Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.O.[NH2:14][NH2:15]>C(O)C>[Cl:8][C:7]1[C:2]([NH:14][NH2:15])=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: NN
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Solvent: O
Solvent: CCO
Product: NNc1ncc(C(F)(F)F)cc1Cl
Temperature: 50 °C
Reaction time: 8 h
Yield: 113.6 %

Procedure:
To a solution of 2,3-dichloro-5-(trifluoromethyl)pyridine (6.8 g) in ethanol (50 mL) was added hydrazine hydrate (3.15 g) in an ice bath, and the mixture was stirred overnight at 50° C. The mixture was allowed to be cooled to room temperature, and the solvent was evaporated under reduced pressure. The obtained residue was treated with IPE, and the precipitated solid was collected by filtration to give the title compound (7.57 g).
Reaction SMILES: [C:1]([C:5]1[CH:37]=[CH:36][C:8]([CH2:9][N:10]([CH2:34][CH3:35])[C:11](=[O:33])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][O:22][C:23]3[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=3[C:25]([O:27]C)=[O:26])=[CH:16][CH:15]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O>C1COCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]([CH2:34][CH3:35])[C:11](=[O:33])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][O:22][C:23]3[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=3[C:25]([OH:27])=[O:26])=[CH:16][CH:15]=2)=[CH:36][CH:37]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCN(Cc1ccc(C(C)(C)C)cc1)C(=O)COc1ccc(CCOc2ccccc2C(=O)OC)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCN(Cc1ccc(C(C)(C)C)cc1)C(=O)COc1ccc(CCOc2ccccc2C(=O)O)cc1
Yield: 73.2 %

Procedure:
Methyl 2-[2-(4-{2-[(4-tert-butylbenzyl)(ethyl)amino]-2-oxoethoxy}phenyl)-ethoxy]benzoate (0.2290 g, 0.455 mmol) was dissolved in a mixture of THF (freshly distilled)/water (2/1, 3 ml), lithium-hydroxide (0.218 g, 0.909 mmol) was added. The reaction was performed in a single node microwave oven (5 min, 150 deg). THF was removed by evaporation. Water was added (10 ml) and the basic water phase was washed with diethyl ether (2×10 ml). Addition of HCl (2 ml, 1 M, pH 1). The water phase was extracted with two portions of DCM (20 ml), the organic phase was dried (MgSO4) and the solvent was removed by evaporation to give 0.163 g of 2-[2-(4-{2-[(4-tert-butylbenzyl)(ethyl)amino]-2-oxoethoxy}phenyl)ethoxy]benzoic acid (yield 73.2%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1.[CH3:15][S:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>C1(C)C=CC=CC=1.C(O)C.C([O-])([O-])=O.[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[C:20]2[CH:21]=[CH:22][C:17]([S:16][CH3:15])=[CH:18][CH:19]=2)=[CH:9][CH:10]=1
Reactant: Fc1ccc(-c2ccccc2Br)cc1
Reactant: CSc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CSc1ccc(-c2ccccc2-c2ccc(F)cc2)cc1
Yield: 93.4 %

Procedure:
Under nitrogen, 200 mg of Pd(PPh3)4 was added to a stirred solution of 500 mg (2.0 mmol) of 1-bromo-2-(4-fluorophenyl)benzene (Step 1) and 500 mg (3.0 mmol) of 4-methylthiophenylboronic acid (Step 2) in 7 mL of toluene, 7 mL of ethanol and 7 mL of 2M Na2CO3. After vigorous stirring at reflux overnight, the solvent was removed in vacuo. The residue was dissolved in ethyl acetate. The resulting solution was washed with water and dried over MgSO4. Purification by silica gel chromatography (Waters LC-2000) with ethyl acetate/hexane (2:98) as the eluent gave 550 mg of 1-(4-fluorophenyl)-2-[4-(methylthio)phenyl]benzene as a semi-solid: NMR (CDCl3) δ 2.46 (s, 3H), 6.92 (t, J=8 Hz, 2H), 7.02-7.14 (m, 6H), 7.37-7.42 (m, 4H). MS (EI): m/e (rel intensity) 294 (100), 279 (39), 277 (56), 246 (74), 227 (40), 190 (43), 190 (38), 140 (44).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:6]([C:7](O)=[O:8])=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=1.[NH4+:17].[OH-]>O=S(Cl)Cl>[CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:6]([C:7]([NH2:17])=[O:8])=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=1
Reactant: COc1cc(C(=O)O)c([N+](=O)[O-])cc1OC
Reactant: [NH4+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Product: COc1cc(C(N)=O)c([N+](=O)[O-])cc1OC
Temperature: 0 °C

Procedure:
A suspension of 4,5-dimethoxy-2-nitrobenzoic acid 1 (2 g; 8.8 mmol) in SOCl2 (10 mL) was stirred under reflux for 50 minutes. After cooling, the reaction mixture was poured into a mixture of concentrated NH4OH (50 mL) and ice (30 g). The precipitate were collected by filtration, washed with water, and dried to give 1.85 g crude crystals. After recrystallization from DMF, 1.76 g pure product was obtained (88.5%). 1H NMR(DMSO-d6): δ 7.60(s, 2H, —NH2), 7.57(s, 1H, 6-H), 7.12(s, 1H, 3-H), 3.90, 3.87(s, s, 6H, —OCH3); IR(Kr) υmax: 3454, 2840, 1670, 1512, 1274, 1227 cm−1; GC/MS m/z 226(M+, 10.0), 178(98.5), 163(100.0), 135(51.0).
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:30][CH3:31])[C:25](OCC)=[O:26])[C:5]1=[O:32])[CH:2]=[CH2:3].[N+](=[CH:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[N-]>C(Cl)Cl.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[CH2:1]([C@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:30][CH3:31])[CH2:25][O:26][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:5]1=[O:32])[CH:2]=[CH2:3]
Reactant: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(=O)OCC)C1=O
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)COCC(=O)OCC)C1=O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 203 mg (0.47 mmol) of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)piperidin-2-one (Example 9, Step B) and rhodium(II)acetate dimmer (10.4 mg, 0.047 mmol) in CH2Cl2 (1.90 mL) was added dropwise ethyl diazoacetate (286 μL, 2.35 mmol) at 25° C. After being stirred at 25° C. for 14 h, the reaction was concentrated under reduced pressure and purified by chromatography on silica gel (20% to 30% EtOAc/Hexanes, gradient elution) to provide the title compound as a colorless liquid:
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].IC.[OH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][I:19])=[CH:12][CH:11]=1>CC(C)=O>[CH3:1][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][I:19])=[CH:12][CH:11]=1
Reactant: Oc1ccc(CCCI)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc(CCCI)cc1
Temperature: 70 °C
Yield: 73.6 %

Procedure:
Anhydrous potassium carbonate (4.14 g, 30.0 mmol), iodomethane (3.74 mL, 60.0 mmol), and 3-(4-hydroxyphenyl)-1-iodopropane (1.58 g, 6.0 mmol) were added to acetone (25 mL) at rt. The mixture was heated to 70° C. for 8 h. The resulting solution was gravity filtered to remove salts and the filtrate was concentrated in vacuo to afford 3-(4-methoxyphenyl)-1-iodopropane (1.22 g, 73%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:32]([O:36][CH3:37])(=[O:35])[CH:33]=[CH2:34].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:37][O:36][C:32](=[O:35])/[CH:33]=[CH:34]/[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1
Reactant: C=CC(=O)OC
Reactant: O=C(c1ccc(Br)cc1)C1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1ccc(C(=O)C2CC2)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 47.1 %

Procedure:
A mixture of (4-bromophenyl)-(cyclopropyl)methanone (0.450 g, 2.00 mmol), palladium acetate 49 mg, 0.220 mmol), triphenylphosphine (55 mg, 0.21 mmol), methyl acrylate (0.43 g, 2.50 mmol) and triethylamine (10 ml, 72 mmol) was heated to 100° C. for 48 in a closed reaction vial. The reaction mixture was cooled to room temperature. The solid was removed by filtration. A mixture of ice and 1 N hydrochloric acid was added to the liquid. The mixture was stirred for 1 h at room temperature. It was extracted with ethyl acetate (2×150 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate (100 ml) and dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (40 g) using a mixture of dichloromethane/ethyl acetate/heptane (1:1:1) as eluent, to give 217 mg of (E)-3-(4-(cyclopropanecarbonyl)phenyl)acrylic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:11][CH:10]=[C:9]([OH:21])[C:8]=2[C:7]1=[O:22].C([O-])(=[O:29])C.[Na+].C(OO)(=O)C.OS([O-])(=O)=O.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:11][C:10]([OH:29])=[C:9]([OH:21])[C:8]=2[C:7]1=[O:22]
Reactant: CCOC(=O)c1ncc(O)c2c1CCN(Cc1ccc(F)c(Cl)c1)C2=O
Reactant: CC(=O)[O-]
Agent: CC(=O)OO
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1nc(O)c(O)c2c1CCN(Cc1ccc(F)c(Cl)c1)C2=O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a stirred solution of ethyl 6-(3-chloro-4-fluorobenzyl)-4-hydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate (5.0 g; see Example 12, Step 6) and sodium acetate (0.89 g) in acetic acid (90 mL) was added peracetic acid (28 mL). The mixture was then heated at 50° C. overnight. The mixture was cooled to 5° C. and saturated NaHSO4 (17 mL) added, keeping the temperature at less than 25° C. The mixture was concentrated to 50% original volume and partitioned between tert-butyl methyl ether (100 mL) and water (50 mL). The organic phase collected and the volatiles evaporated. The residue was dissolved in toluene (50 mL) and volatiles evaporated, the residue dissolved in toluene (50 mL) and evaporation repeated. Finally the residue was dissolved in toluene (20 mL). Acetic anhydride (3.9 mL) was added and the mixture heated at reflux until complete by HPLC analysis. The mixture cooled to ambient temperature and sodium ethoxide in ethanol (20 mL) was added. The reaction mixture stirred overnight. 2N HCl (31 mL) was added and the title product isolated by filtration.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][NH2:5].C(N(CC)CC)C.[Br:18][CH:19]([CH3:23])[C:20](Br)=[O:21]>C(Cl)CCl>[Br:18][CH:19]([CH3:23])[C:20]([NH:5][CH2:4][C:3]1[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:2]=1[Cl:1])=[O:21]
Reactant: Cc1cccc(Cl)c1CN
Reactant: CC(Br)C(=O)Br
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1cccc(Cl)c1CNC(=O)C(C)Br
Temperature: -35 °C

Procedure:
A mixture of 35 parts of 2-chloro-6-methylbenzylamine and 30 parts of triethyl amine in 400 parts of ethylene chloride is stirred and cooled to -35°C. While keeping the temperature between -35° and -20° C., there is added dripwise a solution of 50 parts of 2-bromopropionyl bromide in 160 parts of ethylene chloride. Upon completion, the whole is stirred for one hour at room temperature. The reaction mixture is washed with diluted hydrochloric acid and once with water. The organic phase is dried over magnesium sulfate, filtered and evaporated. The solid residue is crystallized from a mixture of 400 parts of ethanol and 150 parts of water, yielding 40 parts of N-(2-bromopropionyl)-2-chloro-6-methylbenzylamine; mp. 168° -169° C.
Reaction SMILES: [CH:1]([S:14]([CH2:16][C:17]([OH:19])=O)=[O:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[N:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH2:21][NH:20][C:17](=[O:19])[CH2:16][S:14]([CH:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:15]
Reactant: O=C(O)CS(=O)C(c1ccccc1)c1ccccc1
Reactant: NCc1ccccn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(CS(=O)C(c1ccccc1)c1ccccc1)NCc1ccccn1

Procedure:
To a suspension of 15.44 g (0.06 mol) of benzhydrylsulphinylacetic acid in 90 ml of methylene chloride are added 6.48 g (0.06 mol, i.e. 6.17 ml) of 2-aminomethylpyridine and 12.36 g (0.06 mol) of dicyclohexylcarbodiimide are added to the solution thus obtained. The mixture is heated at reflux for about 3 to 4 hours, then left to cool.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[CH:12]1[C:21]2[C:20](=[O:22])[CH2:19][CH2:18][CH2:17][C:16]=2[N:15]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[C:14](=[O:33])[NH:13]1)[C:7]#[N:8].[CH3:34][S:35](Cl)(=[O:37])=[O:36].O>O1CCCC1>[Cl:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[CH:12]1[C:21]2[C:20](=[O:22])[CH2:19][CH2:18][CH2:17][C:16]=2[N:15]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:31])([F:32])[F:30])[CH:24]=2)[C:14](=[O:33])[N:13]1[S:35]([CH3:34])(=[O:37])=[O:36])[C:7]#[N:8]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CCC3)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Sodium hydride (60% in mineral oil, 14 mg, 0.36 mmol) is added to a solution of 3-chloro-4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4,5,6,7,8-octahydroquinazolin-4-yl)-benzonitrile (example 56, 60 mg, 0.13 mmol) in tetrahydrofuran (3 mL), and the mixture is stirred at room temperature for 20 min. Methanesulfonyl chloride (21 μL, 0.27 mmol) is added, and the mixture is stirred at room temperature over night. Water is added, and the mixture is extracted with dichloromethane. The phases are separated, and the organic phase is concentrated under reduced pressure. The residue is purified by preparative HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 40 mg; ESI mass spectrum [M+H]+=524; Retention time HPLC: 0.70 min (X012_S01).
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.C(N(CC)CC)C.[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20]>ClCCl>[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([NH:7][C:6]1[CH:5]=[CH:4][C:3]([OH:8])=[CH:2][CH:1]=1)=[O:20]
Reactant: Nc1ccc(O)cc1
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(O)cc1)c1ccccc1Cl
Reaction time: 1 h

Procedure:
A suspension of p-aminophenol linked to the Wang's resin from Step A (1 eq) in dichloromethane was treated with triethylamine (2 ml/mmol) and 2-chloro-benzoyl chloride (10 eq). The mixture reaction was stirred for 1 hour and then the resin was filtered, washed with MeOH/CH2Cl2 several times and dried. The resin was then treated with TEA 95% H2O 5% and stirred at room temperature for 30 minutes. Filtered and washed with dichloromethane/methanol and concentrated to dryness to afford the title compound.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[H-].[Na+].[C:8]([C:11]1[CH:12]=[C:13]([CH:17]2[CH2:26][C:25]([CH3:28])([CH3:27])[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:29](O)=[O:30])[CH:23]=3)[NH:18]2)[CH:14]=[CH:15][CH:16]=1)(=[O:10])[NH2:9].C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[CH3:1][S:2]([NH:5][C:29]([C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]([C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[C:8]([NH2:9])=[O:10])[CH2:26][C:25]2([CH3:28])[CH3:27])=[O:30])(=[O:4])=[O:3]
Reactant: CC1(C)CC(c2cccc(C(N)=O)c2)Nc2ccc(C(=O)O)cc21
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CC(c2cccc(C(N)=O)c2)Nc2ccc(C(=O)NS(C)(=O)=O)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 9.8 %

Procedure:
To a suspension of methanesulfonamide (160 mg, 1.65 mmol) in N,N-dimethylformamide (3 mL) was added sodium hydride (66 mg, 1.65 mmol). The resulting mixture was stirred at 25° C. for 1 h to afford Solution A32. A solution of 2-(3-carbamoyl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (100 mg, 0.33 mmol) and 1,1′-carbonyldiimidazole (110 mg, 0.66 mmol) in N,N-dimethylformamide (3 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B32. Solution B32 was added to Solution A32 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 3-(6-methanesulfonylaminocarbonyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-benzamide (13 mg, 10%) as a white solid: MS (ESI) M+1=402.3.
Reaction SMILES: CC1(C)[O:7][CH2:6][C:5]([NH:32]C(=O)OC(C)(C)C)([CH2:8][N:9]2[C:17]3[C:12](=[C:13]([C:18]4[N:22]=[C:21]([C:23]5[CH:24]=[N:25][C:26]([CH2:29][CH2:30][CH3:31])=[CH:27][CH:28]=5)[O:20][N:19]=4)[CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10]2)[CH2:4][O:3]1.[Na+].[I-].CO>CC#N.[Si](Cl)(C)(C)C>[NH2:32][C:5]([CH2:8][N:9]1[C:17]2[C:12](=[C:13]([C:18]3[N:22]=[C:21]([C:23]4[CH:24]=[N:25][C:26]([CH2:29][CH2:30][CH3:31])=[CH:27][CH:28]=4)[O:20][N:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)([CH2:4][OH:3])[CH2:6][OH:7]
Reactant: CCCc1ccc(-c2nc(-c3cccc4c3CCN4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)no2)cn1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: CCCc1ccc(-c2nc(-c3cccc4c3CCN4CC(N)(CO)CO)no2)cn1
Yield: 48.8 %

Procedure:
To a solution of the product of Step E (0.018 g; 0.033 mmol), NaI (0.015 g; 0.0981 mmol) in anhydrous CH3CN (0.6 ml), Me3SiCl (0.08 ml) was added at room temperature with stirring under N2. After stirring for 30 min MeOH (0.5 ml) was added and solvents were removed under reduced pressure. The residue was purified by FCC (SiO2; NH4OH saturated CH2Cl2:MeOH 95:5) to give the title compound (0.0066 g; 49%) as colourless solid. 1H-NMR (CDCl3+CD3OD) 0.93 (tr, 3H, J=(Hz); 1.67-1.81 (m, 2H); 2.81 (tr, 2H, J=9 Hz); 2.99 (broad s, CD3OH); 3.07 (s, 2H); 3.26-3.65 (m, 8H); 6.74 (d, 1H, J=9 Hz); 7.15 (m, 1H); 7.31 (d, 1H, J=9 Hz); 7.42 (d, 1H, J=9 Hz); 8.32 (dd, 1H, J=3, 9 Hz); 9.33 (d, 1H, 3 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5](O)[C:4]=2[CH:3]=1.[O:17]=[C:18]([CH:25]1[CH2:28][CH:27]([C:29]([O:31][CH2:32][C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:34])=[O:30])[CH2:26]1)[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(O)(=O)C.C(O)C>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]([CH:19]([C:18](=[O:17])[CH:25]3[CH2:28][CH:27]([C:29]([O:31][CH2:32][C:33]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)=[O:34])=[O:30])[CH2:26]3)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:4]=2[CH:3]=1
Reactant: CCOC(=O)CC(=O)C1CC(C(=O)OCC(=O)c2ccccc2)C1
Reactant: OC1c2ccccc2Sc2ccc(Cl)cc21
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(C(=O)C1CC(C(=O)OCC(=O)c2ccccc2)C1)C1c2ccccc2Sc2ccc(Cl)cc21
Temperature: 60 °C

Procedure:
2-Chloro-9-hydroxythioxanthene (0.72 g, 2.89 mmol) was allowed to react with ethyl 3-oxo-3-(3-phenacyloxycarbonylcyclobutyl)propanoate (0.8 g, 2.41 mmol) in acetic acid (4 ml) and ethanol (4 ml) for 4 days and then heated at 60° C. for 4 hours. Worked up following procedure described in Example 6(i) to give a yellow oil. The crude product was purified by chromatography on flash silica eluting with chloroform then chloroform-methanol (99.5:0.5 then 99:1) to give the title compound as an oil.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:18][CH:17]3[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6]=2[N:25]=1.[NH2:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][C:28]=1[O:36][CH3:37]>C(O)C.O.Cl>[F:14][C:9]1([F:15])[CH2:8][N:7]([C@@H:16]2[CH2:18][C@H:17]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:6]2[N:25]=[C:2]([NH:26][C:27]3[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][C:28]=3[O:36][CH3:37])[N:3]=[CH:4][C:5]=2[N:11]([CH3:12])[C:10]1=[O:13]
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CN1C(=O)C(F)(F)CN(C2CC2c2ccccc2)c2nc(Cl)ncc21
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N([C@@H]1C[C@H]1c1ccccc1)CC(F)(F)C(=O)N2C
Yield: 69.9 %

Procedure:
A mixture of 1.0 g (0.0028 mole) of 2-chloro-7,7-difluoro-5-methyl-9-(2-phenyl-cyclopropyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-287) and 0.55 g (0.0034 mole) of 4-amino-3-methoxy-benzoic acid in 6.4 mL of ethanol-water-hydrochloric acid (20:80:1) was refluxed for 18 hours, then cooled and partially concentrated under reduced pressure. The resulting solid was collected by filtration, washed with water and dried to give 0.97 g of 4-[7,7-difluoro-5-methyl-6-oxo-9-(trans-2-phenyl-cyclopropyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-3-methoxy-benzoic acid (I-287).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[C:12]([CH3:13])=[C:11]([I:14])[N:10]=[C:9]2[CH3:15])[CH:5]=[CH:4][N:3]=1.[OH-:16].[K+]>C(O)(C)(C)C>[I:14][C:11]1[N:10]=[C:9]([CH3:15])[N:8]([C:6]2[CH:5]=[CH:4][NH:3][C:2](=[O:16])[CH:7]=2)[C:12]=1[CH3:13]
Reactant: [OH-]
Reactant: Cc1nc(I)c(C)n1-c1ccnc(Cl)c1
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cc1nc(I)c(C)n1-c1cc[nH]c(=O)c1

Procedure:
The title compound, white crystalline solid, MS: m/e=315.9 (M+H+), was prepared in accordance with the general method of example 1a from 2-chloro-4-(4-iodo-2,5-dimethyl-imidazol-1-yl)-pyridine and KOH in tert-butanol.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([NH:21][C@H:22]([CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])=[O:20])=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([NH:21][C@H:22]([CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:23][C:24]([OH:26])=[O:25])=[O:20])=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)N[C@@H](CC(=O)OC(C)(C)C)CC(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)N[C@@H](CC(=O)O)CC(C)C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
To a solution of 216 mg of tert-butyl (3R)-3-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)-5-methylhexanoate in 2 ml of dichloromethane was added 2 ml of trifluoroacetic acid, followed by stirring overnight. The solvent was evaporated under reduced pressure, and water, a saturated aqueous sodium hydrogen carbonate solution, 1 M hydrochloric acid, and chloroform were added thereto to carry out a layer separation operation. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography. To the obtained purified product were added ethyl acetate and diisopropyl ether, and the resulting solid was collected by filtration and dried to obtain 147 mg of (3R)-3-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)-5-methylhexanoic acid.