Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][N:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29]#[CH:30])=[N:27][CH:28]=2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29]#[C:30][C:2]3[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][N:11]4[CH2:15][CH2:14][CH2:13][CH2:12]4)=[CH:4][N:3]=3)=[N:27][CH:28]=2)=[CH:21][CH:22]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: Brc1ccc(OCCN2CCCC2)cn1
Product: Clc1ccc(-c2ccc(C#Cc3ccc(OCCN4CCCC4)cn3)nc2)cc1

Procedure:
Prepared according to general working method I from 2-bromo-5-(2-pyrrolidin-1-yl-ethoxy)-pyridine (271 mg, 0.50 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (106 mg, 0.50 mmol).
Reaction SMILES: [CH3:1][N:2]1[C:6]([SH:7])=[N:5][N:4]=[N:3]1.C(=O)([O-])[O-].[K+].[K+].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]([CH2:22][CH2:23][CH2:24]Cl)=[O:21]>CC(C)=O>[CH3:1][N:2]1[C:6]([S:7][CH2:24][CH2:23][CH2:22][C:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=2)=[O:21])=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1S
Reactant: O=C(CCCCl)c1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1nnnc1SCCCC(=O)c1ccccn1
Reaction time: 2 h
Yield: 50 %

Procedure:
1-Methyl-5-mercapto-1,2,3,4-tetrazole (1.2 g), potassium carbonate (2.1 g) and 3-chloropropyl 2-pyridyl ketone (2.8 g) are added to acetone (50 ml) and the mixture is refluxed with stirring for 2 hours. The reaction mixture is concentrated to dryness under reduced pressure and the residue is dissolved in chloroform. Insolubles are filtered off and the filtrated is concentrate under reduced pressure. The residue is purified by silica gel column chromatography (Kieselgel 60, eluant: benzene-ether (10:1)) and the product is recrystallized from hexane-ether to obtain 1-methyl-5-[3-(2-pyridylcarbonyl)propyl]thio-1,2,3,4-tetrazole (yield 50%) as colorless needles, m.p. 73°-75° C.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[OH:16][C:17]1[S:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)=[CH:20][CH:21]=1.[C:40](O)(=[O:46])/[CH:41]=[CH:42]/[CH2:43][CH2:44][CH3:45]>CN(C)C1C=CN=CC=1.ClCCl>[C:40]([O:16][C:17]1[S:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)=[CH:20][CH:21]=1)(=[O:46])/[CH:41]=[CH:42]/[CH2:43][CH2:44][CH3:45]
Reactant: CCC/C=C/C(=O)O
Reactant: CCCCCCc1ccc(-c2ccc(-c3ccc(O)s3)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC/C=C/C(=O)Oc1ccc(-c2ccc(-c3ccc(CCCCCC)cc3)cc2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.8 %

Procedure:
Dicyclohexylcarbodiimide (0.4 g) is added to a solution of 2-hydroxy-5-(4′-hexylbiphenyl-4-yl)thiophene (0.25 g), (E)-hex-2-enoic acid, (0.2 g) 4-(dimethylamino)pyridine (0.10 g) and dichloromethane (50 cm3) at 0° C. under an atmosphere of nitrogen. The reaction mixture is stirred overnight at room temperature, filtered to remove inorganic material and the filtrate evaporated down. The residue is purified by column chromatography on silica gel using hexanelethyl acetate (9/1 v/v) as eluent and recrystallisation from hexane to yield 0.16 g of 2-[(E)-hex-2-enoyloxy]-5-(4′-hexylbiphenyl-4-yl)thiophene.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:4][C:3]1([CH3:18])[CH3:17].C[N+]1([O-])CCOCC1>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH3:17][C:3]1([CH3:18])[C:2](=[O:1])[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:4]1
Reactant: CC1(C)CN(C(=O)OCc2ccccc2)CC1O
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Product: CC1(C)CN(C(=O)OCc2ccccc2)CC1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.4 %

Procedure:
A suspension of benzyl 4-hydroxy-3,3-dimethylpyrrolidine-1-carboxylate (4.07 g, 16.3 mmol) in acetonitrile (50 mL), was added 4-methylmorpholine-4-oxide (3.82 g, 32.7 mmol) and tetrapropylammonium perruthenate (0.42 mL, 1.63 mmol). The mixture was stirred at rt for 18 h. The reaction was concentrated and purified using silica gel chromatography, eluting with 0-30% ethyl acetate in hexanes. Benzyl 3,3-dimethyl-4-oxopyrrolidine-1-carboxylate (2.92 g, 68% yield) was obtained as a colorless oil. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.49-7.31 (m, 5H), 5.19 (s, 2H), 3.93 (br. s., 2H), 3.61 (s, 2H), 1.17 (s, 6H); MS (ES+) m/z: 248.1 (M+H); LC retention time: 3.24 min (analytical HPLC Method I).
Reaction SMILES: CS[C:3]1[N:4]=[N:5][C:6]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH2:20][CH2:21][CH3:22])[NH:10][C:9](=[O:23])[C:7]=2[N:8]=1.[CH3:24][NH2:25]>>[CH3:24][NH:25][C:3]1[N:4]=[N:5][C:6]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH2:20][CH2:21][CH3:22])[NH:10][C:9](=[O:23])[C:7]=2[N:8]=1
Reactant: CN
Reactant: CCCOc1ccccc1-c1nc2nnc(SC)nc2c(=O)[nH]1
Product: CCCOc1ccccc1-c1nc2nnc(NC)nc2c(=O)[nH]1

Procedure:
5,6-Dihydro-3-methylthio-5-oxo-7-(2-propoxyphenyl)pyrimido[5,4-e][1,2,4]triazine (340 mg) was treated with a solution of methylamine in industrial methylated spirit (33%, 15 ml) at 70° C. in a pressure vessel (172 kPa) for 10 hours. The cooled reaction mixture was evaporated under reduced pressure to afford a yellow solid (290 mg) which was recrystallized from ethanol and then acetonitrile to afford the title compound, 120 mg, m.p. decomposes over 260° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:7][CH2:6][C:5](=[C:8]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19]C(C)(C)C)=[O:18])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C:2]1([CH3:31])[CH2:7][CH2:6][C:5](=[C:8]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: CC1(C)CCC(=C(c2ccc(O)cc2)c2ccc(/C=C/C(=O)OC(C)(C)C)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CCC(=C(c2ccc(O)cc2)c2ccc(/C=C/C(=O)O)cc2)CC1
Reaction time: 1 h
Yield: 82.3 %

Procedure:
To a stirred solution of 1,1-dimethylethyl (2E)-3-{4-[(4,4-dimethylcyclohexylidene)(4-hydroxyphenyl)methyl]phenyl}-2-propenoate (21) (0.24 g, 0.57 mmol) in CH2Cl2 (5 mL) was added trifluoroacetic acid (4 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 1 h and concentrated in vacuo to give an oil. The oil was dissolved in CH2Cl2 and the solvent was removed in vacuo to give a solid which was dried under vacuum at 90° C. to give 0.170 g (82%) of compound 22 as a pale tan solid. 1H NMR (400 MHz, DMSO-d6): δ 0.93 (s, 6H), 1.31 (m, 4H), 2.16 (m, 4H), 6.44 (d, J=15.9 Hz, 1H), 6.65 (d, J=8.4 Hz, 2H), 6.84 (d, J=8.3 Hz, 2H), 7.05 (d, J=7.9 Hz, 2H), 7.52 (d, J=15.9 Hz, 1H), 7.57 (d, J=8.1 Hz, 2H), 9.32 (s, 1H), 12.33 (br s, 1H). The compound was silated prior to EI analysis. HRMS (EI) Calcd for C30H42O3Si2: 506.2673 (M+). Found: 506.2669.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[N:3]1.C([Li])CCC.[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH:23]([C:25]3[C:26]([CH3:32])=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=3)[OH:24])[CH:21]=2)[N:16]=[C:15]([O:33][CH3:34])[C:14]=1[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=1>C1COCC1>[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([C:25]3[C:26]([CH3:32])=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=3)([C:6]3[N:2]([CH3:1])[N:3]=[N:4][CH:5]=3)[OH:24])[CH:21]=2)[N:16]=[C:15]([O:33][CH3:34])[C:14]=1[CH2:35][C:36]1[CH:37]=[CH:38][C:39]([C:42]([F:44])([F:43])[F:45])=[CH:40][CH:41]=1
Reactant: Cn1ccnn1
Reactant: COc1nc2ccc(C(O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3ccc(C)nc3C)c3cnnn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
To a flask containing 1-methyl-1H-1,2,3-triazole (275 mg, 3.31 mmol, prepared according to PCT Int. Appl., 2008098104) was added THF (35 mL) and the colorless solution was cooled to −50° C. Then, n-butyllithium (2.5 M in hexanes, 1.2 mL, 3.0 mmol) was added dropwise which afforded a dark reddish-brown viscous solution. The mixture was stirred between −20 to −10° C. for 30 minutes, then a homogeneous THF solution of (4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(2,6-dimethylpyridin-3-yl)methanone (700 mg, 1.44 mmol in 4 mL THF, Intermediate 12: step f) was introduced at 0° C. The reaction mixture became a dark brown color and was allowed to warm gradually to room temperature. The mixture was stirred for 60 minutes at room temperature then quenched with aqueous NH4Cl solution. The aqueous portion was extracted with EtOAc, 3×50 mL. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to provide a brown oil. Chromatography on silica gel (1% MeOH-DCM increasing to 5% MeOH-DCM) provided the title compound as a light brown solid. Racemic (4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(2,6-dimethylpyridin-3-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanol was separated into its individual enantiomers using the following conditions: Chiralcel OD, 20 uM (Diacel) using ethanol with 242 nM detection to give the first eluting enantiomer as Intermediate 84b and the second eluting enantiomer as Intermediate 84c.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:6]=[N:7][C:8]([CH2:14][CH3:15])=[C:9]([CH2:11][C:12]#[N:13])[CH:10]=1.Cl.N[C:19]1[C:24]([F:25])=[C:23]([F:26])[CH:22]=[C:21]([F:27])[C:20]=1[SH:28]>>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:6]=[N:7][C:8]([CH2:14][CH3:15])=[C:9]([CH2:11][C:12]2[S:28][C:20]3[C:21]([F:27])=[CH:22][C:23]([F:26])=[C:24]([F:25])[C:19]=3[N:13]=2)[CH:10]=1
Reactant: Nc1c(F)c(F)cc(F)c1S
Reactant: CCc1ncc(CC(=O)OC)cc1CC#N
Agent: Cl
Product: CCc1ncc(CC(=O)OC)cc1Cc1nc2c(F)c(F)cc(F)c2s1
Temperature: 120 °C
Yield: 78.6 %

Procedure:
A mixture of 5-cyanomethyl-6-ethyl-pyridin-3-yl-acetic acid methyl ester (0.51 g, 2.34 mmol), 2-amino-3,4,6-trifluorothiophenol hydrochloride (0.54 g, 2.53 mmol) and BHT (10 mg) in a sealed reaction vessel is heated to 120° C. for 9 h. After cooling to room temperatue, the resulting slurry is adsorbed onto silica gel and purified by flash column chromatography (10-30% ethyl acetate in hexanes) to give 6-ethyl-5-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyridin-3-yl-acetic acid-methyl ester as a yellow oil (0.70 g, 79%): Rf 0.36 (50% ethyl acetate in n-heptane), 1H NMR (CDCl3, 300 MHz) δ 8.46 (s, 1 H), 7.64 (s, 1 H), 7.08-6.97 (m, 1 H), 4.50 (s, 2 H), 3.72 (s, 3 H), 3.65 (s, 2 H), 2.90 (q, J=7.4 Hz, 2 H), 1.29 (t, J=7.4 Hz, 3 H); ESI-LCMS m/z calcd for C18H15F3N2O2S: 380.1; found 381.0 (M+1)+.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[N:18]=[C:17]([C:19]3[N:23]4[CH:24]=[CH:25][CH:26]=[C:27]([C:28]([OH:31])([CH3:30])[CH3:29])[C:22]4=[N:21][CH:20]=3)[CH:16]=[CH:15][N:14]=2)[CH2:8][CH2:7]1)=[O:5])C.O[Li].O.C1COCC1.CCO>O>[OH:31][C:28]([C:27]1[C:22]2[N:23]([C:19]([C:17]3[CH:16]=[CH:15][N:14]=[C:13]([NH:12][CH:9]4[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]4)[N:18]=3)=[CH:20][N:21]=2)[CH:24]=[CH:25][CH:26]=1)([CH3:29])[CH3:30]
Reactant: CCOC(=O)C1CCC(Nc2nccc(-c3cnc4c(C(C)(C)O)cccn34)n2)CC1
Agent: [Li]O
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O)c1cccn2c(-c3ccnc(NC4CCC(C(=O)O)CC4)n3)cnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.2 %

Procedure:
A mixture of 4-{4-[8-(1-hydroxy-1-methyl-ethyl)-imidazo[1,2-a]pyridin-3-yl]-pyrimidin-2-ylamino}-cyclohexanecarboxylic acid ethyl ester (0.215 g), LiOH—H2O (0.106 g), THF (20 mL), EtOH (5 mL) and water (5 mL) was stirred at RT overnight. The reaction mixture was then concentrated to remove THF and EtOH, neutralized with HCl (1 N), and the resulting solid filtered and dried at 50° C. under vacuum overnight to provide 4-{4-[8-(1-hydroxy-1-methyl-ethyl)-imidazo[1,2-a]pyridin-3-yl]-pyrimidin-2-ylamino}-cyclohexanecarboxylic acid (0.175 g), which was used without further purification.
Reaction SMILES: CS([C:4]1[N:9]=[C:8]([N:10]2[C:18]3[C:13](=[C:14]([O:19][CH2:20][CH2:21][CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)[CH:7]=[CH:6][N:5]=1)=O.C([O-])(=O)C.[OH:31][C:32]([CH:35]1[CH2:40][CH2:39][CH:38]([NH3+:41])[CH2:37][CH2:36]1)([CH3:34])[CH3:33].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH3:26][S:23]([CH2:22][CH2:21][CH2:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[CH:12]=[CH:11][N:10]2[C:8]1[CH:7]=[CH:6][N:5]=[C:4]([NH:41][CH:38]2[CH2:39][CH2:40][CH:35]([C:32]([OH:31])([CH3:33])[CH3:34])[CH2:36][CH2:37]2)[N:9]=1)(=[O:25])=[O:24]
Reactant: CC(C)(O)C1CCC([NH3+])CC1
Reactant: CS(=O)c1nccc(-n2ccc3c(OCCCS(C)(=O)=O)cccc32)n1
Agent: CC(=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)(O)C1CCC(Nc2nccc(-n3ccc4c(OCCCS(C)(=O)=O)cccc43)n2)CC1
Temperature: 126 °C
Yield: 57.4 %

Procedure:
1-(2-Methanesulfinyl-pyrimidin-4-yl)-4-(3-methanesulfonyl-propoxy)-1H-indole (538 mg, 1.4 mmol), 4-(2-hydroxyprop-2-yl)-cyclohexylammonium acetate (400 mg, 2 mmol), and DIEA (0.8 mL, 5 mmol) were combined in NMP (10 mL) and heated to 126° C. in a sealed tube for 4 h, cooled, and partitioned between water and EtOAc. The organic layer was separated and washed twice with water, dried over sodium sulfate, filtered and purified by flash chromatography (SiO2) with 3:97 MeOH/DCM, and recrystallized from MeOH/DCM, triturated with EtOAc and solvent evaporated to yield 2-(4-{4-[4-(3-methanesulfonyl-propoxy)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexyl)-propan-2-ol (Compound 166, 391 mg, 59%) as a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])/[CH:5]=[CH:6]/[C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH:8]=1)[CH3:2]>[Pd].CCO>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH2:6][C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)/C=C/c1cc2ccccc2s1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1cc2ccccc2s1
Reaction time: 3 h
Yield: 96.8 %

Procedure:
A mixture of (E)-3-(benzo[b]thienyl)-2-propenoic acid ethyl ester (3.65 g, 15.7 mmol), absolute EtOH (200 mL) and 5% Pd/C (800 mg) was hydrogenated at 1 atm for 3 h. An additional 200 mg of 5% Pd/C was added and the mixture was again hydrogenated for 1.5 h. The mixture was filtered through a pad of Celite washing thoroughly with CH2Cl2. The combined filtrates were concentrated to dryness and the resulting glass was purified by flash chromatography, eluting with 15% EtOAc/hexane to give benzo[b]thiophene-2-propanoic acid ethyl ester (3.55 g, 15.2 mmol) in 96.5% as a glass.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7](Cl)=[O:8].[Cl:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([NH2:20])=[N:16][NH:17]2)=[CH:13][CH:12]=1>N1C=CC=CC=1>[Cl:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([NH:20][C:7](=[O:8])[CH2:6][C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[N:16][NH:17]2)=[CH:13][CH:12]=1
Reactant: Nc1n[nH]c2cc(Cl)ccc12
Reactant: O=C(Cl)Cc1cccs1
Solvent: c1ccncc1
Product: O=C(Cc1cccs1)Nc1n[nH]c2cc(Cl)ccc12
Temperature: 3 °C
Reaction time: 21 h

Procedure:
0.73 cm3 of 2-thiopheneacetyl chloride is added to 1 g of 6-chloro-1H-indazole-3-amine in 15 cm3 of pyridine, cooled to about 3° C. The reaction medium is allowed to return to about 19° C. over 21 hours and is then evaporated under reduced pressure (2 kPa; 50° C.). The residue is taken up in 25 cm3 of ethyl acetate, 10 cm3 of tetrahydrofuran and 25 cm3 of distilled water. The organic phase is washed with 25 cm3 of distilled water and 25 cm3 of saturated aqueous sodium chloride solution. The resulting solution is dried over magnesium sulphate, filtered on a sinter funnel, rinsed with 5 cm3 of dimethylformamide and then evaporated under reduced pressure (2 kPa; 50° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 4 cm), eluting with a dichloromethane/methanol mixture (99/1 by volume) and collecting 15 cm3 fractions. The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). After drying (90 Pa; 45° C.), 210 mg of N-[6-chloro-1H-indazol-3-yl]-2-thiophenacetamide are obtained in the form of a white solid melting at 210° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([S:10][CH2:11][CH3:12])=S)[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:14][OH:15].C(N(CC)CC)C.BrCCBr>O.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[S:10][CH2:11][CH2:12][O:15][N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NO
Reactant: CCSC(=S)c1cccc(Cl)c1
Agent: Cl
Solvent: BrCCBr
Solvent: CCO
Solvent: CCN(CC)CC
Product: Clc1cccc(C2=NOCCS2)c1
Temperature: 25 °C

Procedure:
Ethyl 3-chlorobenzenecarbodithioate (106 g, 0.5 mol) and ethanol (400 ml) was treated with finely powdered hydroxylamine hydrochloride (36 g, 0.5 mol, 97%) with stirring, triethylamine (50.5 g, 70 ml, 0.5 mol) was added dropwise. A slight exotherm was observed. After the addition, the reaction was stirred for 11/2 hours. Ethyl mercaptan was removed using a scrubber and vacuum trap. 1,2-Dibromoethane (95 g, 0.5 mol) was added to the reaction and with stirring, triethylamine (101 g, 140 ml, 1 mol) added dropwise. The initial red colour was completely discharged. When the addition was complete, the reaction was refluxed for 1 hour, cooled to room temperature and the solvent removed to leave a solid. Water was added, the product extracted into ether which was subsequently washed successively with water, 5% potassium hydroxide, water and then dried over anhydrous magnesium sulphate. After evaporation, a white solid remained, 3-(3-chlorophenyl)-5,6-dihydro-1,4,2-oxathiazine, mp 65° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH2:5][S:6][C@@H:7]2[CH:27]([NH:28][C:29](=[O:36])[CH2:30][C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)[C:26](=[O:37])[N:8]2[C:9]=1[C:10]([O:12][CH:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].C[Li].Cl[O:41][C:42](C)(C)C>CO>[CH3:1][O:2][CH2:3][C:4]1[CH2:5][S:6][C@@H:7]2[C:27]([O:41][CH3:42])([NH:28][C:29](=[O:36])[CH2:30][C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)[C:26](=[O:37])[N:8]2[C:9]=1[C:10]([O:12][CH:13]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:11]
Reactant: COCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Reactant: CC(C)(C)OCl
Agent: [Li]C
Solvent: CO
Product: COCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)(OC)[C@H]2SC1

Procedure:
In accordance with the procedures described by Example 1, benzhydryl 3-methoxymethyl-7-[2-(2-thienyl)acetamido]-3-cephem-4-carboxylate was reacted at a temperature of -80° C. with methyl lithium in the presence of methanol and t-butyl hypochlorite to provide benzhydryl 3-methoxymethyl-7-methoxy-7-[2-(2-thienyl)acetamido]-3-cephem-4-carboxylate.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[N:8]1[C:17]2[C:12](=[CH:13][C:14]([CH2:18][C:19]([OH:21])=[O:20])=[CH:15][CH:16]=2)[N:11]=[CH:10][CH:9]=1>C1(C)C=CC=CC=1.CO>[CH3:1][O:20][C:19](=[O:21])[CH2:18][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[N:8]=[CH:9][CH:10]=[N:11]2
Reactant: O=C(O)Cc1ccc2nccnc2c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)Cc1ccc2nccnc2c1

Procedure:
Trimethylsilyldiazomethane [2.0M in hexanes] (0.08 mL) was added dropwise to a solution of quinoxalin-6-yl-acetic acid (0.030 g, 0.159 mmol) in toluene/methanol [8/1] (0.5 mL) and stirred until the bubbling stopped. The reaction was then evaporated and the crude product was purified via silica gel column chromatography in hexane:ethyl:acetate (1:1) to give 0.013 g of quinoxalin-6-yl-acetic acid methyl ester. This was added to a solution of hydrazine (0.10 mL) in methanol and stirred at room temperature overnight. The reaction mixture was evaporated in vacuo to give 0.019 g of quinoxalin-6-yl-acetic acid hydrazide. 1H NMR (400 MHz, DMSO-d6) δ 9.77 (bs, 1H), 9.35 (m, 2H), 8.46 (d, 1H, J=8.8 Hz), 8.39 (m, 1H), 8.19 (dd, 1H, J=2.0, 8.8 Hz), 4.68 (bs, 2H), 4.07 (s, 2H).
Reaction SMILES: [CH2:1]([CH:3]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[C:10]2[CH:9]=[C:8]([CH3:18])[CH:7]=[CH:6][C:5]=2[N:4]1[S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28]C)=[CH:24][CH:23]=1)(=[O:21])=[O:20])[CH3:2].C1CCCCC=1.B(Br)(Br)Br.ClCCl>>[CH2:1]([CH:3]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[C:10]2[CH:9]=[C:8]([CH3:18])[CH:7]=[CH:6][C:5]=2[N:4]1[S:19]([C:22]1[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=1)(=[O:21])=[O:20])[CH3:2]
Reactant: CCC1c2cc(F)ccc2-c2cc(C)ccc2N1S(=O)(=O)c1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Solvent: ClCCl
Product: CCC1c2cc(F)ccc2-c2cc(C)ccc2N1S(=O)(=O)c1ccc(O)cc1
Yield: 60.7 %

Procedure:
The title compound was prepared from 6-ethyl-8-fluoro-5-[(4-methoxyphenyl)sulfonyl]-2-methyl-5,6-dihydrophenanthridine (0.24 g, 0.58 mmol), cyclohexene (2.1 mL, 21 mmol), and 1 M boron tribromide in dichloromethane (7.0 mL, 7.0 mmol) according to the procedure and in the same manner as described in Example 47, Step b. The crude product was purified by flash column chromatography on silica gel, eluting with a mixture of ethyl acetate-hexane (1:4), followed by re-crystallization from a mixture of ethyl acetate-hexane (2×), to afford 4-[(6-ethyl-8-fluoro-2-methylphenanthridin-5(6H)-yl)sulfonyl]phenol as a homogeneous solid (0.14 g, 59%), m.p. 197-200° C.;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[N:7]=[C:6]2[C:22](O)=[O:23].Cl.[OH:26][C:27]1[C:36]([O:37][CH3:38])=[CH:35][CH:34]=[C:33]2[C:28]=1[CH2:29][CH2:30][NH:31][CH2:32]2>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1)[N:7]=[C:6]2[C:22]([N:31]1[CH2:30][CH2:29][C:28]2[C:33](=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:27]=2[OH:26])[CH2:32]1)=[O:23]
Reactant: COc1cc2nc(-c3ccc(F)cc3)nc(C(=O)O)c2cc1OC
Reactant: COc1ccc2c(c1O)CCNC2
Agent: Cl
Product: COc1cc2nc(-c3ccc(F)cc3)nc(C(=O)N3CCc4c(ccc(OC)c4O)C3)c2cc1OC
Yield: 18 %

Procedure:
Reaction of 6,7-dimethoxy-2-(4-fluorophenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 109 (18.0% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.67 and 2.92 (2t, 2H), 3.45-4.06 (m, 11H), 4.37 and 4.90 (2s, 2H), 6.27-7.11 (m, 3H), 7.36-7.42 (m, 1H), 7.50-7.65 (m, 2H), 8.12-8.20 (m, 1H), 8.29-8.35 (m, 1H), 8.68 and 8.73 (2s, 1H); MS (ESI) m/z 490 ([M+H]+).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:16][CH2:15][C:14](O[Si](C)(C)C)=[C:13](O[Si](C)(C)C)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:27].Cl.[NH2:29][CH2:30][C:31]([NH2:33])=[NH:32]>>[ClH:27].[ClH:27].[NH2:33][C:31]1[CH:30]=[N:29][C:14]2[CH2:15][CH2:16][N:10]([CH2:9][CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:11][CH2:12][C:13]=2[N:32]=1
Reactant: N=C(N)CN
Reactant: C[Si](C)(C)OC1=C(O[Si](C)(C)C)CCN(CCCc2ccccc2)CC1
Agent: Cl
Product: Nc1cnc2c(n1)CCN(CCCc1ccccc1)CC2

Procedure:
This compound was prepared analogous to Example 22 from 1-(3-phenyl-propyl)-2,3,6,7-tetrahydro-4,5-bis(trimethylsilyloxy)-azepine and α-amino-acetamidine dihydrochloride.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([O:7][C:8]2[C:9]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:10][C:11]([C:18]([OH:20])=[O:19])=[CH:12][C:13]=2[S:14]([NH2:17])(=[O:16])=[O:15])=[CH:5][CH:6]=1.[C:26]([O:32][CH2:33]Cl)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].C(N(CC)CC)C.[I-].[Na+]>CN(C=O)C>[NH2:17][S:14]([C:13]1[CH:12]=[C:11]([CH:10]=[C:9]([N:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)[C:8]=1[O:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)[C:18]([O:20][CH2:33][O:32][C:26]([C:27]([CH3:30])([CH3:29])[CH3:28])=[O:31])=[O:19])(=[O:16])=[O:15]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(N2CCCC2)c1Oc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)OCOC(=O)c1cc(N2CCCC2)c(Oc2ccccc2)c(S(N)(=O)=O)c1

Procedure:
In a similar manner to Example 12, piretanide can be reacted with chloromethyl pivalate, triethylamine and sodium iodide in DMF to yield_t-butylcarbonyloxymethyl 3-aminosulfonyl-4-phenoxy-5-(1-pyrrolidinyl)benzoate.