Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]3[N:28]=[C:27]([C:29]([OH:31])=[O:30])[C:26]([O:32][CH2:33][CH2:34][O:35][C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([NH:42]C(OC(C)(C)C)=O)[CH:37]=4)=[CH:25][CH:24]=3)[CH:21]=2)[CH2:16][CH2:15][CH2:14]1)=[O:12]>CS(C)=O>[NH2:42][C:38]1[CH:37]=[C:36]([CH:41]=[CH:40][CH:39]=1)[O:35][CH2:34][CH2:33][O:32][C:26]1[C:27]([C:29]([OH:31])=[O:30])=[N:28][C:23]([C:20]2[CH:21]=[C:22]3[C:17]([CH2:16][CH2:15][CH2:14][N:13]3[C:11](=[O:12])[NH:10][C:2]3[S:1][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=3)=[CH:18][CH:19]=2)=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(OCCOc2ccc(-c3ccc4c(c3)N(C(=O)Nc3nc5ccccc5s3)CCC4)nc2C(=O)O)c1
Solvent: CS(C)=O
Product: Nc1cccc(OCCOc2ccc(-c3ccc4c(c3)N(C(=O)Nc3nc5ccccc5s3)CCC4)nc2C(=O)O)c1

Procedure:
The title compound 3-(2-(3-aminophenoxy)ethoxy)-6-(1-(benzo[d]thiazol-2-ylcarbamoyl)-1,2,3,4-tetrahydroquinolin-7-yl)picolinic acid (42) was prepared by the following procedure: compound 3-(2-(3-aminophenoxy)ethoxy)-6-(1-(benzo[d]thiazol-2-ylcarbamoyl)-1,2,3,4-tetrahydroquinolin-7-yl)picolinic acid (42) was prepared following a similar procedure as that described in example 34, except 6-(1-(Benzo[d]thiazol-2-ylcarbamoyl)-1,2,3,4-tetrahydroquinolin-7-yl)-3-(2-(3-(tert-butoxycarbonylamino)phenoxy)ethoxy)picolinic acid (42G) was used instead of 6-(1-(Benzo[d]thiazol-2-ylcarbamoyl)-1,2,3,4-tetrahydroquinolin-7-yl)-3-(3-((3-(tert-butoxycarbonylamino)phenoxy)methyl)phenyl)picolinic acid (34E) in step 6 of example 34. 1H NMR (300 MHz, DMSO)S 8.29 (1H, s), 7.97 (1H, d), 7.81 (1H, d), 7.77 (1H, d), 7.68 (1H, dd), 7.46 (1H, m, br), 7.37 (1H, dt), 7.29-7.12 (3H, m), 6.61-6.50 (3H, m), 4.47 (2H, t), 4.28 (2H, t), 3.94 (2H, t), 2.81 (2H, t), 1.94 (2H, m). MS (ESI(+)): m/z 582.1 (M+H).
Reaction SMILES: [C:1]([CH:4]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[C:5]1=O)(=O)[NH2:2]>C1COCC1>[NH2:2][CH2:1][CH:4]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[CH2:5]1
Reactant: NC(=O)C1CCN(Cc2ccc(Cl)cc2)C1=O
Solvent: C1CCOC1
Product: NCC1CCN(Cc2ccc(Cl)cc2)C1
Temperature: 65 °C
Reaction time: 15 h
Yield: 66.7 %

Procedure:
To a solution of 3-carbamoyl-1-(4-chlorobenzyl)pyrrolidin-2-one (1.45 g) in THF (15 mL) was added 1.0 N BH3 in THF (25 mL). The reaction mixture was stirred at 65° C. for 15 h. After cooling to room temperature, the solvent was removed under reduced pressure. Water (30 mL) and conc. HCl (10 mL) were added and the mixture was stirred at 100° C. for 2 h and room temperature for 1 h. 2 N NaOH aqueous solution (100 mL) was added and the mixture was extracted with AcOEt (50 mL×3). The combined organic layers were dried over K2C3, filtered and concentrated. Column chromatography (SiO2, 15% CH3OH-5% Et3N in CH2Cl2) afforded 3-(aminomethyl)-1-(4-chlorobenzyl)pyrrolidine (860 mg, 19%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:3]2[C@H:10]([CH3:11])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:12][C@@H:13]1[NH:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1.C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1.C(OCC)(=O)C>[CH3:12][C@@H:13]1[N:18]([C:2]2[C:3]3[C@H:10]([CH3:11])[CH2:9][CH2:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:14]1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: C[C@@H]1CCc2ncnc(Cl)c21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: C[C@@H]1CCc2ncnc(N3CCN(C(=O)OC(C)(C)C)C[C@@H]3C)c21
Temperature: 100 °C
Yield: 18.6 %

Procedure:
To a solution of (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (0.5 g, 3.0 mmol) in NMP (5 mL) were added (S)-tert-butyl 3-methylpiperazine-1-carboxylate (0.59 g, 3 mmol) and diisopropylethylamine (0.52 mL). The mixture was heated to 100° C. for 6 hours. The mixture was cooled and diluted with ethyl acetate (200 mL) and washed with water (6×100 mL). The organic phase was dried and concentrated. The residue was purified by silica gel chromatography, eluting with Hexane/ethyl acetate (1:1) to give (S)-tert-butyl 3-methyl-4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (0.186 g, 19%). 1H NMR (CDCl3, 400 MHz) δ 8.46 (s, 1H), 4.66 (m, 1H), 4.30-3.80 (m, 3H), 3.47 (m, 1H), 3.20 (m, 1H), 3.20-2.80 (m, 4H), 2.22 (m, 1H), 1.70 (m, 1H), 1.49 (s, 9H), 1.29 (m, 3H), 1.17 (m, 3H). MS (APCI+) [M+H] +333.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[N+:14]([O-])=O)C.[H][H]>[Pd].CO>[F:13][C:11]1[CH:12]=[C:7]2[C:8](=[CH:9][CH:10]=1)[NH:14][C:4](=[O:3])[CH2:5][NH:6]2
Reactant: CCOC(=O)CNc1cc(F)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C1CNc2cc(F)ccc2N1

Procedure:
A mixture of N-(5-fluoro-2-nitrophenyl)glycine ethyl ester (XI, EXAMPLE 5, 28.60 g), palladium on carbon (10%, 1.01 g) and methanol (500 ml) is shaken under 45 psi of hydrogen on a Parr shaker. After 2 hr an additional 0.54 g of 10% palladium on carbon catalyst is added. The mixture is shaken for an hour at 42 psi and then the catalyst is removed by filtration. p-Toluenesulfonic acid (0.314 g) is added to the filtrate. The solution is concentrated under reduced pressure to a volume of about 250 ml and then stirred at 20°-25°. The reaction is then further concentrated and dichloromethane is added. The solid that formed is collected and chromatographed on 800 ml of silica gel (column) eluting with dichloromethane/methanol (98/2). The appropriate fractions are pooled and concentrated and triturated with a small amount of dichloromethane. The solid is collected, dried, and triturated a second time with dichloromethane and redried to give the title compound, mp 176.0°-177.5°; NMR (CDCl3) 3.95, 3.99, 6.42, 6.63 and 8.33 δ.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([NH2:12])[C:8]([NH2:11])=[CH:9][CH:10]=1.[C:13](OCC)(=[O:19])[C:14](OCC)=[O:15].CCN(CC)CC>>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:8](=[CH:9][CH:10]=1)[N:11]=[C:14]([OH:15])[C:13]([OH:19])=[N:12]2
Reactant: COc1ccc(N)c(N)c1
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Solvent: CCN(CC)CC
Product: COc1ccc2nc(O)c(O)nc2c1
Temperature: 150 °C
Yield: 69 %

Procedure:
A suspension of 4-methoxybenzene-1,2-diamine dihydrochloride in diethyl oxalate (8 eq) was treated with Et3N (2 eq) and then heated at 150° C. for 2 h. The mixture was cooled and filtered, and then the collected solid was washed with H2O and EtOH. The residue was dried to give the title compound (69%). MS (ES+) m/z 193 (M+H)+
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.[C:13](=O)([O:19]C(C)(C)C)[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].[OH-].[Na+]>C1COCC1>[C:13]([NH:8][C:7]1[CH:9]=[CH:10][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:5][CH:6]=1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:19]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
4-Trifluoromethoxyaniline (100 g, 0.58 mol), di-tert-butyl carbonate (127 g, 0.58 mol) and 1 N NaOH solution (250 mL) are dissolved in THF (200 mL) and stirred at room temperature for 12 hours. The reaction mixture is extracted with EtOAc (500 mL). The organic layer is washed with 1 N HCl (500 mL), brine (250 mL) and dried (MgSO4). The solvent is removed by rotary evaporator to give N-BOC-4-trifluoromethoxyaniline.
Reaction SMILES: [CH2:1]([C:5]1[C:9](/[CH:10]=[CH:11]/[C:12]2[S:13][C:14]([C:18]([OH:20])=O)=[C:15]([CH3:17])[N:16]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[NH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[N:23]1([NH:22][C:18]([C:14]2[S:13][C:12](/[CH:11]=[CH:10]/[C:9]3[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=3[CH3:21])=[N:16][C:15]=2[CH3:17])=[O:20])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)O)s1
Reactant: NN1CCOCC1
Product: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)NN2CCOCC2)s1
Yield: 37 %

Procedure:
As described for example 102, 2-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-4-methyl-thiazole-5-carboxylic acid (90 mg, 0.29 mmol) was converted, using 4-aminomorpholine instead of 1,1-dimethylhydrazine, to the title compound (43 mg, 37%) which was obtained as an off white solid. MS: m/e=391.3 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])=[CH:10][C:9]=1[N+:21]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Ni]>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccccc1-c1ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Agent: [Ni]
Product: Cc1ccccc1-c1ccc(NC(=O)OC(C)(C)C)c(N)c1

Procedure:
Prepared from (2′-methyl-3-nitro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example C9) by catalytic hydrogenation with Raney-Ni according to the general procedure G (method a). Obtained as a white powder (281 mg).
Reaction SMILES: [BH4-].[Li+].Cl[Si](C)(C)C.[CH3:8][O:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1/[CH:20]=[CH:21]/[N+:22]([O-])=O>C1COCC1>[CH3:8][O:9][C:10]1[CH:15]=[C:14]([C:16]([F:17])([F:19])[F:18])[CH:13]=[CH:12][C:11]=1[CH2:20][CH2:21][NH2:22]
Reactant: COc1cc(C(F)(F)F)ccc1/C=C/[N+](=O)[O-]
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(C(F)(F)F)ccc1CCN
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 95.4 %

Procedure:
A portion of lithium borohydride (0.458 g, 21.0 mmol) was diluted with THF (30 mL) followed by the dropwise addition of chlorotrimethylsilane (5.34 ml, 42.1 mmol). After stirring for 15 minutes, argon was bubbled through the reaction mixture for 2 minutes to eliminate trimethylsilane present in the reaction. (E)-2-methoxy-1-(2-nitrovinyl)-4-(trifluoromethyl)benzene (1.3 g, 5.26 mmol) was added portionwise (gas evolution occurred). The reaction was heated to reflux for 2 hours, cooled to 0° C. and carefully quenched with methanol (8 mL). The reaction mixture was concentrated, diluted with dichloromethane and 20% aqueous KOH. The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated to yield 2-(2-methoxy-4-(trifluoromethyl)phenyl)ethanamine (1.1 g, 5.02 mmol, 95.4% yield).
Reaction SMILES: B(F)(F)F.CC[O:7][CH2:8][CH3:9].NC1[CH:12]=[C:13](C)[C:14]([Cl:17])=[N:15][CH:16]=1.N(OC(C)(C)C)=O.CCCCC>COCCOC>[Cl:17][C:14]1[C:13]([CH3:12])=[CH:9][C:8]([OH:7])=[CH:16][N:15]=1
Reactant: Cc1cc(N)cnc1Cl
Reactant: CCOCC
Agent: CC(C)(C)ON=O
Agent: FB(F)F
Solvent: CCCCC
Solvent: COCCOC
Product: Cc1cc(O)cnc1Cl
Reaction time: 0.25 h
Yield: 151.6 %

Procedure:
To a solution of boron trifluoride diethyl etherate (5.8 mL, 47.5 mmol) in DME (18 mL) at −14° C. was added dropwise a solution of 5-amino-2-chloro-3-methylpyridine (4.5 g, 31.7 mmol) in DME (60 mL). The mixture was stirred for 15 minutes and then a solution of t-butyl nitrite (4.5 mL, 38 mmol) in DME (60 mL) was added dropwise. The mixture was stirred for 1 hour at 0° C., then pentane (100 mL) was added to give a solid. The solid was collected by filtration and dried to give the title compound (6.9 g): 1H NMR (MeOH-d4, 300 MHz) δ2.58 (s, 3H), 8.86 (d, J=2.1 Hz, 1H), 9.41 (d, J=2.4 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:3]=1[C:4]([NH:6][C:7]1[CH:34]=[CH:33][C:10]([C:11]([N:13]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[C:17]3=[N:24][N:25]([CH2:27][C:28]([O:30]CC)=[O:29])[CH:26]=[C:16]3[CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=1)=[O:5].O1CCCC1.[OH-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:3]=1[C:4]([NH:6][C:7]1[CH:34]=[CH:33][C:10]([C:11]([N:13]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[C:17]3=[N:24][N:25]([CH2:27][C:28]([OH:30])=[O:29])[CH:26]=[C:16]3[CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=1)=[O:5]
Reactant: CCOC(=O)Cn1cc2c(n1)-c1ccccc1N(C(=O)c1ccc(NC(=O)c3ccc(Cl)cc3Cl)cc1)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)Cn1cc2c(n1)-c1ccccc1N(C(=O)c1ccc(NC(=O)c3ccc(Cl)cc3Cl)cc1)CC2
Temperature: 25 °C
Reaction time: 6 h
Yield: 0.1 %

Procedure:
To a stirred slurry of 0.477 g of 6-[4-[(2,4-dichlorobenzoyl)amino]benzoyl]-5,6-dihydropyrazolo[4,3-d][1]benzazepine-2(4H)-acetic acid, ethyl ester in 15 ml of ethyl alcohol is added 5 ml of tetrahydrofuran followed by 1.30 ml of 1M NaOH. The reaction mixture is stirred at room temperature for 6 hours followed by the addition of 0.750 ml of 2M HCl. The acidic reaction mixture is evaporated in vacuo, triturated with CHCl3, combined, treated with activated carbon, filtered through MgSO4 and evaporated in vacuo to give 0.380 mg of the desired product as a clear foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:10]O)=[O:9])[CH:3]=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[C:8]([OH:10])=[O:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: O=C(O)c1cccc(Cl)c1

Procedure:
Compounds of Formula Ib wherein R4 =R9SO can be prepared from the appropriate compounds of Formula Ia wherein R4 =R9S by oxidation with m-chloroperbenzoic acid as shown in Equation 10. The reaction can be carried out by stirring equivalent amounts of Ia with m-chloroperbenzoic acid (MCPBA) in an inert solvent such as chloroform at 0° to reflux for 12-24 hours. The insoluble m-chlorobenzoic acid produced is removed by filtration and the chloroform solution is concentrated to yield the crude product. Purification by standard techniques will give the desired product. Oxidation of Ia with one equivalent of hydrogen peroxide in acetic acid at room temperature will also give the sulfoxides Ib. ##STR24##
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]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([C:26](O)=[O:27])=[CH:21][CH:20]=[CH:19]2.[NH2:29][CH2:30][C:31]1[CH:32]=[C:33]([CH:44]=[CH:45][CH:46]=1)[C:34]([NH:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[NH2:43])=[O:35]>>[NH2:43][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[NH:36][C:34]([C:33]1[CH:32]=[C:31]([CH:46]=[CH:45][CH:44]=1)[CH2:30][NH:29][C:26]([C:22]1[C:23]2[C:18](=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)=[CH:25][CH:24]=2)[CH:19]=[CH:20][CH:21]=1)=[O:27])=[O:35]
Reactant: NCc1cccc(C(=O)Nc2ccccc2N)c1
Reactant: COc1cc2ncnc(Oc3ccc4c(C(=O)O)cccc4c3)c2cc1OC
Product: COc1cc2ncnc(Oc3ccc4c(C(=O)NCc5cccc(C(=O)Nc6ccccc6N)c5)cccc4c3)c2cc1OC
Yield: 80.9 %

Procedure:
The title compound (48.5 mg, 81% yield) was prepared as a brown solid from 6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naphthoic acid (37.6 mg, 0.1 mmol) and 3-(aminomethyl)-N-(2-aminophenyl)benzamide (28.9 mg, 0.12 mmol) by an analogous procedure to that described in example 16. LC-MS (m/z) 600 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:12]=[N:13][N:14]([CH2:16][CH2:17][CH2:18][O:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][O:21]3)[CH:15]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl[C:29]([O:31][CH2:32][C:33]([Cl:36])([Cl:35])[Cl:34])=[O:30]>O.CCOC(C)=O>[Cl:34][C:33]([Cl:36])([Cl:35])[CH2:32][O:31][C:29](=[O:30])[NH:10][C:8]1[N:7]([C:11]2[CH:12]=[N:13][N:14]([CH2:16][CH2:17][CH2:18][O:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][O:21]3)[CH:15]=2)[N:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:9]=1
Reactant: CC(C)(C)c1cc(N)n(-c2cnn(CCCOC3CCCCO3)c2)n1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cnn(CCCOC3CCCCO3)c2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.5 %

Procedure:
To a stirred mixture of Intermediate 113b (1.14 g, 3.28 mmol) in water (6 mL) and EtOAc (12 mL) was added NaOH (263 mg, 6.57 mmol). After 10 min, 2,2,2-trichloroethyl chloroformate (543 μL, 3.94 mmol) was added and the reaction mixture was stirred at RT for 1 h. The aqueous layer was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-100% EtOAc in cyclohexane, to afford the title compound (1.57 g, 91%). LCMS (Method 4): Rt 3.99 min, m/z 522, 524 [MH+].
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[S:6][C@@H:5]2[C@H:7]([NH:10]C(CC3C=CC=CC=3)=O)[C:8](=[O:9])[N:4]2[C@H:3]1[C:20]([O-:22])=[O:21].[K+].CN(C)C1C=CC=CC=1.Cl[Si](Cl)(C)C.P(Cl)(Cl)(Cl)(Cl)Cl.C(N)(=S)C.ClC(Cl)(Cl)SCl.N.O.N>ClCCl.O.CO>[CH3:1][C:2]1([CH3:23])[S:6][C@@H:5]2[C@H:7]([NH2:10])[C:8](=[O:9])[N:4]2[C@H:3]1[C:20]([OH:22])=[O:21]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)[O-]
Agent: CC(N)=S
Agent: C[Si](C)(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Solvent: O
Product: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Temperature: 25 °C

Procedure:
In dichloromethane (25 volume parts) was suspended potassium salt of benzylpenicillin (6.0 parts) and to the suspension, under stirring at room temperature, N,N-dimethylaniline (5.2 volume parts) and dichlorodimethylsilane (1.6 volume parts) were added in succession and, the mixture was stirred for 30 minutes. Then, the mixture was chilled to -30° C and phosphorus pentachloride (3.6 parts) was added, followed by stirring for 2 hours at -30° C. Then, to the resultant thioacetamide (1.5 parts) was added and the mixture was further stirred at -40 to -25° C for 1.5 hours. Then, under stirring at -40° C, to the mixture methanol (20 volume parts) was added drop by drop in such a manner that the temperature of -30° C was not exceeded, followed by the addition of trichloromethanesulfenyl chloride (2.3 volume parts). The mixture was stirred for 30 minutes. Under stirring at -30° C to the mixture water (5 volume parts) was added and, then, to the mixture concentrated aqueous ammonia (20 volume parts) was slowly added dropwise. Then, on an icewater bath, the resultant was adjusted to pH 4.1 with ammonia water, followed by stirring for 1 hour. The resultant precipitate was recovered by filtration, washed with 50% methanol and dichloromethane and dried. The procedure yielded 6-aminopenicillanic acid (2.2 part). In IR spectrum, this product was found in good agreement with an authentic sample.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=4)([C:20]4[N:24]([CH3:25])[C:23](SC)=[N:22][N:21]=4)[NH2:19])[CH:16]=3)[N:11]3[N:35]=[N:36][N:37]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1>[Ni].CC(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=4)([C:20]4[N:24]([CH3:25])[CH:23]=[N:22][N:21]=4)[NH2:19])[CH:16]=3)[N:11]3[N:35]=[N:36][N:37]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CSc1nnc(C(N)(c2ccc(Cl)cc2)c2ccc3c(c2)c(-c2cccc(Cl)c2)nc2nnnn23)n1C
Agent: [Ni]
Solvent: CC(C)=O
Product: Cn1cnnc1C(N)(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)nc1nnnn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18.2 %

Procedure:
Raney nickel (6.5 g) was added to a solution of 5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-[4-methyl-5-(methylthio)-4H-1,2,4-triazol-3-yl)-tetrazolo[1,5-a]quinazoline-7-methanamine (0.0012 mol) in 2-propanone (30 ml) under N2 flow. The mixture was stirred at room temperature for 1 hour and 30 minutes, filtered over celite and rinsed with CH2Cl2/CH3OH. The solvent was evaporated. The residue was taken up in DCM. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (0.4 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH; 96/4/0.5; 15–35 μm). The pure fractions were collected and the solvent was evaporated The residue was crystallized from CH3CN/diethyl ether. The precipitate was filtered off and dried, yielding 0.11 g (18%) of 5-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(4-methyl-4H-1,2,4-triazol-3-yl)-tetrazolo[1,5-a]quinazoline-7-methanamine, mp. 220° C.
Reaction SMILES: CO[C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[O:23]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24]1>>[CH2:18]([C:13]1[C:12]([CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH:28][CH:25]3[CH2:26][CH2:27][O:23][CH2:24]3)=[O:22])=[CH:5][N:6]=2)=[C:16]([CH3:17])[O:15][N:14]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)OC)cn1
Reactant: NC1CCOC1
Product: CCCCc1noc(C)c1COc1ccc(C(=O)NC2CCOC2)cn1
Yield: 68 %

Procedure:
As described for example 5d, 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (150 mg, 0.49 mmol) was converted, using tetrahydrofuran-3-amine instead of isopropylamine, to the title compound (120 mg, 68%) which was obtained as a white solid after purification by chromatography (silica, 0 to 5% methanol in dichloromethane). MS: m/e=360.4 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][NH:9][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]=[C:12]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][C:28]([F:31])([F:30])[F:29])[N:11]=2)[CH2:4][CH2:3]1.ClC(Cl)(Cl)S(O[CH2:38][C:39]([F:42])([F:41])[F:40])(=O)=O>CC#N>[N+:16]([C:15]1[C:10]([NH:9][CH2:8][C@H:5]2[CH2:4][CH2:3][C@H:2]([NH:1][CH2:38][C:39]([F:42])([F:41])[F:40])[CH2:7][CH2:6]2)=[N:11][C:12]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][C:28]([F:30])([F:31])[F:29])=[N:13][CH:14]=1)([O-:18])=[O:17]
Reactant: O=S(=O)(OCC(F)(F)F)C(Cl)(Cl)Cl
Reactant: N[C@H]1CC[C@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Solvent: CC#N
Product: O=[N+]([O-])c1cnc(NCc2ccccc2OC(F)(F)F)nc1NC[C@H]1CC[C@H](NCC(F)(F)F)CC1
Temperature: 0 °C

Procedure:
N4-[(trans-4-aminocyclohexyl)methyl]-5-nitro-N2-[2-(trifluoromethoxy)benzyl]pyrimidine-2,4-diamine (200 mg, 0.45 mmol) was suspended in CH3CN (4 mL) and cooled to 0° C. 2,2,2-Trifluoroethyl trichloromethanesulphonate (66 mg, 0.23 mmol) in CH3CN (1 mL) was added dropwise to the reaction mixture and the reaction mixture was heated to 90° C. for 5 h. The reaction mixture was concentrated and the resulting residue was diluted with ethyl acetate. The solution was treated with 1M Na2CO3 and the organic phase was separated. The aqueous phase was re-extracted with CH2Cl2. The combined organic phase was dried over Na2SO4 and concentrated. Silica gel prep TLC using 98:2 CH2Cl2:MeOH, then 7:3 Hexanes:ethyl acetate afforded 74 mg of the title compound, m/z 523.0 [M+1]+.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].O[CH:5]=[C:6]1[C:10]([CH3:12])([CH3:11])[O:9][C:8]([CH3:14])([CH3:13])[C:7]1=[O:15]>C(Cl)(Cl)Cl>[CH3:13][C:8]1([CH3:14])[C:7](=[O:15])[C:6](=[CH:5][NH:3][CH2:1][CH3:2])[C:10]([CH3:12])([CH3:11])[O:9]1
Reactant: CCN
Reactant: CC1(C)OC(C)(C)C(=CO)C1=O
Solvent: ClC(Cl)Cl
Product: CCNC=C1C(=O)C(C)(C)OC1(C)C
Yield: 65 %

Procedure:
Ethylamine gas was bubbled through a solution of 4-hydroxymethylene-dihydro-2,2,5,5-tetramethyl-3(2H)furanone (4.0 g, 24 mmol) in 50 mL of chloroform at room temperature for 15 min. The solvents were evaporated and the residue was recrystallized from hexanes to give 3.0 g (65%) of dihydro-2,2,5,5-tetramethyl-4-ethylaminomethylene-3(2H)furanone as a light brown solid.