Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[C:6](O)=[N:7][C:8]([S:11][CH3:12])=[N:9][CH:10]=1.O=P(Cl)(Cl)[Cl:21].CC(=O)OCC>[N+](C)(C)(C)C.[Cl-].CC#N>[Cl:21][C:6]1[C:5]([O:4][C:3]2[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:2]=2[F:1])=[CH:10][N:9]=[C:8]([S:11][CH3:12])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1ncc(Oc2ccc(F)cc2F)c(O)n1
Agent: C[N+](C)(C)C
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CSc1ncc(Oc2ccc(F)cc2F)c(Cl)n1
Temperature: 0 °C
Yield: 70.6 %

Procedure:
The title compound of step 1 (5.30 g, 19.63 mmol), POCl3 (18.06 g, 117.78 mmol), (Me)4NCl (3.23 g, 29.47 mmol) in dry CH3CN (60 mL) was refluxed for 12 h. The mixture was poured into ice-water (50 mL) and subjected to EA extractive work up. Concentration under vacuum gave impure title compound (4.0 g), which was carried on to the next step.
Reaction SMILES: C([O:4][C@H:5]1[C:14]2[N:13]=[C:12]([CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:11]3[C@@H:21]([C:28]4[CH:33]=[CH:32][C:31]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:30][CH:29]=4)[O:22][C:23]4([CH2:27][CH2:26][CH2:25][CH2:24]4)[C:10]=3[C:9]=2[C@@H:8]([O:38][Si](C(C)(C)C)(C)C)[CH2:7][C:6]1([CH3:47])[CH3:46])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)C>[C:34]([C:31]1[CH:32]=[CH:33][C:28]([C@@H:21]2[C:11]3[C:12]([CH:15]4[CH2:16][CH2:17][O:18][CH2:19][CH2:20]4)=[N:13][C:14]4[C@H:5]([OH:4])[C:6]([CH3:47])([CH3:46])[CH2:7][C@H:8]([OH:38])[C:9]=4[C:10]=3[C:23]3([CH2:24][CH2:25][CH2:26][CH2:27]3)[O:22]2)=[CH:29][CH:30]=1)([CH3:35])([CH3:36])[CH3:37]
Reactant: CC(=O)O[C@H]1c2nc(C3CCOCC3)c3c(c2[C@@H](O[Si](C)(C)C(C)(C)C)CC1(C)C)C1(CCCC1)O[C@@H]3c1ccc(C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CO
Product: CC(C)(C)c1ccc([C@H]2OC3(CCCC3)c3c2c(C2CCOCC2)nc2c3[C@@H](O)CC(C)(C)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
17 mg (3′R,6′R,9′S)-9′-(tert-butyldimethylsilyloxy)-3′-(4-tert-butylphenyl)-7′,7′-dimethyl-4′-(tetrahydro-2H-pyran-4-yl)-6′,7′,8′,9′-tetrahydro-3′H-spiro[cyclopentane-1,1′-furo[3,4-c]quinoline]-6′-yl acetate are dissolved in 1 ml methanol and treated with 200 mg potassium carbonate. The mixture is stirred for 36 hours at room temperature, diluted with diethylether and washed with water and saturated aqueous sodium bicarbonate. The organic phase is dried with magnesium sulphate and the solvent is evaporated in vacuo. The residue is chromatographed on silica gel (petrole ether/ethylacetate 80:20 to 40:60).
Reaction SMILES: OOS([O-])=O.[K+].[C:7]([C:11]1[N:16]=[CH:15][C:14]([CH:17]=O)=[CH:13][N:12]=1)([CH3:10])([CH3:9])[CH3:8].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH2:26].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[C:7]([C:11]1[N:16]=[CH:15][C:14]([C:17]2[NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:26]=2)=[CH:13][N:12]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)c1ncc(C=O)cn1
Reactant: Nc1ccccc1N
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ncc(-c2nc3ccccc3[nH]2)cn1
Reaction time: 0.25 h

Procedure:
16.9 g (55 mmol) of oxone [70693-62-8] are added in portions with stirring at 10° C. to a solution of 16.4 g (100 mmol) of 2-tert-butylpyrimidine-5-carboxaldehyde [104461-06-5] and 11.9 g (110 mmol) of 1,2-diaminobenzene in a mixture of 100 ml of DMF and 3 ml of water, and the mixture is subsequently stirred at room temperature until conversion of the aldehyde is complete (about 2 h). The reaction mixture is stirred into a solution of 40 g of potassium carbonate solution in 2000 ml of water, stirred for a further 15 min., the solid formed is filtered off with suction, washed three times with 100 ml of water each time and dried in vacuo. The solid is dissolved in about 50 ml of hot ethyl acetate, and, during cooling, diethyl ether is added until slightly cloudy, the mixture is stirred for a further 12 h, the crystals are filtered off with suction, washed once with 50 ml of diethyl ether and dried in vacuo. Yield: 16.6 g (66 mmol), 66%. Purity: >95% according to 1H-NMR.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([CH2:12][C:13]([NH:15][C:16]2[S:20][C:19]3[CH2:21][CH2:22][CH2:23][CH2:24][C:18]=3[C:17]=2C(O)=O)=[O:14])[N:4]=1.Cl>N1C2C(=CC=CC=2)C=CC=1.O.[Cu]>[S:20]1[C:16]([NH:15][C:13](=[O:14])[CH2:12][N:5]2[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=3[C:3]([C:2]([F:29])([F:1])[F:28])=[N:4]2)=[CH:17][C:18]2[CH2:24][CH2:23][CH2:22][CH2:21][C:19]1=2
Reactant: O=C(Cn1nc(C(F)(F)F)c2c1CCCC2)Nc1sc2c(c1C(=O)O)CCCC2
Agent: [Cu]
Agent: Cl
Solvent: O
Solvent: c1ccc2ncccc2c1
Product: O=C(Cn1nc(C(F)(F)F)c2c1CCCC2)Nc1cc2c(s1)CCCC2
Temperature: 200 °C
Yield: 93.6 %

Procedure:
2-[2-(3-Trifluoromethyl-4,5,6,7-tetrahydroindazol-1-yl)-acetylamino]-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (200 mg, 0.47 mmol) and copper powder (45 mg, 0.70 mmol) were suspended in quinoline (4 mL) and the resulting mixture heated in a Biotage SmithCreator microwave at 200° C. for 10 min. The mixture was diluted with water (5 mL), acidified to pH 1 with 5 M HCl, and extracted with diethyl ether (3×50 mL). The combined organics were dried over sodium sulfate and concentrated in vacuo. The residue obtained was purified by silica gel chromatography using DCM as eluent, to afford the title compound as an off-white solid (170 mg, 0.44 mmol, 95%).
Reaction SMILES: [OH:1][CH:2]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[C:31]1(O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH3:30][O:29][C:26]1[CH:25]=[CH:24][C:23]([CH:2]([O:1][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=3)[CH2:7][CH2:6]2)=[CH:28][CH:27]=1
Reactant: Oc1ccccc1
Reactant: COc1ccc(C(O)CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)cc1
Product: COc1ccc(C(CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)Oc2ccccc2)cc1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-hydroxy-3-(4-methoxyphenyl)propyl]-4-piperidinyl}phenyl)-2-methylpropanamide and phenol: ESMS m/e: 487.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](O)(=[O:19])=[O:18])[C:14]([F:21])=[CH:13][C:11]=2[N:12]=1.FC1C=CC2SC(C3C(C)=NNC=3N)=[N:28]C=2C=1.N>C(O)C>[NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17]([NH2:28])(=[O:19])=[O:18])[C:14]([F:21])=[CH:13][C:11]=2[N:12]=1
Reactant: Cc1n[nH]c(N)c1-c1nc2cc(F)ccc2s1
Reactant: Cc1n[nH]c(N)c1-c1nc2cc(F)c(S(=O)(=O)O)cc2s1
Agent: N
Solvent: CCO
Product: Cc1n[nH]c(N)c1-c1nc2cc(F)c(S(N)(=O)=O)cc2s1
Yield: 25 %

Procedure:
The title compound (30 mg) was prepared in two steps from crude 2-(5-amino-3-methyl-1H-pyrazol-4-yl)-5-fluorobenzothiazole-6-sulfonic acid, which had been derived from the chlorosulfonation of 90 mg of 4-(5-fluorobenzothiazol-2-yl)-5-methyl-2H-pyrazol-3-ylamine, and a solution of excess ammonia dissolved in ethanol. MS (m/z, ES+): 328.0 (M+1,100%). Yield=25%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:11])[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][C:4]1[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=[C:2]([C:17]2[CH:18]=[CH:19][C:14]([C:13]([F:24])([F:23])[F:12])=[CH:15][CH:16]=2)[CH:3]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1cc(Br)cn2ccnc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2ccnc12
Temperature: 23 °C
Yield: 90.9 %

Procedure:
A mixture of 6-bromo-8-methyl-imidazo[1,2-a]pyridine (example C.20 step 1) (7.0 g, 33 mmol), commercially available 4-(trifluoromethyl)phenylboronic acid (6.929 g, 36 mmol), Pd(PPh3)4 (383 mg, 1 mol %) and 1M Na2CO3-solution (77 mL, 77 mmol) in DME (150 mL) was stirred at reflux for 1 h. Cooled to 23° C., diluted with water, extracted with EtOAc, washed the organic layer with brine, dried over MgSO4. Removal of the solvent in vacuum left a brown solid, which was purified by silica gel column chromatography with EtOAc/MeOH to give the title compound as a white solid (8.29 g, 91%). MS (ISP) 277.1 [(M+H)+].
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([Br:15])[C:12]([OH:16])=[C:11]([NH2:17])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].Cl[C:21](=[N+:23]([CH3:25])[CH3:24])Cl>C(Cl)Cl>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([Br:15])[C:12]2[O:16][C:21]([N:23]([CH3:25])[CH3:24])=[N:17][C:11]=2[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[N+](C)=C(Cl)Cl
Reactant: CC(C)(C)OC(=O)NCc1cc(N)c(O)c(Br)c1
Agent: [Cl-]
Solvent: ClCCl
Product: CN(C)c1nc2cc(CNC(=O)OC(C)(C)C)cc(Br)c2o1

Procedure:
A mixture of tert-butylN—(3-amino-5-bromo-4-hydroxybenzyl)carbamate (300 mg, 0.95 mmol) and dichloromethylenedimethylammonium chloride (phosgene iminium chloride, 240 mg, 1.48 mmol) in 10 mL of dry CH2Cl2 was refluxed for 6 h. After cooling the solution was extracted with EtOAc, washed with NaHCO3, brine and dried (MgSO4). After purification by column chromatography (1% MeOH in CH2Cl2) 192 mg (55%) of tert-butylN-{[7-bromo-2-(dimethylamino)-1,3-benzoxazol-5-yl]methyl}carbamate were obtained. 1H NMR (CDCl3) δ 7.14 (s, 1H, H-6); 7.04 (s, 1H, H-4); 5.11 (bs, 1H, NH); 4.31 (d, 2H, J=5.6 Hz, CH2); 3.23, 3.22 (s, 6H, NCH3 2×); 1.48 (s, 9H, (CH3)3C); 13C NMR (CDCl3) δ 163.3 (C-2), 156.2 (CO), 146.6 (C-7a), 145.1 (C-3a), 137.0 (C-5), 122.8 (C-6), 114.3 (C-4), 100.6 (C-7), 79.9 ((CH3)3C), 44.7 (CH2), 38.1 (NCH3×2), 28.8 ((CH3)3C).
Reaction SMILES: O1CCCC1.[F:6][C:7]1[CH:8]=[C:9]([CH:17]=[C:18]([F:27])[C:19]=1[C:20]([CH3:26])([CH3:25])[C:21]([F:24])([F:23])[F:22])[O:10][CH2:11][C:12]([O:14]CC)=[O:13].[OH-].[Na+].Cl>CO>[F:6][C:7]1[CH:8]=[C:9]([CH:17]=[C:18]([F:27])[C:19]=1[C:20]([CH3:25])([CH3:26])[C:21]([F:22])([F:23])[F:24])[O:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)COc1cc(F)c(C(C)(C)C(F)(F)F)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(c1c(F)cc(OCC(=O)O)cc1F)C(F)(F)F
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a tetrahydrofuran (1 ml) solution of ethyl [3,5-difluoro-4-(2,2,2-trifluoro-1,1-dimethylethyl)phenoxy]acetate (267 mg, 0.82 mmol) and methanol (1.5 ml) was added 2 N sodium hydroxide aqueous solution (1 ml) and the mixture was stirred at 60° C. for 30 minutes. After the reaction was complete, the basic mixture was acidified with 2 N hydrochloride aqueous solution and the product was extracted with ethyl acetate which was dried over sodium sulfate. The organic layer was filtered and concentrated to give 242 mg (99% yield) of the title compound as a brown solid.
Reaction SMILES: [C:1]([CH2:4][C@H:5]1[CH2:16][CH2:15][C:14]2[S:13][C:12]3[C:7](=[C:8]([O:17][CH:18]4[CH2:23][CH2:22][CH:21]([NH:24]C(=O)OC(C)(C)C)[CH2:20][CH2:19]4)[N:9]=[CH:10][N:11]=3)[C:6]1=2)(=[O:3])[NH2:2].Cl.C(=O)(O)[O-].[Na+]>ClCCl>[NH2:24][CH:21]1[CH2:22][CH2:23][CH:18]([O:17][C:8]2[N:9]=[CH:10][N:11]=[C:12]3[C:7]=2[C:6]2[C@@H:5]([CH2:4][C:1]([NH2:2])=[O:3])[CH2:16][CH2:15][C:14]=2[S:13]3)[CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)NC1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(N)=O)CC4)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: NC(=O)C[C@H]1CCc2sc3ncnc(OC4CCC(N)CC4)c3c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl N-(4-[[(3R)-3-(carbamoylmethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-12-yl]oxy]cyclohexyl)carbamate (120 mg, 0.27 mmol, 1.00 equiv) in dichloromethane (15 mL) was added hydrochloric acid (conc.) (0.2 mL). The resulting solution was stirred for 1 h at room temperature. The pH value of the solution was adjusted to pH>8 with saturated sodium bicarbonate solution. The solids were collected by filtration and then washed with water and methanol. This afforded 33.2 mg (36%) of 2-[(3R)-12-[(4-aminocyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]acetamide as a white solid. 1H NMR (300 MHz, CD3OD, ppm): δ 1.32-1.46 (m, 2H), 1.61-1.70 (m, 2H), 1.98-2.03 (m, 2H), 2.17-2.30 (m, 4H), 2.62-2.74 (m, 1H), 2.82-3.20 (m, 4H), 2.72-3.80 (m, 1H), 5.23-5.31 (m, 1H), 8.42 (s, 1H).
Reaction SMILES: [NH3:1].[F:2][C:3]1[CH:30]=[C:29]2[C:6]([CH:7]([CH2:31][C:32](O)=[O:33])[CH2:8][C:9]32[CH2:14][CH2:13][N:12]([C:15](=[O:28])/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([F:27])([F:26])[F:25])[CH2:11][CH2:10]3)=[CH:5][CH:4]=1>O1CCOCC1>[F:2][C:3]1[CH:30]=[C:29]2[C:6]([CH:7]([CH2:31][C:32]([NH2:1])=[O:33])[CH2:8][C:9]32[CH2:10][CH2:11][N:12]([C:15](=[O:28])/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([F:26])([F:25])[F:27])[CH2:13][CH2:14]3)=[CH:5][CH:4]=1
Reactant: N
Reactant: O=C(O)CC1CC2(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC2)c2cc(F)ccc21
Solvent: C1COCCO1
Product: NC(=O)CC1CC2(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC2)c2cc(F)ccc21

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 7 using 0.5 M NH3 in dioxane and (±)-(E)-2-(6-fluoro-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic acid. LC-MS Method 1 tR=1.67, min, m/z=461.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][OH:13])=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][O:13][S:23]([CH3:22])(=[O:25])=[O:24])=[CH:6][CH:5]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(CCCO)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(CCCOS(C)(=O)=O)cc1
Temperature: -15 °C
Reaction time: 4 h

Procedure:
4-(3-Hydroxy-propyl)-benzoic acid methyl ester (1.27 g, 6.5 mmol) and triethylamine (1 ml, 7.1 mmol) are dissolved in dichloromethane (30 ml), cooled to −15° C., methanesulfonylchloride (510 μl, 6.5 mmol) is added and stirred at room temperature for 4 h. The reaction mixture is diluted with dichloromethane, washed with potassiumhydrogensulfoate solution and potassiumcarbonate solution, the organic phase is dried over Na2SO4 and concentrated in vacuo. LC (method F): tR=1.88 min; Mass spectrum (ESP): m/z=295 [M+Na]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][N:14]2[CH:22]=[CH:23][CH:24]=[C:13]2[CH2:12]1)=[O:10].[H-].[Na+].CCCCCC.[F:33][C:34]([F:41])([F:40])[C:35]1[CH:39]=[CH:38][NH:37][N:36]=1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([N:37]2[CH:38]=[CH:39][C:35]([C:34]([F:41])([F:40])[F:33])=[N:36]2)[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][N:14]2[CH:22]=[CH:23][CH:24]=[C:13]2[CH2:12]1)=[O:10]
Reactant: O=C(c1ccc(F)cc1Cl)N1Cc2cccn2Cc2ccccc21
Reactant: FC(F)(F)c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: O=C(c1ccc(-n2ccc(C(F)(F)F)n2)cc1Cl)N1Cc2cccn2Cc2ccccc21

Procedure:
In the manner of Example 9's Method 1, employing (2-chloro-4-fluorophenyl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (0.8 g), 60% sodium hydride in oil (0.25 g, degreased with hexane), 3-trifluoromethylpyrazole (0.61 g) and dimethylformamide (25 ml), the title compound was obtained as an amorphous solid, MS, m/z: 457.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:16](=[O:17])[C:10]3[N:11]=[C:12]([CH3:15])[N:13]([CH3:14])[C:9]=3[CH:8]=[CH:7][C:6]=2[CH:18]=1.[BH4-].[Na+]>C(O)C.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:16]([OH:17])[C:10]3[N:11]=[C:12]([CH3:15])[N:13]([CH3:14])[C:9]=3[CH:8]=[CH:7][C:6]=2[CH:18]=1
Reactant: Cc1nc2c(=O)c3ccc(Cl)cc3ccc2n1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: Cc1nc2c(n1C)C=Cc1cc(Cl)ccc1C2O
Temperature: 50 °C

Procedure:
A mixture of the product from step (ii) (1.43 g), and sodium borohydride (0.42 g) in ethanol (100 ml) and dichloromethane (20 ml) were heated at 50° C. for 4 h. The solvents were evaporated under reduced pressure and the residue was dissolved in dichloromethane, washed with dilute aqueous sodium hydroxide solution, dried (CaCl2), and evaporated to give the subtitled product as a brown solid.
Reaction SMILES: C([O:5][C:6]([C:8]([O:11]/[N:12]=[C:13](/[C:46]1[N:47]=[C:48]([NH:51]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:49][CH:50]=1)\[C:14]([NH:16][CH:17]1[C:44](=[O:45])[N:19]2[C:20]([C:28]([O:30]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:29])=[C:21]([CH:24]=[CH:25][CH2:26]I)[CH2:22][S:23][C@H:18]12)=[O:15])([CH3:10])[CH3:9])=[O:7])(C)(C)C.[N:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1>ClCCl.C(OC(C)C)(C)C>[NH2:51][C:48]1[S:49][CH:50]=[C:46](/[C:13](=[N:12]/[O:11][C:8]([C:6]([OH:7])=[O:5])([CH3:10])[CH3:9])/[C:14]([NH:16][CH:17]2[C:44](=[O:45])[N:19]3[C:20]([C:28]([O-:30])=[O:29])=[C:21](/[CH:24]=[CH:25]/[CH2:26][N+:71]4[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=4)[CH2:22][S:23][C@H:18]23)=[O:15])[N:47]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CCI)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: c1ccncc1
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Product: CC(C)(O/N=C(\C(=O)NC1C(=O)N2C(C(=O)[O-])=C(/C=C/C[n+]3ccccc3)CS[C@H]12)c1csc(N)n1)C(=O)O
Reaction time: 3.5 h
Yield: 7 %

Procedure:
A mixture of diphenylmethyl 7-[(Z)-2-(2-t-butoxycarbonyl-2-propoxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-(3-iodo-1-propen-1-yl)-3-cephem-4-carboxylate (X-4', 497 mg, 0.5 mmole) and pyridine (0.08 ml, 1 mmole) in dichloromethane (5 ml) was allowed to stand at room temperature for 3.5 hours, and was then diluted with diisopropyl ether. The resulting precipitate was collected by filtration and treated with trifluoroacetic acid (5 ml) and anisole (1 ml) at room temperature for 1 hour, and the resulting mixture was concentrated and triturated with ether to give crude product I-4B which was purified by HP-20 column chromatography, eluted with water (300 ml), 10% methanol (500 ml) and 30% methanol (300 ml). The eluate of 30% methanol was concentrated to a small volume, adjusted to pH 7 with sodium bicarbonate and lyophilized to afford 23 mg (7%) of the title compound I-4B. M.p. >150° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([NH:27][S:28]([C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)(=[O:30])=[O:29])[CH2:23][CH2:22]3)[CH2:15][CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)#[N:2].C([O-])([O-])=[O:38].[K+].[K+].OO.O>CS(C)=O>[NH2:2][C:1]([C:3]1[CH:4]=[C:5]([N:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([NH:27][S:28]([C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)(=[O:30])=[O:29])[CH2:23][CH2:22]3)[CH2:17][CH2:18]2)[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1)=[O:38]
Reactant: N#Cc1cc(N2CCN(CC[C@H]3CC[C@H](NS(=O)(=O)c4cccnc4)CC3)CC2)cc(C(F)(F)F)c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1cc(N2CCN(CC[C@H]3CC[C@H](NS(=O)(=O)c4cccnc4)CC3)CC2)cc(C(F)(F)F)c1

Procedure:
0.37 g (0.7 mmol) of trans-N-(4-{2-[4-(3-cyano-5-trifluoromethyl-phenyl)-piperazin-1-yl]-ethyl}-cyclohexyl)-pyridine-3-sulfonamide was dissolved in 2 ml dimethylsulfoxide, 80 mg K2CO3 was added and 0.15 ml of 30% H2O2 was dropped in while keeping the temperature at 20° C. After stirring for 2 h 20 ml of water was added, the precipitate filtered, washed with water giving the title compound, melting point:191° C. (0.2 g; 53%).
Reaction SMILES: [H][H].[NH2:3][C:4]1[C:9]([N+:10]([O-])=O)=[CH:8][C:7]([N+:13]([O-])=O)=[C:6]([NH2:16])[CH:5]=1>>[NH2:3][C:4]1[CH:5]=[C:6]([NH2:16])[C:7]([NH2:13])=[CH:8][C:9]=1[NH2:10]
Reactant: Nc1cc(N)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: [H][H]
Product: Nc1cc(N)c(N)cc1N

Procedure:
contacting the reaction mixture formed in step (f) with hydrogen at a pressure in the range of about 0.31 to about 3.45 MPa and a temperature in the range of about 20° C. to about 100° C. to hydrogenate the 1,3-diamino-4,6-dinitrobenzene and produce 1,2,4,5-tetraminobenzene;
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:4][N:3]=1.[C:18]([N:25]1[CH2:30][C@@H:29]2[CH2:31][C@H:26]1[CH2:27][NH:28]2)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>ClCCl>[C:12]1([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([N:28]3[CH2:27][C@@H:26]4[CH2:31][C@H:29]3[CH2:30][N:25]4[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N:3][N:4]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Clc1nnc(-c2ccccc2)c2ccccc12
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1nnc(-c2ccccc2)c2ccccc12
Temperature: 90 °C

Procedure:
To a 20 mL reaction vial was added 1-chloro-4-phenylphthalazine BSL-1 (300 mg, 1.25 mmol) and (1S,4S)-2-boc-2,5-diazabicyclo[2.2.1]heptane (494 mg, 2.5 mmol, 2 eq). The mixture was heated under nitrogen at 90° C. for 1 h. The reaction was cooled to room temperature and the solid mass was dissolved in dichloromethane (50 mL) and washed once with 5 mL of sat. NaHCO3 and once with 50 mL of sat. NaCl solution. The organic layer was dried over MgSO4, filtered, and concentrated. Purification by column chromatography (70% ethyl acetate in hexanes) afforded (1S,4S)-tert-butyl 5-(4-phenylphthalazin-1-yl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylate (BSL-3). MS (M+H)+=403.1.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]=1[C:6]#[N:7])([O-])=O.[OH2:22].NN>C(O)C.[Ni]>[NH2:1][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]=1[C:6]([NH2:7])=[O:22]
Reactant: N#Cc1c(OCCOc2ccccc2)cccc1[N+](=O)[O-]
Reactant: O
Agent: [Ni]
Agent: NN
Solvent: CCO
Product: NC(=O)c1c(N)cccc1OCCOc1ccccc1
Yield: 50.2 %

Procedure:
The crystallized 2-nitro-6-(2-phenoxyethoxy)benzonitrile (5.82 g, 0.0205 mole) is stirred in 116 ml absolute ethanol at 50° C. and 3.62 ml. (0.0615 mole) 85 percent hydrazine hydrate is added, followed by small scoops of Raney nickel. The temperature is kept at 50°-60° C. while the Raney nickel is added, and after gas evolution and the exotherm ceases, the mixture is filtered through diatomaceous earth. The filter cake is washed with hot ethanol and the filtrate is concentrated, giving 2.804 g of 2-amino-6-(2-phenoxyethoxy)benzamide m.p. 127°-130° C.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([O:11][C:12](=[O:27])[NH:13][C:14]2[C:15]([CH3:26])=[N:16][O:17][C:18]=2[C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=2)[CH3:10])=[CH:5][CH:4]=1.[CH2:30]([O:32][C:33]([C:35]1([C:38]2[CH:43]=[CH:42][C:41](B3OC(C)(C)C(C)(C)O3)=[CH:40][CH:39]=2)[CH2:37][CH2:36]1)=[O:34])[CH3:31]>>[CH2:30]([O:32][C:33]([C:35]1([C:38]2[CH:43]=[CH:42][C:41]([C:22]3[CH:23]=[CH:24][C:19]([C:18]4[O:17][N:16]=[C:15]([CH3:26])[C:14]=4[NH:13][C:12]([O:11][CH:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:29])([F:28])[F:1])=[CH:4][CH:5]=4)[CH3:10])=[O:27])=[CH:20][CH:21]=3)=[CH:40][CH:39]=2)[CH2:36][CH2:37]1)=[O:34])[CH3:31]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)OC(C)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)OC(C)c4ccc(C(F)(F)F)cc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 6, Step 3 using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid 1-(4-trifluoromethyl-phenyl)-ethyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester; the isolated material was then purified by preparative HPLC, using a chiral column (95:5 hexanes:EtOAc) to provide enantiomer A and enantiomer B. Enantiomer A had a retention time of 30 minutes, enantiomer B had a retention time of 50 minutes.