Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C([BH3-])#N.[Na+]>C(O)(=O)C.O.[OH-].[Na+]>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2
Reactant: Fc1ccc2[nH]ccc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Fc1ccc2c(c1)CCN2
Reaction time: 1 h

Procedure:
5-Fluoroindole (3 g, 22.2 mmol) in glacial acetic acid (35 mL) was treated with sodium cyanoborohydride (2.79 mg, 44.4 mmol) portionwise at room temperature with stirring. After one hour, the reaction was diluted with water and basified with 40% sodium hydroxide with cooling. The mixture was extracted 3 times with dichloromethane, dried and concentrated to give 5-fluoroindoline. It was used in the next step without further purification. 1H-NMR (300 MHz, dimethylsulfoxide-d6) δ 6.86 (m, 1H), 6.68 (dt, 1H), 6.42 (dd, 1H), 5.32 (br s, 1H, NH), 3.38 (m, 2H, CH2), 2.87 (t, 2H, CH2).
Reaction SMILES: [Li]CCCC.[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22](Br)=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1.[CH3:32][N:33]1[C:37]([C:38]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)=[O:39])=[CH:36][N:35]=[CH:34]1>C1COCC1>[N:6]1([C:11]2[CH:31]=[CH:30][C:14]([CH2:15][C:16]3[C:17]([O:28][CH3:29])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22]([C:38]([C:37]3[N:33]([CH3:32])[CH:34]=[N:35][CH:36]=3)([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=3)[OH:39])=[CH:21][CH:20]=4)=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1
Reactant: Cn1cncc1C(=O)c1ccccn1
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3ccccn3)c3cncn3C)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 0.28 mL, 0.7 mmol) was added dropwise by syringe to a solution of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline (0.303 g, 0.707 mmol, Intermediate 10) in dry THF (7 mL) in a dry ice-acetone bath. After 1-2 minutes, a solution of (1-methyl-1H-imidazol-5-yl)(pyridin-2-yl)methanone (0.144 g, 0.769 mmol, Intermediate 33: step b) in dry THF (0.5 mL) was added dropwise. The reaction was stirred for 5 minutes, switched to an ice bath for 10 minutes, then removed from the cold bath and allowed to warm to ambient temperature. The reaction was quenched with methanol. The mixture was partitioned between water and ethyl acetate. The separated aqueous phase was further extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered, and concentrated to dryness. The crude product was purified by flash column chromatography (silica gel, 100% EtOAc) followed by reverse-phase chromatography (acetonitrile/H2O+0.05% TFA). The isolated product fractions were basified with saturated aqueous sodium bicarbonate, extracted with DCM, dried (Na2SO4), filtered, and concentrated to dryness. Impurities remained in the sample, therefore the product was taken forward to the chiral separation step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.Cl[CH2:24][CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27].ClCCl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH2:24][CH2:25][C:26](=[O:27])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(CCCl)c1ccccc1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(-c2ccc(F)cc2F)n1CCC(=O)c1ccccc1
Temperature: 100 °C
Yield: 61.5 %

Procedure:
A mixture of (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 14; 330 mg, 1.08 mmol), tetrabutylammonium iodide (400 mg, 1.08 mmol) and 3-chloropropiophenone (Acros; 820 mg, 4.86 mmol) in dimethylformamide (6 mL) was heated at 100° C. for 3.5 h. The reaction mixture was cooled to room temperature. Dichloromethane (100 mL) was added and the solution was washed with water (4×25 mL), aqueous sodium thiosulfate (25 mL), and brine (25 mL). The solution was dried (magnesium sulfate), filtered, evaporated, and purified using an ISCO 40 g column, eluting with 50-100% ethyl acetate/hexane. The resulting material was dried under high vacuum at 70° C. for 3 h to give (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1-(3-oxo-3-phenyl-propyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (290 mg, 61%) as a tan solid. APCI(+)-MS (M+H) 437.
Reaction SMILES: [CH2:1]([CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][C:16]=1[O:23][CH3:24])[O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[O:11][CH3:12].[C:25]([NH:28][NH2:29])([NH2:27])=[NH:26].[ClH:30]>CO.Cl.Cl.NNC(N)=N>[ClH:30].[ClH:30].[C:25]([NH:28][N:29]=[CH:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH2:1][CH2:13][O:14][C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[N:29][NH:28][C:25](=[NH:26])[NH2:27])=[CH:17][C:16]=2[O:23][CH3:24])=[C:4]([O:11][CH3:12])[CH:5]=1)(=[NH:27])[NH2:26]
Reactant: N=C(N)NN
Reactant: COc1cc(C=O)ccc1OCCOc1ccc(C=O)cc1OC
Agent: Cl
Solvent: CO
Product: COc1cc(C=NNC(=N)N)ccc1OCCOc1ccc(C=NNC(=N)N)cc1OC
Yield: 98.4 %

Procedure:
4,4'-(ethylenedioxy)di-m-anisaldehyde (0.99 g), aminoguanidine hydrochloride (0.829 g), and aminoguanidine dihydrochloride (0.01 g) were heated in 95% methanol (10.5 mL) under nitrogen for 16 hr. Cooling and filtration gave 1.52 g of 4,4'-(ethylenedioxy)di-m-anisaldehyde bis(amidinohydrazone) dihydrochloride, mp 322°-3° C. dec.
Reaction SMILES: [F:1][C:2]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:36]=[CH:35][C:20]([O:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[C:26]([OH:28])[CH:27]=2)=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15].[C:42]([O:46][CH2:47][CH3:48])(=[O:45])[CH2:43]O>>[F:1][C:2]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:36]=[CH:35][C:20]([O:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[C:26]([CH:27]=2)[O:28][CH2:43][C:42]([O:46][CH2:47][CH3:48])=[O:45])=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15]
Reactant: CCOC(=O)CO
Reactant: CCCCCCc1ccc(Oc2ccc(CN(Cc3ccc(F)cc3F)c3cccc([N+](=O)[O-])c3C)cc2)cc1O
Product: CCCCCCc1ccc(Oc2ccc(CN(Cc3ccc(F)cc3F)c3cccc([N+](=O)[O-])c3C)cc2)cc1OCC(=O)OCC

Procedure:
The product from Example 238F and ethyl glycolate were processed as described in Example 62A to provide the titled compound. MS (ESI+) m/z 597 (M+H)+.
Reaction SMILES: O.[OH-].[Li+].[NH2:4][C:5]1[C:40]([Br:41])=[CH:39][C:8]([C:9]([C@@H:11]2[CH2:13][C@H:12]2[C:14]([N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[CH2:31][C:30]4[C:25](=[CH:26][CH:27]=[C:28]([O:32][CH2:33][C:34]([O:36]C)=[O:35])[CH:29]=4)[NH:24][C:23]3=[O:38])[CH2:18][CH2:17]2)=[O:15])=[O:10])=[CH:7][C:6]=1[Br:42].[K+].[Br-].BrBr>O.C1COCC1.CO>[NH2:4][C:5]1[C:40]([Br:41])=[CH:39][C:8]([C:9]([C@@H:11]2[CH2:13][C@H:12]2[C:14]([N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[CH2:31][C:30]4[C:25](=[CH:26][CH:27]=[C:28]([O:32][CH2:33][C:34]([OH:36])=[O:35])[CH:29]=4)[NH:24][C:23]3=[O:38])[CH2:18][CH2:17]2)=[O:15])=[O:10])=[CH:7][C:6]=1[Br:42]
Reactant: COC(=O)COc1ccc2c(c1)CN(C1CCN(C(=O)[C@@H]3C[C@H]3C(=O)c3cc(Br)c(N)c(Br)c3)CC1)C(=O)N2
Agent: BrBr
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Nc1c(Br)cc(C(=O)[C@@H]2C[C@H]2C(=O)N2CCC(N3Cc4cc(OCC(=O)O)ccc4NC3=O)CC2)cc1Br
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of 0.15 g (3.57 mmol) of lithium hydroxide hydrate in 10 mL of water was added to a solution of 0.6 g (0.903 mmol) of trans-3-{1-[2-(4-amino-3,5-dibromobenzoyl)cyclopropanecarbonyl]-4-piperidinyl}-3,4-dihydro-6-(methoxycarbonylmethoxy)-2(1H)-quinazolinone (Item No. 22) in a mixture of 10 mL of THF and 10 mL of methanol. After stirring for 14 hours at ambient temperature, the organic solvents were distilled off in vacuo and the residue remaining was combined with 3.6 mL of 1N hydrochloric acid. The precipitate formed was suction filtered and dried in vacuo at 30° C. The residue was taken up in tetrahydrofuran, the solution formed was filtered while hot and, after cooling, combined with diisopropyl ether until the precipitation reaction had ended. The precipitate was suction filtered. After drying in a circulating air drier 0.25 g (43% of theoretical) of colorless crystals were obtained. Rf 0.63 (MP C); IR (KBr): 1730 cm−1 (C═O); MS: ESI: (M−H+2Na)+=693/695/697 (Br2); (M−H)−: 647/649/651 (Br2); (M+Na)+: 671/673/675 (Br2).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)=[N:4][N:3]1[CH2:23][C:24](=[S:26])[NH2:25].[CH2:27](OC(OCC)CBr)[CH3:28]>CO.C(Cl)(Cl)Cl>[O:1]=[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)=[N:4][N:3]1[CH2:23][C:24]1[S:26][CH:27]=[CH:28][N:25]=1
Reactant: CCOC(CBr)OCC
Reactant: NC(=S)Cn1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=c1ccc(-c2c(-c3ccccc3)nn3ccccc23)nn1Cc1nccs1

Procedure:
A mixture of 3-(3-oxo-2-thiocarbamoylmethyl-2,3-dihydropyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridine (0.50 g) and bromoacetaldehyde diethyl acetal (0.54 ml) in a mixture of methanol (2.5 ml) and chloroform (5 ml) was refluxed for 54 hours. After evaporating the solvent, the residue was chromatographed on silica gel (40 ml) using a mixture of chloroform and ethyl acetate (20:1). The desired fractions were collected and evaporated in vacuo. The residue was recrystallized from a mixture of ethyl acetate and n-hexane to give 3-[3-oxo-2-(2-thiazolylmethyl)-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (0.23 g) as yellow needles.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].[CH3:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1[NH:25][C:26](=[O:29])[CH:27]=[CH2:28].C(N(CC)CC)C>CO>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([S:11][CH2:28][CH2:27][C:26]([NH:25][C:19]2[C:20]([CH3:24])=[CH:21][CH:22]=[CH:23][C:18]=2[CH3:17])=[O:29])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:1])[CH3:3]
Reactant: C=CC(=O)Nc1c(C)cccc1C
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1cccc(C)c1NC(=O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
2,6-bis-(1,1-Dimethylethyl)-4-mercaptophenol(1.19 g, 0.005 mole), N-(2,6-dimethylphenyl)-2-propenamide (0.87 g, 0.005 mole) and triethylamine (0.5 ml) in methanol (100 ml) were stirred at room temperature under argon for 12 hours. The solvent and triethylamine were removed on a rotary evaporator and the product purified by chromatography on silica. The solvents were removed and the product recrystallized from ethyl acetate/hexane, filtered and dried in vacuo to yield the title compound, m.p. ca. 142.5°-144° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:32]=1[C:33](=[O:42])[N:34]([CH3:41])[C:35]2=[O:40]>>[CH3:29][O:28][C:14]1[CH:15]=[C:16]([CH:26]=[CH:27][C:13]=1[NH:12][C:4]1[N:3]=[C:2]([NH:30][C:31]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:32]=2[C:33](=[O:42])[N:34]([CH3:41])[C:35]3=[O:40])[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=1)[CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: CN1C(=O)c2cccc(N)c2C1=O
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3cccc4c3C(=O)N(C)C4=O)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared using the procedure for Example 102 with diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and the commercially available 4-amino-2-methyl-1H-isoindole-1,3(2H)-dione. MS (ES+): m/z 594.34 (100) [MH+]; HPLC: tR=1.17 min (UPLC, purity).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:8]([O:10]C)=O.[CH3:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20].Cl>CCCCCC.O1CCCC1>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:8](=[O:10])[CH2:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: CC(=O)C(C)(C)C
Reactant: COC(=O)c1ccc(OC)c(OC)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(C(=O)CC(=O)C(C)(C)C)cc1OC
Reaction time: 7 h
Yield: 66 %

Procedure:
In a 200 ml three-necked flask equipped with a mechanical stirrer, dropping funnel, reflux condenser, and a nitrogen-inlet tube, 2.45 gm (61 mmol) of 60% sodium hydride, 10 gm (51 mmol) of methyl 3,4-dimethoxybenzoate, and 100 ml of anhydrous tetrahydrofuran were mixed with stirring under nitrogen stream, and refluxed with heating while 6.1 gm (61 mmol) of pinacolone was added dropwise. The refluxing under heat was continued for 7 hours. After cooling the reaction mixture, 30 ml of 2N hydrochloric acid was added and the mixture was extracted twice with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was removed by evaporation to give a crude product. Hexane was added to the crude product and insoluble substances were filtered off. The filtrate was concentrated by evaporation, and recrystallization afforded 8.9 gm of the target compound as colorless needles (yield: 65%).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7](Br)[C:5]=1[NH2:6])([O-:3])=[O:2].C[Sn](C)(C)C>CN(C=O)C>[N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7]([C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:5]=2)[C:5]=1[NH2:6])([O-:3])=[O:2]
Reactant: Nc1c(Br)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: C[Sn](C)(C)C
Solvent: CN(C)C=O
Product: Nc1c(-c2ccccc2)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 80 %

Procedure:
A solution of 2,4-dinitro-6-bromoaniline (2.5 g, 9.5 mmol), tetramethyltin (6.1 g, 14.3 mmol) and Cl2Pd(PPh3)2 (100 mg) in 10 ml of DMF was stirred at 140° C. for 12 h. Reaction mixture was concentrated in vacuo, yielding an oil which was purified on silica gel column chromatography (CH2Cl2, neat) to provide 1.0 g (3.8 mmol, 41%) of 2,4-dinitro-6-phenylaniline, which was converted to the diamine (0.72 g, >95%) on hydrogenation (H2/Pd-C).
Reaction SMILES: [CH2:1]([NH:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[H-].[Na+].Cl[CH2:22][CH:23]([OH:26])[CH2:24][OH:25]>CN(C)P(N(C)C)(N(C)C)=O>[CH2:1]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([O:16][CH2:22][CH:23]([OH:26])[CH2:24][OH:25])=[O:15])=[CH:17][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCNc1ccc(C(=O)O)cc1
Reactant: OCC(O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCNc1ccc(C(=O)OCC(O)CO)cc1

Procedure:
A solution of 4-(n-octylamino)benzoic acid (4.97 g.) in 25 ml. of hexamethylphosphoramide is treated with sodium hydride and then 1-chloro-2,3-propanediol in the manner described in Example 2 to produce white crystals of 2,3-dihydroxypropyl 4-(n-octylamino)benzoate.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([C:17]4([CH2:23][OH:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:3][CH2:2]1.[C:30](Cl)(=[O:32])[CH3:31]>>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([C:17]4([CH2:23][OH:24])[CH2:22][CH2:21][N:20]([C:30](=[O:32])[CH3:31])[CH2:19][CH2:18]4)(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:3][CH2:2]1
Reactant: CC(=O)Cl
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)C3(CO)CCNCC3)ccc2n1CC1CC1
Product: CC(=O)N1CCC(CO)(S(=O)(=O)c2ccc3c(c2)nc(CC(C)(C)C)n3CC2CC2)CC1

Procedure:
The title compound was prepared according to the procedure described in STEP D of Example 6 using (4-(1-(cyclopropylmethyl)-2-neopentyl-1H-benzo[d]imidazol-5-ylsulfonyl)piperidin-4-yl)methanol (STEP G) and acetyl chloride instead of methanesulfonyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:11][CH2:12][O:13][CH3:14])[CH3:10])=[CH:5][C:4]=1[NH2:15].[C:16]([N:24]=[C:25]=[S:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(C)=O>[C:16]([NH:24][C:25]([NH:15][C:4]1[CH:5]=[C:6]([N:9]([CH2:11][CH2:12][O:13][CH3:14])[CH3:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])=[S:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COCCN(C)c1ccc(OC)c(N)c1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Product: COCCN(C)c1ccc(OC)c(NC(=S)NC(=O)c2ccccc2)c1
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
To a stirred solution of 1.89 g (8.99 mmol) 4-methoxy-N1-(2-methoxy-ethyl)-N1-methyl-benzene-1,3-diamine in 60 ml acetone was added dropwise a solution of 1.38 ml (10.3 mmol) benzoyl isothiocyanate in 30 ml acetone and stirring continued at room temperature for 30 minutes. The mixture was then concentrated in vacuo. Trituration in ether afforded 2.05 g (61%) 1-benzoyl-3-{2-methoxy-5-[(2-methoxy-ethyl)-methyl-amino]-phenyl}-thiourea as a yellow solid. ES-MS m/e ((Y)): 374 (M+H+, 100).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH2:17][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1(=O)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]2[CH2:13][CH2:14][N:15]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:16][CH2:17][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCCC1
Reactant: c1ccc(COc2ccc3c(c2)CCNCC3)cc1
Product: c1ccc(COc2ccc3c(c2)CCN(C2CCCCC2)CC3)cc1

Procedure:
Example 139 (E139) was prepared from Description 2 (D2) and cyclohexanone using the method described for Example 1; MS (ES+) m/e 336 [M+H]+.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH:7]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[CH:29]=1)[C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]1)=[N+]=[N-]>CO.[Pd]>[NH2:1][CH2:4][CH2:5][O:6][C@@H:7]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[CH:29]=1)[C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]1
Reactant: Cc1cccc(-c2c(F)cccc2C(OCCN=[N+]=[N-])[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1
Agent: [Pd]
Solvent: CO
Product: Cc1cccc(-c2c(F)cccc2[C@H](OCCN)[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1
Reaction time: 8 h
Yield: 26.2 %

Procedure:
A solution of (3R)-tert-butyl 3-((2-azidoethoxy)(6-fluoro-3′-methylbiphenyl-2-yl)methyl)piperidine-1-carboxylate (0.89 g) in methanol (20 mL) was added to wetted Pd/C (200 mg). After 3 cycles of evacuation and refilling with H2, a balloon of H2 was attached to the vessel and the mixture was stirred overnight. The reaction mixture was filtered through a pad of Celite and the solvent was removed to give the crude amine. Purification by preparative HPLC gave (3R)-tert-butyl 3-((R)-(2-aminoethoxy)(6-fluoro-3′-methylbiphenyl-2-yl)methyl)piperidine-1-carboxylate (220 mg, 26%). 1H NMR (400 MHz, CDCl3): 1.10 (m, 2H), 1.43 (s, 9H), 1.49 (m, 2H), 1.89 (m, 1H), 2.10 (m, 1H), 2.39 (s, 3H), 3.16 (m, 2H), 3.51 (m, 2H), 4.15 (m, 1H), 6.97 (m, 3H), 7.10 (m, 1H), 7.30-7.48 (m, 3H).
Reaction SMILES: [CH2:1]([N:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:9][C:10]([C:12]1[CH:20]=[C:16]([C:17]([NH2:19])=[O:18])[C:15]([OH:21])=[CH:14][CH:13]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].Cl[CH2:31][CH2:32][CH2:33][CH2:34][O:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][O:37]1>CC(=O)CC>[CH2:22]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]([O:21][CH2:31][CH2:32][CH2:33][CH2:34][O:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][O:37]2)=[C:16]([CH:20]=1)[C:17]([NH2:19])=[O:18])=[O:11])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: ClCCCCOC1CCCCO1
Reactant: NC(=O)c1cc(C(=O)CN(Cc2ccccc2)Cc2ccccc2)ccc1O
Agent: [Na]
Solvent: CCC(C)=O
Product: NC(=O)c1cc(C(=O)CN(Cc2ccccc2)Cc2ccccc2)ccc1OCCCCOC1CCCCO1

Procedure:
A mixture of 5-(N,N-dibenzylglycyl)salicylamide, sodium salt (3.96 g), 2-(4-chlorobutoxy)tetrahydropyran (1.92 g) sodium iodide (1.40 g) and butanone (100 ml) was heated under reflux for 30 hours and filtered. The filtrate was evaporated to give an oil which crystallised from isopropanol to afford the ether as colourless crystals (2.95 g), m.p. 118°-123°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[CH:10])=[CH:5][CH:4]=1.I[C:12]1[CH:17]=[CH:16][C:15]([C:18]#[C:19][Si:20]([CH3:23])([CH3:22])[CH3:21])=[CH:14][CH:13]=1>C1COCC1.C(N(CC)CC)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:21][Si:20]([C:19]#[C:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]#[C:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:13][CH:14]=1)([CH3:22])[CH3:23]
Reactant: C#Cc1ccc(OC)cc1
Reactant: C[Si](C)(C)C#Cc1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(C#Cc2ccc(C#C[Si](C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 98.5 %

Procedure:
Into a 50 ml round bottom flask was placed a mixture of 0.72 g (0.0054 mole) of p-methoxyphenylacetylene, 1.51 g (0.005 mole) of 4-iodophenyltrimethylsilylacetylene, 0.0102 g (0.0053 mmole) of CuI, 0.102 g (0.146 mmole) of bis(triphenylphosphine)palladium(II)dichloride in 10 ml of THF and 10 ml of triethylamine. The light orange brown mixture was stirred at room temperature under nitrogen for 3 days. The reaction mixture was then filtered and the filtrate concentrated under reduced pressure. The residue was redissolved in 10 ml of chloroform and the solution was washed two times with water (10 ml each) and then dried over anhydrous MgSO4, filtered and concentrated. 1.5 g (98.7% yield) of solid was obtained. 1HNMR: 0.28 ppm (s, 9H); 3.85 ppm (s, 3H); 6.90 ppm (d, 2H); 7.45 ppm (s, 4H); 7.48 ppm (d, 2H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=2)=[CH:5][N:6]=1.ClC1C=CC=C(C(OO)=[O:26])C=1>ClCCl>[NH2:1][C:2]1[S:3][C:4]([S:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=2)=[O:26])=[CH:5][N:6]=1
Reactant: Nc1ncc(Sc2ccc(C(F)(F)F)cn2)s1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Nc1ncc(S(=O)c2ccc(C(F)(F)F)cn2)s1
Yield: 81.9 %

Procedure:
To a solution of 2-amino-5-(5-trifluoromethylpyridin-2-ylthio)thiazole (0.6 g) in dichloromethane (20 ml) was added portionwise 3-chloroperbenzoic acid (0.6 g) at 5° C. with stirring. The mixture was stirred at 5° C. for 3 hours. The reaction mixture was washed with aqueous sodium bicarbonate and dried over magnesium sulfate. The solvent was concentrated under reduced pressure to give solid. The solid was subjected to column chromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 30 g) and eluted with a mixture of chloroform and methanol (10:1). The fractions containing the objective compound were combined and concentrated under reduced pressure to give 2-amino-5-(5-trifluoromethylpyridin-2-ylsulfinyl)thiazole (0.52 g, yield: 81.9%). mp: 144°-145° C.