Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[CH2:13]([C:20](=[CH2:24])[C:21]([OH:23])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[P:25]([O-:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28]>ClCCl.C(OCC)(=O)C>[CH2:27]([O:26][P:25]([CH2:24][CH:20]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:21]([OH:23])=[O:22])([O:29][CH2:30][CH3:31])=[O:32])[CH3:28]
Reactant: C=C(Cc1ccccc1)C(=O)O
Reactant: CCOP([O-])OCC
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOP(=O)(CC(Cc1ccccc1)C(=O)O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
Bis(trimethylsilyl)acetamide (5 g, 0.024 mole, 6 ml) was added, at room temperature, to a solution of benzyl acrylic acid (2 g, 0.012 mole) and diethyl phosphite (3.3 g, 0.024 moles) in dichloromethane (30 ml). The mixture was stirred at ambient temperature for 30 minutes, concentrated in vacuo at room temperature, and the residue was heated at a bath temperature of 100°-110° for 16 hours. The colorless oil reaction mixture was dissolved in ethyl acetate and extracted with 5% sodium bicarbonate (pH 9-10). The aqueous alkaline solution was washed with ether and acidified to a pH of 1-2 with concentrated hydrochloric acid. The colorless oil that separated was extracted into ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give a colorless oil (3.6 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][S:19](Cl)(=[O:21])=[O:20]>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:17][S:19]([CH3:18])(=[O:21])=[O:20])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(O)cc2C1
Reactant: CS(=O)(=O)Cl
Product: CC(C)(C)OC(=O)N1Cc2ccc(OS(C)(=O)=O)cc2C1
Yield: 69 %

Procedure:
The title compound (2.3 g, 69%) was prepared from 2-(tert-butyloxycarbonyl)-5-hydroxy-2,3-dihydro-1H-isoindole (2.5 g) and methanesulfonyl chloride (1.7 ml) using the method of Description 6.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]([OH:22])=O)[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[F:23][C:24]([F:29])([F:28])[CH2:25][NH:26][NH2:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>O.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]([NH:27][NH:26][CH2:25][C:24]([F:29])([F:28])[F:23])=[O:22])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:18])([F:17])[F:19])=[CH:4][CH:3]=1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: NNCC(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NNCC(F)(F)F)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 27.1 %

Procedure:
5-(4-Chlorophenyl)-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (1000 mg, 3.02 mmol; CAN 1018782-82-5) and (2,2,2-trifluoroethyl)hydrazine (380 mg, 3.33 mmol; CAN 5042-30-8) were combined with DMF (10 mL) to give a colorless solution. TBTU (1.06 g, 3.32 mmol) and DIPEA (1.56 g, 2.05 mL, 12.1 mmol) were added. The reaction mixture was stirred for 15 h at room temperature. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (2×50 mL). The organic layers were combined and washed with water (1×50 mL) and brine (1×50 mL). The organic layers were dried with MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 50 g, 0% to 50% EtOAc in hexane) to give the title compound (0.35 g, 27%) as white solid; LC-MS (UV peak area/ESI) 100%, 426.0451 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[C:17]([O-:20])([O-:19])=O.[K+].[K+].[CH2:23]([CH:25]1[O:27][CH2:26]1)Br>C(#N)C>[C:4]([OH:27])(=[O:8])/[CH:5]=[CH:15]/[C:17]([OH:20])=[O:19].[O:27]1[CH2:26][CH:25]1[CH2:23][N:12]1[CH2:11][CH2:10][CH:9]([C:6]2[C:5]3[CH:15]=[CH:16][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:14][CH2:13]1
Reactant: O=C([O-])[O-]
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: BrCC1CO1
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc2c(C3CCN(CC4CO4)CC3)noc2c1
Product: O=C(O)/C=C/C(=O)O
Yield: 33.3 %

Procedure:
A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (11 g, 50 mmol), K2CO3 (7.5 g, 54 mmol) and epibromohydrin (9 g, 54 mmol) in acetonitrile (150 ml) was heated at reflux for 16 hours. The mixture was filtered and concentrated to dryness. The crude product was purified by flash chromatography (SiO2, 180 g, eluted with methylene chloride (DCM), and 1-2% CH3OH in DCM). The material thus purified as off-white solids weighed 8.7 g (63%). This material (3 g) was converted to fumarate salt in ethanol and isopropyl ether to give 3.27 g of white crystals, m.p.=145°-147° C.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][S:11][CH2:10][CH2:9][NH:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1[Cl:23])[CH:19]([C:24](Cl)=[O:25])[CH2:18][C:17]2=[O:27]>C(N(CC)CC)C>[ClH:13].[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1[Cl:23])[CH:19]([C:24]([N:8]1[CH2:9][CH2:10][S:11][CH2:12][CH:7]1[CH2:6][N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:25])[CH2:18][C:17]2=[O:27]
Reactant: O=C1CC(C(=O)Cl)c2cc(Cl)c(Cl)cc21
Reactant: C1CCN(CC2CSCCN2)C1
Solvent: CCN(CC)CC
Product: Cl
Product: O=C1CC(C(=O)N2CCSCC2CN2CCCC2)c2cc(Cl)c(Cl)cc21
Yield: 45.7 %

Procedure:
The procedure described in Example 24 was repeated, but using 0.6 g of 3-(pyrrolidin-1-ylmethyl)thiomorpholine, 0.6 g of triethylamine and 1.0 g of 5,6-dichloro-3-oxoindan-1-carbonyl chloride, to afford 0.39 g of the title compound, melting at 215°-223° C.
Reaction SMILES: [C:1](/[C:9](=C(/OC)\C)/[C:10]#[N:11])(=O)[C:2]1C=CC=CC=1.[F:16][C:17]1[CH:31]=[CH:30][C:20]([C:21](/[C:23](=[C:26](/OC)\[CH3:27])/[C:24]#[N:25])=[O:22])=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:31]=[CH:30][C:20]([C:21](/[C:23](=[C:26](/[NH:11][CH2:10][CH2:9][CH2:1][CH3:2])\[CH3:27])/[C:24]#[N:25])=[O:22])=[CH:19][CH:18]=1
Reactant: CO/C(C)=C(\C#N)C(=O)c1ccccc1
Reactant: CO/C(C)=C(\C#N)C(=O)c1ccc(F)cc1
Product: CCCCN/C(C)=C(\C#N)C(=O)c1ccc(F)cc1

Procedure:
By replacing the 2-benzoyl-3-methoxycrotononitrile employed in Example 16 with an equimolar amount of 2-(p-fluorobenzoyl)-3-methoxycrotononitrile, there is obtained the title compound in equally good yield.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([OH:25])=O)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[O:25])=[CH:17][CH:16]=2)=[CH:13][CH:14]=1
Reactant: Nc1ccccn1
Reactant: O=C(O)COc1ccc(-c2ccc(F)cc2)nc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(COc1ccc(-c2ccc(F)cc2)nc1)Nc1ccccn1

Procedure:
The title compound was prepared analogously as described in Example 30(d) from 95 mg (0.26 mmol) of [6-(4-fluoro-phenyl)-pyridin-3-yloxy]-acetic acid trifluoroacetic acid salt and 39.5 mg (0.39 mmol) of 2-aminopyridine. Yield: 9.3 mg.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[F:13][C:14]([F:26])([F:25])[S:15]([C:18]1[CH:23]=[CH:22][C:21](Cl)=[CH:20][CH:19]=1)(=[O:17])=[O:16].C(=O)([O-])[O-].[K+].[K+].[OH2:33]>CN(C=O)C>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:3]=[C:2]([O:1][C:21]2[CH:22]=[CH:23][C:18]([S:15]([C:14]([F:26])([F:25])[F:13])(=[O:17])=[O:16])=[CH:19][CH:20]=2)[CH:11]=[C:10]([O:12][C:21]2[CH:20]=[CH:19][C:18]([S:15]([C:14]([F:26])([F:13])[F:25])(=[O:16])=[O:33])=[CH:23][CH:22]=2)[CH:9]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C(F)(F)F
Reactant: COC(=O)c1cc(O)cc(O)c1
Reactant: O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Oc2ccc(S(=O)(=O)C(F)(F)F)cc2)cc(Oc2ccc(S(=O)(=O)C(F)(F)F)cc2)c1
Temperature: 100 °C

Procedure:
A mixture of methyl 3,5-dihydroxybenzoate (100 mg, 0.595 mmol), 4-(trifluoromethylsulfonyl)chlorobenzene (291 mg, 2 equiv.) and potassium carbonate (330 mg, 4 equiv.) in DMF was heated to 100° C. overnight. The reaction was poured into water, extracted with EtOAc, washed the organic layer with water, brine, dried and concentrate. The residue was column chromatographed (1:2 EtOAc: Hex) to give 3,5-bis-(4-trifluoromethanesulfonyl-phenoxy)-benzoic acid methyl ester. 1HNMR (360 MHz, DMSO-d6) δ 8.12 (d, J=7.86 Hz, 4H), 7.67 (d, J=2.17 Hz, 2H), 7.61 (t, J=2.17 Hz, 1H), 7.42 (d, J=7.86 Hz, 4H), 3.85 (s, 3H, OCH3).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]([N:13]2[CH:18]([CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:17][CH2:16][C:15](=[O:25])[CH2:14]2)=[O:12])[CH:6]=[CH:7][C:8]=1[Cl:9].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:37](O)([OH:39])[CH3:38]>C1(C)C=CC=CC=1.ClCCl>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]([N:13]2[CH:18]([CH2:19][N:20]3[CH2:21][CH2:22][CH2:23][CH2:24]3)[CH2:17][CH2:16][C:15]3([O:39][CH2:37][CH2:38][O:25]3)[CH2:14]2)=[O:12])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: O=C1CCC(CN2CCCC2)N(C(=O)Cc2ccc(Cl)c(Cl)c2)C1
Reactant: CC(O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(Cc1ccc(Cl)c(Cl)c1)N1CC2(CCC1CN1CCCC1)OCCO2
Yield: 135.3 %

Procedure:
A mixture of the product of Example 25 (0.16 g) p-toluenesulphonic acid (0.14 g) and ethanediol (0.1 g) in dry toluene (10 ml) was heated under Dean and Starke conditions for 2 hours. The cooled reaction mixture was diluted with dichloromethane (50 ml) and the organic solution was washed with aqueous sodium carbonate solution (1M; 2×15 ml). The organic solution was dried and evaporated in vacuo. The residue was purified by flash chromatography eluting with dichloromethane/methanol/ammonia (200:8:1) to give the free base of the title compound as a gum (0.12 g). A solution of the free base in dry diethyl ether (10 ml) was treated with ethereal hydrogen chloride. The resulting precipitate was washed with diethyl ether (10 ml) to give the title compound as a solid (0.10 g) m.p. 255° dec. T.l.c. SiO2 (dichloromethane/methanol/ammonia 150:8:1) Rf 0.3.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([S:9][C:10]#N)[CH:6]=[CH:5][C:3]=1[NH2:4].CN(C)C=O.[S-2].[Na+].[Na+].I[C:21]1[CH:26]=[CH:25]C=[CH:23][CH:22]=1>O>[Br:1][C:2]1[CH:8]=[C:7]([S:9][C:10]2[CH:25]=[CH:26][CH:21]=[CH:22][CH:23]=2)[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: N#CSc1ccc(N)c(Br)c1
Reactant: Ic1ccccc1
Agent: [Na+]
Agent: [S-2]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(Sc2ccccc2)cc1Br
Temperature: 50 °C

Procedure:
A solution of 2-bromo-4-thiocyanoaniline (91.6 g., 0.4 mole) and dimethylformamide is added dropwise to a solution of sodium sulfide (0.48 mole) and water, under nitrogen, and the resulting solution is heated at 50° C. for one hour. Cuprous oxide (34.33 g., 0.24 mole) and iodobenzene (97.9 g., 0.48 mole) are added and the mixture is heated at a heating bath temperature of 150° C. for 4.5 hours. The reaction is quenched with water, methylene chloride is added and the resulting mixture is filtered through filter aid to remove suspended solids. The aqueous and organic layers are separated, and the aqueous layer is extracted three times with methylene chloride. The methylene chloride extracts are combined, washed with water and dried. Removal of the drying agent and methylene chloride gives the desired product in 95% of the theoretical yield. A purified sample melts at 61°-63° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[NH:3][Si:4]([CH3:7])([CH3:6])[CH3:5].[CH2:10](N)[CH:11]=[CH2:12]>C(C1C=CC=CC=1S(O)(=O)=O)CCCCCCCCCCC>[CH3:1][Si:2]([CH3:9])([CH3:8])[N:3]([CH2:12][CH:11]=[CH2:10])[Si:4]([CH3:7])([CH3:6])[CH3:5]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: C=CCN
Agent: CCCCCCCCCCCCc1ccccc1S(=O)(=O)O
Product: C=CCN([Si](C)(C)C)[Si](C)(C)C
Reaction time: 3 h
Yield: 79.4 %

Procedure:
A 500-ml flask equipped with a distillation column, stirrer, thermometer and dropping funnel was charged with 193.7 g (1.2 mol) of hexamethyldisilazane and 7.0 g (0.02 mol) of dodecylbenzenesulfonic acid. To the flask kept at 70° C., 114.2 g (2.0 mol) of allylamine was added over one hour from the dropping funnel. The contents were stirred for 3 hours under reflux. Subsequently, the allylamine was distilled off over 8 hours. From the reaction solution, a fraction of 89 to 90° C. at 40 mmHg was collected by vacuum distillation, yielding 192.0 g of N,N-bis(trimethylsilyl)allylamine.
Reaction SMILES: [C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH:12]=O)=[CH:8][C:7]([CH2:14][CH2:15][CH3:16])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:19]=[C:20]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:21]=[CH:22][C:23]=1[Cl:24].CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH2:12][N:28]2[CH2:27][CH2:26][N:25]([C:20]3[CH:21]=[CH:22][C:23]([Cl:24])=[C:18]([Cl:17])[CH:19]=3)[CH2:30][CH2:29]2)=[CH:8][C:7]([CH2:14][CH2:15][CH3:16])=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCc1cc(CCC=O)n(C(C)(C)C)n1
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3ccc(Cl)c(Cl)c3)CC2)n(C(C)(C)C)n1

Procedure:
199 mg (93%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-3-propyl-1H-pyrazol-5-yl)propanal (100 mg, 0.450 mmol), 1-(3,4-dichlorophenyl)piperazine (104 mg, 0.450 mmol), DIPEA (0.118 mL, 0.675 mmol) and NaBH(OAc)3 (286 mg, 1.350 mmol).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:15][CH2:16][C:17]([O:19]CC)=O)[CH2:6]1)(=[O:4])=[O:3].[NH2:22][CH2:23][CH:24]([OH:36])[CH2:25][N:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27]1>CCO.CO>[CH2:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:34][CH2:35][N:26]1[CH2:25][CH:24]([OH:36])[CH2:23][NH:22][C:17](=[O:19])[CH2:16][O:15][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[CH2:13][CH2:14][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6]2
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: CCOC(=O)COc1cccc2c1CCN(S(C)(=O)=O)C2
Solvent: CO
Solvent: CCO
Product: CS(=O)(=O)N1CCc2c(cccc2OCC(=O)NCC(O)CN2CCc3ccccc3C2)C1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 25.3 %

Procedure:
A mixture of ethyl 2-((2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)acetate (140 mg, 0.447 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (184 mg, 0.89 mmol) in EtOH (0.2 mL) was stirred at 120° C. for 30 min under microwave conditions. The mixture was diluted with MeOH and purified by prep-HPLC to afford N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-((2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy)acetamide (53.5 mg, 25%). 1H NMR (400 MHz, MeOD) δ 0.84 (s, 1H), 7.29-7.15 (m, 5H), 6.80 (d, J=8.2 Hz, 1H), 6.83 (d, J=7.7 Hz, 1H), 4.61 (s, 2H), 4.41 (s, 2H), 4.35-4.17 (m, 3H), 3.54 (t, J=6.1 Hz, 2H), 3.48-3.38 (m, 4H), 3.17-3.04 (m, 4H), 2.98 (t, J=6.0 Hz, 2H), 2.92 (s, 3H). LCMS (m/z): 474.2 [M+H]+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:22])=[C:11]([N:15]4[CH2:20][CH2:19][NH:18][CH:17]([CH3:21])[CH2:16]4)[C:12]=3[CH3:14])[C:7](=[O:23])[C:6]([C:24]([OH:26])=[O:25])=[CH:5]2)[CH2:3][CH2:2]1.C=O.[CH:29]([O-])=O.[Na+].C(=O)([O-])O.[Na+]>C(O)=O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:22])=[C:11]([N:15]4[CH2:20][CH2:19][N:18]([CH3:29])[CH:17]([CH3:21])[CH2:16]4)[C:12]=3[CH3:14])[C:7](=[O:23])[C:6]([C:24]([OH:26])=[O:25])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: Cc1c(N2CCNC(C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: O=C[O-]
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Product: Cc1c(N2CCN(C)C(C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 0 °C
Yield: 28.9 %

Procedure:
To 1-cyclopropyl-7-(3-methyl-1-piperazinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.4 g) are added formic acid (3 ml), 37% formalin (3 ml) and sodium formate (0.4 g), and the mixture is refluxed for 5 hours. After cooling, the reaction mixture is poured into ice water and adjusted to below pH 8 with aqueous sodium hydrogen carbonate, and the mixture is extracted with dichloromethane. After removing the solvent by concentration, the resulting residue is recrystallized from ethyl acetate to give 1-cyclopropyl-7-(3,4-dimethyl-1-piperazinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.12 g), as pale yellow powder, m.p. 181°-183° C.
Reaction SMILES: [BH4-].[Li+].Cl[Si](C)(C)C.C([O:15][C:16]1[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:19]=[C:18]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:17]=1[CH:30]=[CH:31][N+:32]([O-])=O)C1C=CC=CC=1.CO>C1COCC1>[C:26]([C:18]1[C:17]([CH2:30][CH2:31][NH:32][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:16]([OH:15])[CH:21]=[C:20]([C:22]([CH3:24])([CH3:23])[CH3:25])[CH:19]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)c1cc(OCc2ccccc2)c(C=C[N+](=O)[O-])c(C(C)(C)C)c1
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(O)c(CCNC2CCCCC2)c(C(C)(C)C)c1
Reaction time: 0.03 h

Procedure:
To a suspension of 0.10 g (4.59 mmol) of lithium borohydride in 3 mL THF was carefully added 1.3 mL (10.2 mmol) of chlorotrimethylsilane. The reaction mixture was stirred for 2 min and then a solution of 0.367 g (1.0 mmol) of 1-(benzyloxy)-3,5-di-tert-butyl-2-[2-nitrovinyl]benzene from Step B of Example 75 dissolved in 1.5 mL of anhydrous THF was slowly added. The resulting reaction mixture was stirred overnight at room temperature then cooled using an external ice water bath and 15 mL of methanol was slowly added. The resulting mixture was evaporated in vacuo, the residue was the treated with 20 mL of 5 N aqueous sodium hydroxide and then the reaction mixture was extracted with 5 times with 20 mL portions of CH2Cl2. The combined extracts were dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified on a silica gel flash chromatography column eluted initially with 5% MeOH in CH2Cl2 followed by a 95/5/0.5 mixture of CH2Cl2—MeOH-conc. NH4OH. Combination of the purified fractions and evaporation in vacuo afforded the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5](=O)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[N+:14]([O-])=O)[CH3:2].CC(O)=O>C(O)C.ClCCl.[Fe]>[CH2:1]([O:3][C:4]([C:5]1[NH:14][C:8]2[C:7]([CH:6]=1)=[CH:12][CH:11]=[C:10]([Cl:13])[CH:9]=2)=[O:18])[CH3:2]
Reactant: CCOC(=O)C(=O)Cc1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: ClCCl
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2ccc(Cl)cc2[nH]1

Procedure:
To crude 3-(4-chloro-2-nitro-phenyl)-2-oxo-propionic acid ethyl ester (151 mmol) in ethanol:glacial HOAc (1:1, v/v, 560 mL) at rt was added iron powder (74.4 g) and the reaction mixture was stirred at reflux for 4 h. The mixture was filtered and evaporated to give a residue which was redistributed in dichloromethane/1N HCl. The organic layer was washed with 1N HCl, NaHCO3, and brine and dried. Evaporation followed by crystallization (DCM) gave 6-Chloro-1H-indole-2-carboxylic acid ethyl ester as a pale yellow solid (16.8 g, 50% over 2 steps).
Reaction SMILES: Cl.Cl.[CH2:3]1[NH:8][CH2:7][CH2:6][N:5]2[CH2:9][C@H:10]([CH2:13][N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:16][C:15]3=[O:23])[CH2:11][CH2:12][C@@H:4]12.Cl[C:25]1[N:30]=[CH:29][CH:28]=[CH:27][N:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[N:26]1[CH:27]=[CH:28][CH:29]=[N:30][C:25]=1[N:8]1[CH2:7][CH2:6][N:5]2[CH2:9][C@H:10]([CH2:13][N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:16][C:15]3=[O:23])[CH2:11][CH2:12][C@H:4]2[CH2:3]1
Reactant: Clc1ncccn1
Reactant: O=C1Cc2ccccc2N1C[C@@H]1CC[C@H]2CNCCN2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C1Cc2ccccc2N1C[C@@H]1CC[C@H]2CN(c3ncccn3)CCN2C1
Temperature: 95 °C
Reaction time: 16 h
Yield: 36.4 %

Procedure:
A mixture of 0.49 g (1.38 mmol) of 1-[(7R,9aS)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazin-7-ylmethyl]-1,3-dihydro-indol-2-one dihydrochloride, 0.157 g (1.37 mmol) of 2-chloropyrimidine and 0.64 g (6.02 mmol) of sodium carbonate in 20 mL of water was stirred at 95° C. for 16 h. The mixture was cooled to room temperature, extracted with chloroform (3×), the combined organic phase was washed with brine, dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with 95:5 ethyl acetate:methanol gave 0.181 g (30%) of the title compound. mp (—HCl) 174-176° C. HRMS calcd for C21H25N5O: 363.2059, found: 363.2032.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:18][CH:17]4[CH:15]([CH:16]4[N:19](C)C)[CH2:14]3)=[O:12])[S:10][C:3]=12.[CH3:22][C:23]1[NH:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([NH2:32])=[CH:27][CH:26]=2>>[NH2:19][CH:16]1[CH:17]2[CH:15]1[CH2:14][N:13]([C:11]([C:9]1[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[NH:32][C:28]3[CH:29]=[C:30]4[C:25](=[CH:26][CH:27]=3)[NH:24][C:23]([CH3:22])=[CH:31]4)[CH:8]=1)=[O:12])[CH2:18]2
Reactant: CN(C)C1C2CN(C(=O)c3cc4nccc(Cl)c4s3)CC21
Reactant: Cc1cc2cc(N)ccc2[nH]1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)N5CC6C(N)C6C5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from (7-chloro-thieno[3,2-b]pyridin-2-yl)-(6-dimethylamino-3-aza-bicyclo[3.1.0]hex-3-yl)-methanone and 2-methyl-1H-indol-5-ylamine by a procedure analogous to example 1C. MS: 432.2 (MH+); HPLC Rf: 4.346 min.; HPLC purity: 99%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:16]([O-])=O)=[C:4]2[C:8](=[CH:9][C:10]=1Br)[CH2:7][CH:6]([NH:12][C:13](=[O:15])[CH3:14])[CH2:5]2.[C:19]([O-:22])(=O)[CH3:20].[Na+].C[OH:25]>[Pd]>[O:25]=[C:20]1[NH:16][C:3]2[C:4]3[CH2:5][CH:6]([NH:12][C:13](=[O:15])[CH3:14])[CH2:7][C:8]=3[CH:9]=[CH:10][C:2]=2[NH:1][C:19]1=[O:22]
Reactant: CC(=O)[O-]
Reactant: CC(=O)NC1Cc2cc(Br)c(N)c([N+](=O)[O-])c2C1
Reactant: CO
Agent: [Pd]
Agent: [Na+]
Product: CC(=O)NC1Cc2ccc3[nH]c(=O)c(=O)[nH]c3c2C1
Temperature: 80 °C
Reaction time: 18 h
Yield: 36 %

Procedure:
A mixture of N-(5-amino-6-bromo-4-nitro-indan-2-yl)acetamide (0.5 g, 1.6 mmol), 5% palladium on carbon (0.2 g) and sodium acetate (0.16 g) in methanol (75 mL) was placed on a Parr hydrogenation apparatus under a hydrogen atmosphere (51 psi) and shaken for 18 h. After removing the catalyst by filtration, the solvent was evaporated and the residue was suspended in 2N HCl, treated with oxalic acid (0.5 g) and then heated at 80° C. for 4 h. The water was evaporated and the residue dissolved in saturated sodium bicarbonate and acetic anhydride (1 mL) was added. The resulting solid was collected by filtration and dried in vacuo to give a brown solid (0.15 g) in 36% yield.
Reaction SMILES: N1C(C2C=CC([C:12]3[C:21](C)=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17]([O:23]C)[CH:18]=4)[N:13]=3)=CC=2)=NN=N1.B(Br)(Br)Br.C(Cl)[Cl:30]>>[Cl:30][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([OH:23])[CH:18]=2)[N:13]=1
Reactant: ClCCl
Reactant: COc1ccc2nc(-c3ccc(-c4nnn[nH]4)cc3)c(C)cc2c1
Agent: BrB(Br)Br
Product: Oc1ccc2nc(Cl)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a solution of 2-chloro-6-methoxyquinoline (Intermediate 1) (2.00 g, 10.4 mmol) in anhydrous DCM (100 mL) was added BBr3 (6 mL, 62.2 mmol) dropwise at 0° C. The reaction mixture was stirred at 25° C. for 2 hours, then quenched with aqueous saturated NH4Cl (50 mL) and filtered. The filtrate was extracted with CH2Cl2/MeOH (v/v=10/1, 30 mL×2) and the combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 2-chloroquinolin-6-ol (1.30 g, yield 70%) as yellow solid. 1H NMR (CDCl3 300 MHz): δ 7.95 (t, J=8.1 Hz, 2H), 7.35 (dd, J=6.0, 3.3 Hz, 2H), 7.13 (d, J=2.7 Hz, 1H).