Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[S:34]1[C:38]([C:39]2([C:43](=[O:45])[CH3:44])[CH2:42][CH2:41][CH2:40]2)=[CH:37][C:36]2[CH:46]=[CH:47][CH:48]=[CH:49][C:35]1=2>O1CCCC1>[S:34]1[C:38]([C:39]2([C:43](=[O:45])[CH2:44][Br:1])[CH2:40][CH2:41][CH2:42]2)=[CH:37][C:36]2[CH:46]=[CH:47][CH:48]=[CH:49][C:35]1=2
Reactant: [Br-]
Reactant: CC(=O)C1(c2cc3ccccc3s2)CCC1
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: O=C(CBr)C1(c2cc3ccccc3s2)CCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.1 %

Procedure:
Phenyltrimethylammonium tribromide (1.72 g) was added in portions at −20° C. to a stirred solution of 1-[1-(benzo[b]thiophen-2-yl)cyclobutyl]ethanone (1.05 g) in tetrahydrofuran (50 ml). The mixture was stirred at ambient temperature for 3 hours, then it was filtered, and allowed to stand at ambient temperature for a further 18 hours. The mixture was filtered once more, and the solvent was removed in vacuo. The residue was purified via flash chromatography over silica using a 1:49 mixture of ether and petroleum ether (b.p. 40-60° C.) as eluant. Appropriate fractions were combined, and the solvents removed in vacuo to give 1-[1-(benzo[b]thiophen-2-yl)cyclobutyl]-2-bromoethanone as an oil (0.46 g).
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[C-:2].C1CCN2C(=NCCC2)CC1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C1COCC1>[CH3:20][C:19]1[O:21][CH:2]=[N:1][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CC(=O)OC(C)=O
Reactant: [C-]#[N+]CC(=O)OC
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1ncoc1C
Temperature: 0 °C
Reaction time: 12 h

Procedure:
A stirred mixture of methyl isocyanoacetate (7.0 g, 70 mmol, 1 eq) and DBU (10.06 g, 70 mmol, 1 eq) in THF was cooled to 0° C., and a solution of acetic anhydride (7.14 g, 70 mmol, 1 eq) in THF was added dropwise over 15 min. The reaction mixture was stirred for 12 h at room temperature. The solvent was removed by Rota-vapor and water was added. The mixture was extracted with EtOAc. The crude product was purified by silica gel (230-400) column chromatography using 30% EtOAc/hexane. Yield: 6.8 g (98%). 1H NMR (400 MHz, CDCl3): δ2.54 (s, 3H), 3.80 (s, 3H), 7.69 (s, 1H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:12]2[N:11]=[C:10]([CH3:13])[N:9]([CH3:14])[C:8]=2[CH:7]=[C:6]([C:15]([O:17][CH3:18])=[O:16])[CH:5]=1.Cl[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[O:23][CH2:22][CH2:21]1>CN(C)C=O>[O:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]([O:3][C:4]2[C:12]3[N:11]=[C:10]([CH3:13])[N:9]([CH3:14])[C:8]=3[CH:7]=[C:6]([C:15]([O:17][CH3:18])=[O:16])[CH:5]=2)[CH2:21][CH2:22]1
Reactant: COC(=O)c1cc(O)c2nc(C)n(C)c2c1
Reactant: ClC1CCOc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OC2CCOc3ccccc32)c2nc(C)n(C)c2c1
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 59.8 %

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 0.71 g, 18 mmol) in N,N-dimethylformamide (40 mL) was added a suspension of methyl 4-hydroxy-1,2-dimethyl-1H-benzimidazole-6-carboxylate (3.0 g, 14 mmol, WO 2004054984) in N,N-dimethylformamide (40 mL) dropwise under nitrogen atmosphere at room temperature. After stirring for 20 minutes, a solution of 4-chlorochromane (4.6 g, 27 mmol, WO 2000078751) in N,N-dimethylformamide (10 mL) was added at room temperature. The reaction mixture was warmed to 70° C. for 2.5 hours, cooled to room temperature, and stirred for 18 hours at the same temperature. The reaction mixture was quenched with water and extracted with ethyl acetate (250 mL×2). The combined extracts were washed with sodium hydrogencarbonate aqueous solution, ammonium chloride aqueous solution and brine, dried over sodium sulfate, and concentrated in vacuum. The resulting solid was suspended with ethyl acetate and diethyl ether, and collected by filtration to give the title compound as a white solid (2.95 g, 61%):
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([O:11][CH3:12])=[O:10])=[C:4]([NH:13][C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)[N:3]=1.[CH3:21][S-:22].[Na+].Cl>CN(C=O)C>[CH3:8][C:6]1[C:5]([C:9]([O:11][CH3:12])=[O:10])=[C:4]([NH:13][C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)[N:3]=[C:2]([S:22][CH3:21])[N:7]=1
Reactant: C[S-]
Reactant: COC(=O)c1c(C)nc(Cl)nc1Nc1cccc(C)c1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)nc(SC)nc1Nc1cccc(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 2-chloro-4-methyl-6-(m-tolylamino)pyrimidine-5-carboxylate (0.078 g, 0.267 mmol) was dissolved in DMF (3 mL). Sodium thiomethoxide (0.019 g, 0.267 mmol) was added and the reaction mixture was allowed to stir at RT for 1 h. The reaction mixture was poured onto ice. The pH was adjusted to 7 with 1 N HCl. The title compound was isolated as a yellow solid by vacuum filtration (72.8 mg, 90%). [M+H] calc'd for C15H17N3O2S, 304; found, 304.
Reaction SMILES: [C:1]1(=[O:13])[O:10][C:8](=O)[CH:7]2[CH2:11][CH2:12][C:2]1([C:4]2([CH3:6])[CH3:5])[CH3:3].[NH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>N1C=CC=CC=1>[CH3:3][C:2]12[C:4]([CH3:5])([CH3:6])[CH:7]([CH2:11][CH2:12]1)[C:8](=[O:10])[N:14]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[C:1]2=[O:13]
Reactant: CC12CCC(C(=O)OC1=O)C2(C)C
Reactant: NCCc1ccccn1
Solvent: c1ccncc1
Product: CC12CCC(C(=O)N(CCc3ccccn3)C1=O)C2(C)C

Procedure:
A mixture of (-) camphoric anhydride 5 g (0.029 mol), 2-(2-aminoethyl)pyridine 3.6 (0.03 mol) and 50 ml of pyridine was refluxed overnight. The solvent is removed under reduced pressure and the remaining oil boiled in 20 ml of ethanol and allowed to cool.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[CH2:22][CH2:23][C:24](O)=[O:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:15]3[C:16](=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)[CH2:22][CH2:23][C:24]2=[O:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Cl)cc2CCC(=O)O)CC1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)CCc3cc(Cl)ccc32)CC1
Yield: 51.6 %

Procedure:
4-[2-(2-Carboxy-ethyl)-4-chloro-phenylamino]-piperidine-1-carboxylic acid tert-butyl ester (3.9 g, 10.1 mmol) and EDC (2.9 g, 15.3 mmol) were set stirring in CH2Cl2 (50 mL) for 2 h. The reaction mixture was dissolved in CH2Cl2 (150 mL), washed with water (2×50 mL) and brine (1×50 mL). The organic layer was dried over Na2SO4 and concentrated. The residue was purified by column chromatography (silica, 30-50% EtOAc/hexanes) to obtain 1.9 g (52%) of the desired product. TLC (silica, 50% EtOAc/hexanes): Rf=0.67. MS (electrospray): exact mass calculated for C19H25ClN2O3, 364.16. m/z found, 365.1 [M++H]. 1H NMR (400 MHz, CDCl3): 7.14-7.08 (m, 2H), 6.98 (d, J=8.61 Hz, 1H), 4.33-3.98 (m, 3H), 2.75 (t, J=7.83 Hz, 4H), 2.55-2.36 (m, 4H), 1.70-1.65 (m, 2H), 1.44 (s, 9H).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH2:14])[CH2:11][CH2:10][N:9]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31]([C:36](O)=[O:37])=[CH:30]2.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][C:36]([C:31]2[NH:32][C:33]3[C:29]([CH:30]=2)=[CH:28][C:27]([O:26][CH3:25])=[CH:35][CH:34]=3)=[O:37])[CH2:11][CH2:10][N:9]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1
Reactant: COc1ccc2[nH]c(C(=O)O)cc2c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Product: COc1ccc2[nH]c(C(=O)N[C@H]3CCN(C(=O)c4cc(Cl)cc(Cl)c4)[C@H](Cc4ccccc4)C3)cc2c1

Procedure:
200 mg (0.550 mmol) of (2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-4-piperidinamine are reacted in analogy to Example 4a with 126 mg (0.661 mmol) of 5-methoxyindole-2-carboxylic acid, 168 mg (0.661 mmol) of bis(2-oxo-3-oxazolidinyl)phosphinic chloride and 169 μl (1.21 mmol) of triethylamine. The title compound ##STR88## is obtained (118 mg, 41%) as white crystals of melting point 251° C. TLC:methylene chloride/methanol/cone. ammonia (2000:50:1) Rf =0.81, FD-MS:M+ =535, 537; IR:3440, 3280, 1625 cm-1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([O:27][C:28]([N:30]1[C@@H:34]([CH3:35])[CH2:33]OS1(=O)=O)=[O:29])([CH3:26])([CH3:25])[CH3:24].CC(C)([O-])C.[K+]>>[CH2:21]([O:20][C:18]([C:13]1[N:14]([CH2:35][C@@H:34]([NH:30][C:28]([O:27][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:29])[CH3:33])[C:15]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[CH:17][CH:16]=2)=[O:19])[CH3:22]
Reactant: C[C@H]1COS(=O)(=O)N1C(=O)OC(C)(C)C
Reactant: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2n1C[C@H](C)NC(=O)OC(C)(C)C
Yield: 100 %

Procedure:
The title compound was synthesized in analogy to example 1, intermediate b), from ethyl 5-benzyloxyindole-2-carboxylate (commercially available), (S)-4-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester (prepared according to WO02/010169) and potassium tert-butoxide, to give the desired compound as a light yellow solid (>100%). The so-obtained product was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([C:12]1[C:13](Cl)=[N:14][C:15]([Cl:19])=[C:16]([F:18])[CH:17]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>CC(N(C)C)=O>[CH2:1]([O:8][N:9]1[C:10](=[O:11])[C:12]2[CH:17]=[C:16]([F:18])[C:15]([Cl:19])=[N:14][C:13]=2[N:30]([C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=2)[C:31]1=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NOCc1ccccc1)c1cc(F)c(Cl)nc1Cl
Reactant: O=C=Nc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=c1c2cc(F)c(Cl)nc2n(-c2ccc(F)cc2)c(=O)n1OCc1ccccc1
Yield: 71.7 %

Procedure:
Using the General Method 5, the reaction of N-benzyloxy-2,6-dichloro-5-fluoro-3-pyridinecarboxamide (Example M-2, 2.00 g, 6.34 mmol) and 60% NaH in oil (300 mg, 7.52 mmol) with 4-fluorophenyl isocyanate (0.86 mL, 9.51 mmol) in DMA afforded 1.89 g of the title compound as a solid, mp 208-209° C.
Reaction SMILES: C(O)(=O)C.[Br:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:8]([N+:19]([O-])=O)[CH:7]=1>O.[Fe]>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:8]([NH2:19])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1Oc1ccccc1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Nc1cc(Br)ccc1Oc1ccccc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
Iron powder (3 g, 53.4 mmol) and acetic acid (10 mL) were added to a stirred suspension of 4-bromo-2-nitro-1-phenoxybenzene (3.1 g, 9.5 mmol) in water (25 mL) of 60° C. The reaction mixture was heated to 80° C. and stirred for 30 min. After cooling to room temperature the reaction mixture was filtered and extracted with toluene. The toluene solution was washed with water (3×) and brine, dried (Na2SO4) and evaporated to give the crude compound (2.3 g, 87%). Data: (m/z)=264+266 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:14]([OH:15])=[C:13]2[C:5]([N:6]3[CH:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:17][O:16][C:8]4[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]3=4)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][C:33]#[N:34]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:17][O:16][C:8]4[CH:9]=[CH:10][CH:11]=[C:12]([C:13]=2[C:14]=1[O:15][CH2:32][C:33]#[N:34])[C:7]3=4
Reactant: Oc1c(Cl)ccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCOc1c(Cl)ccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Temperature: 85 °C
Yield: 90.2 %

Procedure:
To a mixture of 8-chloro-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-ol (0.286 g, 0.851 mmol) in DMF (5.0 mL) is added potassium carbonate (0.59 g, 4.25 mmol) and bromoacetonitrile (0.3 mL, 4.25 mmol). The mixture is heated at 85° C. for 1 h, then cooled and partitioned between water and Et2O. The organic layer is washed three times with water (50 mL), dried over magnesium sulfate and concentrated. Column chromatography (60 g silica gel) using CH2Cl2/hexane (1/1) as eluent gave 0.2876 g (90%) of 2-[(8-chloro-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]acetonitrile.
Reaction SMILES: [NH2:1][C:2]1[C:44]([NH2:45])=[CH:43][CH:42]=[CH:41][C:3]=1[C:4]([NH:6][C:7]1[CH:38]=[CH:37][C:10]([C:11]([N:13]([CH3:36])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:28])=[O:12])=[CH:9][C:8]=1[O:39][CH3:40])=[O:5].[C:46]([CH2:48][C:49](O)=O)#[N:47].C(=O)([O-])O.[Na+]>C(#N)C>[C:46]([CH2:48][C:49]1[NH:45][C:44]2[CH:43]=[CH:42][CH:41]=[C:3]([C:4]([NH:6][C:7]3[CH:38]=[CH:37][C:10]([C:11]([N:13]([CH3:36])[C:14]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=4[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]4)=[O:28])=[O:12])=[CH:9][C:8]=3[O:39][CH3:40])=[O:5])[C:2]=2[N:1]=1)#[N:47]
Reactant: N#CCC(=O)O
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc(N)c1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(CC#N)nc12
Temperature: 100 °C
Yield: 30.9 %

Procedure:
To a solution of 4-(2,3-diaminobenzoyl)amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (240 mg) in acetonitrile (1 ml) was added cyanoacetic acid (662 mg). The solution was heated at 100° C. for 8 hours. After cooling, aqueous sodium hydrogen carbonate was added to the mixture and extracted with ethyl acetate. The extract was washed with brine and dried over sodium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography (7% methanol in chloroform) and preparative thin-layer chromatography (ethyl acetate:methanol=1:1) to give 4-[[2-cyanomethyl-1H-benzimidazol-4-yl]carbonylamino]-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (80 mg).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:35])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[N:22]=[N:23][C:24]([C:27](=[O:34])[NH:28][CH2:29][CH2:30][CH:31]3[CH2:33][CH2:32]3)=[CH:25][CH:26]=2)[CH2:17][CH2:16]1)=[O:14]>O1CCCC1.O>[CH:31]1([CH2:30][CH2:29][NH:28][C:27]([C:24]2[N:23]=[N:22][C:21]([N:18]3[CH2:17][CH2:16][N:15]([C:13]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=4[C:6]([OH:35])=[O:5])=[O:14])[CH2:20][CH2:19]3)=[CH:26][CH:25]=2)=[O:34])[CH2:33][CH2:32]1
Reactant: COC(=O)c1ccccc1C(=O)N1CCN(c2ccc(C(=O)NCCC3CC3)nn2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=O)c3ccccc3C(=O)O)CC2)nn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.1 %

Procedure:
Lithium hydroxide monohydrate (0.066 g, 1.57 mmol) was added to a solution of 2-{4-[6-(2-cyclopropylethylcarbamoyl)pyridazin-3-yl]piperazine-1-carbonyl}benzoic acid methyl ester (0.230 g) in tetrahydrofuran (10 mL) and water (5 mL) stirred at ambient temperature overnight. THF was removed in vacuo, the residue was dissolved in ethyl acetate (100 mL), neutralized by addition of 5% HCl solution, washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was recrystallized from dichloromethane and hexanes to yield 0.107 g of the title compound (42% yield).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:12]=[N:11][CH:10]=[C:9]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[CH3:19])[N:8]=1.O.CN([CH:24]=[O:25])C>>[Cl:6][C:7]1[C:12]([CH:24]=[O:25])=[N:11][CH:10]=[C:9]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[CH3:19])[N:8]=1
Reactant: CC1CCCCN1c1cncc(Cl)n1
Reactant: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CC1CCCCN1c1cnc(C=O)c(Cl)n1
Reaction time: 0.25 h
Yield: 57 %

Procedure:
Phosphoryl chloride (1.62 mL) was added dropwise to DMF (5 mL) at 0° C. The mixture was stirred for 15 min, and a solution of 2-chloro-6-(2-methylpiperidin-1-yl)pyrazine (1.85 g) in DMF (1 mL) was added dropwise thereto. The mixture was stirred at 80° C. for 16 hr, water (5 mL) was added at 0° C., and the mixture was stirred at room temperature for 1.5 hr. The mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by recrystallization (ethyl acetate-hexane) to give the title compound (1.18 g, 57%) as a colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][O:15][CH:16]([C:18]3[CH:19]=[C:20]([N:27]([CH3:29])[CH3:28])[CH:21]=[C:22]4[C:26]=3[NH:25][N:24]=[CH:23]4)[CH3:17])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:30]([BH3-])#N.[Na+].C=O>C(#N)C.C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][O:15][CH:16]([C:18]3[CH:19]=[C:20]([N:27]([CH3:28])[CH3:29])[CH:21]=[C:22]4[C:26]=3[NH:25][N:24]=[CH:23]4)[CH3:17])[CH2:13][CH2:12][N:11]([CH3:30])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: CC(OCC1(c2ccc(F)cc2)CCNCC1)c1cc(N(C)C)cc2cn[nH]c12
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CC(OCC1(c2ccc(F)cc2)CCN(C)CC1)c1cc(N(C)C)cc2cn[nH]c12
Reaction time: 2 h

Procedure:
To a suspension of (±)-7-(1-((4-(4-fluorophenyl)piperidin-4-yl)methoxy)ethyl)-N,N-dimethyl-1H-indazol-5-amine (101 mg, 0.255 mmol) and sodium cyanoborohydride (80 mg, 1.27 mmol) in acetonitrile (6 mL) at 0° C. was added formalin (0.053 mL). The reaction was treated with 5 drops of acetic acid and the ice bath was removed, stirring continued for 2 h. The reaction was concentrated and purified by preparative HPLC to give 78.5 mg (75%). 1H-NMR (CDCl3, 500 MHz) δ 8.17 (s, 1H), 7.90 (s, 1H), 7.38 (s, 1H), 7.23 (m, 3H), 7.10 (m, 2H), 4.66 (q, J=5.0 Hz, 1H), 3.50-3.57 (m, 2H), 3.39 (d, J=10 Hz, 1H), 3.27 (s, 6H), 3.18 (d, J=10 Hz, 1H), 2.74 (s, 3H), 2.50-2.73 (m, 4H), 2.35-2.45 (m,2H), 1.51 (d, J=5.0 Hz, 3H); Mass spec.: 411.45 (MH)+.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([CH2:8][CH2:9][NH:10][S:11]([C:14]2[C:22]3[N:21]=[N:20][NH:19][C:18]=3[CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:24]=[CH:23][C:7]([CH2:8][CH2:9][NH:10][S:11]([C:14]2[C:22]3[N:21]=[N:20][NH:19][C:18]=3[CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(CCNS(=O)(=O)c2cccc3[nH]nnc23)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(CCNS(=O)(=O)c2cccc3[nH]nnc23)cc1
Yield: 71.5 %

Procedure:
N-(4-Nitrophenethyl)benzotriazole-4-sulphonamide (10 g, 29 mM) was suspended in ethanol (250 ml) and hydrogenated at 50 psi over 10 percent palladium on carbon catalyst (1 g) until hydrogen uptake ceased. The mixture was filtered through anhydrous sodium sulphate and the filtrate was concentrated under reduced pressure to leave the product as a pale yellow solid (6.53 g, 71 percent), m.p. 178° to 179° (uncorr.).
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.O[CH:13]([C:20]1[O:21][CH:22]=[CH:23][CH:24]=1)[CH2:14][N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1.FC(F)(F)C(O)=O>>[O:21]1[CH:22]=[CH:23][CH:24]=[C:20]1[CH:13]([S:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[CH2:14][N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: COC(=O)c1ccc(S)cc1
Reactant: OC(Cn1ccnc1)c1ccco1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(SC(Cn2ccnc2)c2ccco2)cc1
Reaction time: 1 h
Yield: 64.2 %

Procedure:
3.5 g of methyl 4-mercaptobenzoate and 2.5 g of 1-[2-hydroxy-2-(2-furyl)ethyl]imidazole were mixed, and 50.7 ml of trifluoroacetic acid were added, whilst ice-cooling, to the resulting mixture. The mixture was stirred at between 0° and 5° C. for 1 hour. At the end of this time, the reaction mixture was treated and purified similarly to the procedure described in Example 13, to yield 2.96 g of the title compound as a colorless oil.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][C@@H:29]4[CH2:34][CH2:33][NH:32][CH2:31][C@H:30]4[OH:35])=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1.C([O:39][CH2:40][C:41](Cl)=[O:42])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][C@@H:29]4[CH2:34][CH2:33][N:32]([C:40](=[O:39])[CH2:41][OH:42])[CH2:31][C@H:30]4[OH:35])=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1
Reactant: COc1cc(-c2ccnc3c(C(=O)N[C@@H]4CCNC[C@H]4O)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: COc1cc(-c2ccnc3c(C(=O)N[C@@H]4CCN(C(=O)CO)C[C@H]4O)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-N-[(3R*,4R*)-3-hydroxypiperidin-4-yl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f25) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([OH:5])[CH:2]([CH3:4])[CH3:3].N1C=CC=CC=1.[Br:12][CH:13]([CH3:17])[C:14](Br)=[O:15]>C(OCC)C>[Br:12][CH:13]([CH3:17])[C:14]([O:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[O:15]
Reactant: CC(C)CO
Reactant: CC(Br)C(=O)Br
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C)COC(=O)C(C)Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of iso-butanol and 1.0 equivalent of pyridine in dry diethyl ether was added dropwise 1.3 equivalents of 2-bromopropionyl bromide at 0° C. After stirring at room temperature for 16 hours, the reaction was diluted with diethyl ether, washed with 1N HCl, water, aqueous NaHCO3, brine and dried over magnesium sulfate or sodium sulfate. Removal of the solvents at reduced pressure gave the title compound as a clear oil.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(#N)C.CS(O[CH:17]1[CH2:20][N:19]([CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18]1)(=O)=O>>[CH:21]([N:19]1[CH2:20][CH:17]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:18]1)([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Nc1ccc(F)cc1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: CC#N
Product: Fc1ccc(NC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4-fluoro aniline (0.412 ml, 4.296 mmol) in acetonitrile (10 ml) potassium carbonate (771 mg, 5.584 mmol) was added followed by addition of 1-benzhydrylazetidin-3-yl methanesulfonate (D19) (1.5 g, 4.72 mmol). The reaction mixture was stirred at 100° C. for 5 minutes under microwave irradiation. Solvents were evaporated under vacuo and the residue was taken in with diethylether (50 ml) then water (50 ml) was added. The aqueous layer was extracted with diethylether (2×30 ml). The organics after solvent evaporation were purified by Biotage SNAP-Si cartridge (25 g) eluting with cyclohexane/ethylacetate from 100-0 to 85/15. Collected fractions, after solvent evaporation afforded the title (D24) (0.5 g)