Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N+:8]=1[O-])(=[O:3])[CH3:2].S(OC)(OC)(=O)=O.CS(C)=O.[C-:25]#[N:26].[K+]>O>[C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:25]#[N:26])[N:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCCc1cccc[n+]1[O-]
Reactant: [C-]#N
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)NCCc1cccc(C#N)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.9 %

Procedure:
A mixture of 2-(2-acetylaminoethyl)pyridine N-oxide (70.8 g) and dimethyl sulfate (41 ml) was stirred at ambient temperature for 1.5 hours. To the mixture was added dimethylsulfoxide (420 ml) and potassium cyanide (25.6 g) and the mixture was stirred at ambient temperature for 3 hours. To the reaction mixture was added water and extracted with chloroform. The extract layer was dried over magnesium sulfate and evaporated in vacuo to give 2-(2-acetylaminoethyl)-6-cyanopyridine (74.3 g)
Reaction SMILES: [CH2:1]([N:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][C:14](=[O:17])[NH:13][CH:12]=2)=[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[N:6]=[C:5]1[NH2:25])[CH:2]=[CH2:3].[C:26](=O)([O-])[O-].[K+].[K+].IC>CS(C)=O>[CH2:1]([N:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][C:14](=[O:17])[N:13]([CH3:26])[CH:12]=2)=[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[N:6]=[C:5]1[NH2:25])[CH:2]=[CH2:3]
Reactant: C=CCn1c(N)nc(-c2cccc(F)c2)c(-c2ccc(=O)[nH]c2)c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CS(C)=O
Product: C=CCn1c(N)nc(-c2cccc(F)c2)c(-c2ccc(=O)n(C)c2)c1=O
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a solution of 3-allyl-2-amino-6-(3-fluorophenyl)-5-(6-oxo-1,6-dihydro-3-pyridinyl)-3,4-dihydro-4-pyrimidinone in dimethyl sulfoxide were added potassium carbonate (2 equivalents) and iodomethane (4 equivalents), followed by stirring at 50° C. for 16 hours. After filtering off the insoluble matters, the filtrate was purified by HPLC, to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10]2)=[CH:5][C:4]=1[N+:16]([O-])=O.COC1C2[N:27]=[C:28](N)[S:29]C=2C(OC2C=CC=CC=2)=CC=1>>[O:14]1[CH2:15][CH:9]([C:6]2[C:5]3[S:29][C:28]([NH2:27])=[N:16][C:4]=3[C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:10][O:11][CH2:12][CH2:13]1
Reactant: COc1ccc(C2COCCOC2)cc1[N+](=O)[O-]
Reactant: COc1ccc(Oc2ccccc2)c2sc(N)nc12
Product: COc1ccc(C2COCCOC2)c2sc(N)nc12
Yield: 57 %

Procedure:
The title compound was prepared from 6-(4-methoxy-3-nitro-phenyl)-1,4-dioxepane in exact the same manner as described in WO01/97786 for 4-methoxy-7-phenoxy-benzothiazol-2-yl-amine in 57% yield (3.7 g). MS: m/e=281(M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:29])=[C:6]([C@:8]2([CH2:27][F:28])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH:18]C(=O)C3C=CC=CC=3)=[N:9]2)[CH:7]=1.N12CCCN=C1CCCCC2>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:29])=[C:6]([C@:8]2([CH2:27][F:28])[CH2:13][C@@H:12]([C:14]([F:16])([F:17])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1
Reactant: O=C(NC1=N[C@](CF)(c2cc(Br)ccc2F)C[C@@H](C(F)(F)F)O1)c1ccccc1
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: NC1=N[C@](CF)(c2cc(Br)ccc2F)C[C@@H](C(F)(F)F)O1
Temperature: 65 °C
Yield: 80.9 %

Procedure:
To a solution of N-((4S,6S)-4-(5-bromo-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (1i, 8.58 g, 17.98 mmol) in MeOH (50 mL) was added 1,8-diazabicyclo-[5.4.0]undec-7-ene (3.22 ml, 21.57 mmol) and the resulting mixture was heated at 65° C. for 5 h. The reaction went to completion. The mixture was concentrated, diluted with EtOAc, washed with water, saturated NH4Cl solution, dried over Na2SO4, filtered, concentrated and chromatographed on silica gel using a gradient of 0-20% EtOAc/hexanes to afford a white solid as (4S,6S)-4-(5-bromo-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (5.43 g, 14.55 mmol, 81% yield). MS m/z=374.9 [M+H]+. Calculated for C12H10BrF5N2O: 373.1
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:8]([NH:9][C@@H:10]2[CH2:17][C@H:13]3[CH2:14][NH:15][CH2:16][C@@:12]3([C:18]([N:20]3[CH2:29][CH2:28][C:27]4[N:26]=[CH:25][C:24]([C:30]([F:33])([F:32])[F:31])=[CH:23][C:22]=4[CH2:21]3)=[O:19])[CH2:11]2)[CH2:7][CH2:6][O:5][CH2:4]1.[N-:34]([C:37]#[N:38])[C:35]#[N:36].[Na+]>O.CC(O)C.C(Cl)Cl>[C:35](/[N:34]=[C:37](/[N:15]1[CH2:16][C@@:12]2([C:18]([N:20]3[CH2:29][CH2:28][C:27]4[N:26]=[CH:25][C:24]([C:30]([F:33])([F:31])[F:32])=[CH:23][C:22]=4[CH2:21]3)=[O:19])[CH2:11][C@H:10]([NH:9][C@H:8]3[CH2:7][CH2:6][O:5][CH2:4][C@H:3]3[O:2][CH3:1])[CH2:17][C@H:13]2[CH2:14]1)\[NH2:38])#[N:36]
Reactant: CO[C@@H]1COCC[C@@H]1N[C@@H]1C[C@H]2CNC[C@@]2(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Reactant: N#C[N-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC(C)O
Product: CO[C@@H]1COCC[C@@H]1N[C@@H]1C[C@H]2CN(/C(N)=N/C#N)C[C@@]2(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Temperature: 120 °C

Procedure:
A mixture of Example 1 (HCl salt, 50 mg, 0.0865 mmol), sodium dicyanamide (10.32 mg, 0.116 mmol) in 5% water in i-PrOH (1.2 mL) in a sealed tube was flushed with Ar and heated at 120° C. for 5 h. After cooling to rt, the mixture was diluted with DCM, filtered and evaporated. The residue was purified by CombiFlash (eluent: 10% 7N NH3 in methanol in DCM) to give the product as a colorless gel. 1H-NMR (400 MHz, CDCl3): δ 1.54-1.92 (m, 5H), 2.37 (br. s., 1H), 2.71 (br. s., 1H), 3.07-4.23 (m, 19H), 4.66-4.96 (m, 2H), 5.80 (m, 2H), 7.73 (s, 1H), 8.71 (br. s., 1H); LC/MS: C25H32F3N7O3: m/z 536.2 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:16]=O>C(O)=O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][N:11]([CH3:16])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: C=O
Reactant: COC1(c2cc(F)cc(F)c2)CCNC1
Solvent: O=CO
Product: COC1(c2cc(F)cc(F)c2)CCN(C)C1

Procedure:
Preparation according to Example 16. (+3-(3,5-difluorophenyl)-3-methoxypyrrolidine (0.02 g, 0.094 mmol), formic acid (1 ml) and formaldehyde (40% solution in water, 1 ml) was heated at 85° C. for 5 h, workup according to preparation 16. MS m/z (relative intensity, 70 eV) 227 (M+, 5), 212 (32), 197 (28), 141 (45), 57 (bp).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Br:12][C:13]1[CH:14]=[C:15]2[N:21]([CH3:22])[CH:20]=[CH:19][C:16]2=[N:17][CH:18]=1>C(Cl)Cl>[Br:12][C:13]1[CH:14]=[C:15]2[N:21]([CH3:22])[CH:20]=[CH:19][C:16]2=[N+:17]([O-:9])[CH:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cn1ccc2ncc(Br)cc21
Solvent: ClCCl
Product: Cn1ccc2c1cc(Br)c[n+]2[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-Chloroperbenzoic acid (77 wt %, 3.46 g, 15.4 mmol) was added to a stirred solution of 6-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridine (2.96 g, 14.0 mmol) in DCM (60 mL) at 0° C. The reaction mixture was stirred at RT for 4 hours and then concentrated and purified by silica gel chromatography (7% MeOH/DCM) to give the title compound as a brown semi-solid, which was used without further purification (3.8 g). ESI-MS m/z [M+H]+ calc'd for C8H7BrN2O, 227, 229; found 227, 229.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C@@H:15]([CH2:16][C@H:17]([OH:27])[CH2:18][CH2:19]2)/[C:14](=[CH:28]\[CH3:29])/[C:13]3=[O:30])[CH2:10][CH2:9]1)[CH3:7].[OH-].[Na+]>>[OH:27][C@@H:17]1[CH2:18][CH2:19][C@@:20]2([CH3:21])[C@H:15](/[C:14](=[CH:28]\[CH3:29])/[C:13](=[O:30])[C@@H:12]3[C@@H:22]2[CH2:23][CH2:24][C@@:25]2([CH3:26])[C@H:11]3[CH2:10][CH2:9][C@@H:8]2[C@H:6]([CH3:7])[CH2:5][CH2:4][C:3]([OH:31])=[O:2])[CH2:16]1
Reactant: C/C=C1/C(=O)[C@@H]2[C@H](CC[C@]3(C)[C@@H]([C@H](C)CCC(=O)OC)CC[C@@H]23)[C@@]2(C)CC[C@@H](O)C[C@@H]12
Agent: [Na+]
Agent: [OH-]
Product: C/C=C1/C(=O)[C@@H]2[C@H](CC[C@]3(C)[C@@H]([C@H](C)CCC(=O)O)CC[C@@H]23)[C@@]2(C)CC[C@@H](O)C[C@@H]12

Procedure:
Step 4 is the reaction of 3α-hydroxy-6-ethylidene-7-keto-5β-cholan-24-oic acid methyl ester (4) with NaOH to form E-3α-hydroxy-6-ethylidene-7-keto-5β-cholan-24-oic acid (5). In one embodiment, prior to step 4, the residue from step 3 is heated to about 45° C. to about 60° C. to remove residual amounts of solvent. In one embodiment, the temperature is about 49° C. to about 55° C. In one embodiment, the ester hydrolysis reaction reacting 3α-hydroxy-6-ethylidene-7-keto-5β-cholan-24-oic acid methyl ester (4) with NaOH is carried out at about 20° C. to about 25° C. in methanol, water, and a NaOH solution.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[N+:13]([O-])=O.[C:16]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+].Cl>O.C1(C)C(C)=CC=CC=1.COCCOCCOC>[C:16]([C:20]1[CH:21]=[CH:22][C:23]([O:26][C:2]2[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=2[NH2:13])=[CH:24][CH:25]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: CS(=O)(=O)Nc1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1C
Solvent: COCCOCCOC
Product: CC(C)(C)c1ccc(Oc2ccc(NS(C)(=O)=O)cc2N)cc1
Reaction time: 24 h

Procedure:
N-(4-chloro-3-nitrophenyl)methanesulphonamide (50 g, 0.2 mole), 4-t-butylphenol (33 g, 0.22 mole), potassium carbonate (62.1 g, 0.45 mole) and diglyme (50 ml) were heated and stirred at 165°-170° for 24 hr. The mixture was cooled to 110° and xylene (150 ml) followed by a mixture of 10M-hydrochloric acid (55 ml) and water (130 ml) added.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23].O>CN(C)C(=O)C>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])=[CH:27][CH:26]=1)(=[O:24])=[O:23]
Reactant: CC(O)(C(=O)O)C(F)(F)F
Reactant: Nc1ccc(S(=O)(=O)c2ccccc2Cl)cc1
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Solvent: O
Product: CC(O)(C(=O)Nc1ccc(S(=O)(=O)c2ccccc2Cl)cc1)C(F)(F)F
Reaction time: 1 h
Yield: 94.8 %

Procedure:
To a stirred, cooled (-20° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.89 g, 5.6 mmol) in N,N-dimethylacetamide (10 mL) was added thionyl chloride (0.67 g, 5.6 mmol) and the mixture stirred at -10° to -15° C. for 1 hour. 4-(2-Chlorophenylsulfonyl)benzenamine (1.00 g, 3.7 mmol) was added in one portion to the orange solution and the mixture stirred at room temperature overnight. The brown solution was poured into water and the aqueous solution extracted with ethyl acetate (2×50 mL). The organics were combined, washed with water, dried (MgSO4), filtered and the solvent distilled to yield a tan solid. Recrystallization from methylene chloride/hexane yielded the title propanamide (1.43 g, 94%) as an off-white solid; mp 136°-138° C. 1H-NMR (250 MHz, d6 -DMSO): 1.58 (s, 3H, CH3), 7.57 (s, 1H, OH), 7.67 (m, 3H, aromatic), 7.88 (d, 2H, J=8.8 Hz, aromatic), 8.02 (d, 2H, J=8.8 Hz, aromatic), 8.26 (d, 1H, J=6.6 Hz, aromatic), 10.46 (s, 1H, NH). MS (CI, CH4): 408(M+1).
Reaction SMILES: [OH:1][C@@H:2]([CH2:6][CH:7]1[CH2:9][CH2:8]1)[C:3]([OH:5])=[O:4].[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][CH:13]=1>CN(C=O)C>[OH:1][C@@H:2]([CH2:6][CH:7]1[CH2:9][CH2:8]1)[C:3]([O:5][CH2:16][C:15]1[CH:18]=[CH:19][C:12]([O:11][CH3:10])=[CH:13][CH:14]=1)=[O:4]
Reactant: O=C(O)[C@@H](O)CC1CC1
Reactant: COc1ccc(CCl)cc1
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)[C@@H](O)CC2CC2)cc1

Procedure:
A solution of 4.30 g (33 mmol) of 2-(S)-hydroxy-3(cyclopropyl)propanoic acid (from Step A), 6.40 mL (46 mmol) of TEA and 5.90 mL (44 mmol) of 4-(methoxy)benzyl chloride in 40 mL of DMF was stirred at rt for 2 h. The mixture was partitioned between 500 mL of ether and 300 mL of H2O and the layers were separated. The organic layer was washed with 300 mL of 2.0 N HCl, 300 mL of sat'd NaHCO3, 2×300 mL of H2O, 300 mL of sat'd NaCl, dried over MgSO4 and concentrated. Flash chromatography on 500 g of silica gel using 5:1 v/v hexanes/EtOAc as the eluant afforded 4.30 g (52%, 97.5% ee) of the title compound: RF: 0.20 (4:1 v/v hexanes/EtOAc); 1H NMR (300 MHz): δ−0.01-0.09 (m, 2H), 0.40-0.45 (m, 2H), 0.84 (m, 1H), 1.55-1.67 (m, 2H), 2.82 (br m, 1H), 3.81 (s, 3H), 4.25 (br m, 1H), 5.14 (ABq, J=11.8, 2H), 6.90 (d, J=8.7, 2H), 7.29 (d, J=8.7, 2H). HPLC: Chiracel OB 4.6×250 mm column, 65:35 v/v hexanes/EtOH, 0.5 mL/min, 220 nm. Retention times: (S)-enantiomer, 20.4 min; (R)-enantiomer, 17.3 min.
Reaction SMILES: O.[OH-].[Li+].[F:4][C:5]([F:31])([F:30])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH:15][C:16]1[S:20][C:19]2[CH2:21][CH2:22][CH2:23][CH2:24][C:18]=2[C:17]=1[C:25]([O:27]CC)=[O:26])(=[O:14])=[O:13]>O1CCOCC1.O>[F:30][C:5]([F:4])([F:31])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH:15][C:16]1[S:20][C:19]2[CH2:21][CH2:22][CH2:23][CH2:24][C:18]=2[C:17]=1[C:25]([OH:27])=[O:26])(=[O:14])=[O:13]
Reactant: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2C(F)(F)F)sc2c1CCCC2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1c(NS(=O)(=O)c2ccccc2C(F)(F)F)sc2c1CCCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 8.3 %

Procedure:
Lithium hydroxide monohydrate (0.188 g) was added to a solution of ethyl 2-(2-trifluoromethylbenzenesulphonylamino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (Intermediate 27, 0.194 g) in dioxane (1 ml) and water (1 ml) and the mixture was stirred at room temperature for 16 hours. The mixture was then warmed to 60° C. for 1 hour and finally heated in the microwave at 160° C. for 15 minutes. After cooling to room temperature the volatile components were removed under reduced pressure. The residual solution was acidified with aqueous hydrochloric acid (1M) and directly purified by preparative HPLC(C18), eluting with a mixture of methanol and water containing 0.1% formic acid and a gradient of 40-95% to give 2-(2-trifluoromethylbenzenesulphonylamino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (0.015 g) as a white solid.
Reaction SMILES: CN(C(ON1N=N[C:11]2C=CC=N[C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([CH2:28][CH2:29][NH:30][C:31]([C:33]1[N:38]=[CH:37][C:36]([C:39]2[CH:47]=[C:46]([Cl:48])[CH:45]=[CH:44][C:40]=2[C:41]([OH:43])=O)=[CH:35][CH:34]=1)=[O:32])([OH:27])=[O:26].CCN(C(C)C)C(C)C.[Cl:58][C:59]1[CH:64]=[CH:63][C:62]([C:65]2[CH:70]=[CH:69][C:68]([NH2:71])=[CH:67][CH:66]=2)=[CH:61][CH:60]=1>CCOC(C)=O.CN(C=O)C>[Cl:48][C:46]1[CH:45]=[CH:44][C:40]([C:41](=[O:43])[NH:71][C:68]2[CH:69]=[CH:70][C:65]([C:62]3[CH:61]=[CH:60][C:59]([Cl:58])=[CH:64][CH:63]=3)=[CH:66][CH:67]=2)=[C:39]([C:36]2[CH:35]=[CH:34][C:33]([C:31]([NH:30][CH2:29][CH2:28][C:25]([O:27][CH2:10][CH3:11])=[O:26])=[O:32])=[N:38][CH:37]=2)[CH:47]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Nc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: O=C(O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2C(=O)O)cn1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2C(=O)Nc2ccc(-c3ccc(Cl)cc3)cc2)cn1
Temperature: 45 °C

Procedure:
Solid HATU (101 mg, 0.27 mmol) was added to a DMF solution (2 mL) of 2-(6-((2-carboxyethyl)carbamoyl)pyridin-3-yl)-4-chlorobenzoic acid (100 mg, 0.27 mmol), i-Pr2NEt (0.2 mL, 1.1 mmol), and 4′-chloro-[1,1′-biphenyl]-4-amine (57 mg, 0.28 mmol) and the resulting mixture was warmed to 45° C. After 16 h the resulting mixture was diluted with EtOAc, washed with water and brine, dried (Na2SO4), concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: BrC1C=C(C(Cl)=O)C=CC=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][N:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.[Br:33][C:34]1[CH:35]=[C:36]([C:40]([N:42]=[C:43]=[S:44])=[O:41])[CH:37]=[CH:38][CH:39]=1>C1(C)C=CC=CC=1.C(O)C>[Br:33][C:34]1[CH:35]=[C:36]([C:40]([N:42]=[C:43]=[S:44])=[O:41])[CH:37]=[CH:38][CH:39]=1.[Br:33][C:34]1[CH:35]=[C:36]([CH:37]=[CH:38][CH:39]=1)[C:40]([NH:42][C:43]([NH:30][C:29]1[CH:31]=[CH:32][C:26]([O:25][C:16]2[C:15]3[C:20](=[CH:21][C:22]([O:23][CH3:24])=[C:13]([O:12][CH3:11])[CH:14]=3)[N:19]=[CH:18][N:17]=2)=[CH:27][CH:28]=1)=[S:44])=[O:41]
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)c1cccc(Br)c1
Agent: O=C(N=C=S)c1cccc(Br)c1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)c4cccc(Br)c4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
3-Bromo-1-benzenecarbonyl isothiocyanate was prepared using commercially available 3-bromo-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3-bromo-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (61 mg, yield 70%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]2[CH2:22][CH2:21][C@:20]([CH2:30][CH2:31][NH:32][C:33](=[O:35])[CH3:34])([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[O:19][C:18]2=[O:36])[CH3:16])=[CH:11][CH:10]=1.[H-].[Na+].I[CH3:40]>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]2[CH2:22][CH2:21][C@:20]([CH2:30][CH2:31][N:32]([CH3:40])[C:33](=[O:35])[CH3:34])([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[O:19][C:18]2=[O:36])[CH3:16])=[CH:11][CH:10]=1
Reactant: CI
Reactant: CC(=O)NCC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(F)cc3F)cc2)C(=O)O1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N(C)CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(F)cc3F)cc2)C(=O)O1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 14.6 %

Procedure:
A solution of N-(2-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl)acetamide (60 mg, 0.121 mmol) in tetrahydrofuran anhydrous (5 mL) was added sodium hydride (15 mg, 0.605 mmol) at 0° C. and then stirred for 30 minutes at the same temperature. Iodomethane (86 mg, 0.605 mmol) was then added to the above mixture. The reaction mixture was stirred at rt for a further 8 h. The reaction mixture was poured into ice/water and extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and concentrated to afford the residue, which was purified by TLC and separated by preparative HPLC to give N-(2-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl)-N-methylacetamide (9 mg, 15%). LC-MS Method 3 tR=1.43, min, m/z=511; 1H NMR (CDCl3): 1.26 (m, 1H), 1.56 (m, 3H), 1.96 (m, 1H), 2.04 (m, 3H), 2.22 (m, 4H), 2.83 (m, 1H), 2.94 (m, 3H), 3.36 (m, 1H), 5.69 (m, 1H), 6.87 (m, 2H), 7.04 (m, 4H), 7.26 (m, 5H).
Reaction SMILES: Cl[CH:2](Cl)[CH2:3][O:4][CH2:5][CH:6](Cl)Cl.[C:10](#[N:14])[CH2:11][C:12]#[N:13].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[O:4]1[CH2:5][CH2:6][C:11]([C:10]#[N:14])([C:12]#[N:13])[CH2:2][CH2:3]1
Reactant: ClC(Cl)COCC(Cl)Cl
Reactant: N#CCC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CC1(C#N)CCOCC1
Yield: 51.7 %

Procedure:
A mixture of 28.6 g of dichloroethyl ether, 13.2 g of malononitrile, 55.28 g of potassium carbonate and 800 ml of acetonitrile was refluxed on a steam bath for 24 hours, then filtered while hot. The filtrate was evaporated and the residue crystallized, with charcoal treatment, from 100 ml of ethanol, giving 9.5 g of tetrahydro-4H-pyran-4,4-dicarbonitrile as colorless plates, mp 110°-112° C.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]1([CH3:22])[CH:15]=[CH:14][C:13]([S:16]([N:19]=C=O)(=[O:18])=[O:17])=[CH:12][CH:11]=1.CNCCCNC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH3:22][C:10]1[CH:11]=[CH:12][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:14][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Agent: CNCCCNC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(S(N)(=O)=O)cc1
Reaction time: 1 h
Yield: 176.8 %

Procedure:
Benzyl ester (100 mg, 0.0842 mmol) and Pd/C (en) (10 mg) were suspended in methanol (1 ml), and the obtained suspension was stirred in a hydrogen atmosphere at room temperature for 8 hours. Thereafter, the catalyst was filtrated with a filter, and was then washed with methanol. The filtrate was distilled away under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=9:1−7:3), so as to obtain carboxylic acid (91.2 mg) in a quantitative manner. The thus obtained carboxylic acid (75.9 mg, 0.070 mg) was dissolved in THF (0.5 ml). Thereafter, diisopropylethylamine (32 μl, 0.184 mmol) and p-toluenesulfonyl isocyanate (39 μl, 0.256 mmol) were added thereto in an argon atmosphere, and the obtained mixture was stirred for 1 hour. Thereafter, N,N′-dimethyl-1,3-propanediamine (0.1 ml) was added dropwise to the reaction solution, and a 10% citric acid aqueous solution was then added thereto. An aqueous layer was extracted with chloroform. An organic layer was washed with a saline solution, and it was then dried over sodium sulfate. The solvent was distilled away under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=9:1), so as to obtain 77.5 mg (87%) of tosylamide.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:27]=[CH:26][C:25]([CH2:28]O)=[CH:24][C:12]=3[N:13]\2[C@@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([O:22][CH3:23])=[O:21])[CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1.[NH:32]1[CH2:37][CH2:36][CH:35]([CH2:38][NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH2:34][CH2:33]1>>[C:42]([O:41][C:40]([NH:39][CH2:38][CH:35]1[CH2:36][CH2:37][N:32]([CH2:28][C:25]2[CH:26]=[CH:27][C:11]3[NH:10]/[C:9](=[N:8]\[C:6](=[O:7])[C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:31][CH:30]=4)/[N:13]([C@@H:14]4[CH2:15][CH2:16][C@H:17]([C:20]([O:22][CH3:23])=[O:21])[CH2:18][CH2:19]4)[C:12]=3[CH:24]=2)[CH2:33][CH2:34]1)=[O:46])([CH3:43])([CH3:45])[CH3:44].[F:1][C:2]1[CH:31]=[CH:30][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:27]=[CH:26][C:25]([CH2:28][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:24][C:12]=3[N:13]\2[C@@H:14]2[CH2:15][CH2:16][C@H:17]([C:20]([O:22][CH3:23])=[O:21])[CH2:18][CH2:19]2)=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CO)cc32)CC1
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Product: COC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CN4CCC(CNC(=O)OC(C)(C)C)CC4)cc32)CC1
Product: COC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CN4CCCCC4)cc32)CC1
Yield: 77 %

Procedure:
The title compound was prepared from cis-methyl 4-((E)-2-(4-fluorobenzoylimino)-6-(hydroxymethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate and tert-butyl piperidin-4-ylmethylcarbamate using a method analogous to the preparation of cis-methyl 4-((E)-2-(4-fluorobenzoylimino)-6-(piperidin-1-ylmethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate (45 mg, 77% yield). MS m/z=622.2 [M+H]. Calc'd for C34H44FN5O5: 621.3.