%) as a light orange solid. ESI MS m/z 404 [C20H26BrN3O+H]+
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:4][C@@H:3]1[C:5](O)=[O:6].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:33][O:34][C:35](=[O:86])[NH:36][C@H:37]([C:41]([N:43]1[CH2:47][CH2:46][CH2:45][C@H:44]1[C:48]1[NH:49][CH:50]=[C:51]([C:53]2[CH:58]=[CH:57][C:56]([C:59]3[CH:64]=[C:63]([Cl:65])[C:62]([NH:66][C:67]([C:69]4[CH:70]=[N:71][C:72]([N:75]5[CH2:80][CH2:79][NH:78][CH2:77][C@H:76]5[CH3:81])=[CH:73][CH:74]=4)=[O:68])=[CH:61][C:60]=3[C:82]([F:85])([F:84])[F:83])=[CH:55][CH:54]=2)[N:52]=1)=[O:42])[CH:38]([CH3:40])[CH3:39].C(N(CC)C(C)C)(C)C>CC(N(C)C)=O>[CH3:33][O:34][C:35](=[O:86])[NH:36][C@H:37]([C:41]([N:43]1[CH2:47][CH2:46][CH2:45][C@H:44]1[C:48]1[NH:49][CH:50]=[C:51]([C:53]2[CH:58]=[CH:57][C:56]([C:59]3[CH:64]=[C:63]([Cl:65])[C:62]([NH:66][C:67]([C:69]4[CH:70]=[N:71][C:72]([N:75]5[CH2:80][CH2:79][N:78]([C:5]([C@H:3]6[CH2:4][C:2]6([CH3:8])[CH3:1])=[O:6])[CH2:77][C@H:76]5[CH3:81])=[CH:73][CH:74]=4)=[O:68])=[CH:61][C:60]=3[C:82]([F:84])([F:85])[F:83])=[CH:55][CH:54]=2)[N:52]=1)=[O:42])[CH:38]([CH3:40])[CH3:39]
Reactant: CC1(C)C[C@@H]1C(=O)O
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3cc(Cl)c(NC(=O)c4ccc(N5CCNC[C@H]5C)nc4)cc3C(F)(F)F)cc2)c[nH]1)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3cc(Cl)c(NC(=O)c4ccc(N5CCN(C(=O)[C@H]6CC6(C)C)C[C@H]5C)nc4)cc3C(F)(F)F)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.5 M (S)-(+)-2,2-dimethylcyclopropane carboxylic acid in DMA (28.9 μL, 0.015 mmol;). and HATU (8.25 mg, 0.022 mmol) dissolved in DMA (0.5 mL), was added ((S)-1-{(S)-2-[4-(5′-Chloro-4′-{[6-((R)-2-methyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethyl-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester 3 TFA (16 mg, 0.014 mmol; Preparation 53) and N,N-diisopropylethylamine (25.2 uL, 0.15 mmol) and the reaction mixture was stirred at RT overnight, concentrated, dissolved in 1:1 acetic acid:water (1.5 mL) and purified by reverse phase HPLC to provide the title compound (8.6 mg) as the di-TFA salt. (m/z): [M+H]+ calcd for C11H50ClF3N8O5 863.35 found 863.4.
Reaction SMILES: [CH3:1][CH:2]([S:5][C:6]1[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][NH2:13])=[CH:8][CH:7]=1)[CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24].O>CN(C=O)C>[CH3:1][CH:2]([S:5][C:6]1[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][NH:13][C:23](=[O:24])[O:25][CH2:26][CH3:27])=[CH:8][CH:7]=1)[CH2:3][CH3:4]
Reactant: CCOC(=O)Cl
Reactant: CCC(C)Sc1ccc(OCCN)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)NCCOc1ccc(SC(C)CC)cc1
Reaction time: 1.5 h

Procedure:
To a solution of the above amine (2.41 g, 10.0 mmol) in 10 ml DMF, cooled to 0° and under N2, is added potassium carbonate (1.66 g, 12.0 mmol) followed by dropwise addition of ethyl chloroformate (1.2 ml, 12.0 mmol) in 5 ml of DMF. After 1.5 hours, water is added and the aqueous phase is extracted with ether. The combined organic layers are washed with water and brine, dried, rotoevaporated and the residue is purified by column chromatography to give ethyl N-{2-[4-(1-methylpropylthio)phenoxy]ethyl}carbamate.