Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:24])(=[N:13][S:14]([C:17]2[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[O:12])=[CH:7][C:6]=1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])(=O)C.C(=O)([O-])[O-].[Na+].[Na+].C(O)C.Cl>O>[CH2:25]([C:6]1[CH:7]=[C:8]([S:11]([CH3:24])(=[N:13][S:14]([C:17]2[CH:18]=[CH:19][C:20]([CH3:21])=[CH:22][CH:23]=2)(=[O:16])=[O:15])=[O:12])[CH:9]=[CH:10][C:5]=1[OH:4])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCc1cc(S(C)(=O)=NS(=O)(=O)c2ccc(C)cc2)ccc1OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCCCc1cc(S(C)(=O)=NS(=O)(=O)c2ccc(C)cc2)ccc1O
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 89.6 %

Procedure:
A suspension of 0.8 g of the product of Step C, 30 ml of a saturated sodium carbonate solution and 15 ml of ethanol was stirred at 50° C. for 15 minutes and the solution was cooled in water. The mixture was acidified with concentrated hydrochloric acid and was extracted with ether. The decanted organic phase was evaporated to dryness to obtain 0.65 g of 2-hexyl-4-(S-methyl-N-tosyl-sulfonimidoyl)-phenol which after crystallization from an ether-petroleum ether mixture melted at 107°-109° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[CH:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][NH:43]3)=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49].[H-].[Na+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:18][CH:19]=2)[CH:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3c(c2)NCCC3)cc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOCc4ccccc4OC)cc3)cc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 33 %

Procedure:
A solution of 0.67 g (1.09 mmol) of (3RS,4RS)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-(1,2,3,4-tetrahydro-quinolin-7-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester in 10 ml of absolute N,N-dimethylformamide was successively treated at 0° C. with 0.21 g (1.30 mmol, 1.2 equiv.) of ethyl bromoacetate and 0.057 g (1.30 g, 1.30 mmol, 1.2 equiv.) of sodium hydride dispersion (55% in mineral oil). The mixture was then stirred for 2 h at 80° C. Then 0.047 g (1.09 mmol, 1.0 equiv.) of sodium hydride suspension (55% in mineral oil) and 0.18 g (1.09 mmol, 1.0 equiv.) of ethyl bromoacetate was added, and the suspension was stirred for another 8 h at 80° C. Subsequently, the suspension was poured into 100 ml of an ice/water mixture and extracted three times with 50 ml of ethyl acetate. The combined organic phases were washed three times with 20 ml of water, dried over magnesium sulphate, evaporated under reduced pressure and dried in a high vacuum. The thus-obtained crude product was purified by chromatography on silica gel using a 19:1 mixture of dichloromethane and ethyl acetate as the eluent and yielded 0.25 g (0.36 mmol, 33.0% of theory) of (3RS,4RS)-3-(1-ethoxycarbonylmethyl-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester as a light yellow oil; MS: 703 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][CH2:10][C:11]2[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][C:12]=2[NH:22][C:23](=[O:38])[C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:36][CH2:35][CH2:34][N:33]([CH3:37])[CH2:32][CH2:31]3)=[CH:26][CH:25]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].Cl.[NH2:40][OH:41].C(N(CC)CC)C>C(O)C>[OH:41][NH:40][C:1]([C:3]1[CH:4]=[C:5]([NH:9][CH2:10][C:11]2[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][C:12]=2[NH:22][C:23](=[O:38])[C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:36][CH2:35][CH2:34][N:33]([CH3:37])[CH2:32][CH2:31]3)=[CH:26][CH:25]=2)[CH:6]=[CH:7][CH:8]=1)=[NH:2]
Reactant: CCOC(=O)c1ccc(CNc2cccc(C#N)c2)c(NC(=O)c2ccc(N3CCCN(C)CC3)cc2)c1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(CNc2cccc(C(=N)NO)c2)c(NC(=O)c2ccc(N3CCCN(C)CC3)cc2)c1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
Ethyl 4-[(3-cyanophenylamino)methyl]-3-[4-(4-methyl-1,4-diazepan-1-yl)benzoylamino]benzoate (1.42 g) was dissolved in 30 ml of ethanol, then 291 mg of hydroxylamine hydrochloride and 0.78 ml of triethylamine were added and the mixture was stirred at 60° C. for 24 hours. The reaction solution was concentrated in vacuo and the resulting residue was purified by silica gel column chromatography using chloroform-methanol-aqueous ammonia (100:0:0 to 92:8:0.8) to give a crudely purified product, ethyl 4-({[3-(N-hydroxycarbamimidoyl)phenyl]amino}methyl)-3-[4-(4-methyl-1,4-diazepan-1-yl)benzoylamino]benzoate. The crudely purified product was further purified by ODS column chromatography using 0.002N aqueous solution of hydrochloric acid-methanol (100:0 to 88:12) as an eluting solvent and freeze-dried to give 1.03 g of ethyl 4-({[3-(N-hydroxycarbamimidoyl)phenyl]amino}methyl)-3-[4-(4-methyl-1,4-diazepan-1-yl)benzoylamino]benzoate hydrochloride.
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:35])[CH:15]([N:20]3[C:25](=[O:26])[CH:24]=[C:23]([NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[Cl:34])[CH:22]=[N:21]3)[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1.Cl>O1CCCC1>[OH:6][C@@H:5]([CH2:4][OH:3])[CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:35])[CH:15]([N:20]2[C:25](=[O:26])[CH:24]=[C:23]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[Cl:34])[CH:22]=[N:21]2)[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]1
Reactant: CC(C)CC(C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)n1ncc(Nc2ccccc2Cl)cc1=O
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)CC(C(=O)Nc1ccn(C[C@@H](O)CO)n1)n1ncc(Nc2ccccc2Cl)cc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
A solution of 2-[4-(2-chloro-phenylamino)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide (41.2 mg, 0.08 mmol) in tetrahydrofuran (2 mL) was treated with a 1 M aqueous hydrochloric acid solution (2 mL), and the reaction stirred at 25° C. overnight. At this point, the reaction was dried under nitrogen and suspended in ethyl acetate (20 mL), then washed with a 1:1 aqueous sodium bicarbonate/water solution (20 mL total) and a saturated aqueous sodium chloride solution (10 mL). The organics were dried over sodium sulfate, concentrated in vacuo, and dried from methylene chloride, ethanol, and diethyl ether, and in a vacuum oven at 50° C. for 3 h to afford 2-[4-(2-chloro-phenylamino)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide as a light yellow solid (29.6 mg, 78%); ES+-HRMS m/e calcd for C22H27N6O4Cl [M+H+] 475.1855 found 475.1855. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.86 (d, J=6.6 Hz, 3H), 0.88 (d, J=6.6 Hz, 3H), 1.44 (br. s., 1H), 1.62-1.81 (m, 1H), 2.00-2.22 (m, 1H), 3.20-3.32 (m, 2H), 3.70-3.92 (m, 2H), 4.08 (dd, J=13.4, 3.8 Hz, 1H), 4.71 (t, J=5.6 Hz, 1H), 4.94 (dd, J=5.1, 1.8 Hz, 1H), 5.49 (dd, J=11.0, 4.1 Hz, 1H), 5.54 (d, J=2.7 Hz, 1H), 6.35 (d, J=2.1 Hz, 1H), 7.28 (td, J=7.8, 1.2 Hz, 1H), 7.40 (td, J=7.8, 1.2 Hz, 1H), 7.47 (dd, J=7.8, 1.2 Hz, 1H), 7.52 (d, J=2.1 Hz, 1H), 7.60 (dd, J=7.8, 1.2 Hz, 1H), 7.86 (d, J=2.7 Hz, 1H), 8.94 (s, 1H), 10.65 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[CH:24]1([NH:27][C:28](=[O:37])[CH2:29][NH:30][C:31]2[CH2:35][S:34][C:33](=[O:36])[N:32]=2)[CH2:26][CH2:25]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:35]2/[C:31]([NH:30][CH2:29][C:28]([NH:27][CH:24]3[CH2:25][CH2:26]3)=[O:37])=[N:32][C:33](=[O:36])[S:34]/2)[CH2:8][CH2:7]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: O=C(CNC1=NC(=O)SC1)NC1CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: O=C(CNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1)NC1CC1
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 63.2 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (2.65 g) and N-cyclopropyl-N2-(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)glycinamide (2 g) in 2-propanol (20 mL) was added piperidinium acetate (1.14 g). The reaction mixture was stirred at 80° C. for 3.5 hr and concentrated. Water and THF were added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) and recrystallized from ethyl acetate/water/heptane to give the title compound (2.64 g).
Reaction SMILES: [NH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:11])[C:5]=2[CH2:4][CH2:3][C:2]1=[O:12].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([O:23][CH3:24])=[O:22].Cl>CN(C)C=O>[C:21]([CH2:20][N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:11])[C:5]=2[CH2:4][CH2:3][C:2]1=[O:12])([O:23][CH3:24])=[O:22]
Reactant: O=C1CCC2=C(CCCC2=O)N1
Reactant: COC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)CCC2=C1CCCC2=O

Procedure:
3.17 g (0.019 mol) of 3,4,7,8-tetrahydro-2,5(1H,6H)-quinolinedione are dissolved in 25 ml of dimethylformamide, mixed with 5.3 g (1.2×0.019 mol) of anhydrous. potassium carbonate and then with 3.52 g (2×0.019 mol) of methyl bromoacetate and the mixture is stirred for 16 hours at ambient temperature. The mixture is neutralised with methanolic hydrochloric acid and evaporated down in a rotary evaporator. The residue is purified by column chromatography (silica gel, eluant: cyclohexane/ethyl acetate (1:1)).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:7][N:6]=1)=[O:4].S(=O)(=O)(O)O.[Br:21]Br.C(O)(=O)C.BrBr.CC(O)=O.C([O-])(O)=O.[Na+]>O>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]([F:15])([F:13])[F:14])=[C:7]([Br:21])[N:6]=1)=[O:4]
Reactant: COC(=O)c1ncc(C(F)(F)F)cc1N
Reactant: BrBr
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1nc(Br)c(C(F)(F)F)cc1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Amino-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (9.49 g, 43.16 mmol) was suspended in water (300 ml). Sulfuric acid (4.60 ml, 86 mmol) was added followed by dropwise addition over 30 minutes of a solution of bromine (2.222 ml, 43.1 mmol) in acetic acid (29.6 ml, 517 mmol). The reaction mixture was stirred at RT for 18 hours. A further 100 ml of water was added, followed by a further 0.25 equivalents of the bromine/AcOH mixture (550 μL bromine in 7.4 ml AcOH) and the reaction mixture stirred at RT for an additional 90 minutes. The reaction mixture was diluted with 500 ml water and neutralised by addition of solid NaHCO3 (˜85 g). The suspension was extracted with DCM (3×300 ml) and the combined organic phases washed with sat. NaHCO3(aq) (250 ml), water (250 ml) and brine (100 ml), dried (MgSO4) and concentrated in vacuo. The crude material was recrystallised from boiling MeOH (˜300 ml) to give the title product as a pale orange solid m/z 301.0 [M+H]+ 1H-NMR: [400 MHz, DMSO-d6 δH 7.77 (1H, s, ArH), 7.17 (2H, s, NH2), 3.86 (3H, s, ArCO2CH3).
Reaction SMILES: Cl.[CH:2]([O:5][CH2:6][CH2:7][N:8]([C:13]1[CH:35]=[CH:34][C:16]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[CH2:21][CH2:20]2)=[O:18])=[CH:15][CH:14]=1)[C:9](=[O:12])[CH2:10]Cl)([CH3:4])[CH3:3].[SH:36][CH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41]>>[CH:2]([O:5][CH2:6][CH2:7][N:8]([C:13]1[CH:35]=[CH:34][C:16]([C:17]([N:19]2[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=3)[CH2:23][CH2:24]2)=[O:18])=[CH:15][CH:14]=1)[C:9](=[O:12])[CH2:10][S:36][CH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])([CH3:3])[CH3:4]
Reactant: O=C(O)CCCS
Reactant: CC(C)OCCN(C(=O)CCl)c1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Agent: Cl
Product: CC(C)OCCN(C(=O)CSCCCC(=O)O)c1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1

Procedure:
Analogously to Example 1, 1-{4-[N-(2-isopropoxyethyl)-N-chloroacetylamino]-benzoyl}-4-[2-(4-chlorophenyl)-ethyl]-piperazine hydrochloride is reacted with 4-mercaptobutyric acid, yielding 1-{4-[N-(2-isopropoxyethyl)-N-(3-carboxy-propylmercapto-acetyl)-amino]-benzoyl}-4-[2-(4-chlorophenyl)-ethyl]-piperazine.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]OC2C=CC=CC=2)[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)[Br:24]>C(Cl)Cl>[Br:24][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([OH:2])[CH:4]=1
Reactant: BrB(Br)Br
Reactant: COc1cccc(CCCCCCCOc2ccccc2)c1
Solvent: ClCCl
Product: Oc1cccc(CCCCCCCBr)c1

Procedure:
7-Bromo-1-(3-hydroxy-phenyl)-heptane (9.2) was synthesized as in 9.1 using 8.2 (0.50 g, 1.68 mmol), in anhydrous CH2Cl2 (16 mL), and BBr3 (1M solution in CH2Cl2, 3.7 mL, 3.7 mmol). The title compound (9.2) was isolated as a viscous liquid after purification by flash column chromatography (0.420 g, 92% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[NH:8][C:9](=[O:13])[CH2:10][CH2:11][CH2:12][C:6]=2[CH:5]=1)([O-:3])=[O:2].Br[CH2:17][C:18]([O:20][CH3:21])=[O:19].[H-].[Na+]>CN(C=O)C>[CH3:21][O:20][C:18](=[O:19])[CH2:17][N:8]1[C:9](=[O:13])[CH2:10][CH2:11][CH2:12][C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:15]=[CH:14][C:7]1=2
Reactant: O=C1CCCc2cc([N+](=O)[O-])ccc2N1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)CCCc2cc([N+](=O)[O-])ccc21
Temperature: 60 °C
Yield: 90 %

Procedure:
7-Nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (375 mg, 1.82 mmol) and methyl bromoacetate (417 mg, 2.73 mmol) were dissolved in anhydrous DMF. Sodium hydride (60% in mineral oil, 146 mg, 3.64 mmol) was added, and the mixture was heated to 60° C. for 2 hours. After cooling to room temperature, the mixture was partitioned between ethyl acetate and water, washed once with water, and concentrated to a brown oil. Preparative TLC (50% EtOAc/hexane) afforded (7-Nitro-2-oxo-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-acetic acid methyl ester as a yellow solid, 454 mg. (90% yield) 1H NMR (400 MHz, DMSO-d6) δ 8.23 (s, 1H), 8.12-8.18 (m, 1H), 7.51-7.56 (m, 1H), 4.60 (s, 2H), 3.62 (s, 3H), 2.93-3.00 (m, 2H), 2.05-2.20 (m, 4H); MS (m/e) 279 (M+1). 8b) 7-Nitro-2-oxo-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-acetic acid methyl ester 9 (454 mg, 1.63 mmol), ammonium formate (400 mg), and 10% palladium on carbon (200 mg) were suspended in ethanol (8 ml) and heated to reflux 30 minutes. The heat was removed, and additional amounts of ammonium formate (400 mg) and 10% palladium on carbon (200 mg) were added. The mixture was refluxed an additional 30 minutes, cooled to room temperature, filtered through Celite, and concentrated. The resulting brown residue was partitioned between ethyl acetate and water, washed once with water, and concentrated. Preparative TLC (50% EtOAc/hexane) afforded (7-Amino-2-oxo-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-acetic acid methyl ester as a white foam, 270 mg. (67% yield) 1H NMR (400 MHz, DMSO-d6) δ 6.86-6.91 (m, 1H), 6.38-6.44 (m, 2H), 5.06 (s, 2H), 4.44 (s, 2H), 3.61 (s, 3H), 2.51-2.82 (m, 2H), 1.92-2.22 (m, 4H); MS (m/e) 249 (M+1). 8c) 7-Amino-2-oxo-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-acetic acid methyl ester (270 mg, 1.09 mmol), 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide (362 mg, 1.09 mmol) and 4N HCl in dioxane (0.273 ml, 1.09 mmol) were dissolved in 2-methoxyethanol (5 ml) and heated to 120° C. for 18 hours. The mixture was concentrated to a brown oil. Preparative TLC (5% MeOH/CH2Cl2) gave the title compound as a white solid, 327 mg. (55% yield) 1H NMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H), 9.23 (s, 1H), 8.38-8.50 (m, 1H), 8.29 (s, 1H), 7.72-7.87 (m, 2H), 7.60-7.68 (m, 1H), 7.54 (s, 1H), 7.46-7.51 (d, 1H), 7.28-7.35 (m, 1H), 7.22-7.29 (m, 1H), 4.48 (s, 2H), 3.63 (s, 3H), 2.53-2.84 (m, 2H), 2.44 (s, 3H), 1.96-2.26 (m, 4H); MS (m/e) 545 (M+1); retention time 8.28 minute; mp 237-239° C.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:19]([NH:21][C:22]1[CH:23]=[C:24]([CH2:29][C@H:30]([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:25]=[CH:26][C:27]=1[F:28])=[O:20])[CH:13]([C:15]([F:18])([F:17])[F:16])[CH3:14])=O)C1C=CC=CC=1>C(O)C.C1COCC1.[Pd]>[F:28][C:27]1[CH:26]=[CH:25][C:24]([CH2:29][C@H:30]([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:23][C:22]=1[NH:21][C:19](=[O:20])[C@H:12]([CH:13]([C:15]([F:18])([F:17])[F:16])[CH3:14])[NH2:11]
Reactant: CCOC(=O)[C@@H](C)Cc1ccc(F)c(NC(=O)[C@@H](NC(=O)OCc2ccccc2)C(C)C(F)(F)F)c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](C)Cc1ccc(F)c(NC(=O)[C@@H](N)C(C)C(F)(F)F)c1
Reaction time: 8 h

Procedure:
2.60 g (5.07 mmol) of ethyl (2S)-3-[3-({N-[(benzyloxy)carbonyl]-4,4,4-trifluorovalyl}amino)-4-fluorophenyl]-2-methylpropanoate (Example 36A, mixture of 4 isomers) were dissolved in a mixture of 10.7 ml of ethanol and 10.7 ml of THF. The solution was inertized with argon, and 322 mg of palladium on carbon (10%) were added. The reaction mixture was stirred vigorously at standard pressure under an atmosphere of hydrogen overnight. After filtration through kieselguhr and washing with dichloromethane/methanol, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10:1→4:1) and separated. This gave 1.39 g of the title compound as diastereomer mixture 1 (72.4% of theory).
Reaction SMILES: C([C:4]([C:22](=O)[CH3:23])([CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21])[CH2:11][C:12]([O-:14])=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=O)C.[C:25](=O)=O>C(O)C>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH:10]1[CH2:11][C:12](=[O:14])[CH:25]=[C:22]([CH3:23])[CH:4]1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: O=C=O
Reactant: CCOC(=O)C(C(C)=O)(C(C)=O)C(CC(=O)[O-])c1ccccc1F
Solvent: CCO
Product: CCOC(=O)C1C(C)=CC(=O)CC1c1ccccc1F

Procedure:
The ethyl α,α-diacetyl-β-(2-fluorophenyl)glutarate was heated under vacuum at 160°-180°/10-15 mm for 1 hr, eliminating carbon dioxide and ethanol and producing 5-(2-fluorophenyl)-3-methyl-4-carbethoxy-2-cyclohexen-1-one. The crude product was distilled under reduced pressure to give 5-(2-fluorophenyl)-3-methyl-4-carbethoxy-2-cyclohexen-1-one (57.3 g); bp, 155°-162°/1.2 mm.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH:45]1[CH:50]=[CH:49][C:48]([CH2:51][NH:52][NH2:53])=[CH:47][CH:46]=1.Cl.Cl.Cl>CN(C=O)C>[CH2:51]([N:52]1[C:2]2[C:3](=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=2)[C:4](=[O:6])[NH:53]1)[C:48]1[CH:49]=[CH:50][CH:45]=[CH:46][CH:47]=1
Reactant: NNCc1ccccc1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=c1[nH]n(Cc2ccccc2)c2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 22 h
Yield: 35.7 %

Procedure:
To a solution of 2-fluoro-5-nitrobenzoic acid (0.5 g) in DMF (9 mL) was added TBTU (1.04 g) followed by N-ethyldiisopropylamine (2.3 mL). After 10 minutes benzylhydrazine.2HCl (0.63 g) was added. The reaction mixture was stirred at ambient temperature for 22 hours and the reaction was poured onto aqueous 1N HCl solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo. Purification via ISCO combiflash chromatography afforded pure desired 1-benzyl-5-nitro-1,2-dihydro-indazol-3-one (0.26 g) as a yellow solid. MS (ESI−):268.3 ([M−H]−).
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:19][C:20]1[S:21][CH:22]=[CH:23][N:24]=1>>[S:21]1[CH:22]=[CH:23][N:24]=[C:20]1[NH:19][C:15]([C:12]1[CH:13]=[CH:14][N:10]([S:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:18])=[CH:6][CH:5]=2)(=[O:8])=[O:9])[CH:11]=1)=[O:17]
Reactant: Cc1ccc(S(=O)(=O)n2ccc(C(=O)O)c2)cc1
Reactant: Nc1nccs1
Product: Cc1ccc(S(=O)(=O)n2ccc(C(=O)Nc3nccs3)c2)cc1
Yield: 78.3 %

Procedure:
1-(Toluene-4-sulfonyl)-1H-pyrrole-3-carboxylic acid thiazol-2-ylamide (68 mg) was prepared from 1-(toluene-4-sulfonyl)-1H-pyrrole-3-carboxylic acid (66 mg, 0.25 mmol) and 2-aminothiazole (25 mg, 0.25 mmol) following the general procedure F.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7].F[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN1CCCC1=O>O>[N:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[N:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7]
Reactant: Fc1ccccn1
Reactant: O=Cc1ccc[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=Cc1cccn1-c1ccccn1
Temperature: 120 °C
Reaction time: 24 h
Yield: 43.4 %

Procedure:
A mixture of 10 g of 2-pyrrolecarbaldehyde, 10 g of 2-fluoropyridine, 24 g of cesium carbonate and 100 ml of N-methylpyrrolidone was stirred at 120° C. for 1 day. The reaction mixture was allowed to cool to room temperature. Water was poured into the mixture, and the mixture was extracted with ethyl acetate two times. The organic layers were combined, washed successively with water and an aqueous saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography to obtain 7.7 g of 1-(2-pyridinyl)-1H-pyrrole-2-carbaldehyde of the formula:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)O1.[Br:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23](Br)[N:22]=1>>[Br:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=2)[N:22]=1
Reactant: Brc1cccc(Br)n1
Reactant: CC1(C)OB(c2cccc(C(F)(F)F)c2)OC1(C)C
Product: FC(F)(F)c1cccc(-c2cccc(Br)n2)c1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using 4,4,5,5-tetramethyl-2-(3-trifluoromethyl-phenyl)-[1,3,2]dioxaborolane and 2,6-dibromo-pyridine.
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].[CH3:6][N:7]1[C:11]([CH3:12])=[C:10]([CH3:13])[N:9]=[C:8]1[SH:14].C(N(CC)CC)C>CC(C)=O>[CH3:6][N:7]1[C:11]([CH3:12])=[C:10]([CH3:13])[N:9]=[C:8]1[S:14][CH2:2][C:3](=[O:5])[CH3:4]
Reactant: CC(=O)CCl
Reactant: Cc1nc(S)n(C)c1C
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(=O)CSc1nc(C)c(C)n1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Chloroacetone, 2.55 grams (0.28 mol) in 250 mL of acetone, was added to a solution of 3.55 g (0.025 mol) of 1,4,5-trimethyl-2-mercaptoimidazole and 3.15 g (0.031 mol) of triethylamine in 250 mL of acetone and the resulting mixture stirred at room temperature for 16 hours. At the end of this period the acetone was removed by evaporation and the residue was partitioned between ethyl acetate and water. The ethyl acetate solution was washed successively with water and brine, and then dried over magnesium sulfate. After drying, the solvent was evaporated from the filtered dry solution to obtain 3.39 grams of 1,4,5-trimethyl-2[(2-oxopropyl)thio]imidazole. The latter was purified by flash chromatography on silica gel using 1 percent methanol in chloroform as an eluant to obtain 3.0 grams of purified 1,4,5-trimethyl-2[(2-oxopropyl)thio]imidazole.