Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]=[N:6][C:7]1([N:13]=[C:14]=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][NH:17][NH2:18].[N-]=C=O>CCCCC>[C:1]([N:5]=[N:6][C:7]1([NH:13][C:14](=[O:15])[N:17]([CH3:16])[NH2:18])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N=NC1(N=C=O)CCCCC1
Reactant: CNN
Agent: [N-]=C=O
Solvent: CCCCC
Product: CN(N)C(=O)NC1(N=NC(C)(C)C)CCCCC1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To 8.2 grams (0.0392 moles) of 1-t-butylazo-1-isocyanatocyclohexane stirred with a magnetic stirrer in a 50 ml erlenmeyer flask and cooled to 5° C. was added 1.82 grams (0.0392 moles) of methylhydrazine. The reaction was very rapid and exothermic and became quite viscous. The reaction mixture was diluted with pentane and stirred for an additional 60 minutes at room temperature. The pentane was evaporated under reduced pressure leaving 9.0 grams (90% crude yield) of a yellow solid. The product melted at 169°-171° C. with decomposition. The infrared spectrum of the product contained a strong carbonyl band at 1660 cm-1 and a moderate NH band at 3320 cm-1. The isocyanate band at 2225 cm-1 was absent.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([NH:17][NH2:18])=[O:16])=[CH:13][N:12]3[CH:19]=[CH:20][N:21]=[C:11]3[C:10]=2[Cl:22])=[C:4]([F:23])[CH:3]=1.[C:24](=S)=[S:25].[OH-].[K+].Cl>C(O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]3[O:16][C:24]([SH:25])=[N:18][N:17]=3)=[CH:13][N:12]3[CH:19]=[CH:20][N:21]=[C:11]3[C:10]=2[Cl:22])=[C:4]([F:23])[CH:3]=1
Reactant: NNC(=O)c1cn2ccnc2c(Cl)c1Nc1ccc(Br)cc1F
Reactant: S=C=S
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Fc1cc(Br)ccc1Nc1c(-c2nnc(S)o2)cn2ccnc2c1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 29.7 %

Procedure:
7-(4-Bromo-2-fluoro-phenylamino)-8-chloro-imidazo[1,2-a]pyridine-6-carboxylic acid hydrazide (50 mg, 0.13 mmol) was suspended in ethanol (2.5 mL) and cooled to 0° C. Carbon disulfide (22 mg, 0.29 mmol) was added, followed by powdered potassium hydroxide (7 mg, 0.13 mmol). The reaction mixture was stirred under N2 for 1 hour at 0° C. and then for 30 minutes at room temperature. The reaction mixture was then brought to reflux and stirred under N2 for 5 days. The reaction mixture was diluted with water and acidified to pH 1-2 with aqueous 1 M HCl. This mixture was then extracted with ethyl acetate (2×). The combined organic layers were washed with saturated aqueous NaHCO3, saturated aqueous NaCl, dried over Na2SO4 and concentrated. Purification of the crude product was achieved by flash column chromatography (gradient of dichloromethane to 15:1 dichloromethane/methanol) and then trituration with diethyl ether and dichloromethane to yield the desired product (17 mg, 31%) as a yellow solid. MS ESI (+) m/z 440, 442 (M+, Cl, Br pattern) detected. 1H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.16 (s, 1H), 8.08 (br s, 1H), 7.73 (s, 1H), 7.49 (d, 1H), 7.15 (d, 1H), 6.59 (t, 1H). 19F (376 MHz, DMSO-d6)−128.7 (s).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[S:20][C:21]([C:24](=[O:26])[NH2:25])=[C:22]([NH2:23])[C:15]=23)[CH2:10][CH2:9]1)=O)(C)(C)C.CO.C(Cl)Cl>C(Cl)Cl>[NH2:23][C:22]1[C:15]2[C:16](=[N:17][CH:18]=[CH:19][C:14]=2[N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[S:20][C:21]=1[C:24]([NH2:25])=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccnc3sc(C(N)=O)c(N)c23)CC1
Solvent: CO
Solvent: ClCCl
Product: NC(=O)c1sc2nccc(N3CCNCC3)c2c1N
Yield: 34.8 %

Procedure:
A solution of 18 mg 4-(3-amino-2-carbamoyl-thieno[2,3-b]pyridin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester in 1 mL CH2Cl2+1 mL trifluoroacetic acid was stirred with a drying tube for 4 h at room temperature. The reaction was concentrated in vacuo and developed prep plate in 25% MeOH—CH2Cl2−2% NH4OH and the band was eluted with 50% MeOH—CH2Cl2 to get an oil that was re-dissolved 10% MeOH—CH2Cl2, filtered, concentrated, and dried in vacuo at 60° C. to provide 4.6 mg of the product as a yellow solid.
Reaction SMILES: C[O:2][C:3]([CH2:5][S:6][C@H:7]1[NH:10][C:9](=[O:11])[C@H:8]1[NH:12][C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O.[NH3:32]>C(O)C>[NH2:32][C:3]([CH2:5][S:6][C@H:7]1[NH:10][C:9](=[O:11])[C@H:8]1[NH:12][C:13]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:2]
Reactant: COC(=O)CS[C@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N
Solvent: CCO
Product: NC(=O)CS[C@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 48 h

Procedure:
To a solution of 4.35 g of (3R,4R)-4-[[(methoxycarbonyl)methyl]thio]-3-tritylamino-2-azetidinone in 45 ml of ethanol is added 11 ml of 25 to 28% aqueous ammonia and the reaction mixture is allowed to stand at room temperature for 2 days. The mixture is further treated in the same manner as described in Reference Example 8 to give 1.804 g of (3R,4R)-4-[[(aminocarbonyl)methyl]thio]-3-tritylamino-2-azetidinone.
Reaction SMILES: [CH3:1][C@H:2]([CH:30]=C)[C:3]([NH:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([C@@H:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:19][CH:20]=C)[CH:13]=1)=[O:4].CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1>[CH3:30][C@H:2]1[C:3](=[O:4])[NH:5][C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:11]=2[C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH:13]=2)[C@@H:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[CH2:19][CH:20]=[CH:1]1
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)c1cc(-c2ccncc2NC(=O)[C@H](C)C=C)ccn1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Agent: C[C@@H]1/C=C/C[C@H](NC(=O)OC(C)(C)C)c2cc(ccn2)-c2ccncc2NC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: C[C@@H]1C=CC[C@H](NC(=O)OC(C)(C)C)c2cc(ccn2)-c2ccncc2NC1=O
Temperature: 40 °C

Procedure:
To a solution of 72D (220 mg, 0.521 mmol), pTsOH (194 mg, 1.020 mmol) in CH2Cl2 (100 mL) was degassed by bubbling Ar through for 10 mins and heated at 40° C. for 10 mins. Then, Grubbs II (190 mg, 0.224 mmol) in 3 ml Ar degassed DCM was added dropwise via a syringe pump under Ar, heated at 40° C. for a total of 24 hrs. The reaction mixture was neutralized with sat. aq. NaHCO3 and the organic phase separated and washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by prep HPLC and the desired fractions neutralized with conc. NaHCO3, concentrated to small volume, extracted with EtOAc, dried over MgSO4, filtered and concentrated to yield the desired product as a white solid (15 mg, 7.3%). 1H NMR (400 MHz, METHANOL-d4) δ 8.65 (dd, J=11.4, 5.1 Hz, 2H), 8.54 (s, 1H), 7.60 (d, J=5.1 Hz, 1H), 7.37 (dd, J=5.1, 1.5 Hz, 1H), 6.99 (s, 1H), 5.76 (ddd, J=15.3, 10.6, 4.7 Hz, 1H), 4.68 (dd, J=11.2, 3.5 Hz, 1H), 4.41 (dd, J=15.2, 9.5 Hz, 1H), 3.18 (dq, J=9.3, 6.7 Hz, 1H), 2.78 (ddd, J=8.4, 7.3, 3.9 Hz, 1H), 2.04 (q, J=11.4 Hz, 1H), 1.47 (s, 9H), 1.10 (d, J=6.8 Hz, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[Cl:21])=[O:12])[N:7]([C:22]2[CH:31]=[C:30]3[C:25]([CH2:26][C@@H:27]([C:39]([O:41]C)=O)[N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29]3)=[CH:24][CH:23]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.[NH3:58].CO>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[Cl:21])=[O:12])[N:7]([C:22]2[CH:31]=[C:30]3[C:25]([CH2:26][C@@H:27]([C:39](=[O:41])[NH2:58])[N:28]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:29]3)=[CH:24][CH:23]=2)[N:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: N
Reactant: COC(=O)[C@@H]1Cc2ccc(-n3nc(C(C)(C)C)cc3NC(=O)Nc3cccc(Cl)c3Cl)cc2CN1C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)N1Cc2cc(-n3nc(C(C)(C)C)cc3NC(=O)Nc3cccc(Cl)c3Cl)ccc2C[C@H]1C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
A solution of (3S)-2-t-butyl 3-methyl 7-(3-t-butyl-5-(3-(2,3-dichlorophenyl)ureido)-1H-pyrazol-1-yl)-3,4-dihydroiso-quinoline-2,3 (1H)-dicarboxylate (from Example 177, 0.100 g, 0.163 mmol) in 7N NH3/MeOH (3 mL) was stirred at RT overnight. The solvent was removed under reduced pressureand the residue was dissolved in CH2Cl2 (2 mL). Boc anhydride (0.036 g, 0.163 mmol) was added and the solution was stirred at room temperature for 30 min. The solvent was evaporated and the residue was purified by column chromatography to yield (3S)-t-butyl 7-(3-t-butyl-5-(3-(2,3-dichlorophenyl)ureido)-1 H-pyrazol-1-yl)-3-carbamoyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (85 mg, 87% yield) as a white solid. 1H-NMR (400 MHz, acetone-d6): δ 8.66 (brs, 1H), 8.27 (dd, J=8.4, and 2.0 Hz, 1H), 8.21 (brs, 1H), 7.42-7.37 (m, 2H), 7.35-7.29 (m, 2H), 7.24 (dd, J=8.0, and 1.6 Hz, 1H), 6.88 (brs, 1H), 6.49 (s, 1H), 6.33 (brs, 1H), 4.97-4.45 (m, 3H), 3.36-3.09 (m, 2H), 1.47-1.45 (m, 9H), 1.32 (s, 9H); MS (ESI) m/z: 601.2 (M+H+). (3S)-t-butyl 7-(3-t-butyl-5-(3-(2,3-dichlorophenyl)ureido)-1H-pyrazol-1-yl)-3-carbamoyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.085 g, 0.14 mmol) was dissolved in 4N HCl in dioxane (5 mL) and the solution was stirred at RT for 30 min. The solvent was removed under reduced pressureand the residue was dissolved in H2O/MeCN (1:1) and lyophilized to yield 1-(3-t-butyl-1-((3S)-3-carbamoyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1 H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea (65 mg, 85% yield) as a white solid. 1H-NMR (CD3OD) shows rotameric mixture. MS (ESI) m/z: 501.2 (M+H+).
Reaction SMILES: C([BH3-])#N.[Na+].[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[NH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2.O>CC(O)=O>[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13]1
Reactant: Nc1ccccc1-c1cc2ccccc2[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccccc1C1Cc2ccccc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
Sodium cyanoborohydride (6.4 g) was added in several portions to a solution of 6.0 g 2-(2-aminophenyl)-1H-indole in 200 ml HOAc at 5° C. The resulting solution was stirred at room temperature overnight. Water was added and the reaction mixture was concentrated. The residue was diluted with ice water and made basic with 50% NaOH. This mixture was extracted with Et2O and the extracts were washed with water and saturated NaCl solution, and dried (MgSO4). Concentration gave 6.1 g crude product which was chromatographed by HPLC to give 3.05 g solid, m.p. 115°-117° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1.[C:31](Cl)(=[O:33])[CH3:32]>N1C=CC=CC=1>[C:31]([NH:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1)(=[O:33])[CH3:32]
Reactant: Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Yield: 60.1 %

Procedure:
Using N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (150 mg, 0.362 mmol), acetyl chloride (31 μL, 0.435 mmol) and pyridine (3 mL) as starting materials and in the same manner as in Example 384, the title compound (99 mg, 60%) was obtained as a pale-yellow powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:5]=[C:4]([NH2:15])[N:3]=1.[F:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1B1OC(C)(C)C(C)(C)O1)[CH2:23][N:22]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:21][CH2:20]2.ClCCl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.CO>[NH2:15][C:4]1[N:3]=[C:2]([C:26]2[CH:25]=[C:24]3[C:19]([CH2:20][CH2:21][N:22]([C:36]([O:38][C:39]([CH3:41])([CH3:40])[CH3:42])=[O:37])[CH2:23]3)=[CH:18][C:17]=2[F:16])[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:5]=1
Reactant: CN1CCN(c2cc(Cl)nc(N)n2)CC1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(F)c(B3OC(C)(C)C(C)(C)O3)cc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: CN1CCN(c2cc(-c3cc4c(cc3F)CCN(C(=O)OC(C)(C)C)C4)nc(N)n2)CC1
Temperature: 105 °C

Procedure:
A mixture of 4-chloro-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (0.045 g, 0.20 mmol), tert-butyl 6-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.15 g, 0.20 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (0.008 g, 0.01 mmol) and potassium carbonate (0.082 g, 0.60 mmol) in 1,4-dioxane (1 mL) and water (0.5 mL) was heated at 105° C. overnight. After cooled to r.t., the mixture was diluted with MeOH, filtered, and concentrated. The residue was purified by RP-LCMS (pH=10) to afford the desired product. Analytic LCMS (M+H)+: m/z=443.2.
Reaction SMILES: [Li+].[OH-].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([NH:15][CH:16]1[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:26][C:27]([O:29]C)=[O:28])[C:17]1=[O:31])=[O:14])=[CH:7]2>O.C1COCC1>[C:27]([CH2:26][N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:25][CH:16]([NH:15][C:13]([C:8]2[NH:9][C:10]3[C:6]([CH:7]=2)=[CH:5][C:4]([Cl:3])=[CH:12][CH:11]=3)=[O:14])[C:17]1=[O:31])([OH:29])=[O:28]
Reactant: COC(=O)CN1C(=O)C(NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CN1C(=O)C(NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21
Reaction time: 3 h
Yield: 115.3 %

Procedure:
LiOH (91.5 g, 2.18 mmol) in H2O (2 mL) was added to a stirring solution of 5-chloro-N-[1-(methoxycarbonylmethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-1H-indole-2-carboxamide (Example 1; 557 mg, 1.09 mmol) in THF (11 mL) and the reaction was stirred for 3 h. The reaction was quenched by addition of 1M aqueous HCl (40 mL) and EtOAc (60 mL) and the organic layer was dried (MgSO4), filtered and evaporated. The resultant white foam was triturated with hot Et2O (20 mL) cooled, filtered, dried and collected by filtration to afford the title compound (500 mg, 92%) as a white solid.
Reaction SMILES: CS([C:5]1[O:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][CH:16]=[C:15]([C:18]4[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=4)[C:14]=3[CH:29]=2)=[N:8][N:9]=1)(=O)=O.[CH3:30][NH2:31].O1CCCC1>>[CH3:30][NH:31][C:5]1[O:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][CH:16]=[C:15]([C:18]4[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=4)[C:14]=3[CH:29]=2)=[N:8][N:9]=1
Reactant: CS(=O)(=O)c1nnc(-c2ccc3occ(-c4ccc(OC(F)(F)F)cc4)c3c2)o1
Reactant: CN
Solvent: C1CCOC1
Product: CNc1nnc(-c2ccc3occ(-c4ccc(OC(F)(F)F)cc4)c3c2)o1
Yield: 33 %

Procedure:
In the same manner as in Example 110 and using 2-(methylsulfonyl)-5-[3-[4-(trifluoromethoxy)phenyl]-1-benzofuran-5-yl]-1,3,4-oxadiazole instead of 2-(2,3-dihydro-1-benzofuran-5-yl)-5-(methylsulfonyl)-1,3,4-oxadiazole and using 2M methylamine-tetrahydrofuran solution instead of 3-fluorobenzylalcohol, the title compound (yield 33%) was obtained as colorless crystals.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:5]([Cl:24])=[C:6]([C:20]([Cl:23])=[CH:21][CH:22]=1)[CH2:7][O:8][C:9]1[C:10]2[N:11]([C:15]([Br:19])=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1.N1C=CC=CC=1.[CH2:31]([N:33]=[C:34]=[O:35])[CH3:32]>CN1CCCC1=O>[Br:19][C:15]1[N:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:7][C:6]3[C:20]([Cl:23])=[CH:21][CH:22]=[C:4]([NH:3][C:34]([NH:33][CH2:31][CH3:32])=[O:35])[C:5]=3[Cl:24])[C:10]2=[N:17][C:16]=1[CH3:18]
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N)c3Cl)cccn2c1Br
Reactant: CCN=C=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CN1CCCC1=O
Product: CCNC(=O)Nc1ccc(Cl)c(COc2cccn3c(Br)c(C)nc23)c1Cl
Temperature: 60 °C
Reaction time: 6 h

Procedure:
To a mixture of 8-(3-amino-2,6-dichlorobenzyloxy)-3-bromo-2-methylimidazo[1,2-a]pyridine dihydrochloride (100 mg), pyridine (0.5 ml) and N-methylpyrrolidone (1.5 ml) was added ethyl isocyanate (0.10 ml). The mixture was stirred at 60° C. for 6 hours. The insoluble material was filtered off and washed with water. The filtrate and washings were combined and separated precipitate was collected by filtration. The precipitate was purified by preparative thin-layer chromatography (20% solution of methanol in dichloromethane) followed by recrystallization from n-hexane to give 3-bromo-8-[2,6-dichloro-3-(N'-ethylureido)benzyloxy]-2-methylimidazo[1,2-a]pyridine (13 mg) as crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:15][CH2:16][CH3:17])=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[H][H]>[Pd].C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:15][CH2:16][CH3:17])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: CCCC(=CC(=O)OCC)c1ccc(F)cc1
Agent: [Pd]
Solvent: CCO
Product: CCCC(CC(=O)OCC)c1ccc(F)cc1
Yield: 99.6 %

Procedure:
A mixture of ethyl 3-(4-fluorophenyl)hexenoate (58.12 g, 0.246 mol) and 10% palladium on carbon (1.1 g, Aldrich) in 95% ethanol was shaken in a Parr hydrogenator under a pressure of 2-4 atm of hydrogen for 0.75 hr. The mixture was filtered and concentrated by spin evaporation in vacuo to give 58.4 g (99.6%) of ethyl 3-(4-fluorophenyl)hexanoate as a clear liquid, NMR (DMSO-d6): d 7.27-7.20 (m, 2H), 7.12-7.04 (m, 2H), 3.91 (q, 2H, J=7.2 Hz), 2.99 (m, 1H), 2.66-2.59 (m, 1H), 2.52-2.44 (m, 1H, partially obscured by DMSO), 1.59-1.46 (m, 2H), 1.13-1.07 (m, 2H), 1.02 (t, 3H, J=7.2 Hz), 0.78 (t, 3H, J=7.5 Hz).
Reaction SMILES: [CH3:1][N:2]([CH3:41])[C:3]1[CH:40]=[CH:39][C:6]([C:7]([NH:9][C:10]2[C:11]([F:38])=[C:12]([C:16]3[C:28]4[C:27]5[C:22](=[CH:23][C:24]([N:29]6[CH2:34][CH2:33][O:32][CH2:31][CH2:30]6)=[CH:25][CH:26]=5)[NH:21][C:20]=4[C:19]([C:35]([OH:37])=O)=[N:18][CH:17]=3)[CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[Cl-].[NH4+].C([N:47](CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C.CO>[CH3:41][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([F:38])=[C:12]([C:16]3[C:28]4[C:27]5[C:22](=[CH:23][C:24]([N:29]6[CH2:34][CH2:33][O:32][CH2:31][CH2:30]6)=[CH:25][CH:26]=5)[NH:21][C:20]=4[C:19]([C:35]([NH2:47])=[O:37])=[N:18][CH:17]=3)[CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:39][CH:40]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)c1ccc(C(=O)Nc2cccc(-c3cnc(C(=O)O)c4[nH]c5cc(N6CCOCC6)ccc5c34)c2F)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CN1CCOCC1
Product: CN(C)c1ccc(C(=O)Nc2cccc(-c3cnc(C(N)=O)c4[nH]c5cc(N6CCOCC6)ccc5c34)c2F)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 23.2 %

Procedure:
A mixture of 4-(3-(4-(dimethylamino)benzamido)-2-fluorophenyl)-7-morpholino-9H-pyrido[3,4-b]indole-1-carboxylic acid (105 mg, 0.190 mmol), ammonium chloride (40.6 mg, 0.759 mmol), N,N-diisopropylethylamine (0.159 mL, 0.910 mmol), BOP (109 mg, 0.247 mmol), N-methylmorpholine (0.081 mL, 0.740 mmol) in DMF (0.5 mL) was stirred at room temperature for 1.5 hr. The mixture was diluted with MeOH (4 mL), divided into three portions, and purified by reverse phase HPLC. The correct fractions were concentrated under vacuum and basified with saturated NaHCO3 solution to pH 10. The precipitating product (24.7 mg, 0.044 mmol, 23.09% yield) was collected as a yellow solid by suction filtration and dried at 50° C. under vacuum. LCMS (M+H)+=553.32. 1H NMR (500 z, DMSO-d6) δ: 11.52 (s, 1H), 9.86 (s, 1H), 8.31 (s, 1H), 8.20 (s, 1H), 7.90 (d, J=9.0 Hz, 2H), 7.84 (m, 1H), 7.76 (s, 1H), 7.45-7.40 (m, 2H), 7.32 (d, J=8.0 Hz, 1H), 7.29 (d, J=2.0 Hz, 1H), 6.86 (dd, J1=9.0 Hz, J2=2.0 Hz, 1H), 6.77 (d, J=9.0 Hz, 2H), 3.79-3.77 (m, 4H), 3.22-3.19 (m, 4H), 2.51 (m, 6H).
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH:10]2[CH2:15][CH2:14][C:13](=[O:16])[CH:12]=[CH:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[Cl-].[NH4+]>C1COCC1>[CH2:4]([C@H:5]1[CH2:6][CH2:7][C@H:1]([CH:4]2[CH2:5][CH2:6][CH:7]([CH:10]3[CH2:15][CH2:14][C:13]([CH2:14][CH2:15][CH2:10][CH2:11][CH3:12])([OH:16])[CH:12]=[CH:11]3)[CH2:8][CH2:9]2)[CH2:2][CH2:3]1)[CH2:1][CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H](C2C=CC(=O)CC2)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCCC1(O)C=CC(C2CCC([C@H]3CC[C@H](CCCC)CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere, 5.0 g of 4-(trans-4-propylcyclohexyl)-2-cyclohexenone (r-11) was dissolved into 50 mL of THF, 27.2 mL of pentylmagnesium bromide THF solution (1 M/L) was added dropwise thereto at room temperature, and the resultant mixture was stirred at 50° C. for 30 minutes, and then stirred at room temperature overnight. A saturated aqueous solution of ammonium chloride was added dropwise under ice-cooling, the resultant mixture was subjected to extraction with ethyl acetate, and then organic layers were combined, the resultant organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate. A solvent was evaporated under reduced pressure, and the resultant residue was purified by fractionation on silica gel column chromatography (eluate:heptane:ethyl acetate=7:3), and thus 6.56 g of 4-(4-(trans-4-butylcyclohexyl)cyclohexyl)-1-pentyl-2-cyclohexene-1-ol (compound (r-12)) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].I[CH:20]([CH3:22])[CH3:21].C(OCC)(=O)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:20]([CH3:22])[CH3:21])[C:5]([O:7][CH3:8])=[O:6]
Reactant: CC(C)I
Reactant: COC(=O)c1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC(C)C)c(Br)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 101.7 %

Procedure:
Methyl 3-bromo-4-hydroxybenzoate (2.5 g, 10.8 mmol) in DMF (35 ml) was treated with potassium carbonate (3.0 g, 21.6 mmol), 2-iodopropane (2.76, 21.6 mmol) and then stirred at 25° C. for 48 h. Work-up with ethyl acetate gave the title compound (3.0 g).
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2=[C:12]3[C:17](=[CH:18][C:7]4=[C:8]2[N:3]1[CH2:4][CH:5]([C:20]([O:22]CC)=[O:21])[C:6]4=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13]3.[OH-].[K+].CC1CCC2=C3C(=CC4=C2N1CC(C([O-])=O)C4=O)C=CC=C3.[K+].Cl>C(O)C.O>[CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2=[C:12]3[C:17](=[CH:18][C:7]4=[C:8]2[N:3]1[CH2:4][CH:5]([C:20]([OH:22])=[O:21])[C:6]4=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13]3
Reactant: CCOC(=O)C1CN2c3c(cc4ccccc4c3CCC2C)C1=O
Agent: CC1CCc2c3c(cc4ccccc24)C(=O)C(C(=O)[O-])CN31
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC1CCc2c3c(cc4ccccc24)C(=O)C(C(=O)O)CN31

Procedure:
A solution of ethyl 1,2-dihydro-3-methyl-7-oxo-3H,5H-naptho[1,2,3-ij]quinolizine-6-carboxylate (12.5 g., 0.0389 mole) in ethanol (175 ml.) was treated with a solution of potassium hydroxide (4.3 g., 0.0786 mole) in ethanol (175 ml.). The mixture was then heated to its reflux temperature and maintained at reflux for two hours. The intermediate formed was potassium 1,2-dihydro-3-methyl-7-oxo-3H,5H-naphtho[1,2,3-ij]quinolizine-6-carboxylate. The mixture was diluted with hot water (350 ml.) then acidified with hydrochloric acid. The precipitate was collected by filtration, washed with a fifty percent ethanol-water mixture and dried. The solid was recrystallized from N,N-dimethylformamide to give yellow needles of 1,2-dihydro-3-methyl-7-oxo-3H,5H-naphtho[1,2,3-ij]quinolizine-6-carboxylic acid, m.p. 270°-273° C.