Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[N:7][C:6]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:5]=2[C:4]=1[NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[CH3:23][C:24]([O:27][C:28]([NH:30][C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33](O)=[O:34])=[O:29])([CH3:26])[CH3:25].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C)C=O>[CH2:14]([N:11]1[C:6]2=[N:7][C:8]([CH2:9][CH3:10])=[C:3]([CH2:2][NH:1][C:33]([C:32]3[CH:36]=[CH:37][CH:38]=[CH:39][C:31]=3[NH:30][C:28](=[O:29])[O:27][C:24]([CH3:25])([CH3:23])[CH3:26])=[O:34])[C:4]([NH:16][CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[C:5]2[CH:13]=[N:12]1)[CH3:15]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1C(=O)O
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccccc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.3 %

Procedure:
A mixture of Intermediate 7 (250 mg, 0,83 mmol) and 2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)benzoic acid (196 mg, 0.83 mmol, e.g. available from Fluka) in N,N-dimethylformamide (4 ml) was treated with N,N-diisopropylethylamine (0.569 ml, 3.3 mmol) and (1H-1,2,3-benzotriazol-1-yloxy)(tri-1-pyrrolidinyl)phosphonium hexafluorophosphate (472 mg, 0.91 mmol) and allowed to stir at room temperature for 4 hours. An additional portion of (1H-1,2,3-benzotriazol-1-yloxy)(tri-1-pyrrolidinyl)phosphonium hexafluorophosphate (0.5 equiv., 0.41 mmol) was added and the mixture stirred for an additional hour. The solvent was evaporated and the residue dissolved in ethyl acetate (50 ml) and washed with aqueous sodium bicarbonate solution (2×50 ml); the organic fraction was dried (Na2SO4) and evaporated. The residue was purified by chromatography on silica gel (50 g SPE cartridge), eluting with a gradient of 0-100% ethyl acetate/cyclohexane followed by a gradient of 0-20% methanol/ethyl acetate over 40 minutes. Fractions containing product were pooled and evaporated to give the title compound (292 mg). LCMS showed MH+=523; TRET=2.71 min.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[N:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[C:8]1([C:7]2[CH:6]=[C:5]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:4]=[N:3][C:2]=2[N:29]2[CH2:30][CH2:31][N:26]([C:21]3[N:20]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:27][CH2:28]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: Clc1nnc(-c2ccccc2)cc1-c1ccccc1
Product: c1ccc(-c2cc(-c3ccccc3)c(N3CCN(c4ncccn4)CC3)nn2)cc1
Reaction time: 72 h
Yield: 81.1 %

Procedure:
A mixture of 3-chloro-4,6-diphenylpyridazine (267 mg, 11.0 mmol), 1-(2-pyrimidyl)piperazine (656 mg, 4.0 mmol) in 3 ml of 1-BuOH was heated with stirring at 130 C for 3 days. The solvent was removed by evaporation in vacuo, the residue was treated with water to give a suspension. The solid was then filtered off, washed with water, dried over filter funnel in vacuo to give light pink solid. (320 mg, 0.81 mmol, yield 81.1%). ESI-MS: m/z 395.5 (M+H+). HRMS calcd 395.1979. found 395.1973. 1H NMR (CDCl3): d 8.329 (d, J=5.0, 2H), 8.101 (d, J=7.5, 2H), 7.734 (d, J=7.5, 2H), 7.655 (s, 1H), 7.509 (m, 6H), 6.530 (t, J=4.5, 1H), 3.836 (t, J=4.5, J=5.0, 4H), 3.394 (t, J=5.0, J=4.5, 4H).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([O:8][C@@H:9]([CH3:16])[C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:7])(=[O:3])[CH3:2]>C(OCC)(=O)C.C(Cl)(Cl)Cl>[C:1]([NH:4][C@@H:5]1[C@H:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C@H:9]([CH3:16])[O:8][C:6]1=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C1=C(NC(C)=O)C(=O)O[C@H]1C
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@@H]1[C@H](C)OC(=O)[C@@H]1NC(C)=O
Reaction time: 21 h

Procedure:
0.45 g of rhodium/Al2O3 catalyst is added to 15 g of (S)-2-acetamido-3-ethoxycarbonyl-2-penten-4-olide dissolved in 100 ml of ethyl acetate and the whole is hydrogenated at 50° C. and 50 bars for 21 hours and worked up as in Example 14. The ratio of the diastereoisomers of the crude product exhibited by HPLC analysis is (2R,3S,4S):(2S,3R,4S):(2R,3R, 4S)=approximately 85:13:2. Diastereoisomerically pure title compound is obtained by crystallisation from ethyl acetate, [α]D20 =-183.2° (3% in CHCl3), m.p. 165°-167° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[O:6][CH2:7][C:8](=O)[C:9]#[C:10][C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].O.[NH2:30][NH2:31]>CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[O:6][CH2:7][C:8]1[NH:31][N:30]=[C:10]([C@@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:9]=1
Reactant: NN
Reactant: COc1ccc(OCC(=O)C#C[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1OC
Solvent: O
Solvent: CCO
Product: COc1ccc(OCc2cc([C@@H]3CCCN3C(=O)OC(C)(C)C)n[nH]2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an EtOH (10 mL) solution of the compound (395 mg) obtained in Example 14-(2), hydrazine hydrate (63 μL) was added and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated, water (50 mL) was added, and the organic layer extracted with AcOEt (50 mL) was dried (MgSO4), filtered and concentrated to give the titled compound (466 mg, pale brown amorphous.)
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[C:25](=[O:26])[C:14]3[CH:15]=[N:16][C:17]4[C:18]([O:23][CH3:24])=[CH:19][CH:20]=[CH:21][C:22]=4[C:13]=3[N:12]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:11]2=[O:33])[CH:7]=[CH:8][CH:9]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>>[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[C:25](=[O:26])[C:14]3[CH:15]=[N:16][C:17]4[C:18]([O:23][CH3:24])=[CH:19][CH:20]=[CH:21][C:22]=4[C:13]=3[N:12]([CH:27]3[CH2:32][CH2:31][N:30]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:29][CH2:28]3)[C:11]2=[O:33])[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc2c1ncc1c(=O)n(-c3cccc(Cl)c3)c(=O)n(C3CCNCC3)c12
Reactant: CS(=O)(=O)Cl
Agent: Cl
Product: COc1cccc2c1ncc1c(=O)n(-c3cccc(Cl)c3)c(=O)n(C3CCN(S(C)(=O)=O)CC3)c12

Procedure:
3-(3-Chloro-phenyl)-1-(1-methanesulfonyl-piperidin-4-yl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (47 mg) was prepared according to general procedure H from 3-(3-chloro-phenyl)-7-methoxy-1-piperidin-4-yl-1H-pyrimido[5,4-c]quinoline-2,4-dione.dihydrochloride (50 mg, 0.1 mmol) and methanesulfonyl chloride. LCMS: m/z 515 [M+1]+. 1H NMR (400 MHz, CDCl3): δ 9.56 (s, 1H), 7.58 (m, 1H), 7.48 (m, 1H), 7.38 (m, 1H), 7.24 (m, 1H), 7.09-7.18 (m, 2H), 6.48 (m, 1H), 5.06 (m, 1H), 4.10 (s, 3H), 4.02 (m, 2H), 3.80-3.92 (m, 7H), 1.84 (m, 2H) ppm.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][C:14]([OH:16])=O)=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.[Cl-].ClC1N(C)CC[NH+]1C.Cl.[NH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[C:32]([F:41])[CH:31]=1>C(N(CC)CC)C>[CH3:17][C:2]1([CH3:1])[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][C:14]([NH:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[C:32]([F:41])[CH:31]=3)=[O:16])=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Reactant: CC1(C)CCOc2cc(OCC(=O)O)ccc21
Agent: CN1CC[NH+](C)C1Cl
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: CC1(C)CCOc2cc(OCC(=O)NCc3ccc(NS(C)(=O)=O)c(F)c3)ccc21
Yield: 19.7 %

Procedure:
[(4,4-Dimethyl-3,4-dihydro-2H-chromen-7-yl)oxy]acetic acid (118 mg, 0.5 mmol), 2-chloro-1,3-dimethylimidazolinium chloride (CDI) (89 mg, 0.55 mmol), triethylamine (0.33 ml) and N{4-(aminomethyl)-2-fluorophenyl]methanesulfonamide hydrochloride (140 mg, 0.55 mmol) were treated in the same procedure described in Example 2(b). The crude residue was applied to a silica gel chromatography column and eluted with a volume mixture of hexane and ethyl acetate (3/1 to 1/1) to furnish 43 mg (20% yield) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C)(C)C.[C:20]([O:24][C:25](OC([O-])=O)=[O:26])([CH3:23])([CH3:22])[CH3:21]>[OH-].[Na+]>[C:20]([O:24][C:25](=[O:26])[NH:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)NC1CCN(Cc2ccccc2)CC1
Yield: 82.8 %

Procedure:
1-Benzylpiperidin-4-ylamine (3 g, 15.8 mmol) as a starting material was dissolved in 1M aqueous sodium hydroxide solution (35.8 ml) and t-butanol (32 ml) in a 250 ml vessel, and t-butyl-dicarbonate ((t-Boc)2O; 3.79 g, 17.38 mmol) was added thereto while stirring. The resulting mixture was reacted at room temperature for 12 hrs. After the completion of reaction, the reaction mixture was extracted with ethyl acetate twice. The organic layer was separated, washed with 0.1N hydrochloric acid aqueous solution and brine in order, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography to obtain 3.801 g of the title compound as a white solid (82.8%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[C:19]2[C:14](=[C:15]([F:20])[CH:16]=[CH:17][CH:18]=2)[NH:13][N:12]=1.[H-].[Na+].[CH2:23](Br)[CH:24]=[CH2:25]>>[CH2:25]([N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[C:11]([C:4]2[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=2[O:2][CH3:1])=[N:12]1)[CH:24]=[CH2:23]
Reactant: COc1ccc(-c2n[nH]c3c(F)cccc23)c(OC)c1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Product: C=CCn1nc(-c2ccc(OC)cc2OC)c2cccc(F)c21
Yield: 57.6 %

Procedure:
Prepared according to Method D step B from 3-(2,4-dimethoxyphenyl)-7-fluoro-1H-indazole (0.300 g, 1.10 mmol), sodium hydride (60% in oil, 0.058 g, 1.50 mmol) and allyl bromide(0.173 mL, 2.00 mmol) to give the title compound (0.198 g) as a white solid.
Reaction SMILES: [N:1]1([C:6]2[CH:26]=[CH:25][C:9]([CH2:10][C:11]3[C:12]([CH3:24])=[C:13]([F:23])[C:14]([CH:21]=C)=[C:15]([CH:20]=3)[C:16]([O:18][CH3:19])=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.CC(C)=[O:29].C(#N)C.I([O-])(=O)(=O)=O.[Na+]>[Os]=O.O>[N:1]1([C:6]2[CH:26]=[CH:25][C:9]([CH2:10][C:11]3[C:12]([CH3:24])=[C:13]([F:23])[C:14]([CH:21]=[O:29])=[C:15]([CH:20]=3)[C:16]([O:18][CH3:19])=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: C=Cc1c(C(=O)OC)cc(Cc2ccc(-n3cccn3)cc2)c(C)c1F
Reactant: CC(C)=O
Agent: O=[Os]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(C)c(F)c1C=O
Reaction time: 8 h

Procedure:
To a mixture of methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-3-fluoro-4-methyl-2-vinylbenzoate (0.21 g), acetone (2.3 mL), acetonitrile (2.3 mL) and water (2.3 mL) were added osmium oxide (fixed catalyst I) (0.08 g) and sodium periodate (0.63 g) at room temperature, and the mixture was stirred overnight at the same temperature. The insoluble substance was removed by filtration, and the filtrate was diluted with ethyl acetate. The solution was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.21 g) as a crude product. This compound was used in the next step without an additional purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.Cl.[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([CH2:22][CH2:23][NH2:24])=[CH:21][C:16]=2[O:15][CH2:14]1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>CN(C=O)C>[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([CH2:22][CH2:23][NH:24][C:9](=[O:11])[CH2:8][C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)=[CH:21][C:16]=2[O:15][CH2:14]1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: O=C(O)Cc1ccc(Br)cc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Cc1ccc(Br)cc1)NCCc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-bromophenyl acetic acid 34 (2.000 g, 9.300 mmol) and 2-benzo[1,3]dioxol-5-yl-ethylamine hydrochloride salt 33 (2.063 g, 10.230 mmol) in anhydrous DMF (25 mL) was added triethyl amine (2.823 g, 27.900 mmol) followed by diethyl cyanophosphonate (1.669 g, 10.230 mmol) at 00 C and the reaction mixture was stirred at room temperature overnight, poured into ice-water. The precipitated was filtered, washed with water and air-dried. The crude product was recrystallized using CHCl3-Hexane to get compound 35 as a white sold (3.133 g, 93%). 1H NMR (300 MHz, DMSO-d6) δ 8.06 (t, J=5.1 Hz, 1H, —NH), 7.47 (d, J=8.4 Hz, 2H, ArH), 7.16 (d, J=8.1 Hz, 2H, ArH), 6.79 (d, J=7.8 Hz, 1H, ArH), 6.74 (s, 1H, ArH), 6.60 (d, J=7.8 Hz, 1H, ArH), 5.96 (s, 2H, —CH2), 3.35 (s, 2H, —CH2), 3.32 (q, J=6.9 Hz, 2H, —CH2), 2.60 (t, J=7.2 Hz, 2H, —CH2). MS (ES+) m/z 384 (M+Na)+.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.Cl.[O:27]1[CH2:32][CH2:31][N:30]([CH:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:34]([OH:36])=[O:35])[CH2:29][CH2:28]1.[N:43]12[CH2:50][CH2:49][CH:46]([CH2:47][CH2:48]1)[C@@H:45](O)[CH2:44]2>C1COCC1>[O:27]1[CH2:28][CH2:29][N:30]([CH:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:34]([O:36][C@@H:45]2[CH:46]3[CH2:49][CH2:50][N:43]([CH2:48][CH2:47]3)[CH2:44]2)=[O:35])[CH2:31][CH2:32]1
Reactant: O[C@H]1CN2CCC1CC2
Reactant: O=C(O)C(c1ccccc1)N1CCOCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(c1ccccc1)N1CCOCC1
Reaction time: 8 h
Yield: 23.5 %

Procedure:
PS-DCC (loading: 1.25 mmol/g; 0.93 g, 1.16 mmol) was suspended in dry THF (11.6 ml) and HOBT (0.18 g, 1.16 mmol), 2-morpholino-2-phenylacetic acid hydrochloride (0.15 g, 0.58 mmol) and (R)-quinuclidin-3-ol (0.22 g, 1.75 mmol) were sequentially added. The mixture was shaken overnight and then PS-DCC was filtered off washing with EtOAc and THF. The solution was evaporated and the residue was dissolved in EtOAc (30 ml) and washed with water and then with a sat. NaHCO3. The organic phase was dried (Na2SO4), filtered and evaporated. The crude was purified by flash chromatography (DCM/MeOH=95/5 to 85/15) to obtain (R)-quinuclidin-3-yl 2-morpholino-2-phenylacetate (45 mg, 23.4% yield) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][C:7]2(O)[CH2:10][CH:9]([C:11]([OH:13])=[O:12])[CH2:8]2)=[CH:4][CH:3]=1.[C-]#[N:18].[K+].OS(O)(=O)=O.[C:25]([OH:31])(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][C:7]2([NH:18][CH:25]=[O:31])[CH2:10][CH:9]([C:11]([OH:13])=[O:12])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: O=C(O)C(F)(F)F
Reactant: O=C(O)C1CC(O)(Cc2ccc(Cl)cc2)C1
Reactant: [C-]#N
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=CNC1(Cc2ccc(Cl)cc2)CC(C(=O)O)C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 45 %

Procedure:
A solution of 3-(4-chlorobenzyl)-3-hydroxycyclobutanecarboxylic acid (1 g, 4.17 mmol) in TFA (17.5 mL) was charged with KCN (813 mg, 12.5 mmol), cooled to 0° C. and treated with H2SO4 (3.5 mL) dropwise. The cooling bath was removed and stirring was continued for 1.5 h. Once the reaction was complete, the mixture was re-cooled to 0° C. diluted with water, and extracted with diethyl ether. The organic layer was washed successively with 1M NaOH and saturated aqueous sodium chloride. The solution was dried over MgSO4, filtered and concentrated. Purification by flash column chromatography (gradient 1-20% methanol in dichloromethane) afforded the subject compound (500 mg, 45% yield). 1H NMR (DMSO-d6, 600 MHz) δ 12.15 (bs, 1H), 8.38 (s, 1H), 7.88 (d, J=1.13 Hz, 1H), 7.36-7.32 (m, 4H), 2.94-2.89 (m, 1H), 2.57-2.53 (m, 1H), 2.36-2.32 (m, 1H), 2.26-2.22 (m, 1H), 2.03-1.96 (m, 1H), 1.95-1.88 (m, 2H). ESI MS found for C13H14ClNO3 m/z [266.1 (M−1)].
Reaction SMILES: CS([C:5]([CH2:12][C:13](=[O:15])[O-:14])([CH2:7][N+:8]([CH3:11])([CH3:10])[CH3:9])[OH:6])(=O)=O.[N-:16]=[N+:17]=[N-:18]>>[N:16]([C:5]([CH2:12][C:13](=[O:15])[O-:14])([CH2:7][N+:8]([CH3:11])([CH3:10])[CH3:9])[OH:6])=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: C[N+](C)(C)CC(O)(CC(=O)[O-])S(C)(=O)=O
Product: C[N+](C)(C)CC(O)(CC(=O)[O-])N=[N+]=[N-]

Procedure:
A process for producing aminocarnitine is described, wherein methanesulfonylcarnitine is converted to a lactone which is reacted with an azide to give azidocarnitine. The catalytic hydrogenation of azidocarnitine gives aminocarnitine.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[NH2:12][C:13]1[CH:14]=[C:15]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:35])([CH3:34])[CH2:26][NH:27][S:28]([CH:31]([CH3:33])[CH3:32])(=[O:30])=[O:29])=[CH:21][CH:20]=2)[CH:16]=[CH:17][CH:18]=1.C(Cl)Cl.Cl[CH2:40][S:41](Cl)(=[O:43])=[O:42]>O>[F:35][C:25]([C:22]1[CH:21]=[CH:20][C:19]([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([NH:12][S:41]([CH3:40])(=[O:43])=[O:42])[CH:14]=2)=[CH:24][CH:23]=1)([CH3:34])[CH2:26][NH:27][S:28]([CH:31]([CH3:32])[CH3:33])(=[O:30])=[O:29]
Reactant: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(-c2cccc(N)c2)cc1
Reactant: O=S(=O)(Cl)CCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: O
Product: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(-c2cccc(NS(C)(=O)=O)c2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 26.5 %

Procedure:
A 50 mL flask fitted with a stirrer and thermometer was charged with DBU (67 mg, 1.1 eq), {2-[4-(3-aminophenyl)phenyl]-2-fluoropropyl}[(methylethyl)sulfonyl]amine (140 mg, 0.44 mmol, prepared in example 5) and methylene chloride (10 mL) under an atmosphere of nitrogen, and cooled to 0° C. To this stirring solution was added dropwise chloro-methane sulfonyl chloride (69 mg, 1.5 eq). The reaction was allowed to warm to room temperature and stirred overnight at this temperature. In the morning, the mixture was poured into H2O and the layers were separated. The organic layer was washed once with H2O, dried over anhydrous Na2SO4, filtered, and concentrated under reduced vacuum to yield the crude material (192 mg) as a yellow oil. This crude material was purified via silica gel chromatography employing the Chromatotron using a 4000 micron rotor and eluting with a solvent of Methylene Chloride/ethyl acetate 9:1 to yield the title compound (50 mg, 29%) as a white foam. Ion spray mass spectra 427.1 (M*−1).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]([F:37])([F:36])[O:15][C:16]1[CH:17]=[C:18]([CH:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:35])([F:34])[F:33])[CH:26]=2)[C:23]#[N:24])[CH:19]=[CH:20][CH:21]=1.[CH2:38](Br)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C1COCC1>[C:39]1([CH2:38][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:35])([F:34])[F:33])[CH:26]=2)([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([O:15][C:14]([F:36])([F:37])[F:13])[CH:17]=2)[C:23]#[N:24])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: BrCc1ccccc1
Reactant: N#CC(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: N#CC(Cc1ccccc1)(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Reaction time: 0.08 h
Yield: 97.7 %

Procedure:
To a solution of diisopropyl amine (2.48 mL, 17.5 mmol) in THF (60 mL) at −78° C. was added dropwise n-BuLi (1.6 M in hexane, 11.5 mL, 18.3 mmol) and the reaction mixture was stirred for 5 min. A solution of (2,2-bis(3-(trifluoromethoxy)phenyl)acetonitrile (5.51 g, 15.3 mmol), prepared as described in Procedure 14, in THF (5 mL) was added dropwise to the reaction mixture and stirred for 1h. Benzyl bromide (2.17 mL, 18.3 mmol) was added dropwise, then the cooling bath was removed and the reaction mixture was stirred at rt for 45 min. The reaction mixture was poured into H2O (75 mL) and extracted with diethyl ether (2×75 mL). The combined organic portions were dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue. The residue was purified on a silica gel ISCO cartridge with elution at 5 to 15% Et2O/hexane to give 3-phenyl-2,2-bis(3-(trifluoromethoxy)phenyl)propanenitrile (6.75 g, 98% yield) as a clear yellow oil. LCMS: RT=2.18 min [M-CN] 425.1 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); NMR: 400 MHz 1H(CDCl3) ppm 3.63 (s, 2 H), 6.87 (d, J=7.03 Hz, 2 H), 7.15-7.26 (m, 9 H), 7.40 (t, J=8.13 Hz, 2 H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]([O:14][CH3:15])=[O:13].[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22](Cl)(=[O:24])=[O:23].N1C=CC=CC=1>ClCCl>[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([NH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]([O:14][CH3:15])=[O:13])(=[O:24])=[O:23]
Reactant: O=S(=O)(Cl)c1ccccn1
Reactant: COC(=O)c1c(N)ccc2ccccc12
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1c(NS(=O)(=O)c2ccccn2)ccc2ccccc12
Reaction time: 0.25 h
Yield: 83.5 %

Procedure:
A solution of methyl 2-amino-1-naphthoate (85 mg, 0.42 mmol) and 2-pyridinesulfonyl chloride (244 mg, 1.3 mmol) in dichloromethane (1.0 mL) was treated with pyridine (0.15 mL, 1.3 mmol), stirred for 15 minutes, treated with dichloromethane (30 mL), washed with 1N HCl (2×20 mL), and concentrated. The crude product was chromatographed on a silica gel column eluting with 30% ethyl acetate/hexanes to provide the desired product (120 mg, 83.5%). 1H NMR (CDCl3) δ 4.09 (s, 3H), 7.35-7.55 (m, 3H), 7.75-7.96 (m, 5H), 8.16 (d, 1H), 8.59 (d, 1H), 9.46 (s, 1H); MS (DCI/NH3) m/e 343 (M+H)+.
Reaction SMILES: [NH:1]([C:3]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([CH3:12])=[CH:11][C:5]=2[N:4]=1)[NH2:2].[C:13]([CH:16]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[C:17](OCC)=[O:18])(=O)[CH3:14]>>[Cl:30][C:25]1[CH:24]=[C:23]([CH2:22][C:16]2[C:13]([CH3:14])=[N:2][N:1]([C:3]3[NH:7][C:6]4[CH:8]=[CH:9][C:10]([CH3:12])=[CH:11][C:5]=4[N:4]=3)[C:17]=2[OH:18])[CH:28]=[CH:27][C:26]=1[Cl:29]
Reactant: Cc1ccc2[nH]c(NN)nc2c1
Reactant: CCOC(=O)C(Cc1ccc(Cl)c(Cl)c1)C(C)=O
Product: Cc1ccc2[nH]c(-n3nc(C)c(Cc4ccc(Cl)c(Cl)c4)c3O)nc2c1

Procedure:
Using 2-hydrazino-5-methyl-1H-benzimidazole (4) obtained in Example 1, step 3 and ethyl 2-acetyl-3-(3,4-dichlorophenyl)propanoate (35), and by a method similar to that in Example 1, step 4, 4-[(3,4-dichlorophenyl)methyl]-3-methyl-1-(5-methyl-1H-benzimidazol-2-yl)-1H-pyrazol-5-ol (36) was obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[C:20]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)#[N:21]>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:26]1[CH:27]=[C:22]([CH:23]=[CH:24][CH:25]=1)[C:20]#[N:21])=[N:3][C:4]([NH:14][C:15]1[CH:19]=[CH:18][NH:17][N:16]=1)=[CH:5]2
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Reactant: N#Cc1cccc(B(O)O)c1
Product: COc1ccc2c(-c3cccc(C#N)c3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 3-cyano phenylboronic acid to give 3-[6-methoxy-3-(1H-pyrazol-3-ylamino)-isoquinolin-1-yl]-benzonitrile. LC-MS m/e 342(MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH:5]([OH:11])[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[CH3:2].CCN(C(C)C)C(C)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:22][S:23]([O:11][CH:5]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:12])(=[O:25])=[O:24]
Reactant: CCOC(=O)C(O)c1cccs1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(OS(C)(=O)=O)c1cccs1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Hydroxy-thiophen-2-yl-acetic acid ethyl ester (4.58 g, 24.6 mmol) is dissolved in dry DCM (125 mL) and cooled at 0° C. DIPEA (5.15 mL, 29.5 mmol) and methanesulphonyl chloride (2.11 mL, 27.1 mmol) are added and the resulting solution is stirred at RT for 1 hour. DIPEA (0.859 ml, 4.92 mmol) and methanesulphonyl chloride (0.19 mL, 2.46 mmol) are added again. After being stirred at room temperature for 1 additional hour, a third portion of DIPEA (0.43 mL, 2.46 mmol) and methanesulphonyl chloride (77 ul, 0.98 mmol) is added. After 1 hour the reaction is completed. The mixture is diluted with DCM, washed with sat. NaHCO3, water and brine, dried (Na2SO4), filtered and evaporated. The resulting yellow oil is used in the next step without any further purification.