Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]2[C:15]([N:16]=[C:17]3[C:22]=1[CH:21]([OH:23])[CH2:20][CH2:19][CH2:18]3)=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[Br:29][CH2:30][CH2:31]O>FC(F)(F)C(O)=O>[CH2:1]([NH:8][C:9]1[C:10]2[C:15]([N:16]=[C:17]3[C:22]=1[CH:21]([O:23][CH2:31][CH2:30][Br:29])[CH2:20][CH2:19][CH2:18]3)=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1CCCc2nc3ccccc3c(NCc3ccccc3)c21
Reactant: OCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: BrCCOC1CCCc2nc3ccccc3c(NCc3ccccc3)c21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 71 %

Procedure:
To a suspension of 9-benzylamino-1,2,3,4-tetrahydroacridin-1-ol (7.20 g) in 2-bromoethanol (45 ml) was added 40 drops of trifluoroacetic acid. The reaction mixture was stirred at ambient temperature for 20 mins, added to iced sodium bicarbonate solution, and the suspension was extracted with ethyl acetate. The combined organic extracts were washed with water, saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and evaporated. The residue was purified by flash chromatography (ethyl acetate→1% triethylamine/ethyl acetate) to give 6.85 g (71%) of product. Recrystallization from cyclohexane gave the analytical sample, mp 89°-91° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14]([C:19]#[C:20][CH2:21]Cl)=[CH:13][CH:12]=3)=[O:5])[CH3:2].CCOCC.[CH2:28]([O:30][P:31]([O:35]CC)[O:32][CH2:33][CH3:34])[CH3:29]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14]([C:19]#[C:20][CH2:21][P:31]([O:32][CH2:33][CH3:34])([O:30][CH2:28][CH3:29])=[O:35])=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccc(C#CCCl)cc12
Reactant: CCOP(OCC)OCC
Solvent: CCOCC
Product: CCOC(=O)c1cc2c(cn1)[nH]c1ccc(C#CCP(=O)(OCC)OCC)cc12

Procedure:
460 mg of 6-(3-chloro-1-propinyl)-beta-carboline-3-carboxylic-acid-ethylester is stirred in 4 ml of triethylphosphite for 3 h at 120°-130° C. The mixture, after being cooled, is thoroughly stirred with ether and the ether-soluble part is chromatographed after evaporation on 50 g of silica gel using methylene-chloride/ethanol (10/2). 105 mg of 6-[3-diethoxyphosphoryl-1-propinyl]-beta-carboline-3-carboxylic-acid-ethylester is obtained in the form of an oil.
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([Cl:12])[CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:37][N:38]1[CH2:43][CH2:42][CH:41]([NH2:44])[CH2:40][CH2:39]1.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([NH:44][CH:41]2[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]2)=[O:8])=[C:4]([Cl:12])[CH:3]=1
Reactant: CN1CCC(N)CC1
Reactant: O=C(O)c1cc(F)c(Br)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(NC(=O)c2cc(F)c(Br)cc2Cl)CC1
Reaction time: 8 h
Yield: 72.2 %

Procedure:
4-bromo-2-chloro-5-fluoro-benzoic acid (Apollo Scientific; 5.0 g, 19.8 mmol) was added to DMF (250 mL), to this was added HBTU (9.8 g, 25.7 mmol), N-methyl-4-aminopiperidine (Fluorochem; 2.5 g, 21.8 mmol) and DIPEA (7.0 mL, 39.5 mmol). The reaction was stirred overnight, evaporated to dryness, quenched with 2.0 N NaOH (100 mL), extracted with DCM (3×100 mL), dried and solvent removed in vacuo. The residue was dissolved in hot acetonitrile, allowed to cool filtered, and the filtrate passed through a SCX column and the residue, after evaporation of product containing fractions, recrystallised from hot acetonitrile to yield the title compound as a white solid (5.0 g, 82%).
Reaction SMILES: C([O:5][C:6](=[O:44])[C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH:15]([C:26](=[O:43])[N:27]([C:34]2[O:42][C:38]3=[CH:39][CH:40]=[CH:41][C:37]3=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:16]2[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[CH3:14])=[CH:9][CH:8]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[O:42]1[C:38]2=[CH:39][CH:40]=[CH:41][C:37]2=[CH:36][CH:35]=[C:34]1[N:27]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:26]([CH:15]([N:13]([CH3:14])[C:10]1[CH:9]=[CH:8][C:7]([C:6]([OH:44])=[O:5])=[CH:12][CH:11]=1)[C:16]1[CH:17]=[CH:18][C:19]([C:22]([CH3:25])([CH3:23])[CH3:24])=[CH:20][CH:21]=1)=[O:43]
Reactant: CN(c1ccc(C(=O)OC(C)(C)C)cc1)C(C(=O)N(c1ccccc1)c1ccc2cccc-2o1)c1ccc(C(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(c1ccc(C(=O)O)cc1)C(C(=O)N(c1ccccc1)c1ccc2cccc-2o1)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 108.7 %

Procedure:
4-{[(4-Benzofuran-2-yl-phenylcarbamoyl)-(4-tert-butyl-phenyl)-methyl]-methyl-amino}-benzoic acid tert-butyl ester (˜140 mg, 0.19 mmol) was taken up in 5 mL of dichloromethane followed by addition of 0.5 mL of TFA and stirred for 16 h at RT. Removal of the organic layer and water was added to give a precipitate, which was filtered to give 110 mg (100%) of pinkish solids. LCMS (M−1=531.1).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].CO.[CH:9]1([NH:15][CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]=2B2OC(C)(C)C(C)(C)O2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.Br[C:37]1[N:42]=[C:41]([CH:43]=[O:44])[CH:40]=[CH:39][CH:38]=1>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.C1(C)C=CC=CC=1>[CH:9]1([NH:15][CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]=2[C:37]2[N:42]=[C:41]([CH:43]=[O:44])[CH:40]=[CH:39][CH:38]=2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: O=Cc1cccc(Br)n1
Reactant: CC1(C)OB(c2c(CNC3CCCCC3)ccc3ccccc23)OC1(C)C
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: O
Solvent: Cc1ccccc1
Solvent: CO
Product: O=Cc1cccc(-c2c(CNC3CCCCC3)ccc3ccccc23)n1
Temperature: 25 °C

Procedure:
A solution of 21.2 g (74.1 mmol) of Na2CO3×10H2O in 660 ml of water and 190 ml of methanol was purged with argon for 30 min. The obtained solution was added to a mixture of 29.9 g (80.0 mmol) of cyclohexyl{[1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-naphthyl]methyl}amine, 14.0 g (80.0 mmol) of 6-bromopyridine-2-carbaldehyde, 4.62 g (4.00 mmol) of Pd(PPh3)4, and 780 ml of toluene in argon atmosphere. This mixture was refluxed for 10 h using a mechanical stirrer, then cooled to room temperature. The organic layer was separated, dried over Na2SO4, evaporated to 300 ml in volume, and then extracted with 3×300 ml of 2M HCl. The combined aqueous layer was alkalified to pH 10 by the saturated aqueous K2CO3, and then extracted with 3×200 ml of dichloromethane. The combined organic extract was dried over Na2SO4 and evaporated to dryness. Yield 23.1 g (84%) of a brown oil. Anal. Calc for C23H24N2O: C 80.20; H 7.02; N 8.13. Found: C 80.78; H 7.11; N 8.01.1H NMR (CDCl3): δ 10.08 (s, 1H, CHO), 7.96-8.03 (m, 2H, 3-H, 4-H in Py), 7.83-7.89 (m, 2H, 8,5-H in Py), 7.59-7.64 (m, 2H, 5-H in Py and 4-H in naphthyl), 7.39-7.43 (m, 1H, 6-H in naphthyl), 7.30-7.34 (m, 1H, 7-H in naphthyl), 7.20-7.23 (m, 1H, 3-H in naphthyl), 3.56 (m, 2H, CH2), 2.21 (m, 1H, 1-H in Cy), 1.57-1.66 (m, 4H, Cy), 1.02-1.11 (m, 4H, Cy), 0.88-0.96 (m, 2H, Cy).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)=[N:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[ClH:32]>O1CCOCC1.CCOCC>[ClH:32].[ClH:32].[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)cn2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCNCC3)nc2)cc1
Yield: 94 %

Procedure:
5-[4-(Methylsulfonyl)phenyl]-2-[(4-piperidinylmethyl)oxy]pyridine dihydrochloride (0.32 g, 94%) was prepared as a light yellow solid from 1,1-dimethylethyl 4-[({5-[4-(methylsulfonyl)phenyl]-2-pyridinyl}oxy)methyl]-1-piperidinecarboxylate (Example 70, 0.36 g, 0.81 mmol), 1,4-dioxane (16 mL), ether (12 mL), 4.0M HCl in 1,4-dioxane (12 mL) and 2M HCl in ether (12 mL) in a manner similar to Example 66, Step 1. 1H NMR (400 MHz, CD3OD): δ 8.48 (d, 1H, J=2.5 Hz), 8.06 (dd, 1H, Ja=8.6 Hz, Jb=2.5 Hz), 8.03 (d, 2H, J=8.5 Hz), 7.86 (d, 2H, J=8.4 Hz), 6.94 (d, 1H, J=8.6 Hz), 4.28 (d, 2H, J=6.1 Hz), 3.50-3.40 (m, 2H), 3.14 (s, 3H), 3.10-3.00 (m, 2H), 2.30-2.15 (m, 1H), 2.15-2.05 (m, 2H), 1.70-1.55 (m, 2H); LRMS (ESI), m/z 347 (M+H).
Reaction SMILES: [Al:1].[CH:2]([OH:5])([CH3:4])[CH3:3]>>[O:5]([Al:1]([O:5][CH:2]([CH3:4])[CH3:3])[O:5][CH:2]([CH3:4])[CH3:3])[CH:2]([CH3:4])[CH3:3]
Reactant: [Al]
Reactant: CC(C)O
Product: CC(C)O[Al](OC(C)C)OC(C)C
Yield: 90 %

Procedure:
360 g anhydrous isopropanol, 0.0959 g mercuric salt and 13.5 g metallic aluminium scraps was refluxed at 83°-90° C. for 2-8 hours, evaporated off excess isopropand under normal pressure, triisopropoxyl aluminum was obtained by collecting distillation fraction of 110°-200° C. under reduced pressure of 1-10 mmHg. yield 90-100%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[N:14][NH:13][C:12](=[O:24])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Cl:25][C:26]1[CH:35]=[CH:34][C:29]([CH:30]=[CH:31][CH2:32]Cl)=[CH:28][CH:27]=1>>[Cl:25][C:26]1[CH:35]=[CH:34][C:29]([CH:30]=[CH:31][CH2:32][N:13]2[C:12](=[O:24])[CH:11]=[C:10]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=3)[C:15]([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)=[N:14]2)=[CH:28][CH:27]=1
Reactant: ClCC=Cc1ccc(Cl)cc1
Reactant: COc1ccc(-c2n[nH]c(=O)cc2-c2ccc(OC)c(F)c2)cc1
Product: COc1ccc(-c2nn(CC=Cc3ccc(Cl)cc3)c(=O)cc2-c2ccc(OC)c(F)c2)cc1
Yield: 58.7 %

Procedure:
Using 5-(3-fluoro-4-methoxyphenyl)-6-(4-methoxyphenyl)-2H-pyridazin-3-one and 4-chlorocinnamyl chloride as starting materials, the procedures of Example 12 were repeated likewise, whereby the title compound was obtained in a yield of 58.7%.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][CH:6]=1)=[O:4].[C:14]1([C@@H:20]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:21]([O:23][C@@H:24]2[CH:29]3[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]3)[CH2:25]2)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCOC(C)=O.CO.[Pd]>[Br-:1].[NH2:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][N+:26]23[CH2:27][CH2:28][CH:29]([CH2:30][CH2:31]2)[C@@H:24]([O:23][C:21](=[O:22])[C@@H:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:25]3)=[CH:6][CH:7]=1
Reactant: O=C(O[C@H]1CN2CCC1CC2)[C@H](Nc1ccccc1)c1ccccc1
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc(C(=O)C[N+]23CCC(CC2)[C@@H](OC(=O)[C@H](Nc2ccccc2)c2ccccc2)C3)cc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.5 %

Procedure:
2-Bromo-1-(4-nitrophenyl)ethanone (290 mg, 1.19 mmol) was added to a solution of (R)—((R)-quinuclidin-3-yl) 2-phenyl-2-(phenylamino)acetate (diastereomer 1 of I2) (400 mg, 1.19 mmol) in EtOAc (15 ml). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into a Parr's vial and diluted with MeOH. Pd/C (cat amount; about 10 mg) was added, and reaction is hydrogenated at 35 pound per square inch (psi) for 8 hours (UPLC-MS: complete conversion). The catalyst was removed by filtration, and the clear solution was concentrated under vacuum. The residue was triturated with Et2O and filtered to obtain (R)-1-(2-(4-aminophenyl)-2-oxoethyl)-3-((R)-2-phenyl-2-(phenylamino)acetoxy)-1-azoniabicyclo[2.2.2]octane bromide (632 mg, 97% yield).
Reaction SMILES: C(N(CC)CC)C.CC1C=CC(S(O)(=O)=O)=CC=1.[NH2:19][CH:20]([C:23]#[N:24])[C:21]#[N:22].C(O[C:28]([O:36][CH2:37][CH3:38])(OCC)[CH2:29]OCC)C.[NH2:39][CH2:40][C:41]([CH3:44])([OH:43])[CH3:42]>C1COCC1>[NH2:22][C:21]1[N:39]([CH2:40][C:41]([OH:43])([CH3:44])[CH3:42])[C:29]([CH2:28][O:36][CH2:37][CH3:38])=[N:19][C:20]=1[C:23]#[N:24]
Reactant: CCOCC(OCC)(OCC)OCC
Reactant: CC(C)(O)CN
Reactant: N#CC(N)C#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOCc1nc(C#N)c(N)n1CC(C)(C)O
Temperature: 25 °C

Procedure:
Triethylamine (5.28 ml, 37.9 mmol) was added with stirring to a suspension of 2-aminomalononitrile 4-methylbenzenesulfonate (8 g, 31.6 mmol) in THF (120 ml) to give a light brown solution. 1,1,1,2-Tetraethoxyethane (7.82 g, 37.9 mmol) was added and the reaction mixture was stirred under argon at reflux temperature. After 4 h an additional amount of 2.3 g 1,1,1,2-tetraethoxyethane was added and the mixture heated for another 2 h. The mixture was allowed to cool to room temperature, triethylamine (5.28 ml, 37.9 mmol) and 1-amino-2-methylpropan-2-ol (3.63 ml, 37.9 mmol) were added and the reaction was stirred overnight. The mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate (200 mL, 2×150 mL) and sodium bicarbonate solution (2 M, 100 mL). The organic phases were combined, dried over MgSO4, concentrated in vacuo and purified by flash chromatography (silica gel, 0% to 100% ethyl acetate in heptane) to give the title compound after a crystallization step from heptane (4.47 g, 59%) as white crystalline solid; LC-MS (UV peak area, ESI) 100%, 239.1514 (MH+).
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:8]=[C:9]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:10][NH:11][C:12](=[NH:20])[CH:13](OCC)OCC.ClC1C=C2C(=CC=1Cl)C(N)=NC=C2>>[Cl:6][C:7]1[C:23]([Cl:24])=[CH:22][CH:21]=[C:9]2[C:8]=1[CH:13]=[C:12]([NH2:20])[N:11]=[CH:10]2
Reactant: CCOC(OCC)C(=N)NCc1ccc(Cl)c(Cl)c1
Agent: Nc1nccc2cc(Cl)c(Cl)cc12
Agent: O=S(=O)(O)O
Product: Nc1cc2c(Cl)c(Cl)ccc2cn1
Temperature: 40 °C
Yield: 85.5 %

Procedure:
To sulfuric acid (4 mL, 75 mmol) was added N-(3,4-dichlorobenzyl)-2,2-diethoxyacetimidamide (2 g, 6.6 mmol) at room temperature. The reaction was heated to 40° C. for 49 hours. TLC and LC/MS indicated the presence of product. The reaction was cooled to room temperature and quenched with aq. NaOH (˜15 M) until the reaction mixture was ˜pH 7. The crude product was extracted with ethyl acetate (2×50 mL) and the organics were dried with MgSO4, filtered, and concentrated in vacuo to yield the product. The crude product was purified by chromatography (Biotage: 100% ethyl acetate to [90/10% ethyl acetate/MeOH]) to yield approximately a 1:1 mixture of regioisomers 6,7-dichloroisoquinolin-1-amine and 5,6-dichloroisoquinolin-3-amine (1.2 g, 5.64 mmol, 86.0% yield) as a dark yellow powder. The regioisomers were carried on without separation. 1H NMR: 1H NMR (500 MHz, DMSO-D6) δ ppm 8.90 (s, 1H), 8.83 (s, 1H), 8.12 (s, 1H), 7.89 (s, 1H), 7.84 (d, J=8.54 Hz, 1H), 7.28 (d, J=8.85 Hz, 1H), 6.83 (s, 1H), 6.58 (s, 1H), 6.48 (s, 2H), 6.25 (s, 2H). MS (LC/MS) R.T.=1.59; [M+H]+=213.0.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[C:3]=1[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][C@:7]1([CH3:14])[C:11]([OH:13])=[O:12])=[O:5].[H][H]>CO.[Pd]>[NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[C:3]=1[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][C@:7]1([CH3:14])[C:11]([OH:13])=[O:12])=[O:5]
Reactant: C[C@]1(C(=O)O)CCCN1C(=O)c1c(N)cccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C[C@]1(C(=O)O)CCCN1C(=O)c1c(N)cccc1N

Procedure:
366 mg (1.25 mmol) (R)-1-(2-amino-6-nitro-benzoyl)-2-methyl-pyrrolidine-2-carboxylic acid are dissolved in 50 mL methanol and combined with 40 mg palladium on charcoal (10% Pd). The reaction mixture is hydrogenated for 9 h at 5 bar hydrogen pressure and at 25° C. Then the catalyst is filtered off, the solvent is eliminated in vacuo and the crude product is purified by chromatography. The carrier material used is C18-RP-silica gel and a gradient is run through which consists of 95% water and 5% acetonitrile at the starting point and 5% water and 95% acetonitrile at the end point.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)[CH:6]=[CH:5]2.I[CH2:18][CH2:19][CH:20]1[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21]1>C(C(C)=O)C(C)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH2:16][CH2:15][N:14]([CH2:18][CH2:19][CH:20]3[CH2:21][C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:28]3)[CH2:13][CH:12]=1)[CH:6]=[CH:5]2
Reactant: Clc1ccc2c(ccn2-c2ccncc2)c1
Reactant: ICCC1Cc2ccccc2C1
Solvent: CC(=O)CC(C)C
Product: Clc1ccc2c(ccn2C2=CCN(CCC3Cc4ccccc4C3)CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27 %

Procedure:
A mixture of 5-chloro-1-(pyridin-4-yl)-1H-indole 26a (4.0 g), 2-(2-iodoethyl)indane 24a (4.8), and methyl isobutyl ketone (100 ml) was boiled under reflux for 20 h. The mixture was cooled, and a crystalline compound collected by filtration (6.5 g). Compound corresponding to 5.5 g was suspended in methanol (100 ml), and NaBH4 (1.5 g) was added in parts of 0.5 g. The resulting mixture was stirred at room temperature for 1 h, and the solvent was removed in vacuo. Conventional work up with ethyl acetate and water followed by purification on silica gel eluted with ethyl acetate-heptane (1:1) gave the crude product, which was crystallized (ethyl acetate) to give the title compound (1.1 g, 27%).
Reaction SMILES: [Cl:1][C:2]([Cl:8])(Cl)[P:3]([Cl:6])([Cl:5])=[O:4].[CH3:9][O:10][C:11](=[O:14])[CH:12]=[CH2:13].[Cl-:15].C([NH+](CC)CC)C>C(#N)C>[Cl:1][C:2]([Cl:8])([P:3]([Cl:6])([Cl:5])=[O:4])[CH2:13][CH:12]([Cl:15])[C:11]([O:10][CH3:9])=[O:14]
Reactant: [Cl-]
Reactant: C=CC(=O)OC
Reactant: O=P(Cl)(Cl)C(Cl)(Cl)Cl
Agent: CC[NH+](CC)CC
Solvent: CC#N
Product: COC(=O)C(Cl)CC(Cl)(Cl)P(=O)(Cl)Cl

Procedure:
To 11.8 g (0.05 mole) distilled trichloromethane phosphonic dichloride and 8.6 g (0.1 mole) methylacrylate was added a solution of 134 mg (1 mmole) anhydrous cupric chloride and 206 mg (1.5 mmole) triethylammonium chloride in 5 ml acetonitrile. The homogeneous solution was heated in the absence of air in a sealed ampoule at 125° for 15 hours. After cooling, the contents of the ampoule was subjected to distillation. 12.9 g 1:1 adduct, 1,1,3-trichloro-3-carbomethoxypropane-1-phosphonic dichloride was obtained, bp/0.04: 83°. Cl-(by half-hydrolysis): 11.23%. Calc. for C5H6Cl5O2P: 11.01%. In the absence of triethylammonium chloride, 3.7 g adduct was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6](Cl)=[CH:7][CH:8]=2)[N:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.[OH-].[K+]>>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][C:6]([O:20][C:17]3[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=3)=[CH:7][CH:8]=2)[N:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Agent: [K+]
Agent: [OH-]
Product: Nc1ccc2ccc(Oc3ccc(F)cc3)nc2n1
Temperature: 115 °C
Yield: 59.8 %

Procedure:
The procedure is similar to that described in Example 4, but starting with 2-amino-7-chloro-1,8-naphthyridine (17.9 g), 4-fluorophenol (44.8 g) and potassium hydroxide pellets (13.2 g; 85% purity). After 2 hours' heating at 115° C. and treatment as described above in Example 4, 2-amino-7-(4-fluorophenoxy)-1,8-naphthyridine (15.2 g) is produced, m.p. 210° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=O)[C:9]([N:14]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:10][N:11](C)C)[CH:5]=[CH:6][CH:7]=1.[NH2:26]N>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([NH2:14])=[CH:10][NH:11][N:26]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=C(C(=O)c1cccc(Cl)c1)N1C(=O)c2ccccc2C1=O
Reactant: NN
Solvent: CCO
Product: Nc1c[nH]nc1-c1cccc(Cl)c1
Yield: 80 %

Procedure:
A mixture of 2-(3-(3-chlorophenyl)-1-(dimethylamino)-3-oxoprop-1-en-2-yl)isoindoline-1,3-dione (255 mg, 0.719 mmol, 1 eq) and hydrazine (0.15 mL, 4.8 mmol, 6.6 eq) in 10 mL ethanol was stirred under reflux for 2 hours. The ethanol and excess hydrazine were removed under vacuum. The crude product was purified by flash chromatography on silica gel (50 to 100% ethyl acetate in heptanes) to yield 111.4 mg (80%) of 3-(3-chlorophenyl)-1H-pyrazol-4-amine LCMS (ESI) m+H=194.0; 1H NMR (400 MHz, CD3OD) δ: 7.75 (broad, 1H), 7.65 (broad, 1H), 7.41 (t, 1H), 7.32 and 7.30 (overlapping s and s, 2H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([S:17]([C:20]3[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=3[CH2:22][NH2:23])(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>[OH-].[Na+].ClCCl>[F:2][C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([S:17]([C:20]3[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=3[CH2:22][NH:23][S:29]([CH3:28])(=[O:31])=[O:30])(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[CH:7][CH:8]=1
Reactant: NCc1ccccc1S(=O)(=O)c1ccc(/C=C/c2ccc(F)cc2)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CS(=O)(=O)NCc1ccccc1S(=O)(=O)c1ccc(/C=C/c2ccc(F)cc2)cc1
Reaction time: 0.5 h
Yield: 22.4 %

Procedure:
[2-({4-[(E)-2-(4-Fluorophenyl)vinyl]phenyl}sulfonyl)benzyl]amine hydrochloride (Example 178, 120 mg, 0.3 mmol) was added to a rapidly stirred mixture of methanesulfonyl chloride (50 μL, 0.6 mmol) in 1M sodium hydroxide (3 mL) and dichloromethane (3 mL). After 30 minutes, further methanesulfonyl chloride (100 μL, 1.2 mmol) and 4M sodium hydroxide (1 mL) were added and the reaction stirred for 30 minutes. The layers were separated and the organic layer washed with 1N HCl, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 60% ethyl acetate/isohexane to give the title compound as a white solid (30 mg, 22%). δH (500 MHz, d6 DMSO): 8.10 (1H, d, J=7.9 Hz), 7.90 (2H, d, J=8.4 Hz), 7.80 (2H, d, J=8.4 Hz), 7.75-7.67 (4H, m), 7.59 (1H, t, J=7.3 Hz), 7.55 (1H, s), 7.44 (1H, d, J=16.4 Hz), 7.29 (1H, d, J=16.5 Hz), 7.22 (2H, t, J=8.8 Hz), 4.44 (2H, s), 2.89 (3H, s).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1>[F:16][C:13]1[CH:12]=[CH:11][C:10]([C:7]2[S:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][CH:8]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(-c2ccc(F)cc2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(-c2ccc(F)cc2)s1
Temperature: 60 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
To a solution of 2-methoxycarbonyl-5-(4-fluorophenyl)thiophene (1.15 g) in methanol (10 ml) and tetrahydrofuran (10 ml) was added an aqueous solution of sodium hydroxide (1N, 7.3 ml) followed by stirring at 60° C. for 3 hours. To the mixture was added hydrochloric acid (1N, 8 ml). The resulting precipitate was collected by filtration and dried to give 5-(4-fluorophenyl)thiophene-2-carboxylic acid (1.06 g, 98.1%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH:13]=[O:14])=[N:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:15]([Mg]Br)[CH3:16].C(OCC)C>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([CH:13]([OH:14])[CH2:15][CH3:16])=[N:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CC[Mg]Br
Reactant: O=Cc1nnc(-c2ccc(F)cc2)s1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(O)c1nnc(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
To a solution of 5-(4-fluorophenyl)-1,3,4-thiadiazole-2-carbaldehyde (0.2 g, 0.961 g mmol) in THF (8 mL) was added ethyl magnesium bromide in diethyl ether (3.0 M; 0.96 mL, 2.88 mmol) at 0° C., the reaction mixture was allowed to warm to room temperature and the mixture then stirred for 2 h. The reaction mixture was quenched with saturated ammonium chloride solution (15 mL) and water (15 mL), extracted with ethyl acetate (100 mL), dried over sodium sulfate and concentrated under reduced pressure to afford 1-(5-(4-fluorophenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol as yellow solid (0.1 g, 45% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.0-8.03 (m, 1H), 7.39-7.35 (m, 2H), 6.36 (d, 1H), 4.92-4.89 (m, 1H), 1.89-1.78 (m, 2H), 0.95 (t, 3H); LC-MS m/z calculated for [M+H]+239.06. found 239.1.