Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].C(N(CC)CC)C.[Cl:13][C:14]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=1[C:16](Cl)=[O:17].O>C(Cl)Cl>[Cl:13][C:14]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=1[C:16]([N:4]([O:3][CH3:2])[CH3:5])=[O:17]
Reactant: CNOC
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc(Cl)cc1Cl

Procedure:
A mixture of 32.6 g of N-methoxymethanamine hydrochloride and 91.2 ml of triethylamine in 500 ml of DCM is cooled in an ice bath, and then 47 ml of 2,4-dichlorobenzoyl chloride are added slowly and the mixture is left to stir while allowing the temperature to rise to AT. After stirring for 1 hour at AT, water is added to the reaction mixture, the mixture is extracted with DCM, the organic phase is dried over Na2SO4 and the solvent is evaporated under vacuum. 53 g of the expected compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2([OH:25])[CH:13]3[CH2:14][CH2:15][CH:9]2[CH2:10][N:11]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH2:12]3)[CH:5]=[CH:6][CH:7]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28].O>N1C=CC=CC=1>[OH:25][C:8]1([C:4]2[CH:3]=[C:2]([NH:1][S:27]([CH3:26])(=[O:29])=[O:28])[CH:7]=[CH:6][CH:5]=2)[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][N:11]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1)[CH2:12]2
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CN2CC3CCC(C2)C3(O)c2cccc(N)c2)cc1
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(CN2CC3CCC(C2)C3(O)c2cccc(NS(C)(=O)=O)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.3 %

Procedure:
8-(3-Amino-phenyl)-3-(4-methoxy-benzyl)-3-aza-bicyclo[3.2.1]octan-8-ol (2.11 g, 6.23 mmol) in pyridine (15 mL) at 0° C. was charged with methanesulfonylchloride (0.72 mL, 9.35 mmol) dropwise. The reaction was warmed to room temperature and judged complete by TLC after 3 h. Following a water addition (20 mL), the product was extracted with EtOAc (4×30 mL), the organic layer was washed with saturated aqueous NaCl solution (6×50 mL), dried over Na2SO4, filtered and concentrated to give a crude orange liquid. Flash chromatography provided the title compound as a yellow semi-solid (1.28 g, 49%). (TLC 50% EtOAc/Hexanes Rf 0.24); 400 MHz 1H NMR (400 MHz, CDCl3) δ 7.30 (d, J=8.7 Hz, 2H), 7.27 (m, 3H), 7.14 (dd, J=7.1, 2.1 Hz, 1H), 6.83 (d, J=8.7 Hz, 2H), 3.77 (s, 3H), 3.53 (m, 2H), 2.96 (s, 3H), 2.82 (m, 2H), 2.60 (m, 2H), 2.36 (br s, 2H), 1.78 (m, 2H), 1.36 (m, 2H); APCI MS m/z 417.1 (M+1)+; LCMS m/z 417.1 (M+1)+.
Reaction SMILES: [NH2:1][CH:2]([CH3:32])[CH:3]([C:14]1[C:15]([CH3:31])=[C:16]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:17]=[CH:18][CH:19]=1)[C:4]1[C:12]2[C:7](=[CH:8][C:9]([Br:13])=[CH:10][CH:11]=2)[NH:6][CH:5]=1.O=[CH:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].C1(C)C=CC=CC=1.Cl>O1CCOCC1>[CH2:23]([O:22][C:21]([NH:20][C:16]1[C:15]([CH3:31])=[C:14]([CH:3]2[C:4]3[C:12]4[C:7](=[CH:8][C:9]([Br:13])=[CH:10][CH:11]=4)[NH:6][C:5]=3[CH:34]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[NH:1][CH:2]2[CH3:32])[CH:19]=[CH:18][CH:17]=1)=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Cc1c(NC(=O)OCc2ccccc2)cccc1C(c1c[nH]c2cc(Br)ccc12)C(C)N
Reactant: CCOC(=O)C=O
Agent: Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1NC(C)C(c2cccc(NC(=O)OCc3ccccc3)c2C)c2c1[nH]c1cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a homogeneous solution of benzyl (3-(2-amino-1-(6-bromo-1H-indol-3-yl)propyl)-2-methylphenyl)carbamate (4.00 g, 8.12 mmol) in dioxane (200 mL) under nitrogen was added 50% ethyl 2-oxoacetate in toluene (3.22 mL, 16.3 mmol) followed by 4 M hydrochloric acid in 1,4-dioxane (4.06 mL, 16.3 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (150 mL), washed with saturated aqueous sodium bicarbonate (75 mL), and washed with brine (75 mL). The organic layer was collected, and the aqueous layers were sequentially extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give ethyl 4-(3-(((benzyloxy)carbonyl)amino)-2-methylphenyl)-7-bromo-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-carboxylate in a quantitative yield as a burgundy solid. The mixture was used in the next step without any further purification. LC/MS M+1=576.2 and 578.2.
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[F:33][C:34]([F:45])([F:44])[C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:32][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:39]3[CH:38]=[CH:37][CH:36]=[C:35]([C:34]([F:45])([F:44])[F:33])[CH:40]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCC(N2CCCC2)CC1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1cccc(C(F)(F)F)c1)N1CCC(N2CCCC2)CC1
Yield: 53 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-indol-2-yl]-methanone (example 169), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a brown oil (53%).
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:14]2[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=2)[CH3:13])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].N1C=CC=CC=1.[CH2:27]([S:30](Cl)(=[O:32])=[O:31])[CH2:28][CH3:29]>ClCCl>[CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:14]2[CH:15]=[C:16]([NH:20][S:30]([CH2:27][CH2:28][CH3:29])(=[O:32])=[O:31])[CH:17]=[CH:18][CH:19]=2)[CH3:13])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCS(=O)(=O)Cl
Reactant: CCCCCCN1CC2C(C1)C2(C)c1cccc(N)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCN1CC2C(C1)C2(C)c1cccc(NS(=O)(=O)CCC)c1
Reaction time: 48 h
Yield: 14.4 %

Procedure:
To a solution of 3-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenylamine (Preparation 12, 200 mg, 0.735 mmol), in dichloromethane (5 ml) at room temperature was added pyridine (0.15 ml, 1.84 mmol) then dropwise over 5 minutes propanesulfonylchloride (0.16 ml, 202 mg, 1.42 mmol). The mixture was stirred for 48 hours, concentrated in vacuo and the residue was purified by silica (10 g) column chromatography eluting with ethyl acetate then 90:10:1 ethyl acetate:methanol:ammonia solution (0.880). Product-containing fractions were combined and concentrated in vacuo to give the title compound as a pale yellow oil (40 mg, 14%).
Reaction SMILES: Br[CH2:2][C:3]([OH:5])=[O:4].[Cl:6][C:7]1[C:16]([C:17]#[C:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][C:10]2[NH:11][C:12](=[S:14])[NH:13][C:9]=2[CH:8]=1.[OH-].[K+].Cl>CCO.O>[Cl:6][C:7]1[C:16]([C:17]#[C:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][C:10]2[N:11]=[C:12]([S:14][CH2:2][C:3]([OH:5])=[O:4])[NH:13][C:9]=2[CH:8]=1
Reactant: S=c1[nH]c2cc(Cl)c(C#Cc3ccccc3)cc2[nH]1
Reactant: O=C(O)CBr
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CSc1nc2cc(C#Cc3ccccc3)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of bromoacetic acid (47.8 mg, 0.344 mmol) in EtOH (1 mL) was added dropwise to a 20 mL scintillation vial equipped with a stirring bar and a septum cap containing a solution of compound 1-3 (49.0 mg, 0.172 mmol) in EtOH (1 mL). To this solution, 1M KOH (2 mL) was added dropwise, and the resulting mixture was stirred at rt for 1 h. The reaction mixture was then diluted with water (4 mL) and acidified with 10% aqueous HCl. The solution was extracted with EtOAc (3 mL then twice 1 mL), extracts were combined and evaporated to dryness in vacuo. The resulting oily residue was dissolved in DMSO (1.0 mL), filtered and purified by reverse-phase HPLC to give the title compound as white solid. LR-MS (API-ES): calculated for C17H11ClN2O2S 342.0, observed m/e 343.1 (M+H)+ (Rt 7.71 min).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([C@@H:11]([NH:13]C(=O)OC(C)(C)C)[CH3:12])[N:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:7]=2[CH:27]=1>O1CCOCC1.C(Cl)Cl>[F:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([C@@H:11]([NH2:13])[CH3:12])[N:8]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:7]=2[CH:27]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1

Procedure:
4.0 M HCl in 1,4-dioxane (1.0 mL) was added to a solution of (S)-tert-butyl 1-(6-fluoro-1-phenyl-1H-benzo[d]imidazol-2-yl)ethylcarbamate (12 mg, 0.034 mmol) in DCM (1 mL). After ˜2 h the reaction mixture was concentrated under reduced pressure to dryness. The resulting solid was partitioned between DCM and satd. aq. NaHCO3 solution. The aq. layer was extracted with DCM. The organic layers were combined, dried with Na2SO4, filtered and concentrated under reduced pressure to give (S)-1-(6-fluoro-1-phenyl-1H-benzo[d]imidazol-2-yl)ethanamine: LC-MS (ESI) m/z 256.1 [M+H]+. The product was carried on crude without purification.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH:12]2[S:24][C:16]3=[N:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[N:15]3[CH2:14][CH2:13]2)(=O)=O)=CC=1.O.[NH3:27].O1CCOCC1>O>[NH2:27][CH2:11][CH:12]1[S:24][C:16]2=[N:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:15]2[CH2:14][CH2:13]1
Reactant: N
Reactant: Cc1ccc(S(=O)(=O)OCC2CCn3c(nc4ccccc43)S2)cc1
Solvent: O
Solvent: C1COCCO1
Product: NCC1CCn2c(nc3ccccc32)S1
Temperature: 120 °C
Yield: 35.1 %

Procedure:
To 2.24 g of 3,4-dihydro-2-p-toluenesulfonyloxymethyl-2H-(1,3)-thiazino[3,2-a]benzimidazole, were added 5 g of 25% ammonia water and 40 ml of dioxane. The mixture were heated in a sealed tube, at 120° C., for 75 hours. The reaction mixture was then condensed under reduced pressure. The residue was added with water and then extracted with chloroform, and dried over anhydrous magnesium sulfate. Chloroform was evaporated under reduced pressure. The residue was chromatographed on silica gel and eluted with chloroform to obtain 0.46 g (yield: 35.1%) of the intended product, m.p. 217°-222° C.; IR νmaxKBr cm-1 3300-2600, 1440; Anal. Calcd. for C11H13N3S: C, 60.25; H, 5.97; N, 19.16; S, 14.62; Found: C, 60.28; H, 5.99; N, 19.60; S, 14.13.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2([C:14]#[N:15])[CH2:13][CH2:12]2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C)C=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:39]=[CH:40][C:41]=1[F:42])[O:25][C:26]1[N:31]=[C:30]2[S:32][C:33]([NH:35][C:36](=[O:38])[CH3:37])=[N:34][C:29]2=[CH:28][CH:27]=1.O>C(Cl)(=O)C(Cl)=O.CN(C)C(=O)C>[C:36]([NH:35][C:33]1[S:32][C:30]2[C:29]([N:34]=1)=[CH:28][CH:27]=[C:26]([O:25][C:24]1[CH:39]=[CH:40][C:41]([F:42])=[C:22]([NH:21][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][CH:9]=[C:10]([C:11]4([C:14]#[N:15])[CH2:13][CH2:12]4)[C:2]=3[Cl:1])[CH:23]=1)[N:31]=2)(=[O:38])[CH3:37]
Reactant: N#CC1(c2cccc(C(=O)O)c2Cl)CC1
Reactant: CC(=O)Nc1nc2ccc(Oc3ccc(F)c(N)c3)nc2s1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1nc2ccc(Oc3ccc(F)c(NC(=O)c4cccc(C5(C#N)CC5)c4Cl)c3)nc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.6 %

Procedure:
To a solution of 2-chloro-3-(1-cyanocyclopropyl)benzoic acid (0.33 g, 1.5 mmol) produced in Example C62(ii) in oxalyl chloride (1.5 mL) was added N,N-dimethylformamide (100 μL), and the mixture was stirred at room temperature for 30 min, and concentrated to dryness under reduced pressure. This was dissolved in a mixture of N,N-dimethylacetamide (1.5 mL) and tetrahydrofuran (1.5 mL), and the solution was added dropwise to a solution of N-[5-(3-amino-4-fluorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]acetamide (0.33 g, 1.00 mmol) produced in Example C64(ii) in N,N-dimethylacetamide (3 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 3 hr, and poured into water (100 mL), and the mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→100/0), and recrystallized from methanol to give the title compound (280 mg, 54%) as colorless crystals.
Reaction SMILES: [OH-:1].[Na+].OO.[CH2:5]([NH:7][C:8]1[CH:15]=[C:14]([C:16]2[N:17]=[CH:18][CH:19]=[C:20]3[C:25]=2[N:24]=[CH:23][CH:22]=[C:21]3[N:26]2[CH:30]=[C:29]([C:31]3[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=3)[N:28]=[CH:27]2)[CH:13]=[CH:12][C:9]=1[C:10]#[N:11])[CH3:6].O>CS(C)=O>[CH2:5]([NH:7][C:8]1[CH:15]=[C:14]([C:16]2[N:17]=[CH:18][CH:19]=[C:20]3[C:25]=2[N:24]=[CH:23][CH:22]=[C:21]3[N:26]2[CH:30]=[C:29]([C:31]3[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=3)[N:28]=[CH:27]2)[CH:13]=[CH:12][C:9]=1[C:10]([NH2:11])=[O:1])[CH3:6]
Reactant: CCNc1cc(-c2nccc3c(-n4cnc(-c5cnn(C)c5)c4)ccnc23)ccc1C#N
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCNc1cc(-c2nccc3c(-n4cnc(-c5cnn(C)c5)c4)ccnc23)ccc1C(N)=O
Reaction time: 0.5 h
Yield: 4 %

Procedure:
A suspension of 3-amino-2-chloropyridine (17.6 g) and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (25.5 g) in isopropanol (274 ml) was heated to reflux for 5 minutes. After cooling, the deposit was filtrated to obtain 5-((2-chloropyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (34.8 g). The obtained 5-((2-chloropyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-di one (8.2 g) was gradually added to Dowtherm heated to 220° C., and the mixture was heated at 220° C. for 30 minutes. After cooling, hexane (300 ml) was added to the reaction solution, and the deposit was filtrated to obtain 8-chloro-1,7-naphthyridin-4(1H)-one (2.02 g). 4-(4-Chloro-1,7-naphthyridin-8-yl)-2-(ethylamino)benzonitrile (0.107 g) was obtained according to Example 5(1) using the obtained 8-chloro-1,7-naphthyridin-4(1H)-one (0.295 g) instead of compound (3a) and 4-cyano-3-(ethylamino)phenylboronic acid pinacol ester instead of 3-quinolineboronic acid. A suspension of the obtained 4-(4-chloro-1,7-naphthyridin-8-yl)-2-(ethylamino)benzonitrile (0.0491 g), 4-(1H-imidazol-4-yl)-1-methyl-1H-pyrazole hydrochloride (0.035 g), copper(II) oxide nanoparticles (0.06 g), and potassium carbonate (0.0883 g) in DMF (1.5 ml) was stirred overnight at 125° C. The reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with brine. The organic layer thus washed was dried over anhydrous sodium sulfate. Then, the solvent was distilled off, and the residue was purified by neutral silica gel column chromatography (chloroform/methanol) to obtain 2-(ethylamino)-4-(4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1,7-naphthyridin-8yl)benzonitrile. An aqueous sodium hydroxide solution (4 M, 0.093 mL) and a 30% aqueous hydrogen peroxide solution (0.045 mL) were added to a solution of the obtained 2-(ethylamino)-4-(4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1,7-naphthyridin-8yl)benzonitrile in DMSO (3 mL) at room temperature, and the mixture was stirred for 30 minutes. Water was added to the reaction solution, and the deposit was collected by filtration, then washed with water and ether by sprinkling, and then dried under reduced pressure to obtain compound (72) (0.040 g, yield based on 6 steps: 4%) as a pale yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:10]2[CH2:13][C:12](=[C:14]([C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=3)[S:15]([CH3:18])(=[O:17])=[O:16])[CH2:11]2)=[CH:5][CH:4]=1.[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>ClCCl>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([C@@H:9]([C:6]2[CH:5]=[CH:4][C:3]([CH2:2][N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[CH:8][CH:7]=2)[N:10]2[CH2:11][C:12](=[C:14]([C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=3)[S:15]([CH3:18])(=[O:16])=[O:17])[CH2:13]2)=[CH:28][CH:29]=1
Reactant: CS(=O)(=O)C(=C1CN([C@@H](c2ccc(Cl)cc2)c2ccc(CCl)cc2)C1)c1cc(F)cc(F)c1
Reactant: C1CCNCC1
Solvent: ClCCl
Product: CS(=O)(=O)C(=C1CN([C@@H](c2ccc(Cl)cc2)c2ccc(CN3CCCCC3)cc2)C1)c1cc(F)cc(F)c1
Yield: 63.9 %

Procedure:
The operation is carried out as described in Example 87, starting with 0.05 g of 1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A isomer, 1.0 cm3 of dichloromethane, and 0.017 g of piperidine. The crude product is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 cm3 of dichloromethane and then with a dichloromethane and methanol mixture (95/5 by volume), collecting 2.5 cm3 fractions immediately after using this eluent mixture. Fractions 5 to 10 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.035 g of 1-{(R*)-(4-chlorophenyl)[4-(piperidin-1-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A isomer, is obtained in the form of a white foam [1H NMR spectrum (300 MHz, CDCl3, δ in ppm): from 1.35 to 1.65 (mt, 6H), 2.35 (unresolved complex, 4H), 2.80 (s, 3H), 3.41 (broad s, 2H), 3.84 (mt, 2H), 4.33 (mt, 2H), 4.50 (s, 1H), 6.84 (tt, J=8.5 and 2.5 Hz, 1H), 6.98 (mt, 2H), from 7.20 to 7.40 (mt, 8H)].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=O)[CH2:7][CH2:6]2.[F:15][C:16]1[CH:17]=[C:18]([N:22]=[C:23]=S)[CH:19]=[CH:20][CH:21]=1.C[Si](C)(C)[Si](C)(C)C.[Li].[NH2:34][NH2:35]>O.C(O)(=O)C.C1COCC1>[F:15][C:16]1[CH:17]=[C:18]([NH:22][C:23]2[NH:35][N:34]=[C:8]3[C:9]4[C:5]([CH2:6][C:7]=23)=[CH:4][C:3]([O:2][CH3:1])=[C:11]([O:12][CH3:13])[CH:10]=4)[CH:19]=[CH:20][CH:21]=1
Reactant: Fc1cccc(N=C=S)c1
Reactant: NN
Reactant: COc1cc2c(cc1OC)C(=O)CC2
Agent: C[Si](C)(C)[Si](C)(C)C
Agent: [Li]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2c(cc1OC)-c1n[nH]c(Nc3cccc(F)c3)c1C2

Procedure:
A mixture of 5,6dimethoxyindan-1-one, Compound 3a, (3.0 g, 0.0154 mole), 3-fluoro-phenyl isothiocyanate, Compound 4a, (2.4 g, 0.0157 mole) and THF (3.0 mL) was added to lithium hexamethyldisilane (15.4 mL, 0.0154 mole) dropwise at room temperature with stirring. The reaction mixture was stirred for 12 hrs. Hydrazine (0.75 mL, 0.0154 mole) and acetic acid (0.96 mL) were added to the reaction mixture, which was then heated at the reflux temperature for 24 hrs. The resulting mixture was first added to water (30 mL) and then extracted with CH2Cl2. The organic layers were combined and washed with aqueous NaHCO3 solution, then washed with water and brine solution, dried (Na2SO4), and solvent was removed in vacuo. The residue was dissolved in hot CH3CN. To the mixture was then added one equivalent of an HCl-ether solution to yield a precipitate of the title compound. The precipitate was dissolved in CH3CN and decolorized with charcoal and re-crystallized to give Compound 14 as an off white solid. MS m/z 326 (M+H)+; 1HNMR (DMSO-d6): 3.44(s, 2H), 3.80(s, 3H), 3.81 (s, 3H), 6.58(t, 1H), 6.85 (d, 1H), 7.1 (d, 1H), 7.21 (s, 1H), 7.23(s, 1H), 7.3(m, 1H), 9.2(br s, 1H).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:9])[CH2:6][CH:7]=[NH:8])[CH3:3].[Cl:10][C:11]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:12]=1N.[CH3:21][OH:22]>>[CH3:21][O:22][C:7](=[N:8][C:12]1[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:11]=1[Cl:10])[CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:9]
Reactant: Nc1cc([N+](=O)[O-])ccc1Cl
Reactant: CO
Reactant: CCOC(=O)CC=N
Agent: Cl
Product: CCOC(=O)CC(=Nc1cc([N+](=O)[O-])ccc1Cl)OC
Temperature: 20 °C
Reaction time: 20 h

Procedure:
To a flask equipped with stirrer and condenser are charged: 156.0 g (0.8 mole of ethyl-3-iminopropionate hydrochloride. 103.0 g (0.6 mole 2- chloro-5-nitroaniline, and 500 ml reagent grade methanol (anhydrous). The resulting mixture is stirred at room temperature (ca. 20° C.) for 20 hours, whereupon it is heated to reflux for one hour while being concentrated to a pot temperature of 100° C. while distilling off methanol at atmospheric pressure, cooled to room temperature, and ammonium chloride filtered off. The resulting salt is washed well with 200 ml of methanol (water free) and the filtrate cooled. The product is filtered to yield 84.6 g (47%), and recrystallized from isopropanol-heptane (50/50 by volume), to yield a product having a melting point of 60-62° C.
Reaction SMILES: [OH-:1].[K+].[NH2:3][C:4]1[N:9]=[C:8]([CH3:10])[C:7]([CH2:11][C:12]2[CH:13]=[C:14]([CH2:18][C:19]#N)[CH:15]=[CH:16][CH:17]=2)=[C:6]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[N:5]=1.[CH3:27][OH:28]>>[NH2:3][C:4]1[N:9]=[C:8]([CH3:10])[C:7]([CH2:11][C:12]2[CH:13]=[C:14]([CH2:18][C:19]([O:28][CH3:27])=[O:1])[CH:15]=[CH:16][CH:17]=2)=[C:6]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[N:5]=1
Reactant: CCCCCNc1nc(N)nc(C)c1Cc1cccc(CC#N)c1
Reactant: CO
Reactant: [OH-]
Agent: [K+]
Product: CCCCCNc1nc(N)nc(C)c1Cc1cccc(CC(=O)OC)c1
Temperature: 65 °C
Reaction time: 15 h

Procedure:
A 5M aqueous solution of potassium hydroxide (5 mL) was added to a stirred solution of the product from step (vi) (0.59 g) in MeOH (10 mL). The mixture was stirred at 65° C. for 15 h and allowed to cool. The organic solvent was removed under reduced pressure and the aqueous phase acidified to pH 7 with concentrated HCl. The aqueous phase was extracted with EtOAc and the combined organic phase dried and evaporated under reduced pressure. The residue was dissolved in MeOH (10 mL) and concentrated sulfuric acid (5 mL) added. The mixture was heated at 70° C. for 2 h and allowed to cool. The mixture was poured into saturated aqueous NaHCO3 (30 mL) and the aqueous phase extracted with EtOAc. The combined organic phase was dried and evaporated under reduced pressure. The residue was purified by chromotography eluting with 5% MeOH in DCM to give the title compound 0.24 g.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12]O.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:47][C:48]1[CH:49]=[CH:50][C:51]2[N:52]([C:54](=[O:57])[NH:55][N:56]=2)[CH:53]=1>C1COCC1>[Br:47][C:48]1[CH:49]=[CH:50][C:51]2[N:52]([C:54](=[O:57])[N:55]([CH2:12][CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)[N:56]=2)[CH:53]=1
Reactant: O=c1[nH]nc2ccc(Br)cn12
Reactant: OCCc1ccc2ccccc2n1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1n(CCc2ccc3ccccc3n2)nc2ccc(Br)cn12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.4 %

Procedure:
In a 1-dram vial were placed 2-(quinolin-2-yl)ethanol (405 mg, 2.80 mmol), DIAD (472 mg, 2.34 mmol) and triphenylphosphine (613 mg, 2.34 mmol) in THF (11.7 mL). The mixture was stirred at room temperature for 10 min, and 3-3 (600 mg, 2.80 mmol) was added in one portion. The reaction was further stirred for 10 min. The crude product was dried under stream of N2 and purified by reversed phase HPLC to give 480 mg (55%) of 3-4. HRMS (ES) 369.0348 (M+H) found, 369.0349 required.