Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][CH2:11][CH2:12][OH:13])=[CH:7][C:6]=2[CH:14]=1.[C:15]([C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)#[N:16]>>[OH:13][CH2:12][CH2:11][CH2:10][C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([C:21]3[CH:22]=[C:17]([CH:18]=[CH:19][CH:20]=3)[C:15]#[N:16])=[CH:14][C:6]=2[CH:7]=1
Reactant: OCCCc1cc2cc(Br)ccc2o1
Reactant: N#Cc1cccc(B(O)O)c1
Product: N#Cc1cccc(-c2ccc3oc(CCCO)cc3c2)c1

Procedure:
The product from Example 170A (193 mg, 0.80 mmol) and 3-cyanophenylboronic acid is processed as described in Example 112C to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[NH:16]([C:18]1[S:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1)[NH2:17]>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([C:18]3[S:19][C:20]4[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=4[N:22]=3)[N:17]=[C:10]([CH:11]([CH3:13])[CH3:12])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)CC(=O)c1ccc(F)cc1
Reactant: NNc1nc2ccccc2s1
Solvent: CC(=O)O
Product: CC(C)c1cc(-c2ccc(F)cc2)n(-c2nc3ccccc3s2)n1
Temperature: 25 °C
Yield: 92.2 %

Procedure:
To a solution of the 1,3-diketone (103 g, 495 mmol) (preparation described in Example 1, Step A) in glacial acetic acid (800 mL) was added 2-hydrazinobenzothiazole (85.8 g, 520 mmol). The resulting solution was refluxed for 2.5 hours and then cooled to room temperature overnight. The resulting precipitate was collected, washed with water and dried overnight to give 154 g (92%) of a cream colored solid.
Reaction SMILES: COP([CH2:7][C:8](=[O:16])[C:9]([F:15])([F:14])[CH2:10][CH2:11][CH2:12][CH3:13])(=O)OC.[OH-].[Na+].[C:19]([O:22][C@@H:23]1[C@H:27]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C@@H:26]([CH:38]=O)[C@H:25]([O:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][O:42]2)[CH2:24]1)(=[O:21])[CH3:20].O>COC(C)(C)C>[C:19]([O:22][C@@H:23]1[C@H:27]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C@@H:26](/[CH:38]=[CH:7]/[C:8](=[O:16])[C:9]([F:14])([F:15])[CH2:10][CH2:11][CH2:12][CH3:13])[C@H:25]([O:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][O:42]2)[CH2:24]1)(=[O:21])[CH3:20]
Reactant: COC(=O)CCCCCC[C@@H]1[C@@H](C=O)[C@H](OC2CCCCO2)C[C@@H]1OC(C)=O
Reactant: CCCCC(F)(F)C(=O)CP(=O)(OC)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COC(C)(C)C
Product: CCCCC(F)(F)C(=O)/C=C/[C@@H]1[C@@H](CCCCCCC(=O)OC)[C@@H](OC(C)=O)C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 1.2 h
Yield: 84.7 %

Procedure:
To a solution of dimethyl (3,3-difluoro-2-oxoheptyl)phosphonate (1) (1.109 g, 4.295 mmol) in t-butyl methyl ether (17 ml), sodium hydroxide (0.164 g, 4.10 mmol) was added and the mixture was stirred for approximately 1.2 hours at room temperature. A solution of methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydropyranyl-oxy)cyclopentyl]heptanate (2) (0.955 g, 2.40 mmol) in t-butyl methyl ether (3 ml), and water (0.32 ml) were added thereto, and the mixed solution was heat refluxed for approximately 48 hours. After cooling to room temperature, water (5.6 ml) was added to the solution and stirred, and then, let to stand and separated into two layers. The aqueous layer was extracted twice with ethyl acetate (4 ml). The organic layers were combined, sequentially washed with 3% aqueous sodium chloride (6 ml) and saturated aqueous sodium chloride (6 ml), and then dried with anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (Fuji Silysia BW-300SP: 33 g; ethyl acetate:hexane=1:4) to give methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-4,4-difluoro-3-oxo-1-octenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (3) (1.079 g; 2.033 mmol; yield: 84.8%).
Reaction SMILES: [N:1]1[CH:2]=[C:3]([CH2:10][C:11]([OH:13])=O)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH3:14][NH:15][C@H:16]1[CH2:35][N:20]2[C:21]3[C:26]([C:27]([CH2:28][C:29]([O:31]CCC)=[O:30])=[C:19]2[CH2:18][CH2:17]1)=[CH:25][CH:24]=[CH:23][CH:22]=3>>[N:1]1[CH:2]=[C:3]([CH2:10][C:11]([N:15]([CH3:14])[C@H:16]2[CH2:35][N:20]3[C:21]4[C:26]([C:27]([CH2:28][C:29]([OH:31])=[O:30])=[C:19]3[CH2:18][CH2:17]2)=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:13])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: O=C(O)Cc1cnc2ccccn12
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Product: CN(C(=O)Cc1cnc2ccccn12)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from imidazo[1,2-a]pyridin-3-ylacetic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 417.
Reaction SMILES: [C:1]([S:4][CH:5]([CH:10]([C:15]([NH:17][C@H:18]([C:28]([NH:30][CH3:31])=[O:29])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:16])CC(C)C)[CH2:6][C:7]([OH:9])=O)(=[O:3])[CH3:2].[NH3:32]>>[C:1]([S:4][CH:5]([CH2:10][C:15]([NH:17][C@H:18]([C:28]([NH:30][CH3:31])=[O:29])[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)=[O:16])[CH:6]([CH2:19][CH:20]([CH3:25])[CH3:21])[C:7]([NH2:32])=[O:9])(=[O:3])[CH3:2]
Reactant: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C(CC(C)C)C(CC(=O)O)SC(C)=O
Reactant: N
Product: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)CC(SC(C)=O)C(CC(C)C)C(N)=O

Procedure:
The title compound, m.p. 235°-240° C., was prepared from the compound of Example 5 and ammonia by an analogous procedure to that described in Example 11.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9].C(O)(=O)C.C(OC(=O)C)(=O)C.S(=O)(=O)(O)O.[N+:41]([O-])([OH:43])=[O:42]>>[N+:41]([C:11]1[CH:12]=[CH:13][C:5]([O:4][C:3]2[CH:14]=[CH:15][C:16]([C:18]([F:23])([F:24])[C:19]([F:22])([F:21])[F:20])=[CH:17][C:2]=2[Cl:1])=[CH:6][C:7]=1[C:8]([OH:10])=[O:9])([O-:43])=[O:42]
Reactant: O=C(O)c1cccc(Oc2ccc(C(F)(F)C(F)(F)F)cc2Cl)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C(O)c1cc(Oc2ccc(C(F)(F)C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 83.9 %

Procedure:
A 50 ml 3-neck round bottom flash was charged with 2.5 gm (6.83 mmol) of 3-(2-chloro-4-pentafluoroethylphenoxy)benzoic acid, 2.18 gm (2.08 ml, 36.19 mmol) of glacial acetic acid, 2.1 gm (20.49 mmol) of acetic anhydride and 70 mg (683 mmol) of concentrated sulfuric acid. The resulting slurry was stirred vigorously while cooling to 0°-5° C. with the aid of an icewater bath. To the cooled slurry was added dropwise a mixture 280 mg (2.73 mmol) of concentrated sulfuric acid and 620 mg (9.56 mmol) to 97% nitric acid (red fuming). The yellow solution was maintained at 0°-5° C. for about 1.5 hours at which time the reaction mixture was poured into stirred ice water. The gummy residue that formed in the bottom of the flask was extracted with 100 ml of ether, the ether layer separated, and the aqueous acid layer reextracted with a second portion of ether. The combined ether layers were washed with brine, dried and evaporated in vacuo leaving a yellow oil. Much of the yellow color was removed by dissolving the oil in 300 ml of chloroform and eluting through a pad of silica gel. Evaporation of the eluent yielded 2.36 gm (83.9%) of a light yellow oil which crystallized on standing. The product had the following elemental analysis, calculated (found): C: 43.76 (44.43); H: 1.71 (2.24); Cl: 8.61 (8.83); F: 23.07 (18.90); N: 3.40 (2.47); O: 19.43.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([I:11])[CH:9]=2)[NH:4][C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].Cl.O>C(O)C.[Zn]>[I:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:2]2
Reactant: CCOC(=O)c1[nH]c2ccc(I)cc2c1I
Agent: Cl
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc2cc(I)ccc2[nH]1
Reaction time: 0.75 h

Procedure:
Ethyl 3,5-diiodo-1H-indole-2-carboxylate (12.1 g, 26.4 mmol) was suspended in 250 mL of absolute ethanol, to which concentrated aqueous hydrogen chloride (22.0 mL, 264 mmol) was added. Zinc dust (17.3 g, 264 mmol) was added portionwise over 30 minutes. After stirring for 45 minutes, two additional portions of zinc were added slowly (5.2 and 4.4 g, 146 mmol). After stirring for 30 minutes, the mixture was poured into water and extracted four times with ethyl acetate. The combined organic extracts were washed once with aqueous saturated NaHCO3 and once with aqueous saturated NaCl. The organic extract was dried with Na2SO4, filtered and concentrated in vacuo. The residue was crystallized three times from hexanes and ethyl acetate, providing the title compound. The mother liquor was columned by flash chromatography (0 to 8% ethyl acetate in hexanes) to provide an additional amount of the title compound. HRMS (ES) exact mass calculated for C11H10INO2 (M+Na+): 377.9648. Found 377.9649.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([NH:9][CH3:10])[N:3]=1.[OH-].[K+].[F:13][C:14]([F:18])([F:17])[CH2:15][OH:16]>>[NH2:1][C:2]1[N:3]=[C:4]([NH:9][CH3:10])[N:5]=[C:6]([O:16][CH2:15][C:14]([F:18])([F:17])[F:13])[N:7]=1
Reactant: OCC(F)(F)F
Reactant: CNc1nc(N)nc(Cl)n1
Agent: [K+]
Agent: [OH-]
Product: CNc1nc(N)nc(OCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Amino-4-chloro-6-methylamino-1,3,5-triazine (0.2 mole) was slurried in 80 ml of 2,2,2-trifluoroethanol at room temperature. Potassium hydroxide pellets (0.2 mole) were added portionwise and the mixture was stirred at room temperature overnight. The following day the reaction was heated at gentle reflux for 2 hours during which time the solids gradually dissolved. The solution was cooled and the solvent was removed under vacuum. The residue was washed with water and filtered to give 20.9 g shining off-white crystals of the product named above with the following characteristics: m.p. 204°-205° C. NMR (DMSO-d6): δ 2.75, d, (NHCH3); 4.8, q, (OCH2CF3); 6.5-7.3, m, (NH2 +NHCH3).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH:22]2[CH2:24][CH2:23]2)=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)[C:6]=2[C:18]([NH:20][CH3:21])=[O:19].CCN(C(C)C)C(C)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36].[OH-].[K+].Cl>C(Cl)Cl.C(O)C>[Br:17][C:14]1[CH:13]=[CH:12][C:11]([N:7]2[C:6]([C:18]([NH:20][CH3:21])=[O:19])=[C:5]3[C:9]([CH:10]=[C:2]([NH:1][S:35]([CH3:34])(=[O:37])=[O:36])[C:3]([CH:22]4[CH2:24][CH2:23]4)=[CH:4]3)=[N:8]2)=[CH:16][CH:15]=1
Reactant: CNC(=O)c1c2cc(C3CC3)c(N)cc2nn1-c1ccc(Br)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCO
Product: CNC(=O)c1c2cc(C3CC3)c(NS(C)(=O)=O)cc2nn1-c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
To a suspension of compound (ix) (320 mg, 0.83 mmol) in DCM (20 mL) was added DIPEA (0.43 mL, 2.49 mmol) followed by methanesulfonyl chloride (0.32 mL, 4.15 mmol) and the reaction mixture was stirred at RT for 3 h (monitored by LCMS). The mixture was diluted with DCM (20 mL), washed with saturated ammonium chloride (20 mL), brine (20 mL) and dried (MgSO4). The solvent was removed in vacuo to give a yellow solid. This material was taken up in ethanol (20 mL) and treated with powdered potassium hydroxide (210 mg, 3.80 mmol) and stirred for 5 min. The mixture was neutralized by addition of 1M aqueous hydrochloric acid and the resulting suspension was concentrated in vacuo to give an orange residue. The residue was taken up in DCM (20 mL), washed with water (20 mL), dried over MgSO4 and the solvent was removed in vacuo to give 2-(4-bromophenyl)-5-cyclopropyl-N-methyl-6-[(methylsulfonyl)amino]-2H-indazole-3-carboxamide (1) (300 mg, 86%) as yellow solid. ESI-MS m/z calculated for [M+H]+: 463.04/465.04; found: 463.05/465.05. 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J=0.4 Hz, 1H), 7.68 (d, J=0.5 Hz, 1H), 7.65 (brd, J=8.8 Hz, 2H), 7.47 (d, J=8.8 Hz, 2H), 7.09 (s, 1H), 5.80 (brd, J=4.1 Hz, 1H), 3.13 (s, 3H), 3.00 (d, J=4.9 Hz, 3H), 1.80 (dddd, J=13.6, 8.1, 5.4, 1.3 Hz, 1H), 1.16-0.99 (m, 2H), 0.79-0.67 (m, 2H).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][C:20]=1[N+:27]([O-:29])=[O:28].C(OCC)(=O)C>O1CCCC1.O>[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22](/[CH:23]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:21][C:20]=1[N+:27]([O-:29])=[O:28]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: COc1ccc(C=O)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1ccc(OC)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.40 g of sodium hydride (purity: 60%) was suspended in 60 ml of tetrahydrofuran. To the suspension was dropwise added 13.5 g of ethyl diethylphosphonoacetate with ice-cooling. The mixture was stirred for 30 minutes at room temperature. To the resulting reaction mixture was dropwise added a solution of 9.06 g of 4-methoxy-3-nitrobenzaldehyde dissolved in 30 ml of tetrahydrofuran, with ice-cooling. The mixture was stirred for 30 minutes at the same temperature. To the reaction mixture was added 100 ml of ethyl acetate and 50 ml of water, and the organic layer was separated. The organic layer was washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain ethyl (E)-3-(4-methoxy-3-nitrophenyl)acrylate.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][C:7]1[CH:8]=[C:9]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:10]=[C:11]([CH2:13][P:14]([OH:17])([OH:16])=[O:15])[CH:12]=1)[C:3]([OH:5])=[O:4].[C:24](Cl)(=[O:40])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>CN(C)C=O.C(N(C(C)C)C(C)C)C>[C:24]([NH:1][CH:2]([CH2:6][C:7]1[CH:8]=[C:9]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:10]=[C:11]([CH2:13][P:14]([OH:17])([OH:16])=[O:15])[CH:12]=1)[C:3]([OH:5])=[O:4])(=[O:40])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: NC(Cc1cc(CP(=O)(O)O)cc(-c2ccccc2)c1)C(=O)O
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCCCCCCC(=O)NC(Cc1cc(CP(=O)(O)O)cc(-c2ccccc2)c1)C(=O)O
Temperature: 25 °C
Reaction time: 26 h

Procedure:
To a mixture of 335 mg (±)-α-amino-3-(5-phosphonomethyl-[1.1'-biphenyl]3-yl) propanoic acid in 30 ml dimethyl formamide and 0.76 ml N-ethyldiisopropylamine under nitrogen are added dropwise at room temperature within 10 minutes 0.4 ml palmitic acid chloride. The mixture is stirred at room temperature for 26 hours. The solvent is evaporated in vacuo. The oily residue is taken up in water, acidified with 2N HCl to pH 1 and extracted with diethyl ether. The extract is washed with saturated aqueous sodium chloride solution, dried (Na2SO4) and evaporated. The residue is recrystallized from diethyl ether/petroleum ether to yield the title compound, m.p. 130°-140°. MS (FAB):574(MH+).
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[CH2:16][N:17]([CH:23]1[C:32]2[N:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH2:26][CH2:25][CH2:24]1)[CH2:18][CH2:19][CH2:20][CH2:21][NH2:22].FC(F)(F)C(O)=O>C(Cl)Cl>[NH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[CH2:16][N:17]([CH:23]1[C:32]2[N:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH2:26][CH2:25][CH2:24]1)[CH2:18][CH2:19][CH2:20][CH2:21][NH2:22]
Reactant: C[Si](C)(C)CCOCn1c(CN(CCCCN)C2CCCc3cccnc32)nc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCCCN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21
Yield: 66.2 %

Procedure:
To a solution of N1-(1-(2-(trimethylsilyl)ethoxymethyl)-1H-Benzimidazol-2-ylmethyl)-N1-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine (73 mg, 0.16 mmol) in CH2Cl2 (2 mL) was added trifluoroacetic acid (4 mL) and the resultant solution was stirred at room temperature overnight then concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (10 mL) and water (5 mL) and treated with NaOH (10 M, ˜2 mL) until the aqueous phase was basic (pH 14). The phases were separated and the aqueous phase was extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by radial chromatography on silica gel (1 mm plate, 15:1:1 CH2Cl2—CH3OH—NH4OH) provided 37 mg of N1-(1H-Benzimidazol-2-ylmethyl)-N1-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine as a white foam.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][N:7]([CH3:12])[CH:8]=[CH:9][CH:10]=[O:11].[CH2:13]=[O:14].[CH3:15]O>>[CH3:6][N:7]([CH3:12])[CH:8]=[C:9]([CH2:13][O:14][CH3:15])[CH:10]=[O:11]
Reactant: CO
Reactant: CN(C)C=CC=O
Reactant: C=O
Agent: O=S(=O)(O)O
Product: COCC(C=O)=CN(C)C
Yield: 87 %

Procedure:
Concentrated sulfuric acid (1 mL) is slowly added to a solution of 3-(dimethylamino)-2-propenal (200 g, 2.01 mol) and paraformaldehyde (90 g, 3 mol) in methanol (1 L). The resultant solution is refluxed overnight, concentrated in vacuo to a volume of 200 mL, diluted with toluene and distilled until the vapor temperature is 105° C. The solution is then concentrated in vacuo to give the title product as an orange oil (251.4 g, 87% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][CH2:11][NH:12][CH2:13][CH3:14])[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH:16]([CH2:29]Br)[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:18]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:10][CH2:11][N:12]([CH2:13][CH3:14])[CH:16]([C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)=[O:18])[CH2:29]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCNCCNc1ccc(Cl)c(Cl)c1
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1)C(Br)CBr
Product: CCN1CCN(c2ccc(Cl)c(Cl)c2)CC1C(=O)Nc1ccc([N+](=O)[O-])cc1

Procedure:
In a manner similar to preparation 23, react N-(3,4-dichlorophenyl)-N'-ethyl-1,2-ethanediamine with 2,3-dibromo-N-(4-nitrophenyl)propanamide to obtain the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[ClH:10].[Cl:11]N1C(=O)CCC1=O>C(OCC)C>[ClH:11].[Cl:10][CH2:2][C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(=O)c1cccnc1
Agent: Cl
Solvent: CCOCC
Product: O=C(CCl)c1cccnc1
Reaction time: 4 h
Yield: 83 %

Procedure:
To a solution of 12 g (11 mL, 100 mmol) of 3-acetylpyridine in 100 mL of ethylether was added 100 mL of 1M ethereal hydrogen chloride. The resultant precipitate was filtered and 15.0 g (95.2 mmol) was collected and placed in a 500-mL round bottom flask equipped with a magnetic stir bar. To this was added 95 mL of 1M hydrogen chloride in acetic acid. After the mixture was stirred until is all the solid had dissolved, 12.7 g (95.2 mmol) of N-chlorosuccinimide (NCS) was added in one portion. The solution turned yellow and the NCS gradually dissolved. After 4 h, a white precipitate had formed. The mixture was allowed to stir for 2.5 days. It was then filtered. The solid collected was washed with 10 mL of acetic acid and 200 mL of ethylether to give 15.2 g (83%) of the title compound as a white solid: 1H NMR (200 MHz, d6 -DMSO) δ9.22 (t, 1H, J=1 Hz), 8.29 (dd, 1H, J=1.6, 5.1 Hz), 8.55 (td, 1H, J=2, 8.1 Hz), 7.82 (ddd, 1H, J=0.8, 5.1, 8.1 Hz), 5.27 (s, 2H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=2)[CH2:15][CH2:14]1
Reactant: Cc1ccc(F)cc1[N+](=O)[O-]
Reactant: CN1CCNCC1
Product: Cc1ccc(N2CCN(C)CC2)cc1[N+](=O)[O-]
Temperature: 200 °C
Yield: 48.3 %

Procedure:
In a cylindrical quartz tube were placed 4-fluoro-1-methyl-2-nitro-benzene (20.0 g, 129 mmol) and N-methyl-piperazine (26 g, 258 mmol). The reaction was heated for 48 hours at 200° C. until HPLC revealed the disappearance of the starting material. The solvent was removed under reduced pressure and the residue was dissolved in DCM. The solution was washed twice with water and the organic phase was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The final compound (14.65 g, 48% yield) was obtained as a brown oil.
Reaction SMILES: [ClH:1].[CH2:2]([N:9]1[CH2:14][CH2:13][C:12](=O)[CH:11]([C:16](OC)=O)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)(O)O.[NH2:24][C:25]([NH2:27])=[NH:26]>CCO>[CH2:2]([N:9]1[CH2:14][CH2:13][C:12]2[N:26]=[C:25]([NH2:27])[N:24]=[C:16]([Cl:1])[C:11]=2[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cl
Reactant: COC(=O)C1CN(Cc2ccccc2)CCC1=O
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: CCO
Product: Nc1nc(Cl)c2c(n1)CCN(Cc1ccccc1)C2
Temperature: 25 °C
Yield: 131.6 %

Procedure:
To EtOH (16 mL) cooled to 0° C. (ice/H2O bath) was added Na spheres (204 mg, 8.9 mmol). The mixture was stirred until all Na dissolved. Methyl 1-benzyl-4-oxo-3-piperidine-carboxylate hydrochloride (3.0 g, 10.1 mmol) and guanidine carbonate (1.4 g, 7.6 mmol) were added. The mixture was refluxed for 16 h. After the reaction was cooled to room temperature, the solid was collected by filtration, washed with EtOH, and dried under vacuum. Desired compound (2.58 g, 10.0 mmol; 99+% yield); mp=202-212° (dec.); ES MS [M+H]+=257; TLC (CH2Cl2—MeOH, 90:10); Rf=0.20. Step 2. Preparation of 6-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5](I)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[CH3:14][S:15]([C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1)(=[O:17])=[O:16].[NH2:27][C:28]1[S:29][CH:30]=[C:31]([CH3:33])[N:32]=1>>[CH3:14][S:15]([C:18]1[CH:19]=[C:20]([C:5]2[CH:4]=[N:3][C:2]([NH:27][C:28]3[S:29][CH:30]=[C:31]([CH3:33])[N:32]=3)=[C:11]3[C:6]=2[CH:7]=[CH:8][C:9]([CH3:12])=[N:10]3)[CH:21]=[CH:22][CH:23]=1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Cc1csc(N)n1
Reactant: Cc1ccc2c(I)cnc(Cl)c2n1
Product: Cc1csc(Nc2ncc(-c3cccc(S(C)(=O)=O)c3)c3ccc(C)nc23)n1

Procedure:
The title compound, MS: m/e=411.1 (M+H+), was prepared in accordance with the general method of example 15 step 1 and step 3 from 8-chloro-5-iodo-2-methyl-[1,7]naphthyridine (Example I), (3-methylsulfonylphenyl)boronic acid and 2-amino-4-methylthiazole.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH:7]([CH2:11][S:12](Cl)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]1[CH2:28][NH:29][CH2:30][CH2:31][C:22]2=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6](=[O:16])[CH:7]([CH2:11][S:12]([N:29]1[CH2:30][CH2:31][C:22]2[C:21]3[C:25](=[CH:26][CH:27]=[C:19]([O:18][CH3:17])[CH:20]=3)[NH:24][C:23]=2[CH2:28]1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc2[nH]c3c(c2c1)CCNC3
Reactant: CC(C)C(CS(=O)(=O)Cl)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2[nH]c3c(c2c1)CCN(S(=O)(=O)CC(C(=O)OC(C)(C)C)C(C)C)C3
Reaction time: 0.33 h
Yield: 64.5 %

Procedure:
A solution of 2-chlorosulfonylmethyl-3-methylbutyric acid tert-butyl ester (WO 99/24399) (470mg) in dichioromethane (10 ml) was added to a mixture of 6-methoxy-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole (350 mg) and triethylamine (0.72 ml) in dichloromethane (10 ml) at room temperature under nitrogen. The mixture was stirred for 20 minutes before being evaporated to dryness and the residue chromatographed (SiO2, 1:1 heptane-ethyl acetate) to give the title compound (487 mg, 66%) as a white solid.