Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.O.NN>CO.[Ni]>[CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc2[nH]cc(C3=CCN4CCCC4C3)c2c1
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: Nc1ccc2[nH]cc(C3=CCN4CCCC4C3)c2c1
Yield: 81.2 %

Procedure:
A solution of compound 141 (0.12 g, 0.423 mmol) in dry methanol (5 mL) was treated with Ra—Ni (˜0.05 g), hydrazine hydrate (0.13 mL, 4.235 mmol) at room temperature. The resulting mixture was refluxed for 2 min, in pre-heated oil bath. The reaction was brought to room temperature, filtered through celite bed and washed with methanol (2 20 m L). The combined methanol layer was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH: CH2Cl2, 95:5) to obtain 3-(1,2,3,5,8,8a-Hexahydroindolizin-7-yl)-1H-indol-5-amine, (0.087 g, 81%) as a solid. mp 208-210° C.; 1H NMR (DMSO-d6) δ 1.33-1.48 (m, 1H), 1.67-1.79 (m, 2H), 1.94-2.13 (m, 2H), 2.16-2.26 (m, 2H), 2.58-2.65 (m, 1H), 2.85 (d, 1H, J=15.6 Hz), 3.08-3.17 (m, 1H), 3.59 (dd, 1H, J=4.5, 15.7 Hz), 4.49 (s, 2H), 6.01 (d, 1H, J=4.5 Hz), 6.48 (dd, 1H, J=1.8, 9.1 Hz), 7.01 (d, 1H, J=1.5 Hz), 7.05 (d, 1H, J=8.4 Hz), 7.17 (d, 1H, J=2.7 Hz), 10.60 (s, 1H); ESI-MS (m/z, %) 254 (MH+, 62), 185 (100). A solution of the amine (0.053 g, 0.209 mmol) in dry ethanol (3 mL) was treated with thiophene-2-carboximidothioic acid methyl ester hydroiodide (0.12 g, 0.418 mmol) at room temperature and the solution was stirred for 24 h. Solvent was evaporated, crude was diluted with sat. NaHCO3 solution (20 mL) and product was extracted into CH2Cl2 (2 20 mL). The combined CH2Cl2 layer was washed with brine (15 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH: CH2Cl2, 5:95) to obtain compound 142 (0.06 g, 79%) as a solid. mp 122-124° C.; 1H NMR (DMSO-d6) δ 1.38-1.46 (m, 1H), 1.70-1.78 (m, 2H), 1.93-2.12 (m, 2H), 2.20-2.28 (m, 2H), 2.62-2.72 (m, 1H), 2.83 (d, 1H, J=15.9 Hz), 3.07-3.13 (m, 1H), 3.59 (dd, 1H, J=4.5, 16.0 Hz), 6.07 (d, 1H, J=3.9 Hz), 6.22 (brs, 2H), 6.66 (d, 1H, J=8.1 Hz), 7.09 (dd, 1H, J=3.9, 4.9 Hz), 7.22 (s, 1H), 7.30-7.32 (m, 2H), 7.58 (d, 1H, J=4.5 Hz), 7.71 (d, 1H, J=2.7 Hz), 10.92 (s, 1H); ESI-MS (m/z, %) 363 (MH+, 20), 294 (100), 182 (15); ESI-HRMS calculated for C21H23N4S (MH+), calculated: 363.1655; observed: 363.1637.
Reaction SMILES: [C:1]([C:5]1[CH2:9][CH2:8][CH2:7][C:6]=1[S:10]([N:13]=[C:14]=[O:15])(=[O:12])=[O:11])([O:3][CH3:4])=[O:2].[CH3:16][O:17][C:18]1[CH:23]=[C:22]([CH3:24])[N:21]=[C:20]([NH2:25])[N:19]=1>C(#N)C.CCOCC>[CH3:16][O:17][C:18]1[CH:23]=[C:22]([CH3:24])[N:21]=[C:20]([NH:25][C:14]([NH:13][S:10]([C:6]2[CH2:7][CH2:8][CH2:9][C:5]=2[C:1]([O:3][CH3:4])=[O:2])(=[O:11])=[O:12])=[O:15])[N:19]=1
Reactant: COc1cc(C)nc(N)n1
Reactant: COC(=O)C1=C(S(=O)(=O)N=C=O)CCC1
Solvent: CC#N
Solvent: CCOCC
Product: COC(=O)C1=C(S(=O)(=O)NC(=O)Nc2nc(C)cc(OC)n2)CCC1

Procedure:
The sulfonyl isocyanate product (5 g) of Example 3 was diluted to a concentration of 1.5M with dry acetonitrile and 2.0 ml of this solution was added to a stirred suspension of 0.31 g 4-methoxy-6-methylpyrimidine-2-amine in 4.0 ml of dry acetonitrile under a nitrogen atmosphere at room temperature. After stirring several hours, the mixture was diluted with ether to precipitate the product which was collected by filtration and dried; m.p. 161°-163°. An infrared spectrum (nujol) exhibited absorptions at 1730 and 1700 cm-1, and an NMR (90 MHz) in CDCl3 solution exhibited absorptions at 2.1 (CH2), 2.45 (CH3), 3.0 (CH2 ×2), 3.75 (CH3O), 3.95 (CH3O), 6.3 (CH), 7.9 (NH), 13.8 (NH), ppm indicating the title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]([CH:10]([C:23]1[CH:24]=[C:25]([Si:28]([CH2:33][CH3:34])([CH2:31][CH3:32])[CH2:29][CH3:30])[O:26][CH:27]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[N+]=[N-]>C1COCC1>[NH2:7][CH:10]([C:23]1[CH:24]=[C:25]([Si:28]([CH2:33][CH3:34])([CH2:31][CH3:32])[CH2:29][CH3:30])[O:26][CH:27]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCC(N=[N+]=[N-])c1coc([Si](CC)(CC)CC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(N)c1coc([Si](CC)(CC)CC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of lithium aluminum hydride (a 1.0 M solution in THF; 4.22 ml, 4.22 mmol) was added slowly to a solution of 4-(1-azidotridecyl)-2-triethylsilylfuran (1.55 g, 3.84 mmol) at 0 degrees C under argon. After stirring at room temperature for 2 hours, the mixture was cooled to 0 degrees C. and quenched with 2M sodium hydroxide. Anhydrous sodium sulfate was added to coagulate the aluminum salt and the mixture was extracted thoroughly with ethyl acetate. Evaporation of the dried (magnesium sulfate) extracts gave an oil, which was purified by flash chromatography on silica using 5% methanol/dichloromethane to give the titled amine.
Reaction SMILES: C[O:2][C:3](=[O:17])[CH:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+]>CO.O>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:3]([OH:17])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C(CC1CCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To title A compound, 3-cyclopentyl-2-phenylpropionic methyl ester (13.0 g, 56 mmol) in 100 mL of methanol is added a solution of 5.6 g (140 mmol) of NaOH in 8 mL of water. The reaction mixture is stirred at ambient temperature overnight. The methanol is evaporated and the residue is dissolved in 200 mL of water and extracted with ethyl ether. The aqueous phase is separated and adjusted to pH 2-3 with 1 N HCl and extracted with MTBE twice. The combined extracts are washed with saturated sodium chloride and dried over anhydrous magnesium sulfate. The material is evaporated to a yellow oil that crystallizes to provide 3-cyclopentyl-2-phenylpropionic acid as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 1.7 (m, 2H), 2.1 (m, 2H), 2.2 (m, 3H), 2.4(m, 3H), 2.4 (m, 1H), 4.2 (t, J=7.7 Hz, 1H), 7.9 (m, 5H); LC/MS 236 (M+NH4+).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[F:1][C:2]([F:11])([F:12])[C:3]([O:10][S:19]([C:16]1[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=1)(=[O:21])=[O:20])=[CH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C=C(OS(=O)(=O)c1ccc(C)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.1 %

Procedure:
To a solution of 2.0 g (10.8 mmol) of ethyl 4,4,4-trifluoroacetoacetate in 10 ml of DMF was added 2.28 g of p-toluenesulfonyl chloride and 4.24 g of cesium carbonate and stirred at room temperature overnight. The reaction solution was poured into water and extracted with tert-butyl methyl ether. The organic layer was washed with a saturated NaCl solution, dried over anhydrous MgSO4, and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 2.27 g of ethyl 4,4,4-trifluoro-3-p-toluenesulfonyloxy-2-butenoate.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:24]=[CH:23][CH:22]=[CH:21][C:6]=1[C:7]1[O:8][C:9]2[C:14]([C:15](=[O:17])[CH:16]=1)=[CH:13][C:12]([C:18](Cl)=[O:19])=[CH:11][CH:10]=2)([CH3:3])[CH3:2].[OH:25]CCN1CCOCC1.N1C=CC=CC=1>C1C=CC=CC=1>[C:18]([C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([C:6]1[CH:21]=[CH:22][CH:23]=[CH:24][C:5]=1[O:4][CH:1]([CH3:3])[CH3:2])=[CH:16][C:15]2=[O:17])([OH:25])=[O:19]
Reactant: OCCN1CCOCC1
Reactant: CC(C)Oc1ccccc1-c1cc(=O)c2cc(C(=O)Cl)ccc2o1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC(C)Oc1ccccc1-c1cc(=O)c2cc(C(=O)O)ccc2o1
Yield: 88.5 %

Procedure:
2'-isopropoxy-flavone-6-carbonyl-chloride (4.3 g) prepared according to Example 18, dissolved in anhydrous benzene (40 ml) was treated with N-hydroxyethyl-morpholine (3.2 g) and pyridine (1 ml) at room temperature for 24 hours. The benzene solution was washed with aqueous citric acid 40% with sodium bicarbonate and water, then evaporated to dryness. The residue, crystallised from acetone, gave morpholinoethyl-ester of 6-carboxy-2'-isopropoxy-flavone (3.6 g; m.p. 133°-135° C).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][C:16](=O)[O:17]C3C=CC=CC=3)=[CH:9][CH:8]=2)[N:5]=[C:4]([C:25]([F:28])([F:27])[F:26])[C:3]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[C:35]1([S:45]([NH2:48])(=[O:47])=[O:46])[CH:40]=[CH:39][CH:38]=[C:37]([S:41]([NH2:44])(=[O:43])=[O:42])[CH:36]=1>>[CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][C:16]([NH:44][S:41]([C:37]3[CH:38]=[CH:39][CH:40]=[C:35]([S:45]([NH2:48])(=[O:47])=[O:46])[CH:36]=3)(=[O:43])=[O:42])=[O:17])=[CH:9][CH:8]=2)[N:5]=[C:4]([C:25]([F:26])([F:27])[F:28])[C:3]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NS(=O)(=O)c1cccc(S(N)(=O)=O)c1
Reactant: Cc1c(-c2ccccc2)c(C(F)(F)F)nn1-c1ccc(CCNC(=O)Oc2ccccc2)cc1
Product: Cc1c(-c2ccccc2)c(C(F)(F)F)nn1-c1ccc(CCNC(=O)NS(=O)(=O)c2cccc(S(N)(=O)=O)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 42 from phenyl 2-{4-[5-methyl-4-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}ethylcarbamate (step 7 of Example 52) and 1,3-benzenedisulfonamide: MS (ESI) m/z 608 [M+H]+, 606 [M−H]−, 1H-NMR (CDCl3) δ 8.62 (1H, br.s), 8.14 (2H, br.s), 7.70 (1H, br.s), 7.39-7.21 (9H, m), 6.18 (1H, br.s), 3.35 (2H, br.s), 2.76 (2H, br.s), 2.15 (3H, s).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:12][CH2:11]2)=[O:9])=[CH:3][CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:34])C=1>C(Cl)Cl.C(OCC)(=O)C>[O-:34][N+:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:17])[CH2:12][CH2:11]2)=[O:9])=[CH:3][CH:2]=1
Reactant: O=C(Nc1ccncc1)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(Nc1cc[n+]([O-])cc1)C1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
Benzyl 4-[(4-pyridinylamino)carbonyl]-1-piperidinecarboxylate (EXAMPLE 1, Step 1) (615 mg, 1.81 mmol) was dissolved in CH2Cl2 and treated with mCPBA (3.12 g, 18.10 mmol) and aged 18 h. The reaction was diluted with ethyl acetate and washed with sat. NaHCO3. The organics were separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting oil was purified by silica gel chromatography to afford benzyl 4-{[(1-oxido-4-pyridinyl)amino]carbonyl}-1-piperidinecarboxylate as a clear oil.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]([F:26])[C:24]=1[F:25]>>[F:17][C:4]1[CH:3]=[C:2]([C:21]2[CH:20]=[C:19]([F:18])[C:24]([F:25])=[C:23]([F:26])[CH:22]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: OB(O)c1cc(F)c(F)c(F)c1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4cc(F)c(F)c(F)c4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, yellow solid (73 mg, 84%), MS (ISP) m/z=349.5 [(M+H)+], mp 250° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 3,4,5-trifluoro-phenylboronic acid (57.2 mg, 0.325 mmol).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([C:14]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][C:15]=2[C:16]([OH:18])=[O:17])=[O:13])=[C:4]1[CH3:26])[CH3:2].[OH-].[Na+]>Cl>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([C:14]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:15]=2[C:16]([OH:18])=[O:17])=[O:13])=[C:4]1[CH3:26])[CH3:2]
Reactant: CCn1c(C)c(C(=O)c2ccc([N+](=O)[O-])cc2C(=O)O)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCn1c(C)c(C(=O)c2ccc(N)cc2C(=O)O)c2ccccc21
Temperature: 55 °C
Yield: 54.3 %

Procedure:
To a solution of 7.04 g (0.02 mole) of 2-[(1-ethyl-2-methyl-3-indolyl)carbonyl]-5-nitrobenzoic acid, prepared as described in part A of this example, in 70 ml of concentrated hydrochloric acid, there was added 13.5 g (0.06 mole) of stannous chloride dihydrate at such a rate as to allow the reaction to exotherm to 55° C. The temperature was maintained at 55° C. for an additional one-half hour. The reaction was then cooled to room temperature and the pH adjusted to six by the addition of 10 percent aqueous sodium hydroxide solution. The red precipitate thus formed was filtered off and extracted into acetone. The acetone solution was evaporated and the paste-like residue was slurried in diethylether and then the solid was collected by filtration to obtain 3.5 g of 2-[(1-ethyl-2-methyl-3-indolyl)-carbonyl]-5-aminobenzoic acid (Formula VIII: R3 =R2 =R0 =Y1 =H; R1 =NH2 ; R5 =CH3 ; R6 =CH2CH3), a red solid which melted at 187°-189° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10]O)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:32]>C(Cl)Cl>[Br:32][CH2:10][C:9]#[C:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCC#Cc1ccc(F)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1ccc(C#CCBr)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.4 %

Procedure:
A solution of 3-(4-fluorophenyl)prop-2-yn-1-ol (1 g, 6.80 mmol) in DCM (13.6 mL) under N2 was cooled in a ice bath at 0° C. 2.70 g (8.2 mmol, loading 3mmol/g) of triphenylphosphine polymer supported was then added followed by 2.70 g (8.2 mmol) of carbon tetrabromide. The reaction mixture was stirred 15 min at 0° C. and warmed to room temperature for 90 min. After filtration through celite, the solvent was evaporated under reduce pressure. The crude product was purified by flash chromatography (prepacked 25 g silicagel column, DCM 100% as eluent) to afford 1.44 g of 1-(3-bromoprop-1-ynyl)-4-fluorobenzene as a yellow oil (Yield: 99%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]=[O:9].[OH-].[K+].[N+:12]([CH2:14][C:15]([N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16])#[C-:13]>CO>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C@@H:8]1[O:9][CH:13]=[N:12][C@H:14]1[C:15]([N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16]
Reactant: O=Cc1ccncc1Br
Reactant: [C-]#[N+]CC(=O)N1CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C([C@@H]1N=CO[C@H]1c1ccncc1Br)N1CCCC1
Temperature: 0 °C

Procedure:
BAL 01028A was prepared in accordance with method D using 3-bromo-4-pyridinecarboxaldehyde (1.010 g, 5.43 mmol), KOH (0.305 g, 5.43 mmol) in methanol (5 mL) and 2-isocyano-1-pyrrolidin-1-yl-ethanone BLE 04134 (0.75 g, 5.43 mmol). The mixture was stirred at 0° C. until precipitation and concentrated. The mixture was partitioned between EtOAc (50 ml) and H2O (25 ml). The aqueous layer was extracted twice with EtOAc (25 mL). The EtOAc fractions were combined, washed twice with brine (2×25 mL), dried over MgSO4 and filtered. After evaporation and trans-(5-(3-bromopyridin-4-yl)-4,5-dihydrooxazol-4-yl)(pyrrolidin-1-yl)methanone BAL 01028A was obtained (1.20 g, 68% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:9]([NH2:20])=[N:8][C:6]=2[N:7]=1.N[CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1>>[NH2:20][C:9]1[C:10]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])=[CH:11][C:5]2[CH:4]=[N:3][C:2]([NH:1][CH2:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]3)=[N:7][C:6]=2[N:8]=1
Reactant: CN1CCN(CCCCN)CC1
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Product: CN1CCN(CCCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(N)nc3n2)CC1

Procedure:
Following the procedure of Example 20, 2.0 g of 2,7-diamino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]-pyrimidine from Example 1 was reacted with 15 mL of 1-(4-aminobutyl)-4-methyl-piperazine to give the title compound.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19](O)=[O:20])=[CH:14][CH:13]=2)[N:4]=1.[CH:24]1([NH2:29])[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([NH:29][C:19](=[O:20])[CH2:18][C:15]2[CH:14]=[CH:13][C:12]([N:5]3[C:6]4[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=4[C:3]([C:2]([F:22])([F:23])[F:1])=[N:4]3)=[CH:17][CH:16]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: NC1CCCC1
Reactant: O=C(O)Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Product: O=C(Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1)NC1CCCC1

Procedure:
The title compound was prepared from {4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetic acid and cyclopentylamine using a similar procedure to that described for Example 2, except product was purified by mass directed auto-prep.
Reaction SMILES: Br[C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=[C:4]([CH:12]=[O:13])[CH:3]=1.[CH3:14]N(C=O)C>[F-].[K+]>[CH3:14][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=[C:4]([CH:12]=[O:13])[CH:3]=1
Reactant: CN(C)C=O
Reactant: O=Cc1cc(Br)c2c(c1)OCCO2
Agent: [F-]
Agent: [K+]
Product: Cc1cc(C=O)cc2c1OCCO2
Temperature: 70 °C
Yield: 83 %

Procedure:
To a solution of 8-bromo-2,3-dihydro-1,4-benzodioxin-6-carbaldehyde (240 mg, 0.987 mmol) in DMF (5 mL) were added LiCL (126 mg, 2.96 mmol), Me Sn (0.137 mL, 0.987 mmol) and PdCL2(PPh)2 (35 mg, 0.049 mmol). After heated at 70° C. for 12 hr, the mixture was cooled down to room temperature and diluted with aqueous KF solution. The resulting solution was extracted several times with DCM. The organic parts were combined, concentrated and purified with column chromatography (silica, 10-40% Ethyl acetate in hexane) affording the title compound as an off-white solid (145 mg, 83%): MS (ES) m/z 179 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([C:16]#[C:17][C:18]3[CH:19]=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=3)=[C:14]([CH3:25])[N:13]=[CH:12][N:11]=2)=[CH:6][CH:5]=1.[Li+].[OH-]>O.C1COCC1>[NH2:24][C:21]1[N:20]=[CH:19][C:18]([C:17]#[C:16][C:15]2[C:10]([C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:26])=[O:2])=[CH:9][CH:8]=3)=[N:11][CH:12]=[N:13][C:14]=2[CH3:25])=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc(-c2ncnc(C)c2C#Cc2ccc(N)nc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ncnc(-c2ccc(C(=O)O)cc2)c1C#Cc1ccc(N)nc1
Temperature: 50 °C

Procedure:
The title compound is synthesized according to general procedure GP8 starting from 2.2 g (6.3 mmol) 4-[5-(6-amino-pyridin-3-ylethynyl)-6-methyl-pyrimidin-4-yl]-benzoic acid methyl ester using 1.33 g (31.6 mmoL) LiOH in 5 mL water and 50 mL THF. The reaction mixture is stirred over night at 50° C. The solvent is removed under reduced pressure and the residue is taken up in water. Aqueous 1 M HCl is added until pH 5 is reached. The precipitated product is filtered off and taken up in water. After freeze drying 2.7 g of crude product are obtained which is used for the next step without further purification.
Reaction SMILES: [C:1]1([C:7]2[N:16]3[C:10]([CH2:11][C:12](=[O:21])[NH:13][C:14]4[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=43)=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:25][C:26]([N:28]([CH:35]([CH3:37])[CH3:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27]>CN(C=O)C.[Cl-].[Na+].O>[CH:35]([N:28]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:26](=[O:27])[CH2:25][N:13]1[C:12](=[O:21])[CH2:11][C:10]2[N:16]([C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8][N:9]=2)[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]1=2)([CH3:37])[CH3:36]
Reactant: O=C1Cc2nnc(-c3ccccc3)n2-c2ccccc2N1
Reactant: CC(C)N(C(=O)CBr)c1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)N(C(=O)CN1C(=O)Cc2nnc(-c3ccccc3)n2-c2ccccc21)c1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 72.4 %

Procedure:
To a solution of 1-phenyl-4H,6H-2,3,6,10b-tetraaza-benzo[e]azulen-5-one (Preparation 4(A)) (2.5 g, 9.05 mmol) in DMF (40 mL) at 0° C. was added sodium hydride (60% in oil, 0.36 g, 9.0 mmol). The reaction was warmed to room temperature and was stirred for 40 minutes. The reaction was cooled to −6° C. and a solution of 2-bromo-N-isopropyl-N-phenyl-acetamide (Preparation 1(A)) (2.55 g, 9.95 mmol) in DMF (20 mL) was added to the reaction mixture dropwise over 0.5 hour, maintaining the internal reaction temperature below −3° C. The reaction mixture was stirred for 105 minutes below −3° C. and brine (200 mL) was added. The aqueous solution was washed with ethyl acetate (200 mL). The organic layer was washed with brine, dried over sodium sulfate, and concentrated to ⅓ volume. Hexanes were slowly added until a solid crashed out. The white solid was collected by filtration and was rinsed with ether and hexanes to give 2.96 g of N-isopropyl-2-(5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-N-phenyl-acetamide. MS 452 (M+1). This intermediate was carried forward according to Example 3(B), Steps A and B above to afford 2-[4-(1H-indazol-3-ylmethyl)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-N-phenyl-acetamide as a racemic mixture.
Reaction SMILES: [O:1]=[C:2]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=[CH:4][C:5]1[O:9][C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:7][CH:6]=1.[CH3:25]O>>[CH3:25][O:18][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:8]1[O:9][C:5]([CH:4]=[CH:3][C:2](=[O:1])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:6][CH:7]=1
Reactant: CCCCCC(=O)C=Cc1ccc(CCCCCCCC(=O)O)o1
Reactant: CO
Product: CCCCCC(=O)C=Cc1ccc(CCCCCCCC(=O)OC)o1
Temperature: 0 °C
Yield: 79 %

Procedure:
II (2.52 g, 0.00755 mole), methanol (30 ml), and ethyl ether-borontrifluoride complex (0.24 g) were stirred and heated under reflux for 1 hour. After cooling, the reaction mixture was poured into ice-water (150 ml) and extracted with two 80-ml portions of ether. The combined ethereal extracts were washed with cold 10% sodium carbonate (50 ml) and then with two 50-ml portions of cold water. The ethereal solution was dried over magnesium sulfate and evaporated to dryness from a water bath (60°C), at last under 15 mm Hg. Distillation under nitrogen of the residual oil (2.46 g) gave 2.07 g (79%) of III, b0.3 202°-204°C, nD25 1.5262.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]3[S:15][CH:16]=[CH:17][C:13]=3[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.[CH3:18][O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C1(C)C=CC=CC=1.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:14]3[S:15][CH:16]=[CH:17][C:13]=3[CH2:12][CH2:11][N:10]2[C:24]([C:23]2[CH:27]=[CH:28][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)=[O:25])=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)O)cc1
Reactant: COc1ccc(C2NCCc3ccsc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)N2CCc3ccsc3C2c2ccc(OC)cc2)cc1
Reaction time: 8 h

Procedure:
7-(4-methoxyphenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (80 mg) in toluene (10 ml), 4-methoxybenzoic acid (55 mg), EDAC (94 mg) and HOBt (44 mg) were mixed in DMF (3 ml). The mixture was stirred overnight, evaporated to dryness and dissolved in ethyl acetate (10 ml).