Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C[O:3][C:4](=[O:54])[C@H:5]([NH:12][C:13](=[O:53])[C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([C@H:23]2[C@H:27]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=3[F:35])[C@:26]([C:38]3[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][C:39]=3[F:45])([C:36]#[N:37])[C@H:25]([CH2:46][C:47]([CH3:50])([CH3:49])[CH3:48])[NH:24]2)=[O:22])=[C:16]([O:51][CH3:52])[CH:15]=1)[CH2:6][CH2:7][C:8]([O:10]C)=[O:9].[OH-].[Li+]>O1CCCC1.O>[ClH:34].[Cl:44][C:41]1[CH:42]=[CH:43][C:38]([C@@:26]2([C:36]#[N:37])[C@H:25]([CH2:46][C:47]([CH3:49])([CH3:48])[CH3:50])[NH:24][C@@H:23]([C:21]([NH:20][C:17]3[CH:18]=[CH:19][C:14]([C:13]([NH:12][C@H:5]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])[C:4]([OH:54])=[O:3])=[O:53])=[CH:15][C:16]=3[O:51][CH3:52])=[O:22])[C@@H:27]2[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=2[F:35])=[C:39]([F:45])[CH:40]=1.[ClH:1]
Reactant: COC(=O)CC[C@@H](NC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)c(OC)c1)C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(=O)N[C@H](CCC(=O)O)C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(R)-2-(4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoylamino)-pentanedioic acid dimethyl ester, hydrochloride (200 mg, 259 μmol) was suspended in 5 mL of tetrahydrofuran/water (4/1 ratio) then lithium hydroxide (100 mg) was added. After stirring at room temperature for 4 h, the reaction mixture was filtered, and the crude residue was purified by high-performance liquid chromatography (C18, eluting with 40-95% acetonitrile-water) to give (R)-2-(4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoylamino)-pentanedioic acid, hydrochloride after lyophilization with acetonitrile and 1N solution of hydrochloric acid. MS (ES+) m/z calcd. for C36H37Cl2F2N4O7: [(M+H)+]745. found: 745.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:37])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([OH:33])([CH3:32])[CH3:31])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[N:40]1([CH2:46][C:47]([NH2:49])=[O:48])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:37])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:43]3[CH2:44][CH2:45][N:40]([CH2:46][C:47]([NH2:49])=[O:48])[CH2:41][CH2:42]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([OH:33])([CH3:32])[CH3:31])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1
Reactant: NC(=O)CN1CCNCC1
Reactant: CCOc1cc(C(C)(C)O)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1cc(C(C)(C)O)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(N)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(1-hydroxy-1-methyl-ethyl)-phenyl]-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 2-piperazin-1-yl-acetamide dihydrochloride (Matrix Scientific) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 45% of 1:1 ethanol/acetonitrile in carbon dioxide). HR-MS (ES, m/z) calculated for C35H42N5O4Cl2 [(M+H)+] 666.2609, observed 666.2606.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:10]=[CH:11][C:12]=2[OH:13])=[CH:3][N:2]=1.[Cl:20][C:21]1[C:22](F)=[CH:23][C:24]([F:47])=[C:25]([S:27]([N:30]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][C:38]=2[O:45][CH3:46])[C:31]2[S:32][CH:33]=[N:34][N:35]=2)(=[O:29])=[O:28])[CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:20][C:21]1[C:22]([O:13][C:12]2[CH:11]=[CH:10][C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:8][C:7]=2[C:4]2[CH:5]=[CH:6][N:1]=[N:2][CH:3]=2)=[CH:23][C:24]([F:47])=[C:25]([S:27]([N:30]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][C:38]=2[O:45][CH3:46])[C:31]2[S:32][CH:33]=[N:34][N:35]=2)(=[O:28])=[O:29])[CH:26]=1
Reactant: Oc1ccc(-c2ccccc2)cc1-c1ccnnc1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(-c4ccccc4)cc3-c3ccnnc3)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.4 %

Procedure:
3-Pyridazin-4-ylbiphenyl-4-ol (Preparation 4, 50 mg, 0.2 mmol) and 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide (Preparation 16, 93 mg, 0.2 mmol) were dissolved in dimethylsulfoxide (2 mL). Potassium carbonate (83 mg, 0.6 mmol) was added and the reaction stirred at room temperature for 16 hours. The crude material was partitioned between ethyl acetate (20 mL) and water (20 mL), the organic layer separated, concentrated in vacuo and purified by silica gel column chromatography (ISCO™, 12 g silica, 0-100% ethyl acetate in heptane gradient elution). The appropriate fractions were combined and concentrated in vacuo to afford the title compound as a gum (100 mg, 72%).
Reaction SMILES: [Li+].[OH-].[C:3]1([CH2:9][O:10][C:11]2[CH:20]=[CH:19][C:18]([C:21]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:22])=[CH:17][C:12]=2[C:13]([O:15]C)=[O:14])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl>O.O1CCCC1>[C:3]1([CH2:9][O:10][C:11]2[CH:20]=[CH:19][C:18]([C:21]([N:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)=[O:22])=[CH:17][C:12]=2[C:13]([OH:15])=[O:14])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1cc(C(=O)N2CCCCC2)ccc1OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(C(=O)N2CCCCC2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of LiOH (534 mg, 12.73 mmol) in water (8 ml) was added to a stirred solution of methyl 2-[(phenylmethyl)oxy]-5-(1-piperidinylcarbonyl)benzoate (may be prepared as described in Description 52; 450 mg, 1.27 mmol) in tetrahydrofuran (2 ml) at room temperature. The mixture was stirred at room temperature for 3 h. The mixture was then acidified by 6N HCl and the precipitate was collected and dried to yield the title compound as a white solid. 400 mg.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]3[CH:18]=2)=[CH:6][CH:5]=1)([O-])=O.O.O.[Sn](Cl)Cl.CCOC(C)=O.C(Cl)Cl>CCO>[N:11]1[C:10]([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)=[CH:18][N:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=12
Reactant: O=[N+]([O-])c1ccc(-c2cn3ccccc3n2)cc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(-c2cn3ccccc3n2)cc1
Yield: 76.5 %

Procedure:
Prepared as described in the Nitro Reduction section using 2-(4-nitrophenyl)imidazo[1,2-a]pyridine (0.216 g, 0.90 mmol) and tin (II) chloride dihydrate (1.02 g, 4.52 mmol) in EtOH (25 ml) to give the title compound (0.144 g, 76%) as a pale yellow solid after work-up and flash chromatography (9:1 EtOAc/DCM).
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:20][CH2:21][C:22]([OH:25])([CH3:24])[CH3:23])[C@H:12]([CH3:26])[N:11]1[C:27](=[O:37])[CH2:28][C:29]1[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:36])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Cl:36][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]([Cl:35])[C:29]=1[CH2:28][C:27]([N:11]1[C@@H:10]([CH2:9][OH:8])[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:20][CH2:21][C:22]([OH:25])([CH3:23])[CH3:24])[C@@H:12]1[CH3:26])=[O:37]
Reactant: C[C@H]1c2cccc(CCC(C)(C)O)c2C[C@H](CO[Si](C)(C)C(C)(C)C)N1C(=O)Cc1c(Cl)cccc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@H]1c2cccc(CCC(C)(C)O)c2C[C@H](CO)N1C(=O)Cc1c(Cl)cccc1Cl
Reaction time: 0.67 h
Yield: 92.9 %

Procedure:
Dissolve 1-[(1S,3R)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-(3-hydroxy-3-methylbutyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-2-(2,6-dichlorophenyl)ethanone (0.16 g, 0.28 mmol) in THF (2.8 mL). Add tetrabutylammonium fluoride (0.30 mL, 0.30 mmol, 1M in THF). Stir 40 min. Add saturated ammonium chloride solution and extract with ethyl acetate. Combine the ethyl acetate extracts; wash with water and brine, dry over sodium sulfate, filter, and concentrate under reduced pressure to give a residue. Purify the residue by silica gel chromatography, eluting with ethyl acetate: hexanes (gradient, 0-60%) to give the title compound as a white foam (0.12 g, 0.26 mmol). MS (m/z): 450 (M+1).
Reaction SMILES: C([CH2:3][O:4][C:5](=[O:23])[C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[N:8][C:7]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=1)#N.C(N(CC)CC)C>CO>[CH3:3][O:4][C:5](=[O:23])[C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[N:8][C:7]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=1
Reactant: Cc1ccc(C(=O)OCC#N)c(Nc2cccc([N+](=O)[O-])c2)n1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1ccc(C)nc1Nc1cccc([N+](=O)[O-])c1
Yield: 97.5 %

Procedure:
A mixture of 6-methyl-2-(3-nitrophenylamino)nicotinic acid cyanomethyl ester (15.44 g, 49.43 mmol) and triethylamine (1.00 g, 9.89 mmol) in dry methanol (160 ml) was heated under reflux overnight. After cooling, crystals were collected by filtration, washed with methanol, and dried to give 6-methyl-2-(3-nitrophenylamino)nicotinic acid methyl ester (13.84 g, 97%).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[C:9]([C:12]([OH:14])=[O:13])[CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.S(Cl)(Cl)=O.[CH3:19]O>>[O:1]=[C:2]1[C:11]2[CH:10]=[C:9]([C:12]([O:14][CH3:19])=[O:13])[CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: O=C(O)c1ccc2c(c1)C(=O)CCC2
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc2c(c1)C(=O)CCC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 94 %

Procedure:
To a solution of 8-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (16 g, 0.084 mol) in MeOH was added thionylchloride (23 g, 0.2 mol). The mixture was then stirred at rt for 12 h. The solvent was removed under vacuum and the residue was taken up in EtOAc (200 ml). The organic layer was washed with a 10% aqueous solution of NaHCO3, dried over MgSO4 and evaporated to give 16 g (94%) of the titled compound as a liquid. TLC: Chloroform/MeOH (9/1), Rf=0.9.
Reaction SMILES: Cl[Si:2]([C:5]1[CH2:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([CH3:4])[CH3:3].[CH2:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15]1.[Li].O>C(OCC)C>[CH:14]1([CH:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:13]=[C:5]2[SiH:2]([CH3:4])[CH3:3])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15]1
Reactant: C1=Cc2ccccc2C1
Reactant: C[Si](C)(Cl)C1=Cc2ccccc2C1
Agent: [Li]
Solvent: O
Solvent: CCOCC
Product: C[SiH](C)C1=Cc2ccccc2C1C1C=Cc2ccccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 50.9 %

Procedure:
Chloro-2-indenyldimethylsilane (4.95 g, 0.023 mol.) according to Example 1 was dissolved in 20 ml of diethyl ether. The solution was cooled to 0° C., and a solution of lithium indene (1.94 g, 0.022 mol.) in 25 ml of diethyl ether was added dropwise. The mixture was stirred for 2 hours at 25° C. and then heated to reflux. For working up, 60 ml of water were added and the organic phase was washed with water again and dried over Na2SO4. After removal of the solvents under an oil pump vacuum, the light-yellow oil that remained was purified by means of column chromatography. 3.23 g (47%) of 1-indenyl-2-indenyl-dimethylsilane were obtained in the form of a colorless oil which crystallized in the refrigerator at 4° C. M.p.: 45° C.
Reaction SMILES: Cl.C1C2C(COC([N:19]3[CH2:24][C@@H:23]([C:25](=[O:44])[N:26]([CH:41]4[CH2:43][CH2:42]4)[CH2:27][C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([O:35][CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:29]=4)[CH2:22][C@@H:21]([NH2:45])[CH2:20]3)=O)C3C(=CC=CC=3)C=2C=CC=1.[C:46]([N:50]=[C:51]=[O:52])([CH3:49])([CH3:48])[CH3:47].CCN(C(C)C)C(C)C.ClCCCl>C(Cl)Cl>[CH:41]1([N:26]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([O:35][CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:29]=2)[C:25]([C@H:23]2[CH2:22][C@@H:21]([NH:45][C:51]([NH:50][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:52])[CH2:20][NH:19][CH2:24]2)=[O:44])[CH2:42][CH2:43]1
Reactant: CC(C)(C)N=C=O
Reactant: COCCCOc1cc(CN(C(=O)[C@H]2C[C@@H](N)CN(C(=O)OCC3c4ccccc4-c4ccccc43)C2)C2CC2)ccc1C
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCCOc1cc(CN(C(=O)[C@@H]2CNC[C@H](NC(=O)NC(C)(C)C)C2)C2CC2)ccc1C
Temperature: 50 °C
Reaction time: 14 h

Procedure:
A mixture of (3R*,5S*)-3-amino-5{-cyclopropyl-[3-(3-methoxy-propoxy)-4-methyl-benzyl]-carbamoyl}-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester, hydrochloride (110 mg, 0.173 mmol), tert-butyl isocyanate (40 μl, 0.35 mmol), DIPEA (34.2 μl, 0.2 mmol) and 1,2-dichloroethane (2 ml) is shaken for 14 h at 50° C. The mixture is diluted with CH2Cl2 and washed with NaHCO3 solution. The organic layer is dried (Na2SO4) and evaporated. The crude product is stirred with a solution of CH2Cl2/piperidine 4:1 (5 mL) for 1 h, the mixture is evaporated and the residue purified by preparative HPLC (C18 column, 10-100% CH3CN+0.1% TFA/H2O+0.1% TFA, 20 min, flow 20 mL 1 min). The combined pure fractions are treated with K2CO3, CH3CN is removed in vacuo, and the residual aqueous phase is extracted three times with CH2Cl2. The combined organic layers are dried (Na2SO4) and evaporated to afford the title compound as a colorless resin. MS: 475.6 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 5.14 min.
Reaction SMILES: [CH:1]1[C:6](=[O:7])[C:5]([OH:8])=[CH:4][O:3][C:2]=1[CH2:9][OH:10].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:20][CH2:21][CH3:22]>CN(C)C=O>[OH:10][CH2:9][C:2]1[O:3][CH:4]=[C:5]([O:8][CH2:20][CH2:21][CH3:22])[C:6](=[O:7])[CH:1]=1
Reactant: CCCBr
Reactant: O=c1cc(CO)occ1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1coc(CO)cc1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of kojic acid (28.4 g, 0.20 mole), 120 mL of N,N-dimethylformamide, potassium carbonate powder (27.6 g, 0.20 mole), potassium iodide (1.66 g, 0.01 mole), and 1-bromopropane (24.6 g, 0.20 mole) is stirred for 15 minutes at ambient temperature then stirred at 90° C. for 3 hours. The reaction mixture is cooled, evaporated to dryness in vacuo and then portioned between water and chloroform. The aqueous layer is extracted with chloroform (3×100 mL) and ethyl acetate (6×100 mL). The combined organics were dried with sodium sulfate and passed through a pad of magnesol and silica gel eluting with ethyl acetate. The eluate is evaporated in vacuo and crystallized with hexane/ethyl acetate (2/1) to give an off-white solid, 22.60 g, (61%); MS (ES+): m/z 185.3 (M+H).
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[OH:11].[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=[CH2:14]>C(O)C>[Cl:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[O:11][CH2:14][CH2:13][C:12]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: COc1ccc(O)c(Cl)c1
Reactant: C=CC(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CCOc1ccc(OC)cc1Cl
Temperature: 105 °C

Procedure:
Sodium (0.055 g; 2.4 mmol) and ethanol (1.5 mL) was added to a melt of 2-chloro-4-methoxyphenol (5.20 g; 32.8 mmol). When all the sodium was dissolved, ethyl acrylate (4.1 g; 41 mmol) was added and the mixture was heated at 105° C. for 7 days. The mixture was then cooled to RT and partitioned between ether and water. The mixture was made acidic with HCl (2M; aq.) and extracted with ether three times. The combined organic layer was washed with NaOH (2M; aq), dried (CaCl2) and evaporated. The crude product (2.7 g) was purified using preparative RPLC (CH3CN:0.1M ammonium acetate (60:40)). Yield 1.90 g (22%).
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[CH2:10][C:9]2[C:8]([N:11]3[CH2:17][CH2:16][C:15](=[O:18])[NH:14][CH2:13][CH2:12]3)=[N:7][C:6]([C:19]3[CH:24]=[C:23]([F:25])[C:22](F)=[CH:21][C:20]=3[F:27])=[N:5][C:4]=2[CH2:3]1.[CH3:29][S:30](C)=O.C[S-].[Na+]>O>[F:27][C:20]1[CH:21]=[C:22]([S:30][CH3:29])[C:23]([F:25])=[CH:24][C:19]=1[C:6]1[N:7]=[C:8]([N:11]2[CH2:17][CH2:16][C:15](=[O:18])[NH:14][CH2:13][CH2:12]2)[C:9]2[CH2:10][S:2](=[O:28])(=[O:1])[CH2:3][C:4]=2[N:5]=1
Reactant: CS(C)=O
Reactant: O=C1CCN(c2nc(-c3cc(F)c(F)cc3F)nc3c2CS(=O)(=O)C3)CCN1
Agent: C[S-]
Agent: [Na+]
Solvent: O
Product: CSc1cc(F)c(-c2nc3c(c(N4CCNC(=O)CC4)n2)CS(=O)(=O)C3)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 500 mg of 1-[6,6-dioxido-2-(2,4,5-trifluorophenyl)-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl]-1,4-diazepan-5-one and 5 ml of DMSO, 89 mg of sodium thiomethoxide was added, the mixture was stirred at ambient temperature for 1 hour, here was then added 21 mg of sodium thiomethoxide, and the mixture was stirred at ambient temperature for 30 minutes. To the reaction mixture was added 50 ml of water, and the precipitate was collected by filtration, washed with water, and dried under reduced pressure. The filtrate was separately extracted with a mixture of EtOAc and THF, the organic phase obtained was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the solid obtained was combined with the former solid. The mixture was purified by silica-gel column chromatography (chloroform-MeOH) to yield 352 mg of 1-{2-[2,5-difluoro-4-(methylthio)phenyl]-6,6-dioxido-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl}-1,4-diazepan-5-one.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Cl:19])[C:15]([O:17]C)=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].B(Br)(Br)Br>ClCCl>[F:20][C:2]([F:1])([F:21])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Cl:19])[C:15]([OH:17])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: COc1cc2c(cc1Cl)C(C)CN(C(=O)C(F)(F)F)CC2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1CN(C(=O)C(F)(F)F)CCc2cc(O)c(Cl)cc21
Temperature: 20 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
A solution of N-trifluoroacetyl-8-chloro-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (48 mg, 0.15 mmol) in dichloromethane (2 mL) was treated with BBr3 (0.30 mL of a 1.0M solution in CH2Cl2, 0.30 mmol) and stirred overnight at 20° C. The excess BBr3 was quenched with water and the resulting mixture diluted with ether (20 mL), washed with Na2CO3 (10 mL) and brine (10 mL), dried with Na2SO4 and concentrated. Flash chromatography (15% EtOAc in hexane, silica) resulted in 24 mg of a white solid. MS calculated for C13H13ClF3NO2+H: 308, observed: 308.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:29])[CH:11]=[C:12]([CH2:17][NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[O:13][C:14]=1[CH2:15][OH:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C(=O)C=C(CNS(C2C=CC=CC=2)(=O)=O)OC=1C=O)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[C:10](=[O:29])[CH:11]=[C:12]([CH2:17][NH:18][S:19]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)(=[O:21])=[O:20])[O:13][C:14]=1[CH:15]=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(CNS(=O)(=O)c2ccc(Cl)cc2)oc(CO)c1OCc1ccccc1
Agent: O=Cc1oc(CNS(=O)(=O)c2ccccc2)cc(=O)c1OCc1ccccc1
Product: O=Cc1oc(CNS(=O)(=O)c2ccc(Cl)cc2)cc(=O)c1OCc1ccccc1
Yield: 85.3 %

Procedure:
N-(5-Benzyloxy-6-formyl-4-oxo-4H-pyran-2-ylmethyl)-4-chloro-benzenesulfonamide (11-07) (3.4 g, 85.22%) was synthesized as a white solid from N-(5-benzyloxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-4-chloro-benzenesulfonamide (10-07) (4.0 g, 9.19 mmol) following the procedure described for N-(5-benzyloxy-6-formyl-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (11-01).
Reaction SMILES: C[O:2][C:3](=[O:39])[C@@H:4]([NH:28][C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])[CH2:5][NH:6][C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]3[NH:23][CH2:24][CH2:25][CH2:26][N:27]=3)[CH:16]=2)[CH2:11][CH2:10]1)=[O:8].[OH-].[Na+].FC(F)(F)C(O)=O>CO>[CH2:32]([O:31][C:29]([NH:28][C@@H:4]([CH2:5][NH:6][C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]3[NH:23][CH2:24][CH2:25][CH2:26][N:27]=3)[CH:16]=2)[CH2:11][CH2:10]1)=[O:8])[C:3]([OH:39])=[O:2])=[O:30])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COC(=O)[C@H](CNC(=O)N1CCN(c2cccc(NC3=NCCCN3)c2)CC1)NC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=C(N[C@@H](CNC(=O)N1CCN(c2cccc(NC3=NCCCN3)c2)CC1)C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the compound of Example 144 in methanol (5 ml) is added 2M aqueous sodium hydroxide solution (5 ml), and the mixture is stirred at 25° C. overnight. The reaction solution is neutralized with trifluoroacetic acid, and purified by CHP-20 (eluent: gradient, 35% to 100% methanol/0.05% aqueous trifluoroacetic acid solution) to give the title compound (8 mg).
Reaction SMILES: N(OC(C)(C)C)=O.[CH3:8][O:9][C:10](=[O:46])[N:11]([CH2:34][C:35]1[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[C:37](N)[CH:36]=1)[CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[C:23]1[CH:28]=[C:27]([CH:29]([CH3:31])[CH3:30])[CH:26]=[CH:25][C:24]=1[O:32][CH3:33].[ClH:47]>C(#N)C.CCOC(C)=O>[CH3:8][O:9][C:10](=[O:46])[N:11]([CH2:34][C:35]1[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[C:37]([Cl:47])[CH:36]=1)[CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[C:23]1[CH:28]=[C:27]([CH:29]([CH3:31])[CH3:30])[CH:26]=[CH:25][C:24]=1[O:32][CH3:33]
Reactant: COC(=O)N(Cc1cc(N)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)C)ccc1OC
Reactant: Cl
Agent: CC(C)(C)ON=O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)N(Cc1cc(Cl)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)C)ccc1OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of CuCl2 (11.9 mg, 0.09 mmol) in acetonitrile (1 mL) was added t-butyl nitrite (11 μL, 0.092 mmol). Next, the solution was cooled to 0° C. and methyl[3-amino-5-(trifluoromethyl)benzyl]{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate (41 mg, 0.074 mmol) (Example 33) was added as a solution in acetonitrile (1.5 mL). The reaction was slowly warmed to room temperature. After stirring at room temperature for 2 hours, the mixture was diluted with EtOAc (30 mL) and poured into 20% HCl (5 mL). The organic extracts were washed with 20% HCl (2×5 mL), H2O (10 mL), brine (10 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash chromatography with 5% to 80% EtOAc/hexanes afforded methyl[3-chloro-5-(trifluoromethyl)benzyl]{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate. Rf=0.65 (15% EtOAc/hexanes). LCMS=574.3 (M+1)+. 1H NMR (C6D6, 500 MHz, 70° C.) δ 7.68 (s, 1H), 7.36 (d, J=7.5 Hz, 1H), 7.30 (s, 1H), 7.08-7.05 (m, 4H), 6.83 (d, J=2.5 Hz, 1H), 6.60 (d, J=8.5 Hz, 1H), 4.35 (broad singlet, 3H), 4.01 (broad singlet, 1H), 3.36 (s, 3H), 3.26 (s, 3H), 2.74 (m, 1H), 1.16 (d, J=7.0 Hz, 6H).