Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:20][CH2:21][CH2:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([OH:29])[CH2:25][CH2:24]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([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.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)(Cl)Cl>[CH3:30][S:31]([O:29][C@H:26]1[CH2:27][CH2:28][C@H:23]([CH2:22][CH2:21][O:20][C:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:24][CH2:25]1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: O[C@H]1CC[C@H](CCOC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)O[C@H]1CC[C@H](CCOC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
trans-4-[2-(Trityloxy)ethyl]cyclohexanol (1.95 g, 0.00504 mol) was dissolved in chloroform (40.00 mL) and the mixture was cooled to 0° C. To the reaction was added TEA (0.98 mL, 0.0071 mol) and methanesulfonyl chloride (0.47 mL, 0.0060 mol) and this mixture was stirred at 0° C. for 2 hours. The reaction was then extracted with ethyl acetate and the organic extracts were washed with water, and saturated NaCl, then dried (MgSO4) and concentrated in vacuo.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C:14]2[C:10](=[N:11][NH:12][C:13]=2[NH2:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][CH:18]([C:22](=O)[CH3:23])[C:19](=O)[CH3:20]>CC(O)=O>[C:1]([O:5][C:6]([N:8]1[CH2:15][C:14]2=[C:13]3[N:12]([N:11]=[C:10]2[CH2:9]1)[C:22]([CH3:23])=[C:18]([CH3:17])[C:19]([CH3:20])=[N:16]3)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)C(C)C(C)=O
Reactant: CC(C)(C)OC(=O)N1Cc2n[nH]c(N)c2C1
Solvent: CC(=O)O
Product: Cc1nc2c3c(nn2c(C)c1C)CN(C(=O)OC(C)(C)C)C3
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.5 %

Procedure:
A mixture of 3-amino-2,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-5-carboxylic acid tert-butyl ester (2.4 g; 10.7 mmol; 1 eq.) and 3-methyl-2,4-pentanedione (1.75 mL; 15 mmol; 1.4 eq.) in AcOH (25 mL) was stirred at room temperature for 18 hours. The solvent was evaporated in vacuo and the residue partitioned between ethyl acetate and sat. aq. NaHCO3. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was triturated in ACN and the precipitate filtered off to afford the title compound (1.7 g, 52%) as a white solid. The mother liquor was concentrated in vacuo and the residue purified by column chromatography (DCM/EtOH, 95/5) to afford the title compound (1.5 g, 46%) as a white solid. 1H NMR (DMSO-d6) δ 4.59-4.53 (m, 4H), 3.34 (s, 6H), 2.27 (s, 3H), 1.47 (s, 9H). HPLC (max plot) 96.1%; Rt 3.92 min. UPLC/MS: (MS+) 303.1 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[C:6]([CH3:17])[C:5](=[O:18])[N:4]2[CH2:19][CH2:20][O:21][C:3]=12.[CH2:22]([O:29][CH2:30][C:31]1([S:34](Cl)(=[O:36])=[O:35])[CH2:33][CH2:32]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1>[F:16][C:10]1[CH:11]=[C:12]([I:15])[CH:13]=[CH:14][C:9]=1[NH:8][C:7]1[C:2]([NH:1][S:34]([C:31]2([CH2:30][O:29][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:33][CH2:32]2)(=[O:36])=[O:35])=[C:3]2[O:21][CH2:20][CH2:19][N:4]2[C:5](=[O:18])[C:6]=1[CH3:17]
Reactant: O=S(=O)(Cl)C1(COCc2ccccc2)CC1
Reactant: Cc1c(Nc2ccc(I)cc2F)c(N)c2n(c1=O)CCO2
Solvent: c1ccncc1
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2(COCc3ccccc3)CC2)c2n(c1=O)CCO2
Yield: 49.4 %

Procedure:
Using the same reaction conditions and workup as described for the preparation of Example 7A, 8-amino-7-(2-fluoro-4-iodo-phenylamino)-6-methyl-2,3-dihydro-oxazolo[3,2-a]pyridin-5-one (I-7f: 0.35 g, 0.873 mmol) in pyridine (3 mL) was reacted with 1-benzyloxymethyl-cyclopropanesulfonyl chloride (0.34 mg, 1.30 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in CHCl3) afforded 0.27 g of the product (50% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][N:13]([CH:17]3[CH2:20][CH2:19][CH2:18]3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[O:21]1[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23][CH2:22]1.C1OCCOCCOCCOCCOCCOC1.[OH-].[K+]>C1(C)C=CC=CC=1.O>[CH:17]1([N:13]2[CH2:14][CH2:15][CH2:16][N:10]([C:8]([C:5]3[CH:6]=[N:7][C:2]([O:27][CH:24]4[CH2:25][CH2:26][O:21][CH2:22][CH2:23]4)=[CH:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)[CH2:20][CH2:19][CH2:18]1
Reactant: OC1CCOCC1
Reactant: O=C(c1ccc(Cl)nc1)N1CCCN(C2CCC2)CC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(c1ccc(OC2CCOCC2)nc1)N1CCCN(C2CCC2)CC1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
To a solution of (6-chloro-pyridin-3-yl)-(4-cyclobutyl-[1,4]diazepan-1-yl)-methanone (32.7 g, 111.3 mmol) in toluene (470 mL) was added tetrahydro-pyran-4-ol (13.6 g, 133.6 mmol), 18-crown-6 (1.47 g, 5.565 mmol), and then KOH (pulverized solid, 20.6 g, 367.3 mmol). The resulting heterogeneous mixture was warmed to 110° C. and stirred for 3 h. After cooling to room temperature, water (470 mL) was added and the resulting layers were thoroughly mixed and then separated. The organic extract was dried over magnesium sulfate, filtered, and concentrated to yield the title compound as a yellow oil.
Reaction SMILES: C(C[N:5]1[C:9]([SH:10])=[N:8][N:7]=[N:6]1)(O)=O.CC(O[CH2:15][C:16]1[CH2:25][S:24][C@@H:19]2[C@H:20]([NH2:23])[C:21](=[O:22])[N:18]2[C:17]=1[C:26]([OH:28])=[O:27])=O>>[NH2:23][CH:20]1[C:21](=[O:22])[N:18]2[C:17]([C:26]([OH:28])=[O:27])=[C:16]([CH:15]([S:10][C:9]3[NH:5][N:6]=[N:7][N:8]=3)[CH2:17][C:26]([OH:28])=[O:27])[CH2:25][S:24][C@H:19]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=C(O)Cn1nnnc1S
Product: NC1C(=O)N2C(C(=O)O)=C(C(CC(=O)O)Sc3nnn[nH]3)CS[C@H]12

Procedure:
7-Amino-3-(1-carboxymethyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid was prepared as described in Example 17 from reaction of 1-carboxymethyltetrazole-5-thiol and 7-aminocephalosporanic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:13]([CH3:22])=[C:12](C(O)=O)[C:11]=2[CH:26]([CH3:28])[CH3:27])[CH:5]=[C:6]([Cl:8])[CH:7]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.COC1C=C(OC)C=C(OC)C=1CN.C(N1CCOCC1)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:13]([CH3:22])=[CH:12][C:11]=2[CH:26]([CH3:28])[CH3:27])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1c(C(=O)O)c(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1Cc1ccncc1
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: COc1cc(OC)c(CN)c(OC)c1
Solvent: ClCCl
Product: Cc1cc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1Cc1ccncc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 20.2 %

Procedure:
To a solution of 160 mg of 5-(3,5-Dichlorophenylthio)-2-methyl-4-isopropyl-1-[(4-pyridyl)methyl]-1H-pyrrole-3-carboxylic acid in 10 ml of dichloromethane were added 60 mg of EDAC, 40 mg of HOBt, 68 mg of 2,4,6-trimethoxybenzylamine hydrochloride and 0.11 ml of N-ethyl morpholine. The reaction mixture was stirred at room temperature for 18 h. The reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using petrol/ethyl acetate (1:4 then 1:2) then ethyl acetate for the elution to give 29 mg of 5-(3,5-dichlorophenylthio)-4-isopropyl-2-methyl-1-[(4-pyridyl)methyl]-1H-pyrrole as an oil, mass spectrum (ESI) m/z 391 [M+H]+ and 114 mg of 5-(3,5-dichlorophenylthio)-4-isopropyl-2-methyl-1-[(4-pyridyl)methyl]-1H-pyrrole-3-N-[(2,4,6-trimethoxy)benzyl]-carboxamide as an oil, mass spectrum (ESI) m/z 614 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=2)[NH:8][C:7]=1[CH3:16])C.[H-].[Na+].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:31]([CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[CH3:32])(=[O:30])=[O:29])=[CH:24][CH:23]=1.Cl>CS(C)=O.O>[CH:33]1([N:31]([CH3:32])[S:28]([C:25]2[CH:26]=[CH:27][C:22]([CH2:21][N:8]3[C:9]4[C:14](=[CH:13][C:12]([F:15])=[CH:11][CH:10]=4)[C:6]([CH2:5][C:4]([OH:3])=[O:17])=[C:7]3[CH3:16])=[CH:23][CH:24]=2)(=[O:30])=[O:29])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: CN(C1CCCCC1)S(=O)(=O)c1ccc(CBr)cc1
Reactant: CCOC(=O)Cc1c(C)[nH]c2ccc(F)cc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1c(CC(=O)O)c2cc(F)ccc2n1Cc1ccc(S(=O)(=O)N(C)C2CCCCC2)cc1

Procedure:
To a stirring suspension of (5-fluoro-2-methyl-1H-indol-3-yl)-acetic acid ethyl ester (100 mg, 0.43 mmol) in dry DMSO (1 ml), is added NaH (29 mg, 0.73 mmol). The reaction mixture is stirred at room temperature for 15 min after which time 4-bromomethyl-N-cyclohexyl-N-methyl-benzenesulfonamide (149 mg, 0.43 mmol) is added. Reaction mixture is diluted with water (10 ml) and treated with 1N HCl aq to acidic pH. The product is extracted in 1:1 EtOAc:Et2O (20 ml), washed with brine, dried (MgSO4) and evaporated in vacuo. The crude reaction mixture is purified by preparative MS-directed HPLC to afford the title compound; [M+H]+ 474.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH3:33][O:34][CH2:35][C:36]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:37]
Reactant: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c[nH]c23)c(OCC2CC2)c1
Reactant: COCC(=O)Cl
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4ccc(OC)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from trans-4-(2-cyclopropylmethoxy-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A150) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:17][CH2:18][CH3:19]>CN(C)C=O>[CH2:17]([N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1)[CH2:18][CH3:19]
Reactant: c1ccc2[nH]cnc2c1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCn1cnc2ccccc21
Yield: 55.3 %

Procedure:
To a flask were added 2.0 g benzimidazole, 3.5 g potassium carbonate, 4.3 g 1-iodopropane and 20 ml N,N-dimethylformamide. The mixture was heated to 45 C under nitrogen for 16 hours and then quenched with 30 ml water and the product was extracted with ethyl acetate. Following removal of the solvent, the product was purified by silica gel chromatography using 66% ethyl acetate in hexane. The brown oil was again purified by silica gel chromatography using ethyl acetate, giving a slightly yellow oil 1.5 g.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.I[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23](=[O:26])[CH:24]=[CH2:25].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23](=[O:26])[CH:24]=[CH2:25])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: C=CC(=O)OCCCCCCI
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CC(=O)OCCCCCCOc1ccc(-c2ccc(O)cc2)cc1

Procedure:
A solution of 4,4′-dihydroxybiphenyl (3.72 g, 20 mmol), acrylic acid 6-iodohexyl ester (4.21 g, 15 mmol) and potassium carbonate (2.07 g, 15 mmol) in DMF (50 ml) was stirred overnight at room temperature and under argon atmosphere. The reaction mixture was then poured into HCl 3N (100 ml) and extracted with ether (3×200 ml). The combined organic extracts were washed with saturated NaCl solution (200 ml), dried over magnesium sulfate, filtered and evaporated to dryness. The crystalline residue obtained was purified on silica-gel column (CH2Cl2, CH2Cl2/Et2O:19/1). This gave acrylic acid 6-(4′-hydroxybiphen-4-yloxy-)hexyl ester as white crystalline material. Yield 2.5 g.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]2[C:10]([F:32])=[N:11][CH:12]=[C:13]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([CH2:23][N:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)=[C:17]([O:30][CH3:31])[CH:16]=3)[CH:14]=2)[CH:3]=1.[CH3:33][N:34]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[N:35]1>[F-].[K+].C(#N)C.C(OCC)(=O)C>[CH3:31][O:30][C:17]1[CH:16]=[C:15]([C:13]2[CH:14]=[C:9]([C:4]3[CH:3]=[C:2]([C:37]4[CH:36]=[N:35][N:34]([CH3:33])[CH:38]=4)[N:7]=[CH:6][C:5]=3[NH2:8])[C:10]([F:32])=[N:11][CH:12]=2)[CH:20]=[C:19]([O:21][CH3:22])[C:18]=1[CH2:23][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COc1cc(-c2cnc(F)c(-c3cc(Cl)ncc3N)c2)cc(OC)c1CN1CCCCC1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cc(-c2cnc(F)c(-c3cc(-c4cnn(C)c4)ncc3N)c2)cc(OC)c1CN1CCCCC1
Temperature: 100 °C
Yield: 70.2 %

Procedure:
A degassed mixture of 6′-chloro-5-(3,5-dimethoxy-4-piperidin-1-ylmethylphenyl)-2-fluoro-[3,4′]bipyridinyl-3′-ylamine (830 mg, 1.40 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (577 mg, 2.78 mmol), 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (151 mg, 0.19 mmol) in 1N aqueous potassium fluoride solution (10 mL) and acetonitrile (6 mL) was heated under microwave irradiation at 100° C. for 20 minutes. The cooled reaction mixture was diluted with ethyl acetate (100 mL) then washed with water (75 mL). The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 20 g column, ISCO, 0-10% methanol in DCM) to afford the title compound as a white solid (494 mg, 54%). 1H NMR (CDCl3 plus CD3OD, 300 MHz): 8.55 (dd, J=2.5, 1.0 Hz, 1H), 8.22 (dd, J=8.8, 2.5 Hz, 1H), 8.16 (d, J=0.6 Hz, 1H), 7.92 (s, 1H), 7.85 (d, J=0.8 Hz, 1H), 7.37 (s, 1H), 6.95 (s, 2H), 4.35 (s, 2H), 4.01 (s, 6H), 3.95 (s, 3H), 3.61-3.22 (br m, 2H), 3.19-2.90 (br m, 2H), 2.02-1.47 (br m, 6H).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].O=C[C@@H]([C@H]([C@H]([C@@H](CO)O)O)O)O.O=C([O-])[C@@H]([C@H]([C@@H](CO)O)O)O>>[CH2:2]([OH:1])[C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Agent: O=C([O-])[C@H](O)[C@@H](O)[C@H](O)CO
Agent: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Product: OC[C@@H](O)[C@H](O)[C@@H](O)CO

Procedure:
When K. lactis H3765, from which the xylose reductase had been deleted, was grown in 1% w/v galactose and 2% w/v xylose, 8.0±0.8 g xylonate I−1 were produced at a rate of 0.13 g I−1 h−1. Less than 0.4 g xylitol I−1 was produced. K. lactis H3763, from which the xylose dehydrogenase had been deleted, produced 2.0±0.1 g xylonate I−1 with 14.4±0.5 g xylitol I−1 when grown under the same conditions.
Reaction SMILES: CON(C)[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1.[CH:17]1([Mg]Br)[CH2:21][CH2:20][CH2:19][CH2:18]1.N#N.Cl>C1COCC1>[CH:17]1([C:4]([C:5]2[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=2)=[O:15])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Br[Mg]C1CCCC1
Reactant: CON(C)C(=O)c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: N#N
Solvent: C1CCOC1
Product: O=C(c1ccc(C(F)(F)F)cc1)C1CCCC1
Temperature: 25 °C
Yield: 84 %

Procedure:
To a cold (0° C.) solution of N-methoxy-N-methyl-4-(trifluoromethyl)benzamide (3.44 g, 14.75 mmol) in anhydrous THF (70 mL) was added dropwise over a period of 30 minutes a solution of cyclopentylmagnesium bromide (2 M in diethyl ether, 29.5 mmol, 14.75 mL) under inert atmosphere of N2. The reaction mixture was slowly allowed to warm to rt overnight. An aqueous solution of HCl (1N, 50 mL) was added and the resulting mixture was extracted with diethyl ether (3×50 mL). The combined organic layers were washed with brine (1×50 mL), dried over MgSO4, filtered and evaporated under vacuum to give a brown oil (3.0 g). Purification by chromatography (SiO2, DCM/c-Hex 1/3) gave the title compound as a colorless oil (610 mg, 17%). 1H NMR (CDCl3, 300 MHz) δ 8.24 (d, J=8.1 Hz, 2H), 7.90 (d, J=8.1 Hz, 2H), 3.96-3.79 (m, 1H), 2.21-2.00 (m, 4H), 2.01-1.71 (m, 4H). HPLC (Condition A), Rt: 5.22 min (HPLC purity: 98.6%).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[C:12](=[O:13])[CH:11]([CH3:14])[C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[C:8]2[C:19]([NH2:23])=[CH:20][CH:21]=[CH:22][C:7]1=2)=[O:5])[CH3:3].[CH2:24]([S:31](Cl)(=[O:33])=[O:32])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[CH2:24]([S:31]([NH:1][C@H:2]([C:4]([N:6]1[C:12](=[O:13])[CH:11]([CH3:14])[C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[C:8]2[C:19]([NH2:23])=[CH:20][CH:21]=[CH:22][C:7]1=2)=[O:5])[CH3:3])(=[O:33])=[O:32])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC1C(=O)N(C(=O)[C@H](C)N)c2cccc(N)c2-c2ccccc21
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: CN(C)C=O
Product: CC1C(=O)N(C(=O)[C@H](C)NS(=O)(=O)Cc2ccccc2)c2cccc(N)c2-c2ccccc21
Temperature: 25 °C
Reaction time: 84 h
Yield: 34.7 %

Procedure:
To 5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 7B) (0.2050 g, 0.66 mmol) in DMF (5 ml) was added benzylsulfonyl chloride (Aldrich) (0.0632 g, 0.33 mmol), stirred at RT for 3.5 days. The reaction mixture was evaporated to dryness. Water was added, extracted with CH2Cl2, washed with brine, dried over MgSO4. Evaporation and flash chromatography (silica, 5% MeOH /CH2Cl2), gave a residue, which was washed with Et2O /hexane (1:2, v/v) to give the title compound (0.0531 g, 35%) as a light yellow solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=2)[C:4](=O)[NH:3][CH:2]=1.C=CC1C=CC=CC=1.[Cl:24]C(Cl)C>C(Cl)(Cl)(Cl)Cl>[Cl:24][C:4]1[C:5]2[C:10](=[CH:9][C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[CH:6]=2)[N:1]=[CH:2][N:3]=1
Reactant: O=c1[nH]cnc2cc3ccccc3cc12
Reactant: CC(Cl)Cl
Solvent: C=Cc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ncnc2cc3ccccc3cc12
Temperature: 22.5 °C

Procedure:
A mixture of 3H-benzo[g]quinazolin-4-one (1.00 g, 5.07 mmol) and styrene-bound triphenylphosphine (2.53 g (approx. 3 mmoles/g), 7.61 mmol) in 15 mL dichloroethane and 15 mL carbon tetrachloride was heated to reflux for 1 hour, cooled to ambient temperature (20-25° C.) and filtered. Solvents were removed in vacuo to give 4-Chloro-benzo[g]quinazoline: 0.3881 g (36%); 1H NMR (DMSO-d6) δ7.63-7.71 (2H,m), 8.10 (1H, d, J=10 Hz), 8.28 (1H, d, J=10 Hz), 8.32 (1H, s), 8.69 (1H, s), 8.82 (1H, s).
Reaction SMILES: [C:1]1(=O)[CH2:4][CH2:3][CH2:2]1.[NH:6]1[CH2:9][CH:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:22]=[CH:21][C:20]4[N:23]=[C:24]([C:26]5[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=5)[S:25][C:19]=4[C:18]3=[O:33])=[CH:13][CH:12]=2)[CH2:7]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.CCOCC>CO.ClCCl>[ClH:32].[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([C:24]2[S:25][C:19]3[C:18](=[O:33])[N:17]([C:14]4[CH:15]=[CH:16][C:11]([O:10][CH:8]5[CH2:9][N:6]([CH:1]6[CH2:4][CH2:3][CH2:2]6)[CH2:7]5)=[CH:12][CH:13]=4)[CH:22]=[CH:21][C:20]=3[N:23]=2)=[CH:27][CH:28]=1
Reactant: O=c1c2sc(-c3ccc(Cl)cc3)nc2ccn1-c1ccc(OC2CNC2)cc1
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: CO
Product: O=c1c2sc(-c3ccc(Cl)cc3)nc2ccn1-c1ccc(OC2CN(C3CCC3)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 114.7 %

Procedure:
Add cyclobutanone (0.4 mL, 5.4 mmol) to a solution of 5-(4-(azetidin-3-yloxy)phenyl)-2-(4-chlorophenyl)thiazolo[5,4-c]pyridin-4(5H)-one (0.44 g, 1.08 mmol) in methanol (54 mL) and acetic acid (0.31 mL, 5.4 mmol). Stir the mixture at room temperature for one hour, add sodium triacetoxyborohydride (1.4 g, 6.48 mmol) and continue stirring at room temperature overnight. Dilute the mixture with dichloromethane, then wash with saturated NaHCO3 solution and water. Dry the organic portion over Na2SO4, filter, and concentrate. Purify the crude material by flash chromatography, using 0-10% MeOH/CH2Cl2 as eluent. Dissolve the solid with dichloromethane and add 1 M HCl/ether (1 eq). Stir the solution for 15 min. Concentrate the solid and filter with ether to give 0.31 g (58%) of the title compound. ES/MS m/z (35Cl) 464 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([CH:10]([F:12])[F:11])[N:7]=[C:6](Cl)[CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C@@H:67]([NH2:71])([CH2:69][CH3:70])[CH3:68]>C1(C)C=CC=CC=1.C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([CH:10]([F:12])[F:11])[N:7]=[C:6]([NH:71][C@H:67]([CH2:69][CH3:70])[CH3:68])[CH:5]=1
Reactant: COC(=O)c1cc(Cl)nc(C(F)F)c1
Reactant: CC[C@H](C)N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC[C@H](C)Nc1cc(C(=O)OC)cc(C(F)F)n1
Yield: 60 %

Procedure:
Dissolve 2-chloro-6-difluoromethyl-isonicotinic acid methyl ester (200 mg, 0.9 mmol), palladium (II) acetate (20.0 mg, 0.09 mmol), racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (56 mg, 0.09 mmol) and cesium carbonate (438 mg, 1.35 mmol) in toluene (3 mL) in a previously degassed sealed vessel. Flush the mixture with nitrogen gas. Add (S)-(+)-sec-butylamine (0.108 mL, 1.08 mmol) to the solution under nitrogen and heat the sealed mixture overnight at 100° C. Cool the reaction to room temperature. Dilute with diethyl ether and filter through a filtering agent. Concentrate the filtrate and purify (silica gel chromatography, eluting with 10:90 acetate:hexanes) to give the title compound as an oil (60%).
Reaction SMILES: BrC1C=C(C)C=C2C=1C=NN2C1C=CC=CC=1F.[F:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][N:27]=[CH:28][C:29]2[C:34](Br)=[CH:33][C:32]([CH3:36])=[CH:31][C:30]=2[Br:37])=[CH:22][CH:21]=1>>[Br:37][C:30]1[CH:31]=[C:32]([CH3:36])[CH:33]=[C:34]2[C:29]=1[CH:28]=[N:27][N:26]2[C:23]1[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=1
Reactant: Cc1cc(Br)c(C=NNc2ccc(F)cc2)c(Br)c1
Agent: Cc1cc(Br)c2cnn(-c3ccccc3F)c2c1
Product: Cc1cc(Br)c2cnn(-c3ccc(F)cc3)c2c1

Procedure:
Similarly prepared to Intermediate 26 from 2,6-dibromo-4-methylbenzaldehyde (4-fluorophenyl)hydrazone (Intermediate 27).