Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:25](=[O:26])[N:5]2[C:6]([C:22]([O-:24])=[O:23])=[C:7]([CH:10]=[CH:11][CH2:12][N+:13]3[CH:18]=[CH:17][C:16]([C:19](=[O:21])[NH2:20])=[CH:15][CH:14]=3)[CH2:8][S:9][C@H:4]12.Cl.[NH2:28][C:29]1[S:33][N:32]=[C:31]([C:34](=[N:38][O:39][CH:40]2[CH2:44][CH2:43][CH2:42][CH2:41]2)[C:35](Cl)=[O:36])[N:30]=1.C([O-])([O-])=O.[Na+].[Na+].Cl>CC(C)=O>[NH2:28][C:29]1[S:33][N:32]=[C:31]([C:34](=[N:38][O:39][CH:40]2[CH2:44][CH2:43][CH2:42][CH2:41]2)[C:35]([NH:2][CH:3]2[C:25](=[O:26])[N:5]3[C:6]([C:22]([O-:24])=[O:23])=[C:7]([CH:10]=[CH:11][CH2:12][N+:13]4[CH:14]=[CH:15][C:16]([C:19](=[O:21])[NH2:20])=[CH:17][CH:18]=4)[CH2:8][S:9][C@H:4]23)=[O:36])[N:30]=1
Reactant: NC(=O)c1cc[n+](CC=CC2=C(C(=O)[O-])N3C(=O)C(N)[C@H]3SC2)cc1
Reactant: Nc1nc(C(=NOC2CCCC2)C(=O)Cl)ns1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: NC(=O)c1cc[n+](CC=CC2=C(C(=O)[O-])N3C(=O)C(NC(=O)C(=NOC4CCCC4)c4nsc(N)n4)[C@H]3SC2)cc1
Temperature: 10 °C
Reaction time: 1 h
Yield: 59.8 %

Procedure:
To a stirred solution of 139 mg (0.31 mmole) of 7-amino-3-[3-(4-carbamoylpyridinio)-1-propenyl]-3-cephem-4-carboxylate hydrochloride in 3.5 ml of 50% aqueous acetone in an ice-cooling bath was added portionwise 120 mg (0.44 mmole) of 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-cyclopentyloxyiminoacetyl chloride hydrochloride (from Preparation No. 27). The mixture was adjusted to pH 6.5-7.0 with 2N Na2CO3 (0.9 ml) and stirred for 1 hour at 10° C. The reaction mixture was acidified to pH 2 with 1N HCl and evaporated under reduced pressure. The residue was chromatographed on a column of HP-20 resin (20 ml) and was eluted with 300 ml of water and 30% CH3OH-H2O, successively. Fractions containing the product were combined and concentrated in vacuo. The residue was treated with 60 ml of acetone to give 111 mg (83 %) of the title compound I-5H. Mp. 160° C. (dec.). Estimated purity 70%.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6](S(C2C(C)=CC(C)=CC=2C)(=O)=O)[CH:7]=[C:8]([C:10]2[N:15]=[C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:9]=1)=[O:4]>CO.[OH-].[Na+]>[C:17]1([NH:16][C:14]2[N:13]=[CH:12][N:11]=[C:10]([C:8]3[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[NH:6][CH:7]=3)[N:15]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1cc(-c2ncnc(Nc3ccccc3)n2)cn1S(=O)(=O)c1c(C)cc(C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(-c2ncnc(Nc3ccccc3)n2)c[nH]1
Temperature: 80 °C

Procedure:
A 5 mL flask was charged with 4-(4-phenylamino-[1,3,5]triazin-2-yl)- 1 -(2,4,6-trimethyl-benzenesulfonyl)-1H-pyrrole-2-carboxylic acid methyl ester (0.12 mmol, 55 mg) in methanol (2 mL) and sodium hydroxide (0.5 mL, 1 N). The resulting mixture was heated at 80° C. for 5 hours then the solvent was evaporated under vacuum. The crude was dried under high vacuum. HPLC, Rt=4.1 min, FIA, ES+=282.1, ES−=280.2
Reaction SMILES: C(OC([N:11]1[C@H:15]([C:16](=[O:29])[NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=2)[CH2:14][CH2:13][C@@H:12]1[CH2:30][NH:31][C:32](=[O:34])[CH3:33])=O)C1C=CC=CC=1>C1COCC1.[Pd]>[F:27][C:25]([F:26])([F:28])[O:24][C:20]1[CH:19]=[C:18]([NH:17][C:16]([C@@H:15]2[CH2:14][CH2:13][C@H:12]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])[NH:11]2)=[O:29])[CH:23]=[CH:22][CH:21]=1
Reactant: CC(=O)NC[C@H]1CC[C@@H](C(=O)Nc2cccc(OC(F)(F)F)c2)N1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(=O)NC[C@H]1CC[C@@H](C(=O)Nc2cccc(OC(F)(F)F)c2)N1
Reaction time: 5 h

Procedure:
To a solution of (2R,5S)-2-(acetylamino-methyl)-5-(3-trifluoromethoxy-phenylcarbamoyl)-pyrrolidine-1-carboxylic acid benzyl ester (48 mg, 0.1 mmol) in THF (0.3 mL) was added Pd/C (10%, 2.1 mg). The solution was degassed 3 times replacing air by nitrogen and finally nitrogen by hydrogen. The reaction mixture was further stirred under hydrogen atmosphere for 5 h. The catalyst was removed through a pad of Celite and washed with THF. Solvents were concentrated and the resulting residue was used without further purification in the next step. MS (LC/MS): 346 [M+H]+; tR (HPLC conditions b): 2.94 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].CC1C=CC(S(O[CH2:24][CH2:25][Cl:26])(=O)=O)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:24][CH2:25][Cl:26])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)ccc1O
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(Cl)ccc1OCCCl
Temperature: 65 °C
Reaction time: 8 h
Yield: 105.3 %

Procedure:
To a solution of methyl 5-chloro-2-hydroxybenzoate (54.06 g, 0.29 mol) in 300 mL of anhydrous DMF was added 2-chloroethyl 4-methylbenzenesulfonate (81.6 g, 0.35 mol) and Cs2CO3 (142 g, 0.44 mol). The mixture was stirred at 60-70° C. overnight, then water was added. A white solid precipitated from the solution, which was collected by filtration and coevaporated with toluene to afford 76.1 g (88%) of methyl 5-chloro-2-(2-chloroethoxy)benzoate. 1H NMR (400 MHz, CDCl3) δ: 7.76 (d, 1H), 7.40 (dd, 1H), 6.91 (d, 1H), 4.27 (t, 2H), 3.87 (s, 3H), 3.83 (t, 2H).
Reaction SMILES: C([Li])(C)(C)C.CCCCC.[Si:11]([O:18][C:19]1[CH:20]=[C:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:22]=[CH:23][CH:24]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].CN(C)[CH:35]=[O:36]>C(OCC)C>[Si:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH:35]=[O:36])=[C:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:20]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)Nc1cccc(O[Si](C)(C)C(C)(C)C)c1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Nc1cc(O[Si](C)(C)C(C)(C)C)ccc1C=O
Temperature: -40 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyllithium in pentane (1.7 M, 21.8 mL, 37.1 mmol, 2.40 equiv) was added to a solution of tert-butyl 3-{[tert-butyl(dimethyl)silyl]oxy}phenyl carbamate (12-3, 5.00 g, 15.5 mmol, 1 equiv) in ethyl ether (150 mL) at −40° C., and the resulting mixture was stirred at −40° C. for 2 h. N,N-Dimethylformamide (9.57 mL, 124 mmol, 8.00 equiv) was added, and the mixture was then warmed to 0° C. The reaction mixture was partitioned between water (500 mL) and ethyl ether (500 mL). The organic layer was dried over sodium sulfate and concentrated, and the residue was purified by flash column chromatography (hexane, initially, grading to 20% hexane in EtOAc) to give tert-butyl 5-{[tert-butyl(dimethyl)silyl]oxy}-2-formylphenylcarbamate (12-4) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 10.34 (s, 1H), 9.54 (s, 1H), 7.76 (d, 1H, J=1.8 Hz), 7.26 (d, 1H, J=7.8 Hz), 6.35 (dd, 1H, J=7.8, 1.9 Hz), 1.37 (s, 9H), 0.78 (s, 9H), −0.02 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:10][NH:11]C2CCCC2)[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].ClC1N=C(Cl)C([N+]([O-])=O)=CN=1.C(N(CC)CC)C>C(#N)C>[CH3:1][O:2][C:3]([C:5]1([CH2:10][NH2:11])[CH2:6][CH2:7][CH2:8][CH2:9]1)=[O:4]
Reactant: COC(=O)C1(CNC2CCCC2)CCCC1
Agent: O=[N+]([O-])c1cnc(Cl)nc1Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)C1(CN)CCCC1

Procedure:
Methyl1-[(cyclopentylamino)methyl]cyclopentane-1-carboxylate (Intermediate 258; 1.60 g, 7.10 mmol), 2,4-dichloro-5-nitropyrimidine (Aldrich; 1.66 g, 8.52 mmol) and triethylamine (1.2 mL, 8.52 mmol) were stirred in acetonitrile (50 mL) for 4 hours. The reaction mixture was evaporated and the residue dissolved in DCM, washed with water, dried (MgSO4) and evaporated. The residue was purified on a silica column eluting with 1% methanol/DCM to yield the title compound as a yellow oil that crystallised on standing (945 mg, 35%).
Reaction SMILES: [N+]([O-])(O)=O.C[C:6]1[CH:7]=[C:8]2[C:13](=[C:14]([CH3:16])[CH:15]=1)[O:12][C:11](=[O:17])[CH:10]=[C:9]2[OH:18].[CH:19](Cl)(Cl)Cl>>[CH3:19][C:15]1[C:14]([CH3:16])=[C:13]2[C:8]([C:9]([OH:18])=[CH:10][C:11](=[O:17])[O:12]2)=[CH:7][CH:6]=1
Reactant: Cc1cc(C)c2oc(=O)cc(O)c2c1
Reactant: ClC(Cl)Cl
Solvent: O=[N+]([O-])O
Product: Cc1ccc2c(O)cc(=O)oc2c1C
Reaction time: 2 h

Procedure:
Fuming nitric acid (13 ml) was added to a stirred suspension of 6,8-dimethyl-4-hydroxycoumarin (m.p. 253°- 255°; 2.21g) in chloroform (200 ml) at room temperature over 2 hours. After standing for a further 2 hours, the solvent was removed in vacuo at room temperature and 6N hydrochloric acid (50 ml) added to the residue. Filtration and recrystallisation from ethanol gave the product, m.p. 169.5°-170°(d), (C11H9NO5 requires C, 56.18; H, 3.86; N, 5.96. Found; C, 56.22; H, 3.99; N, 5.84).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[C:14]([CH3:18])[C:15](O)=[O:16])=[CH:9][CH:8]=1.C(Cl)(=O)C(Cl)=O.[NH3:28]>ClCCl.CN(C)C=O.C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[C:14]([CH3:18])[C:15]([NH2:28])=[O:16])=[CH:9][CH:8]=1
Reactant: CC(=Cc1ccc(OCc2cccc(F)c2)cc1)C(=O)O
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(=Cc1ccc(OCc2cccc(F)c2)cc1)C(N)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
305 mg (1.07 mmol) of 3-[4-(3-fluoro-benzyloxy)-phenyl]-2-methyl-acrylic acid is dissolved in 8 ml of dichloromethane and one drop of dimethylformamide is added. The solution is cooled to 0° C. and treated dropwise with 676 mg (5.33 mmol) oxalyl chloride. The resulting solution is stirred at 0° C. for additional 30 minutes, then 2 hours at RT. Evaporation of the solvent leaves the crude acid chloride which is dissolved in 5 ml THF. This solution is slowly added under stirring to 10 ml of concentrated ammonia. The precipitate is filtered off and recrystallised from methanol to yield 199 mg (65%) of a colorless solid. MS: m/e=286.2 (M++H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:21]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:20]3[C:11]([C:12]4[CH:13]=[CH:14][C:15]([C:27]([O:29]C)=[O:28])=[N:16][C:17]=4[CH2:18][CH2:19]3)=[N:10]2)=[CH:5][C:4]=1[CH3:31])#[N:2].[OH-].[Na+]>CO.O1CCCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:21]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:20]3[C:11]([C:12]4[CH:13]=[CH:14][C:15]([C:27]([OH:29])=[O:28])=[N:16][C:17]=4[CH2:18][CH2:19]3)=[N:10]2)=[CH:5][C:4]=1[CH3:31])#[N:2]
Reactant: COC(=O)c1ccc2c(n1)CCC1C2=NN(c2ccc(C#N)c(C)c2)C1C1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(N2N=C3c4ccc(C(=O)O)nc4CCC3C2C2CCCC2)ccc1C#N
Temperature: 25 °C
Reaction time: 6 h
Yield: 36 %

Procedure:
In a dried reaction flask, the crude methyl 2-(4-cyano-3-methylphenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-pyrazolo[3,4-f]quinoline-7-carboxylate (0.682 g, about 1.5 mmol) and 10% aqueous NaOH solution (1.97 mL, 4.925 mmol) were dissolved in methanol (3 mL) and tetrahydrofuran (8 mL). The reaction solution was stirred at room temperature for 6 hr. The reaction solution was concentrated at a reduced pressure to reduce the volume to half. The residue was adjusted with 1 M HCl under an ice bath to a pH value of 5-6, and filtered to obtain a crude brick red solid, which was then washed with methanol, ethanol and ethyl acetate to produce a solid (0.216 g) in 36.0% yield.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].O.[OH-].[Li+].CO>C1COCC1.O>[F:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(-c2ccccn2)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(-c2ccccn2)cc1F
Temperature: 60 °C

Procedure:
A solution of methyl 2-fluoro-4-(pyridin-2-yl)benzoate (2.50 g, 11.0 mmol) in a mixture of THF (12 mL) and water was treated with lithium hydroxide monohydrate (0.9 g, 4 mmol) in water (12 mL). Methanol (8 mL) was added until a transparent solution formed. This solution was heated at 60° C. overnight, and the organic solvents were removed under vacuum. The residual aqueous solution was acidified with 2 N HCl to pH=2. Solvents were evaporated under reduced pressure to give 2-fluoro-4-(pyridin-2-yl)benzoic acid as a white solid. LC-MS (ESI) m/z: 218 (M+1)+.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].Cl[S:7]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=[O:14])(=[O:9])=[O:8]>ClCCl>[CH2:1]([N:3]([CH2:4][CH3:5])[S:7]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=[O:14])(=[O:9])=[O:8])[CH3:2]
Reactant: CCNCC
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Solvent: ClCCl
Product: CCN(CC)S(=O)(=O)c1cccc(C(=O)O)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Diethylamine (Aldrich, 2.5 mL, 24 mmol) was added to a solution of 3-(chlorosulfonyl)benzoic acid (Aldrich, 2.0 g, 9.1 mmol) in anhydrous dichloromethane (20 mL) at 0° C. The mixture was then stirred at 0° C. for 2 hours. The volatiles were removed under reduced pressure. The residue was treated with aqueous potassium hydrogensulfate (1 M, 10 mL) and then extracted with ethyl acetate (3×50 mL). The combined extracts were dried over magnesium sulfate filtered and then concentrated to give the title compound. 1H NMR (300 MHz, CD3OD) δ 1.13 (t, J=7.1 Hz, 6H), 3.22-3.30 (m, 4H), 7.69 (t, J=7.8 Hz, 1H), 8.03 (ddd, J=7.9, 1.9, 1.4 Hz, 1H), 8.25 (dt, J=7.8, 1.4 Hz, 1H), 8.40 (t, J=1.7 Hz, 1H) ppm; MS (DCI/NH3) m/z 275 (M+NH4)+.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[O:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O>[Pd].C(OC(=O)C)C>[C:4]1([NH2:1])[C:12]2[C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[O:9][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1cccc2oc3ccccc3c12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cccc2oc3ccccc3c12
Yield: 81.4 %

Procedure:
1-nitrodibenzo[b,d]furan (7.3 g, 34.2 mmol) and 730 mg 10% Pd/C were added to 150 mL ethylacetate and the reaction mixture was hydrogenated at 50 psi. Reaction mixture was then filtered out and concentrated under vacuum. Crude product was purified by flash chromatography over silica gel with 90% DCM/Hexanes. Target compound (5.1 g, 82% yield) was isolated as off white solid.
Reaction SMILES: [C:1]1([CH:7]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:8][CH2:9][O:10][C:11]([C:13]2[CH:14]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=3)[N:15]=[C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[NH:17][C:18]=2[CH2:19][O:20][CH2:21][CH2:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O>C1C=CC=CC=1>[C:42]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9][O:10][C:11]([C:13]2[C:14]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=3)=[N:15][C:16]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[N:17][C:18]=2[CH2:19][O:20][CH2:21][CH2:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:12])[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: O=C(OCCC(c1ccccc1)c1ccccc1)C1=C(COCCC2CCCCC2)NC(c2ccccc2)=NC1c1cccc(Cl)c1
Solvent: O
Solvent: c1ccccc1
Product: O=C(OCCC(c1ccccc1)c1ccccc1)c1c(COCCC2CCCCC2)nc(-c2ccccc2)nc1-c1cccc(Cl)c1

Procedure:
89.8 mg (0.14 mmol) of 4-(3-chlorophenyl)-6-[(2-cyclohexylethoxy) methyl]-2-phenyl-1,4-dihydropyrimidine-5-carboxylic acid 3,3-diphenylpropyl ester and 94.3 mg (0.42 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzochinon (DDQ) were refluxed in 20 ml of benzene for 3 hours. After adding water, the reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=9/1) to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](=[O:17])[CH2:10][CH:11]2[CH2:15][CH2:14][CH2:13][N:12]2[CH3:16])[CH:6]=[CH:7][CH:8]=1.[BH4-].[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([OH:17])[CH2:10][CH:11]2[CH2:15][CH2:14][CH2:13][N:12]2[CH3:16])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C(=O)CC2CCCN2C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cccc(C(O)CC2CCCN2C)c1

Procedure:
50 g of 1-(3-methoxyphenyl)-2-(1-methyl-2-pyrrolidinyl)ethanone are dissolved in 100 ml of methanol and 20 ml of water; thereafter, 4.05 g of sodium borohydride are added portionwise, with stirring. Stirring is continued for a further hour, methanol is largely distilled off, 100 ml of water are added and extraction is effected with methylene chloride. The organic phase is extracted with 400 ml of 10% strength hydrochloric acid, the hydrochloric acid aqueous phase is rendered alkaline with sodium hydroxide solution and the liberated base is extracted with methylene chloride. The organic phase is concentrated and the resulting oily residue is distilled to obtain 47.4 g (94% of theory) of the title compound as a mixture of diastereoisomers of b.p. 128° at 0.001 mm Hg.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]2[NH:8][N:9]=[N:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].C(O)C.[N+]([O-])([O-])=O.[Ag+:20]>O>[Ag:20].[N+:1]([C:4]1[CH:12]=[CH:11][C:7]2[NH:8][N:9]=[N:10][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: O=[N+]([O-])c1ccc2[nH]nnc2c1
Solvent: CCO
Solvent: O
Product: [Ag]
Reaction time: 0.5 h

Procedure:
Solution was prepared by dissolving 18.0 g (0.11 mole) of 5-nitrobenzotriazole into 300 ml of ethanol and whereto a solution prepared by dissolving 16.9 g (0.10 mole) of silver nitrate into 100 ml of water was dropped and the mixture thereof was stirred for 30 minutes. The crystals thus produced were filtrated and were then washed with 100 ml of ethanol, and thus, 26.4 g of 5-nitrobenzotriazole silver were obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.[OH-].[Na+]>C(O)C>[CH3:19][C:15]1[CH:14]=[C:13]([S:10]([C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=2)(=[O:12])=[O:11])[CH:18]=[CH:17][CH:16]=1
Reactant: Cc1cccc(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(S(=O)(=O)c2ccc(N)cc2)c1
Temperature: 0 °C
Yield: 101.1 %

Procedure:
A stirred solution of 3-methylphenyl 4-nitrophenyl sulfone (0.50 g, 1.8 mmol) and stannous chloride dihydrate (2.03 g, 9.0 mmol) in absolute ethanol (5 mL) was heated at reflux for 1 hour. The reaction mixture was poured into ice water and the aqueous solution basified with 15% NaOH and extracted with ethyl acetate (2×100 mL). The combined organic extracts were dried (MgSO4), filtered, and the solvent removed in vacuo to yield an off-white solid. Recrystallization from absolute ethanol/hexane yielded the title benzenamine (0.45 g, 100%) as a white solid; mp 183°-185° C. 1H-NMR (300 MHz, d6 -DMSO): 2.36 (s, 3H, CH3), 6.17 (s, 2H, NH2), 6.61 (dd, 2H, J=7.0, 1.8 Hz, aromatic), 7.43 (d, 2H, J=7.1Hz, aromatic), 7.54 (d, 2H, J=8.7 Hz, aromatic), 7.63 (m, 2H, aromatic). MS (CI, CH4): 248(M+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[NH:21]1[C:29]2[C:24](=[CH:25][C:26](B(O)O)=[CH:27][CH:28]=2)[CH:23]=[CH:22]1>>[CH:13]1([C:9]2[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6](=[O:20])[N:5]3[C:10]=2[C:11]([CH3:12])=[C:2]([C:26]2[CH:25]=[C:24]4[C:29](=[CH:28][CH:27]=2)[NH:21][CH:22]=[CH:23]4)[CH:3]=[CH:4]3)[CH2:15][CH2:14]1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc4[nH]ccc4c3)ccn2c1=O
Yield: 47.4 %

Procedure:
Methyl 1-cyclopropyl-8-(1H-indol-5-yl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and 1H-indol-5-yl-boronic acid (83 mg, 0.51 mmol) to afford the title compound as a yellow solid (60 mg, 47%). ESI-MS m/z: 373 (M+H)+.
Reaction SMILES: O[CH2:2][C:3]1[N:7]([C:8]2[CH:9]=[C:10]([C:14]3[CH2:20][C:19](=[O:21])[NH:18][C:17]4[CH:22]=[C:23]([C:32]([F:35])([F:34])[F:33])[C:24]([N:26]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH3:27])=[CH:25][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[N:6]=[N:5][CH:4]=1.S(Cl)(Cl)=O.[Cl-].[NH:41]1[CH2:45][CH2:44][CH2:43][CH2:42]1>ClCCl.CN(C=O)C>[CH2:28]([N:26]([CH3:27])[C:24]1[C:23]([C:32]([F:33])([F:34])[F:35])=[CH:22][C:17]2[NH:18][C:19](=[O:21])[CH2:20][C:14]([C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([N:7]4[C:3]([CH2:2][N:41]5[CH2:45][CH2:44][CH2:43][CH2:42]5)=[CH:4][N:5]=[N:6]4)[CH:9]=3)=[N:15][C:16]=2[CH:25]=1)[CH:29]([CH3:30])[CH3:31]
Reactant: C1CCNC1
Reactant: CC(C)CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CC(C)CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CN3CCCC3)c1)=N2

Procedure:
The title compound was prepared from 4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-7-(isobutyl-methyl-amino)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 117) (300 mg, 0.62 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with pyrrolidine in DMF according to the method described in Example 45. Obtained as a light orange foam (80 mg, 24%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[S:13][C:12]([CH3:14])=[N:11][C:10]=2[C:15]([OH:17])=O)[CH:5]=[CH:6][C:7]=1[CH3:8].[NH:18]1[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24][C:25]([C:27]2[N:34]3[C:30]([S:31][CH:32]=[CH:33]3)=[N:29][C:28]=2[CH3:35])=[O:26])[CH2:19]1>>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[S:13][C:12]([CH3:14])=[N:11][C:10]=2[C:15]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24][C:25]([C:27]3[N:34]4[C:30]([S:31][CH:32]=[CH:33]4)=[N:29][C:28]=3[CH3:35])=[O:26])[CH2:19]2)=[O:17])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1nc(C(=O)O)c(-c2ccc(C)c(C)c2)s1
Reactant: Cc1nc2sccn2c1C(=O)N[C@@H]1CCCNC1
Product: Cc1nc(C(=O)N2CCC[C@@H](NC(=O)c3c(C)nc4sccn34)C2)c(-c2ccc(C)c(C)c2)s1

Procedure:
prepared by reaction of 5-(3,4-dimethyl-phenyl)-2-methyl-thiazole-4-carboxylic acid with (R)-6-methyl-imidazo[2,1-b]-thiazole-5-carboxylic acid-piperidin-3-ylamide.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:13])[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])([O-:3])=[O:2].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:14]([O:13][C:6]1[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A stirred solution of 3,4-dinitrophenol (1 g) in dimethylformamide (30 mL) was treated with benzyl bromide (723 μL) and potassium carbonate (1.13 g). The reaction mixture was stirred at ambient temperature for 24 hours and then partitioned between ethyl acetate and water. The organic layer was washed with brine, then dried over magnesium sulfate and then evaporated. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and hexane (1:4, v/v) to give 4-benzyloxy-1,2-dinitrobenzene (1.30 g) as a yellow solid. LC-MS (METHOD B): RT=3.31 minutes. 1H NMR [(CD3)2CO, ppm): δ 5.28 (s, 2H), 7.26-7.42 (m, 6H), 7.57 (d, 1H), 8.12 (d, 1H). (b) 1-Ethyl-2-methoxy-benzene