Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[N:27]=[C:26]([C:31](O)=[O:32])[CH:25]=[CH:24]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[CH2:35][N:36](C(C)C)C(C)C.[Cl:43][C:44]1[CH:51]=[CH:50][C:47](NC)=[CH:46][CH:45]=1>O=S(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:19]([O:18][C:16]([C:14]1[CH:13]=[CH:12][C:11]2[N:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:8]([C:21]3[CH:22]=[C:23]4[C:28](=[CH:29][CH:30]=3)[N:27]=[C:26]([C:31](=[O:32])[NH:36][CH2:35][C:47]3[CH:46]=[CH:45][C:44]([Cl:43])=[CH:51][CH:50]=3)[CH:25]=[CH:24]4)=[N:9][C:10]=2[CH:15]=1)=[O:17])[CH3:20]
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3nc(C(=O)O)ccc3c1)n2C1CCCCC1
Reactant: CCN(C(C)C)C(C)C
Reactant: CNc1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3nc(C(=O)NCc4ccc(Cl)cc4)ccc3c1)n2C1CCCCC1
Reaction time: 0.17 h
Yield: 48.3 %

Procedure:
A solution of 100 mg (0.23 mmol) Compound 402a in 1 mL SOCl2 was allowed to stand at room temperature for 10 min and SOCl2 was removed. The residue was dissolved in 5 mL anhydrous CH2Cl2; 89 mg (0.69 mmol) DIEA, 84 mg (0.69 mmol) DMAP, 98 mg (0.69 mmol) 4-chloro-N-methylaniline were added; and the solution was vortexed and allowed to stand at room temperature overnight. The solvent was removed and the residue was chromatographed on silica gel using hexane/EtOAc as the eluent to yield 63 mg of yellow oil. MS: 576.24 (M+H+).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=O)[CH2:10][N:9]=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:7]=2[CH:20]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22]>N1C=CC=CC=1>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[S:22])[CH2:10][N:9]=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:7]=2[CH:20]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CSc1ccc2c(c1)C(c1ccccn1)=NCC(=O)N2
Solvent: c1ccncc1
Product: CSc1ccc2c(c1)C(c1ccccn1)=NCC(=S)N2
Temperature: 115 °C

Procedure:
A stirred solution of 7-methylthio-1,3-dihydro-5-(2-pyridyl)-2H-1,4-benzodiazepin-2-one (0.0206 mole) in dry pyridine (400 ml.) was treated with phosphorus pentasulfide (5.05 g.), warmed, under nitrogen, at 110-120° C. for 1 hour, cooled and concentrated in vacuo. Residual pyridine was removed by the successive addition of xylene and toluene to the residue with concentration after each addition. The resulting residue was mixed with dilute sodium carbonate and extracted with chloroform. The chloroform extract was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was crystallized to give 7-methylthio-1,3-dihydro-5-(2-pyridyl)-2H-1,4-benzodiazepine-2-thione.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](Cl)[CH:8]=2)[N:3]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][NH2:18].[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH2:29])[CH:23]=1>>[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][NH:18][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:29][CH2:28][C:24]3[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=3)[CH:8]=2)[N:3]=1
Reactant: NCc1cccnc1
Reactant: NCc1cccc(F)c1
Reactant: Clc1ccc2nc(Cl)ccc2c1
Product: Fc1cccc(CNc2ccc3cc(NCc4cccnc4)ccc3n2)c1

Procedure:
The title compound, MS: m/e=359.1 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 3-fluorobenzylamine and 3-picolylamine.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:34]1[N:35]=[C:36]([NH:39]C=O)[S:37][CH:38]=1)[C:12]([NH:14][CH:15]1[C:32](=[O:33])[N:17]2[C:18]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[C:19]([CH2:22][O:23][CH3:24])[CH2:20][S:21][C@H:16]12)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>CO.O>[NH2:39][C:36]1[S:37][CH:38]=[C:34]([C:11](=[N:10][O:9][CH2:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:12]([NH:14][CH:15]2[C:32](=[O:33])[N:17]3[C:18]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])=[C:19]([CH2:22][O:23][CH3:24])[CH2:20][S:21][C@H:16]23)=[O:13])[N:35]=1
Reactant: COCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: COCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.5 %

Procedure:
A mixture of tert-butyl 7-[2-tert-butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-methoxymethyl-3-cephem-4-carboxylate (syn isomer) (2.6 g) and conc. hydrochloric acid (0.9 g) in methanol (20 ml) was stirred at ambient temperature for 3 hours. The reaction mixture was added to ethyl acetate and water, and then adjusted to pH 7.5 with a saturated aqueous sodium bicarbonate. The separated organic layer was washed with a saturated aqueous sodium chloride and then dried over magnesium sulfate. Removal of the solvent gave tert-butyl 7-[2-(2-aminothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-carboxylate (syn isomer) (2.17 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:6]([C:7]2[CH:8]=[C:9]([CH2:22]O)[CH:10]=[CH:11][C:12]=2[C:13]2[C:18]([F:19])=[CH:17][N:16]=[C:15]([O:20][CH3:21])[CH:14]=2)=[CH:5][CH2:4][CH2:3]1.CN(C=O)C.S(Cl)([Cl:32])=O>C(Cl)Cl>[Cl:32][CH2:22][C:9]1[CH:10]=[CH:11][C:12]([C:13]2[C:18]([F:19])=[CH:17][N:16]=[C:15]([O:20][CH3:21])[CH:14]=2)=[C:7]([C:6]2[C:2]([CH3:24])([CH3:1])[CH2:3][CH2:4][CH:5]=2)[CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(-c2ccc(CO)cc2C2=CCCC2(C)C)c(F)cn1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(-c2ccc(CCl)cc2C2=CCCC2(C)C)c(F)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To (3-(5,5-dimethylcyclopent-1-enyl)-4-(5-fluoro-2-methoxypyridin-4-yl)phenyl)methanol T19.3 (34.5 mg, 105 μmol) was added DCM (1.1 mL) and DMF (8.2 μL, 105 μmol) followed by thionyl chloride (15 μL, 211 μmol) in an ice bath. The reaction was then stirred at room temperature for 1 hour. The reaction was concentrated and directly purified on silica gel to afford 4-(4-(chloromethyl)-2-(5,5-dimethylcyclopent-1-enyl)phenyl)-5-fluoro-2-methoxypyridine T19 (36 mg) as an oil (99%).
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[C:7]([CH2:9][N:10]2[C:14]3[N:15]=[C:16]([NH2:24])[N:17]=[C:18]([C:19]4[O:20][CH:21]=[CH:22][CH:23]=4)[C:13]=3[N:12]=[N:11]2)[CH:6]=[CH:5][CH:4]=1.[C-:25]#[N:26].[Na+].O>CN(C=O)C>[C:25]([CH2:2][C:3]1[N:8]=[C:7]([CH2:9][N:10]2[C:14]3[N:15]=[C:16]([NH2:24])[N:17]=[C:18]([C:19]4[O:20][CH:21]=[CH:22][CH:23]=4)[C:13]=3[N:12]=[N:11]2)[CH:6]=[CH:5][CH:4]=1)#[N:26]
Reactant: [C-]#N
Reactant: Nc1nc(-c2ccco2)c2nnn(Cc3cccc(CBr)n3)c2n1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1cccc(Cn2nnc3c(-c4ccco4)nc(N)nc32)n1
Yield: 29.1 %

Procedure:
A solution of 3-(6-bromomethyl-2-pyridylmethyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (200 mg, 0.517 mmol) and sodium cyanide (51 mg, 1.03 mmol) in DMF (5 mL) was stirred at 60° C. for 16 h, poured into water (40 mL), extracted with EtOAc (3×8 mL), the combined organic phase dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2;isohexane:EtOAc (1:1)] to give title compound (50 mg, 26%) as a yellow solid.
Reaction SMILES: [CH2:1]([C:8]1[S:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)=[CH:13][C:11]=2[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33]([N:35]=[C:36]=[O:37])[CH3:34]>>[NH2:26][C:24]1[C:25]2=[C:17]([C:14]3[CH:15]=[CH:16][C:10]4[S:9][C:8]([CH2:1][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)=[N:12][C:11]=4[CH:13]=3)[CH:18]=[C:19]([CH:27]3[CH2:32][CH2:31][N:30]([C:36]([NH:35][CH2:33][CH3:34])=[O:37])[CH2:29][CH2:28]3)[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4sc(Cc5ccccc5)nc4c3)c12
Reactant: CCN=C=O
Product: CCNC(=O)N1CCC(c2cc(-c3ccc4sc(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Yield: 12 %

Procedure:
In a manner similar to the procedure described for the preparation of Example 331 and using 5-(2-benzyl-1,3-benzothiazol-5-yl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine and ethylisocyanate as starting material, 7 mg (12%) of the desired product was isolated.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([NH:17][CH3:18])=[O:16])=[CH:13][CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=2[N:7]=1.[F:30][C:31]1([F:36])[CH2:34][CH:33]([OH:35])[CH2:32]1.CC(C)([O-])C.[Na+]>O1CCOCC1.C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([O:35][CH:33]2[CH2:34][C:31]([F:36])([F:30])[CH2:32]2)[C:5]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([C:15]([NH:17][CH3:18])=[O:16])=[CH:19][CH:20]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:27])[CH3:28])[C:6]=2[N:7]=1
Reactant: CNC(=O)c1ccc(-c2cn(COCC[Si](C)(C)C)c3nc(Cl)nc(Cl)c23)cc1
Reactant: OC1CC(F)(F)C1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CNC(=O)c1ccc(-c2cn(COCC[Si](C)(C)C)c3nc(Cl)nc(OC4CC(F)(F)C4)c23)cc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 64.1 %

Procedure:
A solution of 4-(2,4-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-methylbenzamide (1 equiv), 3,3-difluorocyclobutan-1-ol (1.1 equiv), and sodium tert-butoxide (1.2 equiv) in 1,4-dioxane (0.22 M) were combined in a sealable flask. The reaction mixture was put under a nitrogen atmosphere, the sealable flask was sealed, and the mixture was stirred at 70° C. for 16 h. The mixture was cooled to room temperature and concentrated to afford an oil, which was suspended in DCM and purified using silica gel chromatography (0-50% ethyl acetate in hexane) to afford the title product (64.1% yield) as a clear oil. MS (ESI) m/z 523.4 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][S:8][C:4]=2[CH:3]=1.[N:11]([O-])=O.[Na+].O.O.Cl[Sn]Cl.[CH3:20][CH:21]([CH3:27])[C:22](=O)[CH2:23][C:24]#[N:25]>Cl.O.CCO>[S:8]1[C:4]2[CH:3]=[C:2]([N:1]3[C:24]([NH2:25])=[CH:23][C:22]([CH:21]([CH3:27])[CH3:20])=[N:11]3)[CH:10]=[CH:9][C:5]=2[N:6]=[CH:7]1
Reactant: CC(C)C(=O)CC#N
Reactant: O=N[O-]
Reactant: Nc1ccc2ncsc2c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)c1cc(N)n(-c2ccc3ncsc3c2)n1
Temperature: 2.5 °C
Reaction time: 1.25 h
Yield: 93 %

Procedure:
To a stirring suspension of 6-aminobenzothiazole (0.500 g, 3.33 mmol) in conc. HCl (5 ml) at 0-5° C. was added a solution of NaNO2 (0.276 g, 3.99 mmol) in H2O (5 ml). The mixture was stirred at 0-5° C. for 75 min until a clear yellow solution was obtained. To this was then added a solution of SnCl2.2H2O (2.76 g, 13.3 mmol) in conc. HCl (5 ml). After completing the addition, the suspension was stirred at RT for 2 h. 4-Methyl-3-oxopentanenitrile (0.444 g, 3.99 mmol) and EtOH (50 ml) were added and the reaction was stirred with heating at 75° C. After 18 h, the completed reaction was cooled to RT and concentrated to an aqueous residue. This was chilled thoroughly in ice and made strongly basic (pH 12-13) by the addition of 6M NaOH. While still cold the mixture was extracted with EtOAc (2×). The combined organics were washed with H2O (2×), brine (1×), dried (MgSO4), filtered and evaporated to afford crude 1-(benzo[d]thiazol-6-yl)-3-isopropyl-1H-pyrazol-5-amine (0.8 g, 93% yield) as an oil which was used as is in the next reaction. 1H NMR (400 MHz, DMSO-d6) δ 9.36 (s, 1H), 8.30 (d, J=2.4 Hz, 1H); 8.10 (d, J=8.8 Hz, 1H), 7.74 (dd, J=2.4 and 8.8 Hz, 1H), 5.36 (s, 1H), 5.33 (brs, 2H), 2.76 (septet, J=6.8 Hz, 1H), 1.17 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 259.0 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18](O)=[O:19])[NH:11][C:12](=[O:14])[N:13]=2)=[CH:4][C:3]=1[CH3:24].[O:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][NH2:34])[CH2:27][CH2:26]1.ON1C2C=CC=CC=2N=N1.CCN=C=NCCC[N+](C)(C)C.[I-]>ClC(Cl)C.CN(C)C=O>[OH:19][C:18]1[CH:22]=[CH:23][C:15]([C:10]2[CH:9]=[C:8]([C:5]3[CH:6]=[C:7]([CH:24]=[CH:3][CH:4]=3)[C:2]([NH:34][CH2:33][CH2:32][CH2:31][N:28]3[CH2:29][CH2:30][O:25][CH2:26][CH2:27]3)=[O:1])[NH:13][C:12](=[O:14])[N:11]=2)=[CH:16][C:17]=1[CH3:21]
Reactant: Cc1cc(-c2cc(-c3cccc(C(=O)O)c3)[nH]c(=O)n2)ccc1O
Reactant: NCCCN1CCOCC1
Agent: CCN=C=NCCC[N+](C)(C)C
Agent: On1nnc2ccccc21
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CC(Cl)Cl
Product: Cc1cc(-c2cc(-c3cccc(C(=O)NCCCN4CCOCC4)c3)[nH]c(=O)n2)ccc1O
Temperature: 25 °C
Reaction time: 15 h
Yield: 27.9 %

Procedure:
3-[6-(4-hydroxy-3-methylphenyl)-2-oxo-2,3-dihydropyrimidin-4-yl]benzoic acid (Compound 289, 15.5 mg, 48 umol) and commercially available 3-morpholinopropan-1-amine (5.8 mg, 40 umol) were dissolved in dichloroethane (1.25 mL) and N,N-dimethylformamide (0.79 mL). To this solution was added commercially available 1-hydroxybenzotriazole (6.8 mg, 50 umol) followed by commercially available 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide methiodide (17.8 mg, 60 umol). The reaction mixture was stirred at room temperature for 15 hours and was concentrated in vacuo. The reaction mixture was purified by reverse phase HPLC to give 5 mg of product. 1H NMR (400 MHz, d6-DMSO): δ 8.65 (t, 1H), 8.51 (s, 1H), 8.28-8.23 (m, 2H), 8.02-7.96 (m, 2H), 7.87 (dd, 1H), 7.63 (t, 1H), 7.46 (s, 1H), 6.92 (d, 1H), 3.56 (t, 4H), 3.36-3.32 (m, 2H), 2.40-2.33 (m, 6H), 2.20 (s, 3H), 1.78-1.68 (m, 2H). MS (EI): 450 (MH+).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:13]=[C:12]([CH2:14][OH:15])[CH:11]=[CH:10][N:9]=1.CS(C)=O.C(N(CC)CC)C.[NH4+].[Cl-]>ClCCl>[Cl:7][C:8]1[CH:13]=[C:12]([CH:14]=[O:15])[CH:11]=[CH:10][N:9]=1
Reactant: OCc1ccnc(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=Cc1ccnc(Cl)c1
Temperature: -78 °C
Yield: 76 %

Procedure:
In a 250 mL tricol equipped with a low temperature thermometer and two equalizing dropping funnels was charged oxalyl dichloride (1.24 g, 9.81 mmol) in dichloromethane (15 mL) and this solution was stirred under N2 at −78° C. The first equalizing dropping funnel was connected to a nitrogen flow line and was charged with a solution of (2-chloropyridin-4-yl)methanol SLA 07152 (0.94 g, 6.54 mmol) with dichloromethane (15 mL). The other was charged with a solution of dimethyl sulfoxide anhydrous (1.7 mL, 19.63 mmol) in dichloromethane (2 mL) and this solution was added dropwise (25 min) in order to stabilize the temperature between −60° C. and −70° C. At the end of the addition the reaction solution was warmed to −60° C. over a period of 20 min then the solution of (2-chloropyridin-4-yl)methanol SLA 07152 was added dropwise (50 min) keeping the temperature between −50° C. and −60° C. in the reactor then the mixture reaction was warmed to −45° C. over a period of 30 min. The dropping funnel was washed with dichloromethane (2×5 mL) and charged with a solution of triethylamine (480 μl, 6.51 mmol) in dichloromethane (4 mL) which was added (10 min) to the reaction mixture and finally the reaction flask was allowed to warm to 0° C. over 10 min. The reaction solution was transferred to a 500 mL separatory funnel charged with 130 mL of a 5% aqueous NH4Cl solution. The two phases were separated the aqueous phase was extracted with dichloromethane (3×50 mL) and the combined organic phases were washed with 1 M aqueous phosphate buffer (pH=7; 4×100 mL), then dried over MgSO4, filtered and evaporated. 2-Chloropyridine-4-carbaldehyde SLA 07156 was obtained as an orange solid (0.740 g, 76% yield).
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[CH3:11][N:12]1[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:14]2[CH2:21][N:22]([CH2:25][CH2:26][CH2:27][NH2:28])[CH2:23][CH2:24][C:13]1=2>C(Cl)(Cl)Cl.[Cu]>[ClH:1].[ClH:1].[NH:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:28][CH2:27][CH2:26][CH2:25][N:22]1[CH2:23][CH2:24][C:13]2[N:12]([CH3:11])[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14]=2[CH2:21]1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: Cn1c2c(c3ccccc31)CN(CCCN)CC2
Agent: [Cu]
Solvent: ClC(Cl)Cl
Product: Cl
Product: Cn1c2c(c3ccccc31)CN(CCCNc1nc3ccccc3[nH]1)CC2
Temperature: 180 °C
Yield: 33.9 %

Procedure:
A mixture of 2-chloro-1H-benzimidazole (0.015 mol), intermediate 16 (0.015 mol) and copper (0.015 mol) was stirred in an oil bath at 180° C. The mixture was cooled and the product was dissolved in CHCl3 (50 ml). The solution was filtered over dicalite and the filtrate was evaporated. The residue was purified by column chromatography over silica gel (eluent: CHCl3/(CH3OH/NH3) 95/5). The pure fractions were collected and the solvent was evaporated. The residue was dissolved in CH3CN (50 ml) and converted into the hydrochloric acid salt (1:2) with HCl/2-propanol. The salt was filtered off, washed on filter with cold CH3CN (20 ml), then dried, yielding 1.1 g (17%) of N-1H-benzimidazol-2-yl-1,3,4,5-tetrahydro-5-methyl-2H-pyrido[4,3-b]indole-2-propanamine dihydrochloride.hemihydrate (compound 105).
Reaction SMILES: [ClH:1].[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[O:16][C:9]3([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)[CH:8]([CH2:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:7]=2[CH:23]=1.[Br:24]N1C(=O)CCC1=O.O.[OH-].[Na+]>CO.C(OCC)(=O)C>[OH2:16].[ClH:1].[Br:2][C:3]1[CH:4]=[C:5]([Br:24])[C:6]2[O:16][C:9]3([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)[CH:8]([CH2:17][CH2:18][CH2:19][N:20]([CH3:21])[CH3:22])[C:7]=2[CH:23]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CN(C)CCCC1c2cc(Br)ccc2OC12CCCCCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CN(C)CCCC1c2cc(Br)cc(Br)c2OC12CCCCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.7 %

Procedure:
To a stirred solution of 8.4 g of 5-bromo-3-(3-dimethylaminopropyl)-spiro[benzofuran-2(3H),1'-cycloheptane] hydrochloride in 57 ml of methanol, at room temperature under nitrogen, was added 7.44 g of N-bromosuccinimide. All solid dissolved as the pot temperature rose to 37° C. After stirring overnight at room temperature under nitrogen, the mixture was poured into 250 ml of water, made basic by addition of 100 ml of 10% aqueous sodium hydroxide solution, and extracted with ethyl acetate (2×250 ml). The combined organic extracts were washed with water (100 ml) and saturated sodium chloride solution (100 ml) and dried overnight over anhydrous sodium sulfate. Filtration and concentration in vacuo afforded a mixture of oil and solid. This material was taken up in 100 ml of ethyl acetate and gravity-filtered, and the filtrate was stirred and treated dropwise with 10 ml of hydrogen chloride-saturated ether solution. The precipitated salt was filtered off, washed with ether and dried in vacuo to afford 2.85 g of a solid, m.p. sinters 200°, 202°-204° C. A second crop which had precipitated out of the filtrate was filtered off and washed with ether to afford, without drying, an additional 1.2 g of a solid, m.p. sinters 200°, 201°-202.5° C. The two crops of crude salt were combined and dissolved in 50 ml of absolute ethanol and gravity-filtered, and the filtrate was treated dropwise with ether (350 ml) with stirring. After stirring the mixture for a short period of time, the recrystallized solid was filtered off, washed with ether and dried to afford 2.2 g of a solid, m.p. 203.5°-206° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:22])=[C:6]2[C:10]=1[NH:9][C:8]1[C:11]([CH2:18][CH2:19][OH:20])([CH2:15][CH2:16][CH3:17])[O:12][CH2:13][CH2:14][C:7]2=1.I(C1C=CC=CC=1C(O)=O)(=O)=O>CS(C)=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)=[O:22])=[C:6]2[C:10]=1[NH:9][C:8]1[C:11]([CH2:18][CH:19]=[O:20])([CH2:15][CH2:16][CH3:17])[O:12][CH2:13][CH2:14][C:7]2=1
Reactant: CCCC1(CCO)OCCc2c1[nH]c1c(F)ccc(C(=O)N3CCOCC3)c21
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CS(C)=O
Solvent: O
Product: CCCC1(CC=O)OCCc2c1[nH]c1c(F)ccc(C(=O)N3CCOCC3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
The mixture of [8-fluoro-1-(2-hydroxy-ethyl)-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-5-yl]-morpholin-4-yl-methanone (100 mg, 0.256 mmol) and o-iodoxybenzoic acid (IBX, 430 mg, 1.54 mmol) in DMSO (3.5 mL) was stirred overnight at room temperature. The solution was diluted with H2O (7 mL) and the precipitates were filtered and the filter cake was rinsed with EtOAc. The filtrate was extracted with EtOAc (3×10 mL) and the combined organic solution was washed with brine (20 mL), dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (silica, 60% EtOAc in hexanes) to give 89 mg (90%) of the title compound as a pale yellow solid. 1H NMR (CDCl3): 300 MHz δ 9.75 (bs, 1H), 9.05 (bs, 1H), 6.89 (m, 2H), 4.00–2.64 (m, 14H), 1.89 (m, 1H), 1.63 (s, 1H), 1.26 (m, 2H), 0.88 (t, J=5.49 Hz, 3H).
Reaction SMILES: [OH-].[Li+].[O:3]1[C:11]2[CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][C:6]=2[C:5]([C:19]([O:21]CC)=[O:20])=[N:4]1>C(O)C>[C:15]([O:14][C:12]([N:8]1[CH2:9][CH2:10][C:11]2[O:3][N:4]=[C:5]([C:19]([OH:21])=[O:20])[C:6]=2[CH2:7]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(=O)c1noc2c1CN(C(=O)OC(C)(C)C)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2onc(C(=O)O)c2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
An aqueous lithium hydroxide solution (0.54 g, 12.88 mol in 12.8 ml) was added dropwise to a solution of 5-tert-butyl 3-ethyl 6,7-dihydroisoxazolo[4,5-c]pyridine-3,5(4H)-dicarboxylate (3.2 g, 10.73 mmol) in ethanol (48 ml) at 0° C. and the mixture was stirred at room temperature for 3 hours. The mixture was then concentrated in vacuo, the residue was acidified with 10% strength citric acid and the mixture was extracted three times with ethyl acetate. The combined organic phases were dried with Na2SO4, filtered and concentrated in vacuo. The crude product was employed directly in the next stage without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]([CH3:13])[CH3:12])=[C:6]([NH2:14])[CH:5]=1.[NH2:16][C:17]1[S:18][C:19]2[CH:25]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:20]=2[N:21]=1.[C:31](N1C=CN=C1)(N1C=CN=C1)=S.C(Cl)CCl>CN(C=O)C>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]([CH:11]([CH3:13])[CH3:12])[C:31]([NH:16][C:17]3[S:18][C:19]4[CH:25]=[C:24]([O:26][C:27]([F:30])([F:28])[F:29])[CH:23]=[CH:22][C:20]=4[N:21]=3)=[N:14][C:6]=2[CH:5]=1)=[O:15]
Reactant: Nc1nc2ccc(OC(F)(F)F)cc2s1
Reactant: COC(=O)c1ccc(NC(C)C)c(N)c1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C(C)C
Yield: 38.3 %

Procedure:
1-Isopropyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid methyl ester (580.0 mg) was prepared by following General Procedure D starting from 3-amino-4-isopropylamino-benzoic acid methyl ester (700.0 mg), 2-amino-6-(trifluoromethoxy)benzothiazole (930.0 mg), 1,1′-thiocarbonyldiimidazole (700.0 mg), and EDC (770.0 mg) in DMF (8.0 mL). LCMS: m/z 452; and 1H NMR (DMSO-d6, 400 MHz): δ 8.27 and 8.05 (0.6 and 0.47, 1H, m), 7.93 (1H, m), 7.84 (1H, m), 7.73 (2H, m), 7.37 (1H, m), 5.15 (1H, m), 3.88 (3H, s), 1.58-1.57 (6H, d), —NH proton signal was not observed.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[C:4]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:3]=1.[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.[K]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:18]2[C:14](=[O:24])[C:15]3[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:17]2=[O:19])=[C:4]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:3]=1
Reactant: CS(=O)(=O)c1cc(Br)ccc1CBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1cc(Br)ccc1CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.9 %

Procedure:
3.0 g of 4-bromo-1-bromomethyl-2-methanesulfonylbenzene and 2.0 g of potassium phthalimide are stirred at 100° C. for 1 h in 30 ml of anhydrous DMF. The mixture is allowed to cool, diluted with 200 ml of water and the suspension is stirred at RT for 30 minutes. The product is then filtered off and 1.8 g of a colorless solid are obtained, mp 188-190° C.