Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13])(=[O:5])=[O:4].[F:15][C:16]([F:20])=[C:17]([F:19])[F:18].[OH-].[K+].O>CN(C)C=O>[CH3:1][N:2]([C:17]([F:19])([F:18])[CH:16]([F:20])[F:15])[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13])(=[O:5])=[O:4]
Reactant: FC(F)=C(F)F
Reactant: CNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(F)(F)C(F)F)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 80.8 %

Procedure:
A solution of 72 g of N-methyl-2-nitrobenzenesulfonamide, 35 g of tetrafluoroethylene and 4 g of powdered potassium hydroxide in 150 ml of dimethylformamide was heated at 85° for 3 hours in a pressure vessel. The reaction mixture was cooled to 25° and poured into 800 ml of water. A heavy oil was separated and the aqueous layer extracted with 150 ml of 1-chlorobutane. The heavy oil, the 1-chlorobutane extract and an additional 300 ml of 1-chlorobutane were combined and washed three times with water. The organic solution was dried over magnesium sulfate and concentrated in-vacuo to yield 85.1 g of N-methyl-N-(1,1,2,2-tetrafluoroethyl)-2-nitrobenzenesulfonamide as a viscous orange oil.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.[N+:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH:18][CH2:19][CH2:20][CH3:21])(=[O:17])=[O:16])([O-:8])=[O:7].[H-].[Na+].C(Cl)Cl>CN(C=O)C>[Br:1][CH2:2][CH2:3][CH2:4][N:18]([CH2:19][CH2:20][CH3:21])[S:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[N+:6]([O-:8])=[O:7])(=[O:16])=[O:17]
Reactant: BrCCCBr
Reactant: CCCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCN(CCCBr)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 62.4 %

Procedure:
1,3-Dibromopropane (8.5 mL, 82.0 mmol, 10 eq.) was added to a solution of compound 49 (2.0 g, 8.2 mmol) in DMF (20 mL). Then NaH (0.6 g, 15.0 mmol) was added in portions. The temperature rose to 50-60° C. The mixture was stirred at this temperature for 20 min (TLC monitoring, eluent: CH2Cl2). Then the mixture was carefully poured into ice. The product was extracted with ethyl acetate, and the extract was evaporated. The residue was washed from 1,3-dibromopropane with hexane. The resulting product was dissolved in CH2Cl2 and purified on a short thick column with silica gel, eluent: hexane-CH2Cl2 100:0→0:100. Compound 50 (1.87 g, 62%) was isolated as rapidly crystallizable oil.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[N:17]1[CH:18]=[CH:19][C:14]([C:12]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:13]=2)=[CH:15][CH:16]=1
Reactant: N#Cc1ccncc1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1nc(-c2ccncc2)sc2ccccc12
Yield: 30.7 %

Procedure:
Methyl thiosalicylate (2.0 g, 11.9 mM) and 4-cyanopyridine (1.2 g, 11.5 mM) were dissolved in toluene (5 ml), and then triethylamine (2 ml) was added thereto. After heating the mixture under reflux for 22 hours, the same processes as described in Reference Example 1 were performed to give the title compound as crystals (850 mg, 30.7%).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[C:32](Cl)(=[O:35])[CH2:33][CH3:34]>>[C:32]([N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:6][CH2:7]1)(=[O:35])[CH2:33][CH3:34]
Reactant: CCC(=O)Cl
Reactant: O=C(NC1CCNCC1)c1c[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc12
Agent: Cl
Product: CCC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-Cyclopropylmethoxy-4-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A158) and propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[OH:9].[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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:2]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3]([OH:9])=[CH:4][C:5]([OH:6])=[CH:7][CH:8]=1
Reactant: Oc1ccc(Br)c(O)c1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Oc1ccc(-c2ccccc2)c(O)c1
Temperature: 25 °C
Yield: 61 %

Procedure:
The synthesis was performed with reference to the known literature (Journal of Medicinal Chemistry, Vol. 44, p. 664, 2001). A solution of 4-bromoresorcinol (0.42 g, 2.2 mmol) in 1,2-dimethoxyethane (10 mL) was successively added with phenylboronic acid (0.37 g, 3.0 mmol), and 2 M aqueous sodium carbonate (3.5 mL), and the mixture was stirred at room temperature. After the inside of the reaction vessel was replaced with argon, the reaction mixture was added with tetrakis(triphenylphosphine)palladium(0) (0.14 g, 0.12 mmol), and the mixture was stirred at 95° C. for 6 hours in a sealed tube. The reaction mixture was added with ice water, the mixture was extracted with ethyl acetate, and then the organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the residue was subjected to silica gel column chromatography (eluted with hexane/ethyl acetate (75:25)) to obtain biphenyl-2,4-diol (0.25 g, 61%).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].[NH2:15][C@H:16]([CH3:19])[CH2:17][OH:18].C(N(CC)CC)C.CO>>[OH:18][CH2:17][C@H:16]([N:15]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[CH:13][C:4]=2[N+:1]([O-:3])=[O:2])[C:9]1=[O:14])[CH3:19]
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Reactant: C[C@@H](N)CO
Solvent: CCN(CC)CC
Solvent: CO
Product: C[C@H](CO)n1ccc2c([N+](=O)[O-])cccc2c1=O
Temperature: 88 °C
Yield: 40 %

Procedure:
A 250 mL round bottom flask was charged with 5-nitro-isochromen-1-one (40 g, 0.2 mol), (2R)-2-Aminopropan-1-ol (18 g, 0.24 mol), triethylamine (100 mL, 0.7 mol) and methanol (500 mL, 10 mol) and the reaction heated at 88° C. for 1.5 hours. The product precipitated out upon cooling the reaction and was filtered to afford the product as a yellow solid. (17.3 g, 40% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([C@:19]4([C:35](=[O:37])[NH2:36])[CH2:23][CH2:22][CH2:21][N:20]4[C:24](=[O:34])[C@@H:25]([NH:29][C:30](=[O:33])[O:31][CH3:32])[CH:26]([CH3:28])[CH3:27])=[CH:15][CH:14]=3)=[CH:11][CH:10]=[C:9]2[C:38]2[CH:43]=[CH:42][C:41]([C@:44]3([C:60](=[O:62])[NH2:61])[CH2:48][CH2:47][CH2:46][N:45]3[C:49](=[O:59])[C@@H:50]([NH:54][C:55](=[O:58])[O:56][CH3:57])[CH:51]([CH3:53])[CH3:52])=[CH:40][CH:39]=2)=[CH:4][CH:3]=1.[Br:63]N1C(=O)CCC1=O>C(Cl)Cl>[Br:63][C:10]1[CH:11]=[C:12]([C:13]2[CH:18]=[CH:17][C:16]([C@:19]3([C:35](=[O:37])[NH2:36])[CH2:23][CH2:22][CH2:21][N:20]3[C:24](=[O:34])[C@@H:25]([NH:29][C:30](=[O:33])[O:31][CH3:32])[CH:26]([CH3:28])[CH3:27])=[CH:15][CH:14]=2)[N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:9]=1[C:38]1[CH:39]=[CH:40][C:41]([C@:44]2([C:60](=[O:62])[NH2:61])[CH2:48][CH2:47][CH2:46][N:45]2[C:49](=[O:59])[C@@H:50]([NH:54][C:55](=[O:58])[O:56][CH3:57])[CH:51]([CH3:52])[CH3:53])=[CH:42][CH:43]=1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@@]1(C(N)=O)c1ccc(-c2ccc(-c3ccc([C@]4(C(N)=O)CCCN4C(=O)[C@@H](NC(=O)OC)C(C)C)cc3)n2-c2ccc(F)cc2)cc1)C(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N1CCC[C@@]1(C(N)=O)c1ccc(-c2cc(Br)c(-c3ccc([C@]4(C(N)=O)CCCN4C(=O)[C@@H](NC(=O)OC)C(C)C)cc3)n2-c2ccc(F)cc2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.9 %

Procedure:
To a suspension of the product from Example 51 (455 mg, 0.534 mmol) in CH2Cl2 (2.7 mL) was added a mixture of 1-bromopyrrolidine-2,5-dione (95 mg, 0.534 mmol) in CH2Cl2 (2.7 mL). The mixture was stirred overnight at room temperature then concentrated under reduced pressure and triturated with diethyl ether to provide a mixture of compounds that was subjected to reverse phase HPLC purification eluted with a gradient of 60-100% MeOH in 10 mM ammonium acetate to afford the title compound (84 mg, 17% yield). 1H NMR (free base) (400 MHz, DMSO-D6) δ 10.06 (s, 1H), 10.02 (s, 1H), 7.46 (d, J=8.7, 2H), 7.41 (d, J=8.7, 2H), 7.30 (d, J=7.7, 2H), 7.15-7.03 (m, 6H), 6.98 (d, J=8.7, 2H), 6.53 (s, 1H), 4.45-4.33 (m, 2H), 4.01 (t, J=7.7, 2H), 3.85-3.73 (m, 2H), 3.66-3.54 (m, 2H), 3.51 (s, 6H), 2.20-2.05 (m, 2H), 2.03-1.77 (m, 8H), 0.97-0.79 (m, 12H). MS (ESI; M+H) m/z=933.
Reaction SMILES: [Na].[C:2]1([NH:8][CH2:9][C:10]([OH:12])=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C=CC(O)=CC=1)O.[C:21]([O:26][CH2:27][CH:28]1[O:30][CH2:29]1)(=[O:25])[C:22]([CH3:24])=[CH2:23].Cl>O.CO>[OH:30][CH:28]([CH2:27][O:26][C:21](=[O:25])[C:22]([CH3:24])=[CH2:23])[CH2:29][N:8]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][C:10]([OH:12])=[O:11]
Reactant: C=C(C)C(=O)OCC1CO1
Reactant: O=C(O)CNc1ccccc1
Agent: Cl
Agent: Oc1ccc(O)cc1
Agent: [Na]
Solvent: O
Solvent: CO
Product: C=C(C)C(=O)OCC(O)CN(CC(=O)O)c1ccccc1

Procedure:
A sodium salt of N-phenylglycine of 50 g (0.29 mol) was dissolved in water of 50 g and methanol of 50 g and then hydroquinone of 18 mg were added to the resulting solution. This solution was heated up to temperatures of 45° to 50° C. and glycidyl methacrylate of 41 g (0.29 mol) was added dropwise for 20 minutes with stirring followed by stirring for further 2 hours. Water of 200 g was added to the resulting solution and acidified with hydrochloric acid followed by filtering and drying the resulting crystals. N-(2-hydroxy-3-methacryloxypropyl)-N-phenylglycine (hereinafter called GMA-NPG for short) of 45 g was obtained. Then GMA-NPG of 2.0 g, MMA (methyl methacrylate) of 14.0 g, EA (ethyl acrylate) of 2.4 g and MAA (methacrylic acid) of 1.6 g were dissolved in dimethylformamide of 80 g. 20 g of a 1 wt %-solution of benzoyl peroxide in dimethylformamide was added dropwise to the above described solution under an atmosphere of nitrogen at 70° C. followed by stirring for further 6 hours. After cooling, hexane of about 10 times in weight was added to dilute the solution, the resulting polymer being settled and collected, the collected polymer being dissolved in methalethylketone and settled again in hexane, and the settled material being fltered and dried in a vacuum. A white powdery polymer was obtained. The number mean molecular weight of the obtained polymer was 25,000 and its acid value was 75. In addition, it was confirmed from the existence of an absorption having a peak at 300 nm in the UV absorption spectrum of this polymer that GMA was copolymerized with NPG.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([C:18]([CH:21]([CH3:23])[CH3:22])=[N:19][N:20]=2)[CH:17]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[CH:21]([C:18]1[N:16]2[CH:17]=[C:12]([S:11][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[CH2:4][NH2:1])[CH:13]=[CH:14][C:15]2=[N:20][N:19]=1)([CH3:23])[CH3:22]
Reactant: CC(C)c1nnc2ccc(Sc3ccccc3CN=[N+]=[N-])cn12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1nnc2ccc(Sc3ccccc3CN)cn12
Temperature: 25 °C
Reaction time: 12 h
Yield: 60.8 %

Procedure:
To a solution of 6-(2-Azidomethyl-phenylsulfanyl)-3-isopropyl-[1,2,4]triazolo[4,3-a]pyridine (228.0 mg, 0.70 mmol) in THF (2.3 mL) under N2 was added triphenylphosphine (220.0 mg, 0.84 mmol) and water (15.0 μL, 0.84 mmol). The reaction was stirred at ambient temperature under N2 for 12 hours, then warmed to 50° C. for 6 hours. To the reaction mixture was diluted with water, and extracted with ethyl acetate. The extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (10-100% methanol/ethyl acetate), followed by trituration with ethyl acetate/hexane to give the title compound (127 mg, 61%).
Reaction SMILES: [CH:1]12[N:8]([C:9]([C:11]3[S:12][CH:13]=[C:14](Br)[N:15]=3)=[O:10])[CH:5]([CH2:6][CH2:7]1)[CH2:4][O:3][CH2:2]2.C(O)C.[Cl:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[CH:1]12[N:8]([C:9]([C:11]3[S:12][CH:13]=[C:14]([C:24]4[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=4)[N:15]=3)=[O:10])[CH:5]([CH2:6][CH2:7]1)[CH2:4][O:3][CH2:2]2
Reactant: O=C(c1nc(Br)cs1)N1C2CCC1COC2
Reactant: OB(O)c1ccc(Cl)cc1
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C(c1nc(-c2ccc(Cl)cc2)cs1)N1C2CCC1COC2
Temperature: 92.5 °C
Yield: 51.9 %

Procedure:
To a solution of 3-oxa-8-azabicyclo[3.2.1]octan-8-yl(4-bromothiazol-2-yl)methanone (Step-1 of compound 68, 0.35 g, 1.15 mmol) in a mixture of toluene:ethanol (2.5 ml: 7.5 ml) were added (4-chlorophenyl) boronic acid (0.2 g, 1.27 mmol) and potassium carbonate (0.34 g, 2.42 mmol) at 25° C. in a tube, nitrogen gas was bubbled through reaction mixture for 15 minutes. To the reaction mixture was added tetrakis(triphenylphosphine)palladium(0) (0.07 g, 0.06 mmol) under nitrogen, tube was sealed and reaction mixture was heated at 90-95° C. for 18 hr with stirring. The progress of reaction was monitored by TLC. The reaction mixture was cooled to 25° C. and filtered through celite. The residue was washed with ethanol (2×20 ml). The filtrate was concentrated under reduced pressure to obtain a crude product. This crude product was purified by column chromatography over silica gel (100-200 mesh) using 35% ethyl acetate in hexanes as an eluent to obtain the title compound (0.2 g, 51.7%). MS: m/z 335 (M+1).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3([C:14]4[N:18]5[N:19]=[C:20]([C:23](=O)[CH3:24])[CH:21]=[CH:22][C:17]5=[N:16][N:15]=4)[CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.[CH3:30][N:31]([C:33]([NH2:35])=[O:34])[NH2:32]>CO>[CH3:30][N:31]([C:33]([NH2:35])=[O:34])/[N:32]=[C:23](/[C:20]1[CH:21]=[CH:22][C:17]2[N:18]([C:14]([C:11]3([C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:1]=[CH:2][CH:3]=[CH:4]5)[CH2:12][CH2:13]3)=[N:15][N:16]=2)[N:19]=1)\[CH3:24]
Reactant: CN(N)C(N)=O
Reactant: CC(=O)c1ccc2nnc(C3(c4ccc5ncccc5c4)CC3)n2n1
Solvent: CC(=O)O
Solvent: CO
Product: C/C(=N\N(C)C(N)=O)c1ccc2nnc(C3(c4ccc5ncccc5c4)CC3)n2n1
Yield: 40.9 %

Procedure:
A solution of 1-[3-(1-quinolin-6-yl-cyclopropyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]-ethanone (30 mg, 0.091 mmol), acetic acid (0.1 mL) and 1-methylhydrazinecarboxamide (16.2 mg, 0.18 mmol) in methanol (5 mL) was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was diluted with DCM, washed with sat. aqueous NaHCO3. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography in silica gel eluting with a CH2Cl2/MeOH gradient to afford the title compound (14.9 mg, 41%) as yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.84 (dd, 1H), 8.30 (d, 1H), 8.22 (d, 1H), 8.13 (d, 1H), 7.94-7.92 (m, 2H), 7.70 (dd, 1H), 7.49 (dd, 1H), 6.64 (s, 2H), 3.21 (s, 3H), 2.16 (s, 3H), 1.78-1.75 (m, 2H), 1.68-1.65 (m, 2H). LCMS (method A): [MH]+=401, tR=4.11 min.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[CH2:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[C:19]#[N:20])=[O:5])C.O.[OH-].[Li+]>CO>[C:19]([C:13]1[C:12]2[C:16](=[CH:17][CH:18]=[C:10]([CH2:9][CH:7]3[CH2:8][CH:6]3[C:4]([OH:5])=[O:3])[CH:11]=2)[NH:15][CH:14]=1)#[N:20]
Reactant: CCOC(=O)C1CC1Cc1ccc2[nH]cc(C#N)c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#Cc1c[nH]c2ccc(CC3CC3C(=O)O)cc12
Yield: 81.1 %

Procedure:
2-(3-Cyano-1H-indol-5-ylmethyl)-cyclopropanecarboxylic acid ethyl ester (0.62 g, 2.31 mmol), methanol (10 ml), and lithium hydroxide monohydrate (0.48 g, 11.6 mmol) were heated at a gentle reflux for 2 h. The solution was concentrated in vacuo and the residue taken up in 1 N hydrochloric acid (30 ml) and extracted with ethyl acetate (3×10 ml). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-Cyano-1H-indol-5-ylmethyl)-cyclopropanecarboxylic acid (0.45 g, 81%) as a light brown oil which solidified upon standing. LC-MS: 1.21 min; 263.2 (MNa)+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[OH:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(=O)([O-])O.[Na+]>C1COCC1>[OH:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][N:35]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]3[CH2:21][CH2:20][C:19]4[C:14](=[CH:15][C:16]([C:22]5[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=5)=[CH:17][CH:18]=4)[CH:13]=3)=[O:11])=[CH:5][CH:4]=2)[CH2:34][CH2:33]1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CC3)cc1
Reactant: OCCN1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN4CCN(CCO)CC4)cc2)CC3)cc1
Temperature: 25 °C

Procedure:
In THF (7ml) was dissolved N-[4-(chloromethyl)-phenyl]-7-(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (150mg), and to the mixture was added 1-(2-hydroxyethyl)piperazine (142 μl). The mixture was refluxed for 22 hours. The reaction mixture was cooled to room temperature, and to the mixture was added 5% sodium hydrogen carbonate solution (50ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give N-[4-[1-(2-hydroxyethyl)-4-piperazinylmethyl]phenyl]-7-(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (Compound 46) (158mg) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH:12]1([CH2:15]O)[CH2:14][CH2:13]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([CH2:15][CH:12]3[CH2:14][CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2[nH]cc(I)c12
Reactant: OCC1CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ncnc2c1c(I)cn2CC1CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (prepared according to: L. B. Townsend et al., J. Med. Chem. 1990, 33 (7), 1984-92) (419 mg, 1.50 mmol), cyclopropylmethanol (165 μL, 147 mg, 2.04 mmol), and PS-PPh3 (2.12 mmol/g; 1.41 g, 2.99 mmol) in dry THF (10 mL), cooled by ice/water, was added DIAD (440 μL, 452 mg, 2.23 mmol; 1.5 equiv.), then the cooling bath was removed and the mixture was vortexed overnight. The resin was filtered off and washed thoroughly with THF, and the filtrate and washings were combined and concentrated. Chromatography of the crude material thus obtained on silica gel (Jones Flashmaster, 2 columns, 10 g/70 mL cartridge each, eluting with CH2Cl2) gave the title compound as an off-white solid. 1H NMR (CDCl3, 400 MHz): δ=0.41-0.47 (m, 2H), 0.63-0.69 (m, 2H), 1.20-1.31 (m, 1H), 4.12 (d, J=7.2 Hz, 2H), 7.52 (s, 1H), 8.61 (s, 1H). MS (ES+): m/z 333.9/335.9 (100/38) [MH+]. HPLC: tR=3.7 min (OpenLynx, polar—5 min).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH2:28]([O:30][CH2:31][CH2:32][NH2:33])[CH3:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:28]([O:30][CH2:31][CH2:32][NH:33][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12])[CH3:29]
Reactant: CCOCCN
Reactant: Cn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(C(F)(F)F)cc3s1)n2C

Procedure:
1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-ethoxy-ethyl)-amide (36 mg) was prepared by following General Procedure F using 1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzo-imidazole-5-carboxylic acid (39 mg), 2-ethoxy-ethylamine (0.1 ml), HBTU (38 mg), and DIEA (0.1 ml). LCMS: m/z 465; and 1H NMR (DMSO-d6, 400 MHz): δ 8.40 (t, 1H), 7.99 (s, 1H), 7.82 (d, 1H), 7.66 (d, 1H), 7.44 (br, 2H), 7.36 (d, 1H), 7.30 (dd, 1H), 3.61 (s, 3H), 3.46 (q, 2H), 3.41 (t, 2H), 2.82 (m 2H), and 1.07 (t, 3H).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[O:24][CH2:23][C@@H:19]3[CH2:20][NH:21][CH2:22][C@H:18]3[C@@H:17]2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>>[C:34]([N:21]1[CH2:22][C@H:18]2[C@H:17]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH3:31])[C@@H:16]([O:15][C@@H:13]([C:5]3[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:1])([F:32])[F:33])[CH:4]=3)[CH3:14])[O:24][CH2:23][C@@H:19]2[CH2:20]1)(=[O:36])[CH3:35]
Reactant: Cc1ccccc1[C@@H]1[C@@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC[C@@H]2CNC[C@H]21
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1C[C@H]2CO[C@H](O[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccccc3C)[C@@H]2C1

Procedure:
The title compound was prepared from (3aS,6R,7R,7aR)-6-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-7-(2-methylphenyl)octahydropyrano[3,4-c]pyrrole and acetic anhydride according to the procedures used for example 19. MS: (MH)+516.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][O:7][C:8]2[CH:25]=[CH:24][C:11]([C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:16][CH2:15]3)=[O:13])=[CH:10][C:9]=2[N+:26]([O-])=O)=[CH:4][CH:3]=1.O.[Sn](Cl)Cl.C(=O)([O-])O.[Na+]>C(O)C>[NH2:26][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][C:8]=1[O:7][CH2:6][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:30][CH:29]=1)[C:12]([N:14]1[CH2:15][CH2:16][N:17]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:18][CH2:19]1)=[O:13]
Reactant: CC(C)CN1CCN(C(=O)c2ccc(OCc3ccc(F)cc3)c([N+](=O)[O-])c2)CC1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)CN1CCN(C(=O)c2ccc(OCc3ccc(F)cc3)c(N)c2)CC1
Temperature: 70 °C
Reaction time: 0.67 h
Yield: 89.3 %

Procedure:
To 85 ml of an ethanol solution containing 1-[4-(4-fluorobenzyloxy)-3-nitrobenzoyl]-4-isobutylpiperazine (HCl free form of Example 8) (17.5g) was added tin (II) chloride monohydrate (47.4 g) and the resulting mixture was stirred at 70° C. for 40 minutes. The mixture was poured into ice water, neutralized with sodium hydrogencarbonate, and then extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:2 to 1:0), thereby yielding 14.5 g of 1-[3-amino-4-(4-fluorobenzyloxy)benzoyl]-4-isobutylpiperazine as a crystal. This compound (1.30 g) was converted into the corresponding hydrochloride salt as in the case of Example 8 which will be explained later, thereby yielding 1.51 g of the aimed compound. This compound is a crystal with a high hygroscopicity.