Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:14]=[CH:13][N:12]3[C:7](=[C:8]([C:22]([N:24]4[CH2:28][CH2:27][CH2:26][C@@H:25]4[CH2:29][OH:30])=[O:23])[CH:9]=[C:10]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:11]3=[O:15])[C:6]=2[CH:31]=1.[OH-].[Na+].S(OC)(O[CH3:38])(=O)=O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:14]=[CH:13][N:12]3[C:7](=[C:8]([C:22]([N:24]4[CH2:28][CH2:27][CH2:26][C@@H:25]4[CH2:29][O:30][CH3:38])=[O:23])[CH:9]=[C:10]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:11]3=[O:15])[C:6]=2[CH:31]=1
Reactant: COS(=O)(=O)OC
Reactant: O=C(c1cc(-c2ccccc2)c(=O)n2ccc3ccc(Cl)cc3c12)N1CCC[C@@H]1CO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC[C@H]1CCCN1C(=O)c1cc(-c2ccccc2)c(=O)n2ccc3ccc(Cl)cc3c12
Reaction time: 1 h

Procedure:
432 mg of (R)-I-[(10-chloro-4-oxo-3-phenyl-4H-benzo[a]quinolizin-1-yl)carbonyl]-2-pyrrolidinemethanol and 4 mg of tetrabutylammonium iodide in 2 ml of methylene chloride were held in an ultrasound bath for 30 minutes with 104 mg of sodium hydroxide in 0.1 ml of water. 0.19 ml of dimethyl sulfate was then added. After about 1 hour, an additional 0.19 ml of dimethyl sulfate was added and the mixture was allowed to react for an additional 90 minutes. The mixture was diluted with methylene chloride, washed with water, dried over sodium sulfate, filtered and evaporated. The residue was chromatographed on silica gel and the product was recrystallized from cyclohexane/ethanol. There was obtained (R)-1-[(10-chloro-4-oxo-3-phenyl-4H -benzo[a]quinolizin-1-yl)carbonyl]-2-methoxymethylpyrrolidine as yellow crystals of m.p. 137°-140°.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([CH2:17][CH:18]=[O:19])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:20].[Na+]>C(O)C.O.[N+]([O-])([O-])=O.[Ag+]>[C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([CH2:17][C:18]([OH:20])=[O:19])[CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=CCc1ccc2nc(-c3ccccc3)ccc2c1
Reactant: [OH-]
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(O)Cc1ccc2nc(-c3ccccc3)ccc2c1
Reaction time: 3 h

Procedure:
A solution of 2.5 g of crude 2-phenyl-6-quinolineacetaldehyde in 3 ml of ethanol is slowly added dropwise at room temperature to a suspension of 3.4 g of silver nitrate and 1.6 g of sodium hydroxide in 12 ml of water. After completion of the addition, the mixture is stirred for a further 3 hours. Thereafter the suspension is clarified by filtration and the filtrate is washed with ether and adjusted to a pH of 6. The emulsion thereby produced is extracted with ethyl acetate. The ethyl acetate extracts, after drying, evaporation and recrystallisation of the residue from methanol-pentane, yield 2-phenyl-6-quinolineacetic acid of melting point 176°-179°C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#N)[CH:21]=2)(=[O:19])=[O:18])=[CH:13][N:12]=1.[H-].C([Al+]CC(C)C)C(C)C.C[OH:39].Cl>ClCCl.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[N:12]=[CH:13][C:14]([S:17]([C:20]2[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=2)[CH:26]=[O:39])(=[O:19])=[O:18])=[CH:15][CH:16]=1
Reactant: N#Cc1cccc(S(=O)(=O)c2ccc(/C=C/c3ccc(F)cc3F)nc2)c1
Reactant: CO
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=Cc1cccc(S(=O)(=O)c2ccc(/C=C/c3ccc(F)cc3F)nc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
A suspension of 2-[(E)-2-(2,4-difluorophenyl)vinyl]-5-[(3-cyanophenyl)-sulfonyl]pyridine (Example 33, 200 mg, 0.52 mmol) in dichloromethane (2 mL) and toluene (2 mL) was cooled in an ice-bath while stirring under nitrogen. Diisobutylaluminium hydride (1.5M in toluene, 0.38 mL, 0.57 mmol) was added and the reaction stirred at 0° C. then allowed to warm to room temperature over 3 hours. Methanol was added then 1N aqueous hydrochloric acid and the mixture left to stand overnight. The products were extracted into dichloromethane, dried over MgSO4 and concentrated in vacuo. Dry flash column chromatography using 3% methanol/dichloromethane followed by recrystallisation from methanol gave 3-({6-[(E)-2-(2,4-difluorophenyl)vinyl]pyridin-3-yl}sulfonyl)benzaldehyde (93 mg, 46%). δH (400 MHz, CDCl3): 9.07 (1H, d, J=2.2 Hz), 8.23–8.09 (3H, m), 7.89–7.81 (2H, m), 7.74–7.66 (1H, m), 7.61–7.55 (1H, m), 7.48–7.44 (1H, m), 7.25–7.16 (2H, m), 6.93–6.83 (2H, m); m/z (ES+) 386 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:9]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:10]=3[CH2:11][CH2:12][C:3]=12.ClC1C=CC2C(N3CCNCC3)C3=NC=CC=C3CCC=2C=1.[N:46]1[CH:51]=[CH:50][CH:49]=[C:48]([CH2:52][C:53](O)=[O:54])[CH:47]=1.N1C=CC(CC(O)=O)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]([N:18]3[CH2:23][CH2:22][N:21]([C:53](=[O:54])[CH2:52][C:48]4[CH:47]=[N:46][CH:51]=[CH:50][CH:49]=4)[CH2:20][CH2:19]3)[C:9]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:10]=3[CH2:11][CH2:12][C:3]=12
Reactant: O=C(O)Cc1cccnc1
Reactant: Clc1ccc2c(c1)CCc1c(Cl)ccnc1C2N1CCNCC1
Agent: Clc1ccc2c(c1)CCc1cccnc1C2N1CCNCC1
Agent: O=C(O)Cc1ccncc1
Product: O=C(Cc1cccnc1)N1CCN(C2c3ccc(Cl)cc3CCc3c(Cl)ccnc32)CC1
Yield: 88.8 %

Procedure:
By substituting in Example 75, 4,8-chloro-11-(1-piperazinyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (0.3 g, 0.86 mmoles) (Preparative Example 41) for 8-chloro-11-(1-piperazinyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine and 3-pyridylacetic acid (0.1181 g, 0.86 mmoles) for 4-pyridylacetic acid and using the method described in Example 75, one obtains the title compound (0.357 g, 88%, MH+ 467).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[NH:11]C(=O)C)(=[O:3])[CH3:2].Cl.[N:16]([O-])=O.[Na+]>C1COCC1.O>[Br:10][C:8]1[CH:9]=[C:4]2[C:5](=[CH:6][CH:7]=1)[NH:11][N:16]=[CH:2][C:1]2=[O:3]
Reactant: O=N[O-]
Reactant: CC(=O)Nc1ccc(Br)cc1C(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=c1cn[nH]c2ccc(Br)cc12
Temperature: 0 °C
Reaction time: 8 h
Yield: 54.6 %

Procedure:
A solution of Example 34B (6.28 g, 24.4 mmol) in THF (75 mL) was treated with concentrated HCl (aq.) (15 mL) and water (15 mL), heated to reflux for 1 hour, and concentrated to remove the THF. The aqueous solution was treated with additional water (5 mL) and concentrated HCl (5 mL), cooled to 0° C., treated with a solution of NaNO2 (1.85 g, 26.84 mmol) in water (10 mL) in 5 portions, warmed to room temperature gradually over a 2-hour period, and stirred overnight at room temperature. The reaction was heated to reflux for 6 hours, and filtered. The solid was washed with water (50 mL) and diethyl ether (50 mL) and dried under vacuum to provide the desired product (3.0 g, 54%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[NH2:32][C:33]([CH3:37])([CH3:36])[CH2:34][OH:35]>C1COCC1>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]2[C:13]3[CH:12]=[CH:11][C:10](=[O:31])[N:9]([C:3]4[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=4[F:8])[C:14]=3[N:15]=[C:16]([NH:32][C:33]([CH3:37])([CH3:36])[CH2:34][OH:35])[N:17]=2)=[C:20]([CH3:26])[CH:21]=1
Reactant: CC(C)(N)CO
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1-c1nc(NC(C)(C)CO)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reaction time: 72 h

Procedure:
The product of Example 48 (200 mg, 0.45 mmol) and 95% 2-amino-2-methyl-1-propanol (94 mg, 1 mmol) were dissolved in THF (10 ml) and stirred under Ar at 500 for 3 days. The solvents were removed in vacuo, and the residue was partitioned between EtOAc and H2O. The organic phase was washed with H2O, satd aq NaCl, dried over anhyd Na2SO4, filtered and evaporated to give the crude product. Flash chromatography eluted with 0-15% EtOAc/CH2Cl2 gave the title compound as a off-white amorphous solid. mp 99-105° C., LC MS m/z=455 (MH+). Retention time=2.19 min.
Reaction SMILES: CN(C)CCO.[CH3:7][N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.[Cl:19]C(Cl)(Cl)C(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C@@H:9]2[CH2:10][CH2:11][CH2:12][N:8]2[CH3:7])=[CH:14][N:15]=1
Reactant: CN1CCC[C@H]1c1cccnc1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: CN(C)CCO
Solvent: Cc1ccccc1
Product: CN1CCC[C@H]1c1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A 100 mL round-bottomed flask was placed under an argon atmosphere and degassed with argon by vacuum. The solvents (hexanes (4 ml) and toluene 12 ml)) were added to the flask. N,N-dimethylethanolamine (1.07 g, 1.21 ml, 12.0 mmol) was added. The reaction mixture was cooled to 0° C. N-Butyl lithium (8.66 ml of 2.5M in hexanes, 21.6 mmol) was added. The reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was cooled to −20° C. (S)-3-(1-methylpyrrolidin-2-yl)pyridine (650 mg, 0.64 ml, 4.01 mmol) was added. The reaction mixture was stirred −20° C. for 1 h. The reaction mixture was cooled to −78° C. and hexachloroethane (3.8 g, 16.0 mmol) was added in toluene (8 ml). The reaction mixture was stirred at −78° C. for 1 h. The reaction was quenched cold with satd. NaHCO3 (4 mL). LCMS showed that the reaction gave the desired regioisomer in a 6:1 ratio over the undesired 6-chloro pyridine product. The reaction mixture was poured into 50 mL H2O and extracted with CH2Cl2 (3×125 mL). The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 0% to 55% EtOAc in hexanes) to afford the desired product (467 mg, 59%). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.56-2.05 (m, 3 H) 2.16-2.40 (m and overlapping s, 5 H) 3.09 (t, J=8.31 Hz, 1 H) 3.17-3.29 (m, 1 H) 7.23-7.32 (m, 1 H) 7.68 (dd, J=8.12, 2.45 Hz, 1 H) 8.30 (d, J=2.27 Hz, 1 H)
Reaction SMILES: C1(P(C2CCCCC2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[C:19](OC)=[CH:18][CH:17]=[CH:16][C:15]=2OC)CCCCC1.[C:30]1([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:37]=2[NH2:48])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.BrC1C=CC(C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:14]1([C:9]2[CH:8]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:16][C:17]([NH:48][C:37]2[C:38]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:39][CH:40]=[CH:41][C:36]=2[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:18][CH:19]=1
Reactant: Nc1c(-c2ccccc2)cccc1-c1ccccc1
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Pd]
Agent: Brc1ccc(-c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Product: c1ccc(-c2ccc(Nc3c(-c4ccccc4)cccc3-c3ccccc3)cc2)cc1
Yield: 471.7 %

Procedure:
Xylene (250 mL) was bubbled with nitrogen for 15 min, followed by addition of 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (4.6 g, 11.2 mmol) and Pd2(dba)3 (2.6 g, 2.8 mmol). The mixture was bubbled with nitrogen for 15 min, then [1,1′:3′,1″-terphenyl]-2′-amine (13.7 g, 56.0 mmol), 4-bromobiphenyl (13.0 g, 56.0 mmol), sodium tert-butoxide (10.8 g, 112.0 mmol) were added. The mixture was bubbled with nitrogen for 15 min and refluxed for 12 h. After cooling, the reaction mixture was filtered through a silica pad and washed with toluene. The solvent was removed in vacuo and the residue was purified by flash chromatography using 30-40% toluene/hexane to afford N-([1,1′-biphenyl]-4-yl)-[1,1′:3′,1″-terphenyl]-2′-amine (21.0 g, 93% yield) as a white solid.
Reaction SMILES: C([NH:8][C@@H:9]([C:20]([OH:22])=O)[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)(OC(C)(C)C)=O.[NH4+].OC1C2N=N[NH:30]C=2C=CC=1.C(N=C=NC(C)C)(C)C>CN(C)C=O>[NH2:8][C@@H:9]([C:20]([NH2:30])=[O:22])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: Oc1cccc2[nH]nnc12
Agent: CC(C)N=C=NC(C)C
Agent: [NH4+]
Solvent: CN(C)C=O
Product: NC(=O)[C@H](N)Cc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-Boc-D-Tryptophan (9) (1 equiv.; 2.75 mmol; 1.00 g), hydroxybenzotriazole ammonium salt (2 equiv.; 5.50 mmol; 924 mg) and diisopropylcarbodiimide (DIC) (1.1 equiv.; 3.03 mmol; 382 mg; 454 μl) were dissolved in dimethylformamide (DMF) which had been dried over molecular sieves, and the solution was stirred at room temperature for 18 h. The solvent was then removed on a rotary evaporator under reduced pressure, and the residue was taken up in ethyl acetate. Insoluble residues were filtered off, and the organic phase was then washed (1×1 M KHSO4 solution, 2× saturated aqueous sodium carbonate solution, 1× saturated aqueous sodium chloride solution), dried over sodium sulfate and evaporated.
Reaction SMILES: [C:1]([C:5]1[CH:23]=[CH:22][C:8]([C:9]([N:11]2[CH2:21][CH2:20][C:14]3[N:15]=[N:16][C:17](Cl)=[CH:18][C:13]=3[CH2:12]2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)/C=C\C(O)=O.ClC1[N:38]=[N:37]C2CCNCC=2C=1.C(C1C=CC=CC=1C(Cl)=O)(C)(C)C>C(O)C>[C:1]([C:5]1[CH:23]=[CH:22][C:8]([C:9]([N:11]2[CH2:21][CH2:20][C:14]3[N:15]=[N:16][C:17]([NH:37][NH2:38])=[CH:18][C:13]=3[CH2:12]2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1cc2c(nn1)CCNC2
Reactant: CC(C)(C)c1ccc(C(=O)N2CCc3nnc(Cl)cc3C2)cc1
Agent: CC(C)(C)c1ccccc1C(=O)Cl
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCO
Product: CC(C)(C)c1ccc(C(=O)N2CCc3nnc(NN)cc3C2)cc1

Procedure:
The 6-(p-tert.-butylbenzoyl)-3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine, required as starting material, may be obtained in a manner analogous to that described in Example 8(g), from 34.2 g of 3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine maleate and 25 g of tert.butylbenzoyl chloride. M.P. 157°-160° (decomp., from 95% ethanol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](O)([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:22]=2[NH:21][CH:20]=[CH:19]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:22]=2[NH:21][CH:20]=[CH:19]3)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cccc3cc[nH]c23)CC1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N1CC=C(c2cccc3cc[nH]c23)CC1
Reaction time: 24 h
Yield: 90.6 %

Procedure:
To a solution of 4-hydroxy-4-(1H-indol-7-yl)-piperidine-1-carboxylic acid tert-butyl ester (117 mg, 0.37 mmol) in pyridine (5 mL) was added POCl3 (70 μL, 0.74 mmol) in a single portion. The reaction was stirred for 24 h, quenched with the slow addition of water (10 mL) and extracted with EtOAc (3×10 mL). The combined acetate layers were washed with brine, dried (MgSO4) and concentrated to afford 4-(1H-indol-7-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as a light yellow oil (100 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([OH:23])=O)=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:24][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)=[O:23])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)Nc4ccccc4)c3n2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 20.7 %

Procedure:
A mixture of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.07 g, 0.3 mmol), aniline (0.05 g, 0.54 mmol), EDCI (0.057 g, 0.3 mmol), DMAP (0.037 g, 0.3 mmol), and DIPEA (0.163 g, 1.26 mmol) in 10 mL of DMF was stirred at room temperature for 5 hours. And then HATU (0.114 g, 0.3 mmol) was added, the final reaction mixture was stirred for 15 hours. The solvent was removed under reduced pressure at 70° C. The residue was triturated with water and then purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions were: 65% acetonitrile/35% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 72% acetonitrile/28% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.) to give 2-(6-chloro-1-methyl-1H-indazol-3-yl)-N-phenyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (0.025 g, 29%) as a white solid. MS: (M+H)+=403; 1H NMR (300 MHz, DMSO): δ 10.21 (s, 1H), 9.12 (s, 1H), 8.63-8.58 (m, 2H), 8.42 (brs, 2H), 8.04 (s, 1H), 7.83-7.80 (m, 2H), 7.49-7.43 (m, 2H), 7.30 (d, 1H, J=8.7 Hz), 7.17 (d, 1H, J=7.2 Hz), 4.21 (s, 3H).
Reaction SMILES: [CH:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH2:3][CH3:4])[CH3:2].[Br:12]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[Br:12][C:9]1[CH:10]=[C:5]([CH:1]([CH2:3][CH3:4])[CH3:2])[CH:6]=[CH:7][C:8]=1[OH:11]
Reactant: BrBr
Reactant: CCC(C)c1ccc(O)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCC(C)c1ccc(O)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-sec-Butyl-phenol (3.0 g) is dissolved in chloroform and thereto is added bromine (1.02 ml) and the mixture is stirred at room temperature for 30 minutes. Thereto are added a saturated aqueous sodium thiosulfate solution, a saturated aqueous sodium bicarbonate solution and ethyl acetate, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give 2-bromo-4-sec-butyl-phenol (4.57 g). NMR (CDCl3): 0.81 (3H, t), 1.19 (3H, d), 1.56 (2H, m), 2.51 (1H, m), 5.33 (1H, s), 6.93 (1H, d), 7.02 (1H, d), 7.26 (1H, s).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH2:25]([NH2:28])[CH:26]=[CH2:27].C(=O)([O-])O.[Na+]>>[CH2:25]([NH:28][C:2]1[N:3]=[C:4]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1)[CH:26]=[CH2:27]
Reactant: C=CCN
Reactant: CCCCCCCCCCCCNc1nc(Cl)nc2c(C)csc12
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCNc1nc(NCCCCCCCCCCCC)c2scc(C)c2n1
Yield: 44.8 %

Procedure:
442 mg (1.2 mmol) of 2-chloro-4-dodecylamino-7-methylthieno[3,2-d]pyrimidine and 1.10 g (19.2 mmol) of allylamine were heated in a sealed tube at 140° C. for 16 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, followed by adding a saturated aqueous sodium hydrogen carbonate thereto and extraction with ethyl acetate (50 ml×2). After the organic layer was washed with brine and dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/4) to give 209 mg (yield: 44.8%) of the title compound.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][C:15]([F:18])([F:17])[F:16])[N:10]=[C:9]2[CH:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]>ClCCl>[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[F:18][C:15]([F:16])([F:17])[CH2:14][CH2:13][C:11]1[N:10]=[C:9]([CH:19]2[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]2)[N:8]([CH2:7][CH2:6][N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(CCC(F)(F)F)cn2CCN2CCCC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)CCc1cn(CCN2CCCC2)c(C2CCNCC2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Combine tert-butyl 4-(1-(2-(pyrrolidin-1-yl)ethyl)-4-(3,3,3-trifluoropropyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (0.73 g, 1.64 mmol) and dichloromethane (16.2 mL). Place under nitrogen and cool to 0° C. Add trifluoroacetic acid (16.2 mL). After 1 hour, concentrate in vacuo to give 4-(4-(3,3,3-trifluoropropyl)-1-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazol-2-yl)piperidine tris(2,2,2-trifluoroacetate) (1.12 g, 100%). MS (ES) m/z=345 [M]+.
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([N:7]1[C:11]2[CH:12]=[C:13]([CH:16]=O)[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH2:18])[CH:4]([CH3:6])[CH3:5]>CN(C)C=O>[CH2:3]([N:7]1[C:11]2[CH:12]=[C:13]([CH:16]=[N:2][CH3:1])[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH2:18])[CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)Cn1c(N)nc2ccc(C=O)cc21
Reactant: CN
Solvent: CN(C)C=O
Product: CN=Cc1ccc2nc(N)n(CC(C)C)c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.7 %

Procedure:
Add methylamine (3.0 mL, 6 mmol, 2M in tetrahydrofuran) to a solution 1-isobutyl-2-amino-6-formylbenzimidazole (475 mg, 2.19 mmol) in dimethylformamide (5 mL). Stir at room temperature for 18 hours. Concentrate under reduced pressure to provide the title compound (503 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([CH2:17][O:18]C(=O)C)[N:13]=[CH:12][C:11]=2[C:10]([CH3:23])([CH3:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].O>CO>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([CH2:17][OH:18])[N:13]=[CH:12][C:11]=2[C:10]([CH3:23])([CH3:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OCc1cc2c(cn1)C(C)(C)CN2C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(CO)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 117.4 %

Procedure:
To 6-acetoxymethyl-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (0.261 g, 0.82 mmol), in MeOH (8.2 mL) was added potassium carbonate (0.45 g, 3.3 mmol) at ambient temperature. The reaction was stirred for 2 h at ambient temperature. Water (10 mL) was added and the reaction extracted with EtOAc (3×10 mL). The combined organic extracts were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated to give the title compound (0.268 g) as a pale yellow oil, used without further purification. MS: [M+H]+=279.
Reaction SMILES: [NH:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[NH2:2].[OH-].[Na+]>C(O)(=O)CCC>[CH2:5]([C:10]1[N:4]2[C:5]3[C:10]([CH:11]=[CH:12][C:3]2=[N:1][N:2]=1)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:6][CH3:7]
Reactant: NNc1ccc2ccccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCC(=O)O
Product: CCCc1nnc2ccc3ccccc3n12

Procedure:
2-Hydrazinoquinoline (5.0 grams) was placed in a 250-milliliter three-necked flask equipped with a mechanical stirrer and a reflux condenser. To the flask was added 100 milliliters of n-butanoic acid. The reaction mixture was allowed to reflux overnight. In the morning the reaction mixture was cooled and then made basic by the addition of sodium hydroxide. The desired 1-propyl-s-triazolo(4,3-a)quinoline product was extracted from this solution with methylene chloride and the methylene chloride subsequently stripped off. The product was recrystallized from ethanol, m.p., 158.5°-9.5°C.