Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])[C:5]([C:17]([O:19][CH2:20][CH:21]2[CH2:23][CH2:22]2)=[O:18])=[C:4]([CH3:24])[NH:3]1.[H-].[Na+].Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>O1CCCC1.[Na+].[Cl-]>[CH3:1][C:2]1[N:7]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])[C:5]([C:17]([O:19][CH2:20][CH:21]2[CH2:23][CH2:22]2)=[O:18])=[C:4]([CH3:24])[N:3]=1
Reactant: CCOC(=O)Cl
Reactant: CC1=C(C(=O)OCC2CC2)C(c2ccccc2[N+](=O)[O-])=NC(C)N1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)N1C(C)=NC(C)=C(C(=O)OCC2CC2)C1c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 60 %

Procedure:
270 mg (0.82 millimole) of 2,6-Dimethyl-5-cyclopropylmethoxycarbonyl-4-(2-nitrophenyl)-dihydropyrimidine in 4 ml of anhydrous tetrahydrofuran was added to 47 mg (0.98 millimole) of sodium hydride as 50% suspension in oil and stirred at room temperature for 5 minutes. Ethyl chloroformate (120 μl), 1.32 millimole) was added and stirred at room temperature for 30 minutes. The reaction solution was diluted with saturated aqueous NaCl solution and extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure to remove the solvent. The residue was purified on silica gel by thin layer chromatography (developer:chloroform/acetone 10:1, eluant : chloroform/methanol 4:1) to obtain 196 mg (yield 60%) of title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[CH3:17])O)=[C:4]([CH3:18])[CH:3]=1.S(Cl)(Cl)=O.[N:23]1([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C([O-])([O-])=O.[K+].[K+]>[Cl-].[Na+].O.C(#N)C.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[CH3:17])[N:26]2[CH2:25][CH2:24][N:23]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:28][CH2:27]2)=[C:4]([CH3:18])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C(O)c1ccc(Cl)cc1C
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CC#N
Product: Cc1cc(Cl)ccc1C(c1ccc(Cl)cc1C)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A round bottom flask was charged with bis(4-chloro-2-methylphenyl)methanol (200 mg, 0.711 mmol) and CH2Cl2 (7 mL). Thionyl chloride (100 μL, 1.37 mmol) was added and the reaction was stirred at room temperature for 24 h. The reaction was concentrated. Acetonitrile was added and the reaction was concentrated two times. Acetonitrile (6 mL), tert-butyl piperazine-1-carboxylate (200 mg, 1.07 mmol) and K2CO3 (200 mg, 1.42 mmol) were added and the reaction was heated to 80° C. for 4 h and 120° C. for 18 h. The reaction was poured into brine and extracted with EtOAc (2×). The residue was chromatographed on a silica gel column (100% hexanes to 20% EtOAc) and yielded the title (184 mg, 57%) as a clear oil. 1H NMR 400 MHz (CDCl3) δ 7.49 (d, J=8.4 Hz, 2H), 7.16 (d, J=8.4 Hz, 2H), 7.11 (s, 2H), 4.65 (s, 1H), 3.44-3.37 (m, 4H), 2.38 (s, 4H), 2.29 (s, 6H), 1.46 (s, 9H). LCMS (ESI, m/z): 471 [M+H]+.
Reaction SMILES: Cl.C.[Cl:3][CH2:4][CH2:5][CH2:6][C:7]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.C([OH:30])C>>[Cl:3][CH2:4][CH2:5][CH2:6][CH:7]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:30].[Cl:3][CH2:4][CH2:5][CH2:6][C:7]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[C:8]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1
Reactant: CCO
Agent: Cl
Agent: Oc1ccc(C(=C(CCCCl)c2ccccc2)c2ccccc2)cc1
Product: O=C(c1ccccc1)C(CCCCl)c1ccccc1

Procedure:
The evaporation residue obtained in Example 24(b) is dissolved in 300 ml of ethanol, after which 10 ml of concentrated hydrochloric acid is added. The mixture is refluxed for 30 min. The solution is treated with charcoal, and filtered. The solvent is evaporated giving a mixture of the (Z)- and (E)-isomers. The isomer mixture is recrystallized from petrol ether to give 7.7 g (22% from 5-chloro-1,2-diphenylpentan-1-one) of the (Z)-isomer, m.p. 116°-8° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([C:15]3[C:19](=[O:20])[C:18]([CH3:22])([CH3:21])[O:17][N:16]=3)[CH:11]=[CH:12][C:13]=2[CH3:14])=[N:6][CH:7]=1.[O:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH:25]=[C:24]1[C:32](O)=[O:33]>>[CH3:21][C:18]1([CH3:22])[O:17][N:16]=[C:15]([C:10]2[CH:11]=[CH:12][C:13]([CH3:14])=[C:8]([C:5]3[N:6]=[CH:7][C:2]([NH:1][C:32]([C:24]4[O:23][C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=5[CH:25]=4)=[O:33])=[N:3][CH:4]=3)[CH:9]=2)[C:19]1=[O:20]
Reactant: O=C(O)c1cc2ccccc2o1
Reactant: Cc1ccc(C2=NOC(C)(C)C2=O)cc1-c1cnc(N)cn1
Product: Cc1ccc(C2=NOC(C)(C)C2=O)cc1-c1cnc(NC(=O)c2cc3ccccc3o2)cn1

Procedure:
The title compound was prepared by following a procedure similar to that described in method B of Examples 97 to 118 by using Intermediate 1b and benzofuran-2-carboxylic acid. 1HNMR (400 MHz, CDCl3) δ 9.79 (s, 1H), 9.04 (s, 1H, D2O exchangeable), 8.50 (s, 1H), 8.21 (d, J=2.0 Hz, 1H), 8.09 (dd, J=8.0, 2.0 Hz, 1H), 7.74 (d, J=7.5 Hz, 1H), 7.70 (s, 1H), 7.59 (dd, J=8.5, 1.0 Hz, 1H), 7.51 (dt, J=7.5, 1.0 Hz, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.36 (dt, J=8.0, 1.0 Hz, 1H), 2.48 (s, 3H), 1.47 (s, 6H); ESI-MS (m/z) 441 (MH)+.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH2:28]([NH2:30])[CH3:29].CN(C=O)C>O>[CH2:28]([NH:30][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1)[CH3:29]
Reactant: CCN
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCNc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 80 °C
Yield: 62.3 %

Procedure:
A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.55 g of potassium carbonate, 0.16 g of ethylamine hydrochloride and 3 ml of DMF was stirred while heating at 80° C. for 4.5 hours. To the mixture, 0.55 g of potassium carbonate, 0.16 g of ethylamine hydrochloride and 2 ml of DMF were added, and the reaction mixture was stirred while heating for further three hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.19 g of ethyl-[4-(5-trifluoromethylbenzoxazole-2-yl)pyridin-3-yl]amine (hereinafter, referred to as “active compound 84”).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:27]>O1CCOCC1>[ClH:27].[CH2:20]([C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:15][CH:16]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Cc3ccccc3)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc(Cc2ccc(N3CCNCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To 4-(4-Benzyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (1.7 g, 4.8 mmol) was added 4 N HCl in dioxane (25 ml). The reaction solution was stirred at rt for 1 h. The resulting precipitate was collected by filtration and washed with ethyl acetate to furnish the title compound (1.45 g, 98%): MS (ESI) m/z 326 (M+1); 1H NMR (400 MHz, DMSO-d6) δ 3.21 (br, 4H), 3.36 (br, 4H), 3.86 (s, 2H), 6.98 (m, 2H), 7.13-7.21 (m, 5H), 7.25-7.29 (m, 2H).
Reaction SMILES: [NH:1]([C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][OH:20])[O:13]2)=[C:5]([NH:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[N:4]=1)[NH2:2].[CH:27]([CH:29]([CH:35]=O)[C:30]([O:32][CH2:33][CH3:34])=[O:31])=O.C(N(C(C)C)CC)(C)C>C(O)C>[OH:17][C@@H:16]1[C@H:15]([OH:18])[C@@H:14]([CH2:19][OH:20])[O:13][CH:12]1[N:9]1[CH:8]=[N:7][C:6]2[C:10]1=[N:11][C:3]([N:1]1[CH:35]=[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:27]=[N:2]1)=[N:4][C:5]=2[NH:21][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: NNc1nc(NC2CCCC2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Reactant: CCOC(=O)C(C=O)C=O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnn(-c2nc(NC3CCCC3)c3ncn(C4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)c1
Temperature: 25 °C

Procedure:
(4S,2R,3R,5R)-2-[2-hydrazino-6-(cyclopentylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol (0.2 mmol) and ethyl 2,2-diformylacetate (0.28 mmol) were suspended in 3 mL of ethanol and to the suspension was added 5 mmol of diisopropylethylamine. The mixture was heated at reflux for 3 hours. Upon cooling to room temperature, the precipitate thus formed was collected by filtration, and washed with ethanol and ether to afford ethyl 1-{9-[(4S,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(cyclopentylamino)purin-2-yl}pyrazole-4-carboxylate, a compound of Formula I.
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[CH:4]([CH:5](OS(C)(=O)=O)[C:6](Cl)([Cl:11])[C:7]([F:10])([F:9])[F:8])[CH:3]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:23]=1[CH3:34])=[O:19]>CN(C=O)C.[Zn]>[CH3:1][C:2]1([CH3:35])[CH:4]([CH:5]=[C:6]([Cl:11])[C:7]([F:8])([F:9])[F:10])[CH:3]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:23]=1[CH3:34])=[O:19]
Reactant: Cc1c(COC(=O)C2C(C(OS(C)(=O)=O)C(Cl)(Cl)C(F)(F)F)C2(C)C)cccc1-c1ccccc1
Agent: [Zn]
Solvent: CN(C)C=O
Product: Cc1c(COC(=O)C2C(C=C(Cl)C(F)(F)F)C2(C)C)cccc1-c1ccccc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 947.5 %

Procedure:
To a solution of 170 mg (0.0307 mmol) of (2-methyl-3-phenylphenyl)methyl 2,2-dimethyl-3-(1-methyloxy-2,2-dichloro-3,3,3-trifluoropropyl)cyclopropane carboxylate obtained in Example 15 and dissolved in 0.5 ml of DMF, 21 mg (0.32 mmol) of zinc powder was added, and the mixture was stirred at 50° C. for 1 hour. The subsequent operation was conducted in the same manner as in Reference Example 9, whereby 123 mg of (2-methyl-3-phenylphenyl)methyl 2,2-dimethyl-3-(2-chloro-3,3,3-trifluoro-1-propenyl)cyclopropanecarboxylate was obtained.
Reaction SMILES: [S:1]1[C:13]2[C:12]3[CH2:11][CH2:10][N:9]([C:14]4[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=4)[C:17]([O:19]C)=[O:18])[CH2:8][C:7]=3[CH:6]=[N:5][C:4]=2[CH:3]=[CH:2]1.[OH-].[Na+]>O1CCOCC1>[S:1]1[C:13]2[C:12]3[CH2:11][CH2:10][N:9]([C:14]4[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=4)[C:17]([OH:19])=[O:18])[CH2:8][C:7]=3[CH:6]=[N:5][C:4]=2[CH:3]=[CH:2]1
Reactant: COC(=O)c1cccc(N2CCc3c(cnc4ccsc34)C2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1cccc(N2CCc3c(cnc4ccsc34)C2)c1
Temperature: 90 °C
Reaction time: 3.5 h

Procedure:
A solution of methyl 3-(8,9-dihydrothieno[3,2-c]-2,7-naphthyridin-7(6H)-yl)benzoate (3.54 g, 10.91 mmol) in 1,4-dioxane (150 ml) was treated with 1.0 N NaOH(aq.) (32.73 ml, 32.73 mmol) and the reaction mixture was stirred at 90° C. for 3.5 hours. The solvent was removed in vacuo and the residue was partitioned between water and diethyl ether. The organic phase was discarded and the aqueous phase was acidified to pH ˜4-5 with 1.0 N HCl(aq.). The resulting precipitate was collected, washed with water, EtOAc, and dried in vacuo at 35° C. to afford the title compound as a yellow, amorphous solid (2.66 g, 79%). MS (APCl): (M+1)+=311;
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH3:10])[N:7]([CH3:11])[C:6]=2[CH:12]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C(Cl)Cl.CC([O-])=O.[K+].Br[C:40]1[S:41][C:42]2[C:48]([C:49]3[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][CH:50]=3)=[C:47]([C@H:56]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])[C:57]([O:59][CH2:60][CH3:61])=[O:58])[C:46]([CH3:67])=[CH:45][C:43]=2[N:44]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].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>[C:63]([O:62][C@@H:56]([C:47]1[C:46]([CH3:67])=[CH:45][C:43]2[N:44]=[C:40]([C:2]3[CH:3]=[CH:4][C:5]4[N:9]=[C:8]([CH3:10])[N:7]([CH3:11])[C:6]=4[CH:12]=3)[S:41][C:42]=2[C:48]=1[C:49]1[CH:50]=[CH:51][C:52]([Cl:55])=[CH:53][CH:54]=1)[C:57]([O:59][CH2:60][CH3:61])=[O:58])([CH3:64])([CH3:65])[CH3:66]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Reactant: Cc1nc2ccc(Br)cc2n1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4nc(C)n(C)c4c3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A microwave vial was charged with 6-bromo-1,2-dimethyl-1H-benzo[d]imidazole (150 mg, 0.67 mmol), Bis(pinacolato)diboron (189 mg, 0.74 mmol), PdCl2(dppf).CH2Cl2 (55 mg, 0.07 mmol), then KOAc (221 mg, 2.25 mmol). The vial was flushed with argon, diluted with dioxane (3 mL), sealed, then heated to 100° C. for 45 minutes. The reaction mixture was allowed to cool to room temperature and then a portion of this cooled solution (1.0 mL, 0.22 mmol) was added to a vial that was charged with (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (55 mg, 0.10 mmol) and Pd(PPh3)4 (12 mg, 0.01 mmol). The mixture was diluted with dioxane (1.5 mL) and to this was added 2M aqueous K2CO3 (0.21 mL, 0.42 mmol). The vial was sealed, heated to 100° C. for 1 hour, and then allowed to cool to room temperature. The mixture was diluted with EtOAc, dried over Na2SO4, filtered through a small pad of silica gel, and concentrated in vacuo to afford the desired product. LCMS-ESI+: calc'd C31H33ClN3O3S: 562.2 (M+H+); Found: 562.3 (M+H+).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH:14]=[CH:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])C.[OH-].[K+]>CO.O>[F:21][C:18]1[CH:17]=[CH:16][C:15]([N:12]2[C:8]3[CH:9]=[N:10][CH:11]=[C:6]([C:4]([OH:5])=[O:3])[C:7]=3[CH:14]=[CH:13]2)=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1cncc2c1ccn2-c1ccc(F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cncc2c1ccn2-c1ccc(F)cc1

Procedure:
To a solution of 1-(4-fluorophenyl)-1H-pyrrolo[2,3-c]pyridine-4-carboxylic acid ethyl ester (650 mg, 2.3 mmol) in methanol (25 mL) is added in several portions a solution of 85% KOH (1.2 g, 18.2 mmol) in water (15 mL). The mixture is warmed at reflux for 30 minutes and is then diluted with water (20 mL) and washed with ether (2×15 mL). The aqueous layer is made acidic (pH=4) with concentrated HCl and the resulting precipitate is collected by filtration washing with water to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[C@@H:23]([NH:25]C(OCC2C=CC=CC=2)=O)[CH3:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(O)=O>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[C@@H:23]([NH2:25])[CH3:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H](NC(=O)OCc1ccccc1)c1nc2ccccc2n1[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: C[C@H](N)c1nc2ccccc2n1[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 83.3 %

Procedure:
A mixture of (R)-3-[2-((S)-1-benzyloxycarbonylaminoethyl)benzoimidazol-1-yl]piperidine-1-carboxylic acid tertbutyl ester (2.75 g, 5.75 mmol) 10% Pd/C (275 mg) and AcOH (4 mL) in EtOAc (40 mL) was purged with a stream of nitrogen and then was stirred at RT for 20 h under an hydrogen atmosphere. The suspension was then filtered through a PTFE frit and the filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) affording (R)-3-[2-((S)-1-Aminoethyl)benzoimidazol-1-yl]piperidine-1-carboxylic acid tertbutyl ester as a white foam (1.65 g, 83%). LCMS: RT 2.30 min [M+H-tBu]+ 289.2.
Reaction SMILES: C(=O)(O)[O-].[NH2:5][NH:6][C:7]([NH2:9])=[NH2+:8].[S:10](=[O:14])(=[O:13])([OH:12])[OH:11].C(=O)=O>O>[S:10]([O-:14])([O-:13])(=[O:12])=[O:11].[NH2:5][NH:6][C:7]([NH2:9])=[NH2+:8].[NH2:5][NH:6][C:7]([NH2:9])=[NH2+:8]
Reactant: O=S(=O)(O)O
Agent: NNC(N)=[NH2+]
Agent: O=C([O-])O
Agent: O=C=O
Solvent: O
Product: O=S(=O)([O-])[O-]

Procedure:
Aminoguanidinium bicarbonate (27.2 g of 98.5%, 0.2 mole) was slurried in 150 ml of water. Sulfuric acid (10.2 g of 96%, 0.1 mole) was added over 1/4 hour with the evolution of carbon dioxide. After post-reacting one hour at room temperature, 125 ml of water were vacuum stripped. On cooling a white precipitate formed which was filtered and dried. Obtained were 11 g of product.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:30]([F:33])([F:32])[F:31])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=4)[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:34][NH2:35]>>[Cl:29][C:24]1[CH:23]=[C:22]([C:21]2[C:15]3[O:14][CH:13]([CH2:12][NH:35][CH3:34])[CH2:17][C:16]=3[CH:18]=[C:19]([C:30]([F:33])([F:32])[F:31])[CH:20]=2)[CH:27]=[CH:26][C:25]=1[F:28]
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C(F)(F)F)cc(-c4ccc(F)c(Cl)c4)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cc(C(F)(F)F)cc(-c3ccc(F)c(Cl)c3)c2O1

Procedure:
The title compound was prepared (0.014 g, 19%) following the general procedure of Example 390 as a white solid, hydrochloride salt from [7-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.095 g, 0.19 mmol) and methylamine (0.12 g, 3.9 mmol). mp 229-230° C.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16].Cl.N([O-])=O.[Na+].[I-:26].[K+]>O1CCOCC1.O>[F:16][C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[O:8][C:7]1[CH:6]=[CH:5][C:4]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:3][C:2]=1[I:26]
Reactant: [I-]
Reactant: Nc1cc(S(N)(=O)=O)ccc1Oc1ccc(F)cc1F
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: NS(=O)(=O)c1ccc(Oc2ccc(F)cc2F)c(I)c1
Reaction time: 0.25 h
Yield: 58.5 %

Procedure:
To a solution of Example 146b (2.8 g, 9.32 mmol) in dioxane (20 mL) at 0° C. was added concentrated hydrochloric acid (40 mL, 9.32 mmol). The mixture was stirred 15 minutes and a solution of sodium nitrite (0.772 g, 11.19 mmol) in water (10 mL) was added. The mixture was stirred for 1 hour at 0° C. A solution of potassium iodide (3.10 g, 18.7 mmol) in water (10 mL) was added and stirring was continued 1 hour at ambient temperature. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium thiosulfate, water, and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-60% ethyl acetate in hexane) to provide the title compound (2.24 g, 58.4% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[C@H:11]([CH2:21][C:22]2[N:30]=[CH:29][CH:28]=[CH:27][C:23]=2[C:24](O)=[O:25])[O:10][C:9]1([CH3:32])[CH3:31])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:33]1([NH2:36])[CH2:35][CH2:34]1>>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[C@H:11]([CH2:21][C:22]2[C:23]([C:24](=[O:25])[NH:36][CH:33]3[CH2:35][CH2:34]3)=[CH:27][CH:28]=[CH:29][N:30]=2)[O:10][C:9]1([CH3:32])[CH3:31])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccccc2F)[C@H](Cc2ncccc2C(=O)O)OC1(C)C
Reactant: NC1CC1
Product: CC(C)(C)OC(=O)N1[C@H](Cc2ccccc2F)[C@H](Cc2ncccc2C(=O)NC2CC2)OC1(C)C

Procedure:
Using general reaction procedure 5 with 2-[(4R,5S)-3-tert-butoxycarbonyl-4-(2-fluoro-benzyl)-2,2-dimethyl-oxazolidin-5-ylmethyl]-nicotinic acid (0.3 g, 0.67 mmol) and cyclopropylamine (0.23 mL, 3.4 mmol) gives the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]2[N:15]=[C:16]([CH2:23][CH3:24])[C:17]([NH:18][CH2:19][CH2:20][O:21][CH3:22])=[C:13]2[CH:12]=[CH:11][CH:10]=1.[CH:25](=O)[CH2:26][CH3:27].S(=O)(=O)(O)O.[BH4-].[Na+]>O1CCCC1.C(OCC)C.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]2[N:15]=[C:16]([CH2:23][CH3:24])[C:17]([N:18]([CH2:19][CH2:20][O:21][CH3:22])[CH2:25][CH2:26][CH3:27])=[C:13]2[CH:12]=[CH:11][CH:10]=1
Reactant: CCc1nn2c(-c3ccc(Cl)cc3Cl)cccc2c1NCCOC
Reactant: CCC=O
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CCCN(CCOC)c1c(CC)nn2c(-c3ccc(Cl)cc3Cl)cccc12
Reaction time: 0.5 h

Procedure:
N-[7-(2,4-Dichlorophenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N-(2-methoxyethyl)amine (14 mg) was dissolved in tetrahydrofuran (1 mL), and after adding propionaldehyde (0.016 mL) and 3 M aqueous sulfuric acid (0.77 mL), sodium borohydride (5.8 mg) was added in five portions while vigorously stirring on ice, and stirring was continued for 30 minutes. Water was added to the reaction mixture, extraction was performed with diethyl ether and the extract was washed with saturated aqueous sodium hydrogencarbonate and brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure and the residue was purified by preparative TLC [n-hexane:ethyl acetate (5:1), Rf=0.5] to obtain the title compound (9.5 mg) as a light yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:24]4[O:28][C:27]([CH:29]=O)=[CH:26][CH:25]=4)[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[CH:9][C:8]=1[Cl:31].[CH3:35][P:36]([CH2:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)([CH3:38])=[O:37].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:24]4[O:28][C:27]([CH2:29][N:43]5[CH2:42][CH2:41][N:40]([CH2:39][P:36]([CH3:38])([CH3:35])=[O:37])[CH2:45][CH2:44]5)=[CH:26][CH:25]=4)[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[CH:9][C:8]=1[Cl:31]
Reactant: CP(C)(=O)CN1CCNCC1
Reactant: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CP(C)(=O)CN1CCN(Cc2ccc(-c3ccc4ncnc(Nc5ccc(OCc6cccc(F)c6)c(Cl)c5)c4c3)o2)CC1
Temperature: 25 °C

Procedure:
5-(4-(4-(3-fluorobenzyloxy)-3-chlorophenylamino)quinazolin-6-yl)furan-2-carbaldehyde and 1-((dimethylphosphinoyl)methyl)piperazine were suspended in dichloromethane (20 mL). Sequentially, acetic acid (3 drops) and sodium triacetoxyborohydride (2 equiv.) were added at room temperature. The mixture was stirred at room temperature until the starting material disappeared. The reaction was quenched with 2N NaOH aqueous solution and extracted with dichloromethane. The combined organic layer and extracts were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography, eluting with 20% methanol in dichloromethane to give the desired product as yellow crystalline solid. LCMS ESI(+) m/z: 635 (M+1). 1H NMR (300 MHz, CD3OD) δ 8.59 (s, 1H), 8.44 (s, 1H), 8.11 (m, 1H), 7.89 (m, 1H), 7.72 (m, 1H), 7.57 (m, 1H), 7.38 (m, 1H), 7.26 (m, 2H), 7.08 (m, 2H), 6.90 (d, 1H), 6.46 (d, 1H), 5.17 (s, 2H), 3.66 (s, 2H), 2.80 (m, 2H), 2.68 (m, 8H), 1.57 (d, 6H).