Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[C:11](O)(=[O:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:11](=[O:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: NCc1ccc(F)cc1F
Reactant: CCCCCCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCCCCCCC(=O)NCc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
To a solution of 2,4-difluorobenzylamine (0.47 g, 3.3 mmol) in methylene chloride (30 mL) were added nonanoic acid (0.52 g, 3.3 mmol) and DMAP (0.40 g, 3.3 mmol) followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.67 g, 3.5 mmol) and the reaction mixture was stirred at room temperature overnight. The resulting solution was diluted with methylene chloride (100 mL) and the organic phase was washed with 5% HCl (3×75 mL), aqueous NaHCO3 (75 mL), and brine (75 mL) and dried over anhydrous Na2SO4. Concentration in vacuo afforded 0.87 g (93%) of an oil, which solidified upon standing.
Reaction SMILES: [CH:1]1[C:13]([NH2:14])=[CH:12][C:11]2[CH2:15][CH2:16][CH2:17][N:9]3[C:10]=2[C:2]=1[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:8]=13.[C:18](OC(=O)C)(=[O:20])[CH3:19]>ClC(Cl)C>[CH:1]1[C:13]([NH:14][C:18](=[O:20])[CH3:19])=[CH:12][C:11]2[CH2:15][CH2:16][CH2:17][N:9]3[C:10]=2[C:2]=1[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:8]=13
Reactant: Nc1cc2c3c(c1)c1c(n3CCC2)CCCC1
Reactant: CC(=O)OC(C)=O
Solvent: CC(Cl)Cl
Product: CC(=O)Nc1cc2c3c(c1)c1c(n3CCC2)CCCC1
Yield: 22 %

Procedure:
Following the procedure of Example 1, Step 4, 5,6,8,9,10,11-hexahydro-4H-pyrido[3,2,1-jk]carbazol-2-amine (0.10 g, 0.44 mmol), acetic anhydride (0.042 mL, 0.44 mmol) and poly-(4-vinylpyridine) (600 mg) in dichloroethane (15 mL) provided N-5,6,8,9,10,11-hexahydro-4H-pyrido[3,2,1-jk]carbazol-2-ylacetamide (26 mg). MS (ESI) m/z 269; HPLC purity 99.4% at 210-370 nm, 9.1 min.; 98.4% at 248 nm, 9.1 min.; Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 ((Ammon. Form. Buff. pH=3.5/ACN and MeOH) for 10 min, hold 4 min); HRMS: calcd for C17H20N2O+H+, 269.16484; found (ESI, [M+H]+), 269.1646.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH2:12][C:13]1[N:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)[CH:16]=[N:15][CH:14]=1)[CH2:7]2.[Cl:27][C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=1B(O)O>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:27][C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=1[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH2:12][C:13]1[N:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)[CH:16]=[N:15][CH:14]=1)[CH2:7]2
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: N#Cc1ccc(Cn2cncc2CN2CCc3c(Br)cccc3C2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: O
Product: N#Cc1ccc(Cn2cncc2CN2CCc3c(cccc3-c3ccc(Cl)cc3Cl)C2)cc1

Procedure:
A solution of 5-bromo-2-(1-(4-cyanobenzyl)-5-imidazolylmethyl)-1,2,3,4-tetrahydroisoquinoline (Example 10; 100 mg, 250 0.25 mmol), 2,4-dichlorophenyl boronic acid (53 mg, 0.275 mmol) and tetrakis(triphenylphosphine)palladium(0) in DME (2 mL) and water (0.5 mL) was heated to 80° C. for 20 h. The mixture was partitioned between water and EtOAc, washed with aqueous NaHCO3, water (2×), dried and evaporated. Column chromatography of the residue (silica gel; CHCl3 /MeOH 80:1) afforded the title compound as a white solid. FAB ms (m+1) 473.2
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].C1(C)C=CC=CC=1.[CH3:18][C:19](=[O:22])[CH2:20][CH3:21]>O>[CH3:18][C:19]([OH:22])([CH2:20][CH3:21])[C:8]#[C:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC(C)=O
Reactant: C#Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(C)(O)C#Cc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 70.6 %

Procedure:
Phenylacetylene (500 g, 4.2 mol) was added to a mixture of potassium hydroxide flake (290 g) and toluene (3 L). 2-Butanone (425 g, 5.9 mol) was added over 45 minutes keeping the temperature below 30° C. with periodic cooling and the resulting mixture agitated for 20 h at room temperature. Water (1 L) was added, the toluene solution washed until neutral, the solvent evaporated, and the residue distilled to give 517 g (71% yield) of 3-methyl-1-phenyl-1-pentyn-3-ol; bp 107°-110° C./3 mm; IR (film) 3400, 1150, 1000, 920 cm-1 ; NMR (CDCl3) 1.1 (3H, t), 1.6 (3H, s), 1.8 (2H, q), 2.2 (1H, s), 7.2-7.6 (5.H, m) δ; MS (m/e) 174, 156, 145, 43.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH2:3][CH2:4][N:5]1[C:10](=[O:11])[CH:9]=[CH:8][C:7]([C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=2)=[CH:6]1.[O:24]=[C:25]1[NH:30][CH:29]=[C:28]([C:31]2[CH:41]=[CH:40][C:34]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:33][CH:32]=2)[CH:27]=[CH:26]1.[H-].[Na+].[I-].[K+].Cl.[CH3:47][N:48]([CH3:52])[CH2:49][CH2:50]Cl.C(O)(C(F)(F)F)=O>C1COCC1.CN(C=O)C>[CH3:23][N:2]([CH3:1])[CH2:3][CH2:4][N:5]1[C:10](=[O:11])[CH:9]=[CH:8][C:7]([C:12]2[CH:13]=[CH:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:21][CH:22]=2)=[CH:6]1.[CH3:47][N:48]([CH3:52])[CH2:49][CH2:50][O:24][C:25]1[N:30]=[CH:29][C:28]([C:31]2[CH:41]=[CH:40][C:34]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:33][CH:32]=2)=[CH:27][CH:26]=1
Reactant: CN(C)CCCl
Reactant: CCOC(=O)c1ccc(-c2ccc(=O)[nH]c2)cc1
Agent: CCOC(=O)c1ccc(-c2ccc(=O)n(CCN(C)C)c2)cc1
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc(-c2ccc(OCCN(C)C)nc2)cc1
Temperature: 50 °C
Yield: 12.5 %

Procedure:
Ethyl 4-(1-[2-dimethylaminoethyl]-6-oxo-1,6-dihydropyridin-3-yl)benzoate and Ethyl 4-(6-[2-dimethyl-aminoethoxy]pyridin-3-yl)benzoate. To a cooled (0° C.) slurry of ethyl 4-(6-oxo-1,6-dihydropyridin-3-yl)benzoate [0.500 g, 2.06 mmol, reference example 36f] in THF:DMF [30 mL 5:1] is added 60% sodium hydride [0.247 g, 6.18 mmol]. After ten minutes added potassium iodide [2 mg] and 2-dimethylaminoethyl-chloride hydrochloride [Aldrich, 0.386 g, 2.68 mmol] and heated to 50° C. After twenty hours, quenched slowly with H2O [15 ml] and extracted with CH2Cl2. The organic extracts are combined and concentrated, then purified on an HPLC (40 to 60% AcCN in water with 0.1% TFA) to give ethyl 4-(1-[2-dimethylamino-ethyl]-6-oxo-1,6-dihydropyridin-3-yl)benzoate [0.337 g, 38.2% yield] as the TFA salt and ethyl 4-(6-[2-di-methylaminoethoxy]pyridin-3-yl)benzoate [0.110 g, 12.5%] yield as the TFA salt. For ethyl 4-(1-[2-dimethylaminoethyl]-6-oxo-1,6-dihydropyridin-3-yl)benzoate: 1H NMR (CD3OD): δ 1.40 (3H, t, J=7.8 Hz), 3.03 (6H, s), 3.62 (2H, t, J=5.9 Hz), 4.38 (2H, q, J=7.8 Hz), 4.49 (2H, t, J=5.9 Hz), 6.72 (1H, d, J=9.2 Hz), 7.68 (2H, d, J=8.8 Hz), 7.98 (1H, dd, J=9.2 Hz, 3.0 Hz), 8.07 (2H, d, J=8.8 Hz), 8.13 (1H, d, J=3.0 Hz). MS (ion spray) m/z 315 (M+H)+. For ethyl 4-(6-[2-dimethylaminoethoxy]pyridin-3-yl)benzoate: 1H NMR (CD3OD): δ 1.41 (3H, t, J=8.1 Hz), 3.02 (6H, s), 3.64 (2H, t, J=6.1 Hz), 4.39 (2H, q, J=8.1 Hz), 4.74 (2H, t, J=6.1 Hz), 7.01 (1H, d, J=9.4 Hz), 7.73 (2H, d, J=8.8 Hz), 8.07 (1H, dd, J=9.4 Hz, 2.5 Hz), 8.10 (2H, d, J=8.8 Hz), 8.51 (1H, d, J=2.5 Hz). MS (ion spray) m/z 315 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:7]([O:9]CC)=[O:8])[NH:5][CH:6]=1.[OH-].[Na+]>C(O)C>[NH2:1][C:2]1[N:3]=[C:4]([C:7]([OH:9])=[O:8])[NH:5][CH:6]=1
Reactant: CCOC(=O)c1nc(N)c[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1c[nH]c(C(=O)O)n1
Yield: 91.5 %

Procedure:
A solution of ethyl 4-amino-1H-imidazol-2-carboxylate (2.0 g, 12.9 mmol) (E. Gomez, C. Avendano and A. McKillop, Tetrahedron 1986, 42, 2635) in ethanol (50 ml) and 1M aqueous sodium hydroxide (14 ml) was refluxed for 20 minutes. The reaction mixture was concentrated to 20 ml and the pH of the solution adjusted to 5 with concentrated hydrogen chloride. The solid which precipitated, collected by filtration and washed with ethanol and ether to give the title compound (1.5 g, 32%). NMR: δ 7.07 (s, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]([C:12]1[CH:13]=[N:14][C:15]2[CH:16]=[C:17]3[O:25][CH2:24][O:23][C:18]3=[CH:19][C:20]=2[C:21]=1Cl)=[O:11].[SH2:26].[Na]>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]([C:12]1[CH:13]=[N:14][C:15]2[CH:16]=[C:17]3[O:25][CH2:24][O:23][C:18]3=[CH:19][C:20]=2[C:21]=1[SH:26])=[O:11]
Reactant: S
Reactant: O=C(NCCc1ccccn1)c1cnc2cc3c(cc2c1Cl)OCO3
Agent: [Na]
Solvent: CCO
Product: O=C(NCCc1ccccn1)c1cnc2cc3c(cc2c1S)OCO3
Yield: 77 %

Procedure:
To 10.4 g (0.025 mol) of 8-chloro-[1,3]dioxolo [4,5-g]quinoline-7-carboxylic acid (2-pyridin-2yl-ethyl)-amide in 100 mL of ethanol was added 7.2 g (0.1 mol) of sodium hydrogensulfide and the mixture was heated at reflux for 3 hours. The mixture was cooled and the solids filtered, washed with ethanol, and then with water. The filtrate was concentrated and the solids were suspended in water, collected by filtration, and recrystallized from ethanol to give 6.8 g of the title compound, mp 258°-260° C.
Reaction SMILES: [CH3:1][C:2]([CH3:24])=[CH:3][CH2:4][CH:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:6]1=[O:23].[OH-:25].[Na+]>O>[C:11]1([N:8]([C:9](=[O:10])[CH:5]([CH2:4][CH:3]=[C:2]([CH3:24])[CH3:1])[C:6]([OH:23])=[O:25])[NH:7][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)=CCC1C(=O)N(c2ccccc2)N(c2ccccc2)C1=O
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: CC(C)=CCC(C(=O)O)C(=O)N(Nc1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
64 gm (0.2 mol) of 4-(3-methyl-2-butenyl)-1,2-diphenyl-3,5-dioxo-pyrazolidine were dissolved in an aqueous sodium hydroxide solution obtained by dissolving 16 gm (0.4 mol) of sodium hydroxide pellets in 640 ml of water. The solution was heated for 7 hours. The reaction mixture was then cooled to room temperature and washed twice with ether. The ether extract contained a little hydrazobenzene. The aqueous alkaline solution was then made acid to Congo red with 10% hydrochloric acid and quickly extracted with ethyl ether. The organic phase was evaporated to dryness, leaving (3-methyl-2-butenyl)propanedioic acid mono(1,2-diphenyl hydrazide) as an oily residue which was dissolved in a dilute ammonium hydroxide solution obtained by diluting 40 ml of an aqueous 32% ammonium hydroxide solution with 600 ml of water. To this solution was added a solution of 11 gm of calcium chloride in 40 ml of water. The calcium salt of (3-methyl-2-butenyl)propanedioic acid mono(1,2-phenylhydrazide)dihydrate which precipitated upon stirring was suction filtered off and dried for 8 hours at 50° C. and 15 mmHg. The salt was obtained as a white solid. Yield: 54.06 gm (72% of theory), M.p. 166° C.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:3]=1[NH:4][CH:5]=[C:6]2[CH2:7][CH2:8][NH2:9].[C:14](O)(=O)C=O.[ClH:19]>>[ClH:19].[CH3:1][C:2]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:3]=1[NH:4][C:5]1[CH2:14][NH:9][CH2:8][CH2:7][C:6]2=1
Reactant: Cc1cccc2c(CCN)c[nH]c12
Reactant: O=CC(=O)O
Agent: Cl
Product: Cc1cccc2c3c([nH]c12)CNCC3

Procedure:
7-Methyltryptamine (free base, Sigma) was dissolved in aqueous hydrochloric acid and condensed with glyoxylic acid as described in part B. The product was decarboxylated according to part C to yield 8-methyl-1,2,3,4-tetrahydro-beta-carboline hydrochloride, which was recrystallized from ethanol:water R1-7 =R9 =H; R8 =Me).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][C@H:38]([CH3:42])[CH2:37]1>>[F:34][C:2]([F:33])([F:1])[C:3]1[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:39]4[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][C@H:38]4[CH3:42])=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: C[C@@H]1CN(C)CCN1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: C[C@@H]1CN(C)CCN1C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1

Procedure:
5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(2-(R),4-dimethylpiperazin-1-yl)-1,3-thiazol-4(5H)-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 1,3-(R)-Dimethyl-piperazine following general procedure C.
Reaction SMILES: [C:1]([NH:4]/[C:5](=[CH:9]\[O:10][CH3:11])/[C:6]([OH:8])=O)(=[O:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)Cl.O1CCCC1>[C:1]([NH:4]/[C:5](=[CH:9]\[O:10][CH3:11])/[C:6]([NH:34][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: CO/C=C(\NC(C)=O)C(=O)O
Reactant: NCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CO/C=C(\NC(C)=O)C(=O)NCc1ccccc1
Reaction time: 0.33 h

Procedure:
To a solution of (D1) (20 g, 0.125 mol) in CH2Cl2 (300 ml, 15 vol) and tetrahydrofuran (THF) (100 ml, 5 vol), N-methylmorpholine (NMM) (16.6 ml, 0.15 mol) was added slowly at −40° C. After 20 min, isobutylchloroformate (IBCF) (19.67 ml, 0.15 mol) was added at same temperature and stirred for 20 min. Benzylamine (16.5 ml, 0.15 mol) in tetrahydrofuran (40 ml) was added at −40° C., then the reaction mixture was stirred for 1 h and allowed to room temperature. Solvent was evaporated under reduced pressure. The obtained crude was purified by column chromatography in 5% methanol in chloroform to afford (A1) as a white colored powder. Yield: 17 g; 55%.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:20][CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][NH:25][C:24]1=[O:28]>CN1CCCC1=O>[Br:1][C:2]1[C:3]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[N:4][C:5]([NH:20][CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][NH:25][C:24]2=[O:28])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(-c2cccs2)n1
Reactant: NCCN1CCNC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=C1NCCN1CCNc1ncc(Br)c(-c2cccs2)n1
Temperature: 110 °C

Procedure:
5-Bromo-2-chloro-4-(thiophen-2-yl)pyrimidine (2.0 g, 7.25 mmol) dissolved in N-methyl pyrrolidone (25 mL) was treated with potassium carbonate (2 g, 14.5 mmol) and 1-(2-aminoethyl)imidazolidin-2-one (1.125 g, 8.71 mmol). The reaction was heated to 110° C. overnight. The reaction was poured into ice water and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate, water and brine and then dried with sodium sulfate. Purification was achieved by flash chromatography using a gradient of 0 to 10% methanol in dichloromethane to obtain a yellow solid. Yield=2 g. MS (M+H)+ 368/370.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][C@@H:11]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C@H:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:9]1.[NH2:30][C:31]1[C:32]([C:39](O)=[O:40])=[N:33][C:34]([Br:38])=[C:35]([F:37])[CH:36]=1>>[NH2:30][C:31]1[C:32]([C:39]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N:8]2[CH2:13][CH2:12][C@@H:11]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C@H:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:9]2)=[O:40])=[N:33][C:34]([Br:38])=[C:35]([F:37])[CH:36]=1
Reactant: Nc1cc(F)c(Br)nc1C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(c2ccncc2N)CC[C@H]1O[Si](C)(C)C(C)(C)C
Product: CC(C)(C)OC(=O)N[C@@H]1CN(c2ccncc2NC(=O)c2nc(Br)c(F)cc2N)CC[C@H]1O[Si](C)(C)C(C)(C)C

Procedure:
Following Method 11 of Example 305, trans-(+/−)-tert-butyl 1-(3-aminopyridin-4-yl)-4-(tert-butyldimethylsilyloxy)piperidin-3-ylcarbamate and 3-amino-6-bromo-5-fluoropicolinic acid was reacted yielding trans-(+/−)-tert-butyl 1-(3-(3-amino-6-bromo-5-fluoropicolinamido)pyridin-4-yl)-4-(tert-butyldimethylsilyloxy)piperidin-3-yl-carbamate. LCMS (m/z): 641.2 (MH+); LC Rt=4.47 min.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[OH:7][CH2:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15](OC(C)(C)C)=O)[CH2:10]1.O.[OH-].[Na+]>CCOCC.C1COCC1>[CH3:15][N:11]1[CH2:12][CH2:13][CH2:14][C@H:9]([CH2:8][OH:7])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](CO)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CN1CCC[C@H](CO)C1
Reaction time: 1.5 h

Procedure:
To a stirred solution of lithium aluminum hydride (10.5 ml of 1M solution in THF, 10.5 mmol) in ether (15 mL) at 20° C. was added dropwise a solution of 1,1-dimethylethyl (3S)-3-(hydroxymethyl)-1-piperidinecarboxylate (1.50 g, 7.0 mmol) in THF (5 mL). After 1.5 h at room temperature, water (0.4 mL) was added followed by 15% aqueous sodium hydroxide solution (0.4 mL) then water (1.2 mL). This was stirred 20 min then filtered. The filtrate was concentrated under reduced pressure to give 0.87 g used in the next step without further purification. MS (ES+) m/z 130.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:16]=[N:15][C:5]2[NH:6][C:7]3[CH:12]=[N:11][C:10]([CH2:13][OH:14])=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27](B3OC(C)(C)C(C)(C)O3)=[CH:26][CH:25]=2)[CH2:20][CH2:19]1>C(#N)C.C(=O)([O-])[O-].[Na+].[Na+].C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:25]=[CH:26][C:27]([C:2]3[CH:16]=[N:15][C:5]4[NH:6][C:7]5[CH:12]=[N:11][C:10]([CH2:13][OH:14])=[CH:9][C:8]=5[C:4]=4[CH:3]=3)=[CH:28][CH:29]=2)[CH2:20][CH2:19]1
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: OCc1cc2c(cn1)[nH]c1ncc(Br)cc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: CN1CCN(c2ccc(-c3cnc4[nH]c5cnc(CO)cc5c4c3)cc2)CC1
Temperature: 150 °C

Procedure:
A suspension of 3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-methanol (40.7 mg, 0.146 mmol), 4-(4-methylpiperazin-1-yl)phenylboronic acid pinacol ester (46.4 mg, 0.154 mmol) and bis(triphenylphosphine)palladium(II) dichloride (5.1 mg, 7.3 mmol) in acetonitrile (0.73 mL) and 2N aqueous sodium carbonate solution (0.73 mL) was heated at 150° C. under microwave irradiation for 20 minutes. The cooled reaction mixture was diluted with THF, the solid removed by filtration, and washed with THF and DCM. The combined filtrate was concentrated in vacuo and the resultant residue purified by flash chromatography (silica, 1-15% (2N ammonia methanol) in DCM) to afford the title compound. 1H NMR (DMSO-D6, 400 MHz): 12.46 (s, 1H), 9.76 (s, 1H), 9.07 (d, J=1.8 Hz, 1H), 8.97 (d, J=1.8 Hz, 1H), 8.50 (s, 1H), 7.76 (d, J=8.7 Hz, 2H), 7.17 (d, J=8.7 Hz, 2H), 4.13 (s, 2H), 3.38-3.30 (m, 8H), 2.89 (s, 3H). LCMS (Method D): RT=5.24 min, M+H+=374.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([CH2:24][N:25]([CH3:27])[CH3:26])[CH2:20][CH2:19]1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([Cl:44])[C:30]=1[OH:45].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:28].[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([CH2:24][N:25]([CH3:27])[CH3:26])[CH2:20][CH2:19]2)=[N:3][C:2]([C:33]2[CH:34]=[C:29]([Cl:28])[C:30]([OH:45])=[C:31]([Cl:44])[CH:32]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:15][CH2:16]1
Reactant: CN(C)C[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Cl)nc23)CC1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CN(C)C[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)nc23)CC1

Procedure:
Following general procedure II, (6-chloro-4-{trans-4-[(dimethylamino)methyl]-cyclohexyl amino}-1,5-naphthyridin-3-yl)(cyclopropyl)methanone (60 mg, 0.16 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (65 mg, 0.23 mmol) followed by formation of the dihydrochloride salt to afford the desired product (66 mg, 73%) as a light yellow solid: 1H NMR (500 MHz, CD3OD) δ 9.41 (s, 1H), 8.46 (d, J=8.9 Hz, 1H), 8.34 (d, J=8.9 Hz, 1H), 8.12 (s, 2H), 5.74-5.64 (m, 1H), 3.09 (d, J=6.6 Hz, 2H), 2.93 (s, 6H), 2.92-2.85 (s, 1H), 2.47-2.40 (m, 2H), 2.08-1.96 (m, 3H), 1.72-1.60 (m, 2H), 1.47-1.34 (m, 2H), 1.32-1.18 (m, 4H). ESI MS m/z 513 [M+H]+; HPLC>99% (AUC), tR=9.67 min.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[F:11][C:12]([F:23])([F:22])[C:13]1[CH:18]=[C:17]([N:6]2[C:7]3[C:3](=[CH:2][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:5]2)[CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: Brc1cccc2[nH]ccc12
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: FC(F)(F)c1cccc(-n2ccc3ccccc32)c1
Temperature: 75 °C
Reaction time: 16 h
Yield: 88.8 %

Procedure:
To a mixture of 4-bromoindole (3.00 g, 15.3 mmol), and 3-trifluoromethylphenylboronic acid (2.91 g, 15.3 mmol) in THF (52 mL)) were added Palladium catalyst Pd(PPh3)4 (530 mg, 0.46 mmol) and the freshly prepared sodium hydroxide solution (1.84 g, 45.9 mmol in 21 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 75° C. oil bath for 16 hours. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4, and concentrated. The crude product was purified by a silica gel column eluting with hexanes—EtOAc (9:1) to provide 3.55 g (89%) of the product 4-(3-trifluoromethyl-phenyl)-1H-indole.
Reaction SMILES: C(=O)([O:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:11]=[C:10]([C:19]2[CH:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:22]=[CH:23][CH:24]=2)[CH:9]=1)OC(C)(C)C.C(=O)(OC(C)(C)C)OC1N(C2C=CC=CN=2)N=C(C2C=CC(C3C=CC=CC=3)=CC=2)C=1>>[O:31]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:10]2[CH:9]=[C:8]([OH:7])[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[N:11]=2)[CH:20]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)Oc1cc(-c2cccc(-c3ccccc3Oc3ccccc3)c2)nn1-c1ccccn1
Agent: CC(C)(C)OC(=O)Oc1cc(-c2ccc(-c3ccccc3)cc2)nn1-c1ccccn1
Product: Oc1cc(-c2cccc(-c3ccccc3Oc3ccccc3)c2)nn1-c1ccccn1
Yield: 80 %

Procedure:
The title compound was prepared in the same manner as in Example D-1, except that an equimolar amount of Compound 38 of Example C-12 was used in place of Compound 27 of Example C-1.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[ClH:15].[N:16]1[CH:21]=[CH:20][C:19]([CH2:22][Cl:23])=[CH:18][CH:17]=1.[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C1(C)C=CC=CC=1>[ClH:23].[ClH:15].[N:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:5]2([CH2:22][C:19]3[CH:20]=[CH:21][N:16]=[CH:17][CH:18]=3)[C:4]3[CH:3]=[C:2]([F:1])[CH:14]=[CH:13][C:12]=3[C:11]3[C:6]2=[CH:7][CH:8]=[CH:9][CH:10]=3)=[CH:18][CH:17]=1
Reactant: ClCc1ccncc1
Reactant: Fc1ccc2c(c1)Cc1ccccc1-2
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: Fc1ccc2c(c1)C(Cc1ccncc1)(Cc1ccncc1)c1ccccc1-2

Procedure:
The title compound was prepared following the method of Example 1 from 4.0 g (21.74 mmole) of 2-fluorofluorene, 8.92 g of 4-picolylchloride hydrochloride, 120 ml of toluene, 200 mg of benzyltriethylammonium chloride, and 20 ml of 50% sodium hydroxide by reaction at 22° for 17 hrs. The product was chromatographed (silica, CH2Cl2 /MeOH, 10:1) to yield 2.9 g which was recrystallized (ethanol-acetone) and converted to the dihydrochloride, m.p. >300°.