Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]([CH2:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1)C(OC(C)(C)C)=O)=O)(C)(C)C>C(O)(C(F)(F)F)=O.ClCCl>[NH2:22][CH2:21][C:20]1[CH:23]=[CH:24][C:17]([C:16]#[N:8])=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(C#N)cc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 13.6 %

Procedure:
4-(Di-tert-butoxycarbonylaminomethyl)benzonitrile (2 g, 6.0 mmoles) (prepared as described in Preparative Example 247, Step A above) was dissolved in TFA (4 mL) and the solution was stirred at 25° C. for 0.25 h. The reaction mixture was diluted with dichloromethane and extracted with 1N sodium hydroxide. The organic layer was dried (MgSO4), filtered and evaporated to dryness. The residue was chromatographed on a silica gel column (15×5 cm) using 3% (10% conc. ammonium hydroxide in methanol)-dichloromethane as the eluant to give 4-(aminomethyl)benzonitrile (108 mg, 68%): FABMS: m/z 133.1 (MH+); HRFABMS: m/z133.0764 (MH+). Calcd. for C8H9N2: m/z 133.0766; δH (CDCl3) 2.04 (2H, s, —CH2NH2), 3.89 (2H, s, —CH2NH2), 7.40 (2H, d, Ar—H) and 7.59 ppm (2H, d, Ar—H); δC (CDCl3) CH2, 45.7; CH, 127.8, 127.8, 132.4, 132.4; C, 110.6, 118.9, 148.0.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[K].[O-]CCCC.[CH3:34][C:35]1[CH:40]=[CH:39][N:38]=[C:37]([NH:41][C:42]2[N:47]=[C:46]([C:48]3[S:52][C:51]([CH:53]=O)=[N:50][CH:49]=3)[CH:45]=[CH:44][CH:43]=2)[CH:36]=1>C1COCC1.O>[CH3:34][C:35]1[CH:40]=[CH:39][N:38]=[C:37]([NH:41][C:42]2[CH:43]=[CH:44][CH:45]=[C:46]([C:48]3[S:52][C:51](/[CH:53]=[CH:2]/[C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=4)=[N:50][CH:49]=3)[N:47]=2)[CH:36]=1
Reactant: Cc1ccnc(Nc2cccc(-c3cnc(C=O)s3)n2)c1
Reactant: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[O-]
Agent: [Br-]
Agent: [K]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccnc(Nc2cccc(-c3cnc(/C=C/c4ccccc4)s3)n2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of benzyltriphenylphosphonium bromide (176 mg, 0.406 mmol) in dry THF cooled at 0° C. under inert atmosphere was added potassium tot-butoxide (1.0M in THF) (675 μL, 675 μmol). The mixture was stirred at 0° C. for 30 mins, then 5-[6-(4-methyl-pyridin-2-ylamino)-pyridin-2-yl]-thiazole-2-carbaldehyde was added in one portion. After stirring at room temperature for 3 hours, the reaction mixture was treated with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure before purification by column chromatography on SiO2 using combiflash Companion®, eluting with cyclohexane/ethyl acetate. The E-isomer was then further purified by preparative chromatography on silica plate, eluting with 5% methanol in dichloromethane to afford the title compound as a yellow solid. 1H NMR (Acetone-d6, 300 MHz): δ=8.41 (s, 1H), 8.16 (d, J=5.1 Hz, 1H), 8.00 (s, 1H), 7.80-7.70 (m, 3H), 7.65-7.55 (m, 2H), 7.53-7.36 (m, 4H), 7.50 (s, 1H), 6.84 (d, J=5.1 Hz, 1H), 2.47 (s, 3H). (APCI+) m/z 371 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][C:12]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([C:22]([OH:24])=O)=[N:20][CH:21]=3)=[N:13][CH:14]=2)=[CH:5][CH:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:58]([O:62][C:63]([N:65]1[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]1)=[O:64])([CH3:61])([CH3:60])[CH3:59]>CN(C=O)C>[C:58]([O:62][C:63]([N:65]1[CH2:70][CH2:69][N:68]([C:22]([C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:12]3[N:13]=[CH:14][C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)=[CH:10][N:11]=3)=[CH:21][N:20]=2)=[O:24])[CH2:67][CH2:66]1)=[O:64])([CH3:61])([CH3:59])[CH3:60]
Reactant: COc1ccc(-c2cnc(Nc3ccc(C(=O)O)nc3)nc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cnc(Nc3ccc(C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)nc3)nc2)cc1
Reaction time: 0.03 h

Procedure:
To a solution of 5-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-pyridine-2-carboxylic acid 5 (0.12 mmol) in DMF (0.5 mL) is added HATU (0.13 mmol) and DIEA (0.36 mmol) at rt. The resulting mixture is stirred for 2 min and then a solution of piperazine-1-carboxylic acid tert-butyl ester (0.12 mmol) in DMF (1 mL) is added. The reaction mixture is stirred at rt for 4 h and directly purified by preparative LCMS to give 4-{5-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-pyridine-2-carbonyl}-piperazine-1-carboxylic acid tert-butyl ester 6 as a white solid. 1H NMR (400 MHz, d6-DMSO) δ 10.32 (s, 1H), 8.89 (s, 2H), 8.39-8.37 (m., 2H), 7.86 (dd, J=4.0 and 8.0 Hz, 1H), 7.71-7.69 (m, 2H), 7.08-7.06 (m, 2H), 3.81 (s, 3H), 3.55-3.51 (bm, 4H), 3.96-3.94 (bs, 4H), 1.42 (s, 9H). MS (m/z) (M+1)+: 491.1.
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH:12]=[C:11]3[C:17]2[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH:22]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28]>>[Cl:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([N:13]1[C:14]2[C:10](=[CH:9][C:8]([O:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:16][CH:15]=2)[C:11]([C:17]2[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH:22]=2)=[CH:12]1)=[O:28]
Reactant: CN1CC=C(c2c[nH]c3ccc(OC4CCCCC4)cc23)CC1
Reactant: O=C(Cl)c1ccccc1Cl
Product: CN1CC=C(c2cn(C(=O)c3ccccc3Cl)c3ccc(OC4CCCCC4)cc23)CC1

Procedure:
(12.5 mg, 33%); from 5-cyclohexyloxy-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (Example 4c, 25.7 mg, 0.083 mmol) and 2-chlorobenzoyl chloride (25 uL, 0.20 mmol); HRMS-FAB+ for C27H29N2O2Cl: calculated MH+ : 449.19958; found: 449.19815.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29][CH2:30][C:31]1[N:32]=[C:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:34][C:35]=1[CH3:36])[CH2:6][O:7][C:8]1[C:12](/[CH:13]=[CH:14]/[C:15]([O:17]CC)=[O:16])=[CH:11][N:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:9]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29][CH2:30][C:31]1[N:32]=[C:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:34][C:35]=1[CH3:36])[CH2:6][O:7][C:8]1[C:12](/[CH:13]=[CH:14]/[C:15]([OH:17])=[O:16])=[CH:11][N:10]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:9]=1
Reactant: CCOC(=O)/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/C(=O)O)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 60 °C
Reaction time: 5 h
Yield: 94.7 %

Procedure:
A mixture of ethyl (E)-3-(3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-phenyl-1H-pyrazol-4-yl)-2-propenoate (800 mg), 1N aqueous sodium hydroxide solution (3 mL), tetrahydrofuran (10 mL) and ethanol (10 mL) was stirred at 60° C. for 5 hrs. 1N Hydrochloric acid (3 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained colorless crystals were collected by filtration to give (E)-3-(3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-phenyl-1H-pyrazol-4-yl)-2-propenoic acid (720 mg, yield 95%). The crystals were recrystallized from ethyl acetate-hexane. melting point: 188-189° C.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)(=[O:4])=[O:3].[NH:15]1[CH2:17][CH2:16]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([NH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([N:15]2[CH2:17][CH2:16]2)=[O:11])=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: C1CN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(C(=O)N2CC2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
13.0 g (55.6 mmol) of 4-[(methylsulfonyl)amino]benzoyl chloride is suspended in 150 mL of methylene chloride and cooled to about 0° C. 2.40 g (55.7 mmol) of aziridine and 7.75 mL (55.6 mmol) of triethylamine are added and the reaction allowed to warm to room temperature and stir for 2 hours. After 2 hours, the solution is washed with 100 mL of saturated aqueous sodium chloride and placed in the freezer. After 18 hours, the resulting white precipitate is filtered, washed with 50 mL of ether and dried to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10](F)[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[CH3:16][NH2:17].C([O-])([O-])=O.[K+].[K+].CS(C)=O>O>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:17][CH3:16])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Fc1cc(-c2cccnc2Cl)ccn1
Reactant: CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CNc1cc(-c2cccnc2Cl)ccn1
Temperature: 80 °C

Procedure:
To 2-chloro-2′-fluoro-[3,4′]bipyridinyl (5.30 g, 25.4 mmol), methylamine hydrochloride (9.00 g, 133 mmol) and K2CO3 (28.1 g, 203 mmol) was added DMSO (70 mL). The mixture was heated overnight at 80° C. in a sealed tube. The cooled mixture was diluted with water (300 mL) and the resulting solid was filtered, washed with water and dried to yield (2-chloro-[3,4′]bipyridinyl-2′-yl)-methyl-amine. MS m/z=220 [M+1]+. Calc'd for C11H10ClN3: 219.68.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:27][CH2:28][CH2:29][S:30]([C:33]1[CH:34]=[C:35]([CH:37]=[CH:38][CH:39]=1)[NH2:36])(=[O:32])=[O:31]>>[OH:27][CH2:28][CH2:29][S:30]([C:33]1[CH:34]=[C:35]([NH:36][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])[CH:37]=[CH:38][CH:39]=1)(=[O:31])=[O:32]
Reactant: Nc1cccc(S(=O)(=O)CCO)c1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: O=C(Nc1cccc(S(=O)(=O)CCO)c1)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-(2-hydroxy-ethanesulfonyl)-aniline [commercially available] according to general procedure II. Yellow solid. MS (ISP) 559.4 [(M+H)+]; mp 237° C.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12](=[O:17])[CH2:13][N:14]([CH3:16])[CH3:15])[N:10]=2)[N:7]=1.[NH2:18][C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[NH2:18][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=1)[O:25][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12](=[O:17])[CH2:13][N:14]([CH3:16])[CH3:15])[N:10]=2)[N:7]=1
Reactant: CN(C)CC(=O)Nc1cn2nc(I)ccc2n1
Reactant: Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CC(=O)Nc1cn2nc(Oc3cccc(N)c3)ccc2n1
Yield: 83.8 %

Procedure:
A mixture of N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)-N2,N2-dimethylglycinamide (517 mg, 1.5 mmol), 3-aminophenol (491 mg, 4.5 mmol), potassium carbonate (415 mg, 3.0 mmol) and N,N-dimethylformamide (3.0 mL) was stirred using a microwave synthesizer at 180° C. for 40 min. The reaction mixture was diluted with water, and the precipitate was collected by filtration, washed with water, and dried under reduced pressure. The obtained solid was washed with ethyl acetate to give the title compound (410 mg, 84%) as a brown powder.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[F:14])(=[O:3])[CH3:2].[Br:15]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[C:1]([O:4][CH2:5][CH:6]([Br:15])[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[F:14])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCc1ccc(Br)cc1F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)OCC(Br)c1ccc(Br)cc1F
Temperature: 80 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
A solution of 4-bromo-2-fluorophenethyl acetate (2.72 mmol) in carbon tetrachloride (6 mL) was degassed with a stream of nitrogen for five minutes, at which point the solution was treated with N-bromosuccinimide (2.99 mmol) and azobisisobutyronitrile (0.272 mmol). The reaction vessel was purged with nitrogen and sealed, and the mixture stirred at 80° C. for 8 h, at which point the reaction was cooled to room temperature and was stirred overnight. The resulting mixture was concentrated to dryness in vacuo. Purification of the crude material by silica gel chromatography (0-50% ethyl acetate/hexanes) afforded the title compound as a beige oil (790 mg, 77% yield). 1H NMR (400 MHz, DMSO-d6) d ppm 2.00 (s, 3 H) 4.57 (dd, J=11.62, 7.07 Hz, 1 H) 4.67 (dd, J=11.75, 7.20 Hz, 1 H) 5.52 (t, J=7.07 Hz, 1 H) 7.45-7.55 (m, 1 H) 7.59-7.70 (m, 2 H).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][C:11]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([CH:13]=[O:14])[CH2:12][CH:7]2[CH2:6]1)=[O:4].O.O.P([O-])(O)(O)=[O:26].[Na+].Cl([O-])=O.[Na+].CC(=CC)C>O1CCCC1.O>[CH2:15]([C:11]1([C:13]([OH:26])=[O:14])[CH2:12][CH:7]2[CH2:6][N:5]([C:3](=[O:4])[N:2]([CH3:1])[CH3:22])[CH2:9][CH:8]2[CH2:10]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CN(C)C(=O)N1CC2CC(C=O)(Cc3ccccc3)CC2C1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)N1CC2CC(Cc3ccccc3)(C(=O)O)CC2C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
5-Benzyl-5-formyl-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 14b (0.729 g, 2.43 mmol) was dissolved in the solvent mixture of 28 mL of tetrahydrofuran and 14 mL of water under nitrogen atmosphere, followed by addition of sodium dihydrogenphosphate dihydrate (1.14 g, 7.29 mmol), sodium chlorite (0.66 g, 7.29 mmol) and 2-methyl-2-butene (0.513 g, 7.32 mmol) upon cooling to 0° C. The reaction mixture was stirred at 0° C. for 2 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 5-benzyl-2-dimethylcarbamoyl-octahydro-cyclopenta[c]pyrrole-5-carboxylic acid 14c (0.76 g, yield 98%) as a colorless oil.
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:19]=[C:18]([C:20]#[N:21])[C:17]3[N:22]=[CH:23][N:24]([CH3:25])[C:16]=3[CH:15]=2)=[CH:10][C:9]=1[C:26]([F:29])([F:28])[F:27])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[C:39](Cl)(=[O:41])[CH3:40]>C1COCC1>[C:39]([N:4]([CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:19]=[C:18]([C:20]#[N:21])[C:17]3[N:22]=[CH:23][N:24]([CH3:25])[C:16]=3[CH:15]=2)=[CH:10][C:9]=1[C:26]([F:27])([F:28])[F:29])[CH:1]([CH3:3])[CH3:2])(=[O:41])[CH3:40]
Reactant: CC(C)NCCOc1ccc(-c2cc3c(ncn3C)c(C#N)n2)cc1C(F)(F)F
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)N(CCOc1ccc(-c2cc3c(ncn3C)c(C#N)n2)cc1C(F)(F)F)C(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 6-(4-(2-(isopropylamino)ethoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (0.05 mmol, 20 mg) in THF (1 mL) was added DIPEA (0.248 mmol, 44 μL) and acetyl chloride (0.149 mmol, 12 mg). The mixture was stirred at r.t. for 16 h and the product was then purified by HPLC to give 6-(4-(2-(N-acetyl-N-isopropylamino)ethoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile. 1H NMR (CD3OD) δ: 8.38-8.44 (m, 4H), 7.35 (d, 1H), 4.15-4.34 (m, 3H), 4.02 (s, 3H), 3.68-3.85 (m, 2H), 2.19 (2xs, 3H), 1.25-1.29 (m, 6H). MS m/z 446 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O.C(OCC)(=O)C>[Pd].CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[NH2:9]
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1N

Procedure:
To a Paar bottle (250 mL) was added 10% Palladium on Carbon (50% Wet) followed by a solution of 1-[1-(3-Methoxy-4-nitro-phenyl)-piperidin-4-yl]-4-methyl-piperazine (0.90 g, 0.0027 mol) in 2:1 Ethyl acetate:Methanol (100 mL). The mixture was degassed and charged with Hydrogen (50 psi). The reaction was shaken until equilibrium had been reached. A total of 25 psi of Hydrogen was adsorbed. The mixture was degassed and kept under an atmosphere of Nitrogen. The suspension was filtered through a plug of diatomaceous earth and rinsed with dichloromethane. The filtrate was evaporated to yield a light purple solid 2-Methoxy-4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenylamine. (0.82 g). mp=94-99° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 6.63 (d, 1H, J=8.3 Hz), 6.52 (d, 1H, J=1.5 Hz), 6.44-6.39 (m, 1H), 3.83 (s, 3H), 3.75-3.25 (m, 4H), 2.80-2.25 (m, 14H), 1.96-1.87 (m, 2H), 1.78-1.65 (m, 2H). LC/MS=305.16 (MH)+
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]2[N:13]=[CH:14][CH:15]=[CH:16][C:4]=2[C:3]1=[O:17].[H-].[Na+].Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>CN(C)C=O>[C:25]([O:24][C:22]([CH2:21][N:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:2]([CH3:1])[C:3](=[O:17])[C:4]2[CH:16]=[CH:15][CH:14]=[N:13][C:5]1=2)=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: CN1C(=O)c2cccnc2Nc2ccccc21
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)c2cccnc2N(CC(=O)OC(C)(C)C)c2ccccc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 43.8 %

Procedure:
To 0.8 g (3.5 mmoles) of 5,6-dihydro-6-methyl-11H-pyrido[2,3-b][1,5]benzodiazepin-5-one in 75 ml of dimethylformamide was added 0.2 g (4.0 mmol) of 50% sodium hydride in oil, and the reaction mixture was stirred at 60° C. for 2 h. It was then cooled to room temperature and 0.78 g (4.0 mmoles) of t-butyl bromoacetate was added dropwise, and the reaction mixture was allowed to stir overnight. Excess sodium hydride was carefully quenched with water and the solvent was evaporated. The residue was dissolved in methylene chloride, washed with water and dried over anhydrous sodium sulfate. Evaporation of the solvent gave 2.0 g of crude product. Purification by column chromatography (silica gel) using 10% ethyl acetate/methylene chloride afforded 0.52 g of pure 5,6-Dihydro-11-(t-butoxycarbonyl)methyl-6-methyl-11H-pyrido[2,3-b][1,5]benzodiazepin-5-one, m.p. 64°-65° C.
Reaction SMILES: O[C@H]1CCCC[C@@H]1N1C[C:15]2[C:14]3C=CC=C[C:13]=3[C:12](CC3C=NC(SC)=CC=3)=[CH:11][C:10]=2[C:9]1=[O:30].BrC1C2C=CC=CC=2C2CN([C@H]3CCCC[C@@H]3O)C(=O)C=2C=1.CS[C:55]1[CH:64]=[CH:63][C:58]([C:59]([O:61][CH3:62])=[O:60])=[CH:57][N:56]=1>>[CH2:9]([O:30][C:55]1[N:56]=[CH:57][C:58]([C:59]([O:61][CH3:62])=[O:60])=[CH:63][CH:64]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CSc1ccc(Cc2cc3c(c4ccccc24)CN([C@H]2CCCC[C@@H]2O)C3=O)cn1
Reactant: COC(=O)c1ccc(SC)nc1
Agent: O=C1c2cc(Br)c3ccccc3c2CN1[C@H]1CCCC[C@@H]1O
Product: COC(=O)c1ccc(OCc2ccccc2)nc1

Procedure:
The title compound was prepared employing the procedures described for the construction of 2-[(1S,2S)-2-hydroxycyclohexyl]-5-{[6-(methylthio)pyridine-3-yl]methyl}-1,2-dihydro-3H-benzo[e]isoindol-3-one in Example 10, substituting 5-bromo-8-[(1S,2S)-2-hydroxycyclohexyl]-8,9-dihydro-7H-pyrrolo[3,4-h]quinolin-7-one for 5-bromo-2-[(1S,2S)-2-hydroxycyclohexyl]-1,2-dihydro-3H-benzo[e]isoindol-3-one, and substituting methyl 6-(benzyloxy)pyridine-3-carboxylate for methyl 6-(methylthio)nicotinate. The resultant white solid gave a proton NMR spectra consistent with theory: 1H NMR (400 MHz, CDCl3) δ 9.00-8.98 (m, 1H), 8.43-8.41 (m, 1H), 8.06 (s, 1H), 7.80 (s, 1H), 7.54-7.51 (m, 1H), 7.45-7.42 (m, 2H), 7.38-7.28 (m, 4H), 6.70 (d, J=8.5 Hz, 1H), 5.33 (s, 2H), 5.30-4.87 (m, 2H), 4.38 (s, 2H), 4.23-4.17 (m, 1H), 3.79-3.73 (m, 1H), 2.22-2.19 (m, 1H), 2.01-1.98 (m, 1H), 1.86-1.83 (m, 2H), 1.73-1.63 (m, 1H), 1.54-1.31 (m, 3H) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[N:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]([OH:20])[CH2:15]1)([O-:3])=[O:2].N1C=CN=C1.[Si:26](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27].CCOCC>CN(C=O)C>[Si:26]([O:20][C@@H:16]1[CH2:17][CH2:18][CH2:19][N:14]([C:5]2[CH:6]=[CH:7][C:8]([C:10]([F:11])([F:12])[F:13])=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:15]1)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1N1CCC[C@@H](O)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CCCN(c2ccc(C(F)(F)F)cc2[N+](=O)[O-])C1
Reaction time: 14 h

Procedure:
To a solution of (R)-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-ol (3.35 g, 11.5 mmol) and imidazole (1.02 g, 15.0 mmol) in DMF at ambient temperature under nitrogen was added tert-butyldimethylsilylchloride (1.91 g, 12.7 mmol). The reaction was allowed to stir for 24 h, at which point additional 0.3 g tert-butyldimethylsilylchloride was added. The reaction was allowed to stir for an additional 14 h, and was then poured into Et2O/saturated aqueous NaHCO3. The organic layer was washed 2×H2O, 1×brine, dried over anhydrous MgSO4, filtered and concentrated to a yellow oil. The crude material was treated with hexanes and adsorbed onto silica gel and passed through a Redi-Sep® pre-packed silica gel column (80 g) eluting with 0-20% EtOAc/hexane. The product-containing fractions were concentrated to afford (R)-3-(tert-butyldimethylsilyloxy)-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidine as a yellow oil. MS m/z=405 [M+H]+. Calc'd for C18H27F3N2O3Si: 404.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.CN1CCCC1=O.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[C:19]([NH:9][NH:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NNC(=O)c1ccc(Br)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(NNC(=O)c1ccc(Br)cc1)c1ccccc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
In a 200 mL three-necked flask were placed 15 g (71 mmol) of 4-bromobenzoylhydrazine and 20 mL of N-methyl-2-pyrrolidone (abbreviation: NMP). To this mixture was dripped a solution of 9.4 mL (81 mmol) of benzoyl chloride in 5 mL solution of N-methyl-2-pyrrolidone through a 50 mL dropping funnel. This solution was stirred at 80° C. for 3 hours under a stream of nitrogen. After a predetermined time, this solution was added to about 100 mL of water, and the precipitated solid was collected by suction filtration. The collected solid was washed with methanol, and 19 g of a white powder, which was a target substance, was obtained at a yield of 84%.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:12])([CH3:11])[CH:3]1[CH2:13][C:14]#[N:15].CO/[CH:18]=[CH:19]/[CH:20]=[C:21]1\[S:22](=[O:32])(=[O:31])[C:23]2[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=2[C:25]\1=[O:26]>>[O:31]=[S:22]1(=[O:32])[C:23]2[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=2[C:25](=[O:26])/[C:21]/1=[CH:20]/[CH:19]=[CH:18]/[C:13](=[C:3]1/[N:2]([CH3:1])[C:10]2[C:5]([C:4]/1([CH3:12])[CH3:11])=[CH:6][CH:7]=[CH:8][CH:9]=2)/[C:14]#[N:15]
Reactant: CO/C=C/C=C1/C(=O)c2ccccc2S1(=O)=O
Reactant: CN1c2ccccc2C(C)(C)C1CC#N
Product: CN1/C(=C(C#N)/C=C/C=C2/C(=O)c3ccccc3S2(=O)=O)C(C)(C)c2ccccc21
Temperature: 210 °C

Procedure:
A mixture of (1,3,3-trimethyl-2,3-dihydro-1H-indol-2-yl)acetonitrile (397 mg, 2.00 mmol) and (2Z)-2-[(2E)-3-methoxyprop-2-en-1-ylidene]-1-benzothiophen-3(2H)-one 1,1-dioxide (501 mg, 2.00 mmol) were placed in a 10-mL one-necked round bottom flask. The flask was heated in an oil bath at 210° C. for 2 hours and then cooled to room temperature. The reaction mixture was extracted with dichloromethane (100 mL). The organic solution was passed through a short silica column, the dichloromethane was evaporated and the pure dye was obtained by recrystallization from methanol. The yield was 511 mg of green crystals (63% of theory).