Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[C:9]([F:14])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]([CH3:32])=[C:21]([C:33]([OH:35])=O)[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[NH2:36][C@@H:37]1[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][C@H:38]1[OH:50]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[C:9]([F:14])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:30])[CH3:31])[C:22]([CH3:32])=[C:21]([C:33]([NH:36][C@@H:37]4[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:48])([CH3:47])[CH3:49])=[O:44])[CH2:39][C@H:38]4[OH:50])=[O:35])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:2][CH2:3]1
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)cc1F
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](O)C1
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCN(C(=O)OC(C)(C)C)C[C@H]4O)c(C)n(COCC[Si](C)(C)C)c23)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c12) and tert-butyl (3R*,4R*)-4-amino-3-hydroxy-piperidine-1-carboxylate (Example C2) the title compound is obtained as pale yellow foam.
Reaction SMILES: N(CCO)(CCO)CCO.[CH:11](=[O:17])[C:12]1[O:16][CH:15]=[CH:14][CH:13]=1.[C:18](#[N:21])[CH:19]=[CH2:20]>CN(C)C=O.C(O)C>[O:16]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:11]([CH:19]([CH3:20])[C:18]#[N:21])=[O:17]
Reactant: O=Cc1ccco1
Reactant: C=CC#N
Solvent: CCO
Solvent: CN(C)C=O
Solvent: OCCN(CCO)CCO
Product: CC(C#N)C(=O)c1ccco1
Reaction time: 0.5 h

Procedure:
Following the procedure in Example 1, 29.8 g. (0.2 mol) of triethanolamine are added to 48 g (0.5 mol) of furfuraldehyde and 13.5 g of Catalyst 1 (0.05 mol) in a mixture of 300 ml of dimethylformamide and 300 ml of ethanol and the whole is then brought to the reflux temperature while stirring under a stream of nitrogen. After 30 minutes, the dropwise addition of a solution of 26.5 (0.05 mol) of distilled acrylonitrile in a mixture of 50 ml of dimethylformamide and 50 ml of ethanol, over the course of 41/2 hours, is started. The mixture is then kept at the same temperature for 20 hours. The solvent mixture is distilled off and the residue is taken up in 300 ml of chloroform. The chloroform solution is then washed with water, dilute sodium bicarbonate solution and twice more with water. It is then dried with magnesium sulphate and after filtering the solution the solvent is distilled off. The residue which remains is distilled in an oil pump vacuum. The α-furoylpropionitrile thus obtained is recrystallized from isopropanol.
Reaction SMILES: [C:1]([C:5]1[C:9]([CH:10]=O)=[CH:8][N:7]([CH2:12][C:13]([NH:15][C:16]2[S:20][C:19]3[CH2:21][CH2:22][CH2:23][CH2:24][C:18]=3[C:17]=2[C:25]([NH:27][CH2:28][CH2:29][OH:30])=[O:26])=[O:14])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.[CH2:35]([NH2:37])[CH3:36]>C(Cl)Cl.[Pd]>[C:1]([C:5]1[C:9]([CH2:10][NH:37][CH2:35][CH3:36])=[CH:8][N:7]([CH2:12][C:13]([NH:15][C:16]2[S:20][C:19]3[CH2:21][CH2:22][CH2:23][CH2:24][C:18]=3[C:17]=2[C:25]([NH:27][CH2:28][CH2:29][OH:30])=[O:26])=[O:14])[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nn(CC(=O)Nc2sc3c(c2C(=O)NCCO)CCCC3)cc1C=O
Reactant: CCN
Agent: [Pd]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCNCc1cn(CC(=O)Nc2sc3c(c2C(=O)NCCO)CCCC3)nc1C(C)(C)C
Reaction time: 1.5 h
Yield: 45.1 %

Procedure:
2-(2-(3-Tert-butyl-4-formyl-1H-pyrazol-1-yl)acetamido)-N-(2-hydroxyethyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (1.66 g, 3.84 mmol) was dissolved in DCM (40 mL) and acetic acid (20.98 g, 20 mL, 349 mmol). Ethylamine (2M in THF, 7.68 mL, 15.35 mmol) was added and the mixture was stirred for 90 min. A slurry of palladium on charcoal (10%, 1.51 g, 1.420 mmol) in DCM (30 mL) was added and the mixture hydrogenated at 4 barr for 72 h at 20° C. The catalyst was filtered through dicalite and the dicalite washed with water, DCM and MeOH. All volatiles were removed under reduced pressure and the aqueous residue was basified to pH 8 using sodium bicarbonate. The crude product was extracted with EtOAc. The organics were combined and washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by chromatography (DCM, 0-30% MeOH/DCM and 0-20% 7 N NH3 in MeOH/DCM). Concentration in vacuo yielded a white solid (800 mg, 1.73 mmol, 45%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:18]1(I)[CH2:20][CH2:19]1>CS(C)=O>[CH:18]1([N:8]2[CH:7]=[N:6][C:5]3[C:9]2=[N:10][C:2]([Cl:1])=[N:3][C:4]=3[Cl:11])[CH2:20][CH2:19]1
Reactant: IC1CC1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Clc1nc(Cl)c2ncn(C3CC3)c2n1
Yield: 35 %

Procedure:
2,6-Dichloropurine (1 mmol), powdered potassium carbonate (4 mmol) and cyclopropyliodide were vigorously stirred in 5 mL DMSO overnight. After evaporation of the solvent the product was extracted (water/diethylether) and purified by column chromatography (silicagel/1% MeOH in CHCl3). Crystallization from diethylether gave product in 35% yield, mp 121-124° C.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([CH2:8][N:9]2[C:15](=[O:16])[CH2:14][C:13]3[CH:17]=[C:18]4[O:23][CH2:22][O:21][C:19]4=[CH:20][C:12]=3[CH2:11][CH2:10]2)[CH2:2]1.C1(S(O[CH2:34][CH2:35][CH2:36][C:37]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[NH:39][CH:38]=2)(=O)=O)C=CC=CC=1>>[OH2:16].[NH:39]1[C:40]2[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:37]([CH2:36][CH2:35][CH2:34][N:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([CH2:8][N:9]3[C:15](=[O:16])[CH2:14][C:13]4[CH:17]=[C:18]5[O:23][CH2:22][O:21][C:19]5=[CH:20][C:12]=4[CH2:11][CH2:10]3)[CH2:2]2)=[CH:38]1
Reactant: O=C1Cc2cc3c(cc2CCN1CC1CCCCNC1)OCO3
Reactant: O=S(=O)(OCCCc1c[nH]c2ccccc12)c1ccccc1
Product: O
Product: O=C1Cc2cc3c(cc2CCN1CC1CCCCN(CCCc2c[nH]c4ccccc24)C1)OCO3

Procedure:
Prepared from 3-[(hexahydro-azepin-3-yl)-methyl]-7,8-methylenedioxy-2-oxo-1,3,4,5-tetrahydro-2H-3-benzazepin and 3-(3-benzenesulphonyloxy-propyl)-indole analogously to Example 1.
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[F:11][C:12]([F:23])([F:22])[C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C([O-])(=O)C.[K+].CCOC(C)=O>CN(C=O)C.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>[F:10][C:8]1[CH:9]=[C:2]([C:16]2[CH:17]=[CH:18][C:13]([C:12]([F:23])([F:22])[F:11])=[CH:14][CH:15]=2)[C:3]([CH:4]=[O:5])=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(F)cc1Br
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(F)cc1-c1ccc(C(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 79.9 %

Procedure:
A mixture of 2-bromo-4-fluorobenzaldehyde (2 g, 9.85 mmol), (4-(trifluoromethyl)phenyl)boronic acid (2.25 g, 11.82 mmol), potassium acetate (2.42 g, 24.63 mmol) and Pd(PPh3)4 (1.14 g, 0.98 mmol) in DMF (40 mL) and water (13 mL) was stirred at 100° C. for 3 hours under N2, then cooled to 25° C. To the mixture was added EtOAc (250 mL). The organic layer was washed with brine (200 mL×3), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PETROLEUM ETHER/EtOAc (V/V)=70/1) to give the title compound as colorless oil (2.11 g, 79%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:39])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]2[CH:36]=[CH:35][N:34]=[C:33]2[S:37][CH3:38])[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]([F:18])([F:20])[F:19])=[CH:10][C:9]2[NH:21][C:22](=[O:39])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([N:32]4[CH:36]=[CH:35][N:34]=[C:33]4[S:37][CH3:38])[CH:27]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CSc1nccn1-c1cccc(C(=O)CC(=O)Nc2cc(C(F)(F)F)c(N(C)C)cc2NC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSc1nccn1-c1cccc(C2=Nc3cc(N(C)C)c(C(F)(F)F)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from (5-dimethylamino-2-{3-[3-(2-methylsulfanyl-imidazol-1-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example M62) (450 mg, 0.78 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (253 mg).
Reaction SMILES: CS(O[C@H]1CCN(CC2C=CC(C)=CC=2)C1=O)(=O)=O.[F:20][C@H:21]1[C@H:26]([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([F:34])[CH:28]=2)[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]1.CCN(C(C)C)C(C)C>C(#N)C>[F:34][C:29]1[CH:28]=[C:27]([C@@H:26]2[CH2:25][CH2:24][NH:23][CH2:22][C@H:21]2[F:20])[CH:32]=[CH:31][C:30]=1[OH:33]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(O)c(F)c2)[C@H](F)C1
Agent: Cc1ccc(CN2CC[C@H](OS(C)(=O)=O)C2=O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Oc1ccc([C@@H]2CCNC[C@H]2F)cc1F
Temperature: 80 °C
Reaction time: 16 h
Yield: 41 %

Procedure:
A solution of (S)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl methanesulfonate (0.106 g, 0.375 mmol, from example 112, step D) in acetonitrile (1 mL) was added to a mixture of 2-fluoro-4-((3S,4S)-3-fluoropiperidin-4-yl)phenol (0.04 g, 0.188 mmol, from step E) and DIPEA (0.098 mL, 0.563 mmol) in acetonitrile (2 mL) heated at 80° C. The reaction mixture was then stirred at 80° C. for 16 h. The mixture was allowed to cool to rt and then concentrated in vacuo. The residue was purified using preparative LC/MS (Waters XBridge C18, 19×150 mm, 5 μm; Guard Column: Waters XBridge C18, 19×10 mm, 5 μm; Mobile Phase A: 5:95 acetonitrile:water with 10 mM NH4OAc; Mobile Phase B: 95:5 acetonitrile:water with 10 mM NH4OAc; Gradient: 15-60% B over 25 min, followed by a 10 min hold at 60% B and 5 min hold at 100% B; Flow: 15 mL/min). Fractions containing the desired product were combined concentrated in vacuo using a Genevac centrifugal evaporator to the titled compound of Example 115 (31 mg, 0.077 mmol, 41% yield) as pale yellow solid. LC-MS (M+H)+ 401; 1H NMR: (400 MHz, DMSO-d6) d=7.19-7.06 (m, 5H), 6.95-6.84 (m, 2H), 4.70-4.48 (m, 1H), 4.41-4.24 (m, 2H), 3.55 (s, 1H), 3.48-3.29 (m, 3H), 2.76-2.63 (m, 2H), 2.62-2.52 (m, 1H), 2.28 (s, 4H), 2.16-2.03 (m, 1H), 1.89 (s, 3H), 1.79-1.54 (m, 2H).
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[N:11][CH:10]=1.[CH2:23]([NH2:27])[CH:24]([CH3:26])[CH3:25]>ClCCl>[Br:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:27][CH2:23][CH:24]([CH3:26])[CH3:25])=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[N:11][CH:10]=1
Reactant: CC(C)CN
Reactant: O=[N+]([O-])c1cnc2cc(Br)cnc2c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CNc1c([N+](=O)[O-])cnc2cc(Br)cnc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.3 %

Procedure:
Triethylamine (17.97 mL, 129.0 mmol) was added to a solution of 7-bromo-4-chloro-3-nitro[1,5]naphthyridine (24.8 g, 86.0 mmol) in dichloromethane (200 mL) at 0° C. Isobutylamine (9.40 mL, 94.6 mmol) was added dropwise to the mixture, and the mixture was stirred for 3 hours at ambient temperature. The reaction mixture was condensed under reduced pressure to a solid, which was triturated with water (200 mL). The precipitate was filtered, washed sequentially with water and hexanes, and dried to yield 27.5 g of 7-bromo-3-nitro[1,5]naphthyridin-4-yl-(2-methylpropyl)amine as a yellow powder, mp 114-115° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN([CH:9]=[O:10])C.[CH3:11][O:12][C:13]([C:15]1[C:16]2[CH:17]=[C:18]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[NH:19][C:20]=2[CH:21]=[CH:22][CH:23]=1)=[O:14]>C(Cl)Cl>[CH3:11][O:12][C:13]([C:15]1[C:16]2[C:17]([CH:9]=[O:10])=[C:18]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[NH:19][C:20]=2[CH:21]=[CH:22][CH:23]=1)=[O:14]
Reactant: COC(=O)c1cccc2[nH]c(-c3ccc(Cl)cc3)cc12
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1cccc2[nH]c(-c3ccc(Cl)cc3)c(C=O)c12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Phosphorous oxychloride (0.42 g, 2.71 mmol) was added to DMF (0.99 g, 13.57 mmol) at 0° C. The resulting colorless solution was added dropwise to a solution of 2-(4-chloro-phenyl)-1H-indole-4-carboxylic acid methyl ester (0.52 g, 1.81 mmol) in 10 mL dry CH2Cl2 at 0° C. The reaction was stirred at 0° C. for 10 min then quenched by addition of 5 mL 2 M NaOAc(aq). The layers were separated and the aqueous layer extracted once with CH2Cl2. The combined organic layers were dried (MgSO4) then concentrated in vacuo leaving anorange oil which crystallized on standing. The crystals were rinsed with CH2Cl2 then dried in vacuo to yield 2-(4-chloro-phenyl)-3-formyl-1H-indole-4-carboxylic acid methyl ester, 231 mg (41%) as an off-white solid: m.p. 221-222° C.; 1H NMR (300 MHz, d6-DMSO) δ 3.93 (s, 3H), 7.49 (app t, J=7.5 Hz, 1H), 7.71 (m, 4H), 7.94 (d, J=7.8 Hz, 2H), 9.71 (s, 1H), 13.67 (br s, 1H). MS (electrospray, [M−H]) 312.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]([F:15])[F:14].CN([CH:19]=[O:20])C>C1COCC1>[F:14][CH:13]([F:15])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH:19]=[O:20]
Reactant: FC(F)c1ccccc1Br
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccccc1C(F)F
Reaction time: 0.5 h
Yield: 112.3 %

Procedure:
A solution of n-BuLi (4.2 mL, 10.6 mmol) in THF was added to a solution of 1-bromo-2-(difluoromethyl)benzene 51 (2.0 g, 9.7 mmol) in THF (50 mL) at −78° C. The reaction mixture was stirred for 30 min and DMF (1.4 g, 19.3 mmol) was added. Stirring was continued for 1 h at −40° C. and the reaction was quenched by the addition of sat. aq NH4Cl. The crude mixture was extracted with Et2O, dried (MgSO4) and concentrated to give 52 (1.7 g, 94% yield).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[C@H:3]([CH3:5])[OH:4].[C:9]([O-:12])(O)=[O:10].[Na+].[C:14]1([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]C2C(=O)N(C([O-])=O)C=CC=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O.C1COCC1>[OH:4][C@@H:3]([CH3:5])[C@H:2]([NH:1][C:9]([O:12][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:6]([OH:8])=[O:7]
Reactant: O=C([O-])n1cccc(CCCCCc2ccccc2)c1=O
Reactant: O=C([O-])O
Reactant: C[C@H](O)[C@H](N)C(=O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](O)[C@H](NC(=O)OCCCCCc1ccccc1)C(=O)O
Reaction time: 15 h
Yield: 90.5 %

Procedure:
To a stirred mixture of L-allo-threonine (0.150 g, 1.25 mmol) and NaHCO3 (0.158 g, 1.89 mmol) in H2O (3.5 mL), the crude mixture containing 1-(4-phenylphenyl)ethyl-2-pyridyl-carbonate and 5-phenyl-pentyl-2-oxopyridine 1-carboxylate (0.538 g, 1.89 mmol) in THF (3.5 mL) was added. After 15 h at rt, the crude mixture was rotary evaporated to remove the organics and subsequently extracted with Et2O (3×5 mL). The aqueous phase was acidified with 2M HCl solution to pH 2-3 and subsequently extracted with AcOEt (3×10 mL). The organic fraction was dried over Na2SO4, filtered and concentrated to dryness to afford the title compound (0.35 g, 89%) as transparent oil, which was used in the next step without further purification. MS (ESI) m/z: 310 [M−H]+; (ESI) m/z: 308 [M−H]−. 1H NMR (DMSO-d6): δ 1.08 (d, J=6.1 Hz, 3H), 1.28-1.39 (m, 2H), 1.50-1.64 (m, 4H), 2.57 (t, J=7.7 Hz, 2H), 3.83-3.98 (m, 4H), 7.12 (d, J=8.7 Hz, 1H), 7.14-7.21 (m, 3H), 7.23-7.30 (m, 2H) 12.32 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14](=[O:31])[CH2:15][CH2:16][C:17]([C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)=[O:18])[CH:6]=[C:7]([I:13])[C:8]=1[O:9][CH2:10][CH2:11][OH:12].O1CCCC1.CO.[BH4-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]([OH:31])[CH2:15][CH2:16][CH:17]([C:19]2[CH:20]=[C:21]([O:29][CH3:30])[C:22]([O:27][CH3:28])=[C:23]([O:25][CH3:26])[CH:24]=2)[OH:18])[CH:6]=[C:7]([I:13])[C:8]=1[O:9][CH2:10][CH2:11][OH:12]
Reactant: COc1cc(C(=O)CCC(=O)c2cc(OC)c(OC)c(OC)c2)cc(I)c1OCCO
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C(O)CCC(O)c2cc(OC)c(OC)c(OC)c2)cc(I)c1OCCO
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 101 %

Procedure:
1-(3-Methoxy-4-hydroxyethoxy-5-iodophenyl)-4-( 3,4,5-trimethoxyphenyl)-1,4-butanedione (11.6 g, 21.3 mmol), was added to 120 mL tetrahydrofuran and 240 mL methanol. To this solution was added dropwise sodium borohydride (1.45 g, 38.4 mmol), in 60 mL water. The reaction mixture was stirred at room temperature for 2.5 hours, and then cooled, quenched with water, and the aqueous layer extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered and evaporated in vacuo to provide the product (11.8 g, 98.8%). 1H NMR (CDCl3): 1.84 (m, 4H); 3.84 (m, 2H); 3.86 (s, 3H); 3.87 (s, 9H); 4.15 (t, 2H); 4.68 (m, 2H); 6.57 (s, 2H); 6.91 (s, 1H); 7.32 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([NH:14][CH:15]([CH3:19])[CH2:16][O:17][CH3:18])[N:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[Cl:20][C:21]1[CH:22]=[C:23]([NH:24][C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[C:12]([NH:14][CH:15]([CH3:19])[CH2:16][O:17][CH3:18])[N:11]=[CH:10][N:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: COCC(C)Nc1cc(-c2ccnc(Cl)n2)ncn1
Reactant: Nc1cccc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: O
Product: COCC(C)Nc1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ncn1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a solution of 2′-chloro-N-(2-methoxy-1-methylethyl) [4,4′-bipyrimidine]-6-amine (i.e., the product of Step C) (100 mg, 0.357 mmol) and 3-chloroaniline (57 mg, 0.45 mmol) in 1,4-dioxane (3.5 mL) under a nitrogen atmosphere was added p-toluenesulfonic acid monohydrate (57 mg, 0.30 mmol). The resulting mixture was stirred at 100° C. for 18 h. The solution was concentrated under reduced pressure to give a yellow solid residue. The residue was then purified on silica gel eluted with 40% ethyl acetate in hexanes, followed by acetone to give 113 mg of title compound as a solid.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31](=[O:38])[NH:30][N:29]=2)=[CH:23][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][N:9]2[C:12]([C:19]([F:22])([F:21])[F:20])=[N:13][C:14]([C:15]([O:17]C)=[O:16])=[C:8]2[CH2:7]1)=[O:5].[OH-].[Na+].Cl>O1CCCC1.CO.O>[F:1][C:2]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31](=[O:38])[NH:30][N:29]=2)=[CH:23][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][N:9]2[C:12]([C:19]([F:20])([F:21])[F:22])=[N:13][C:14]([C:15]([OH:17])=[O:16])=[C:8]2[CH2:7]1)=[O:5]
Reactant: COC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)c1cc(Cc3n[nH]c(=O)c4ccccc34)ccc1F)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1nc(C(F)(F)F)n2c1CN(C(=O)c1cc(Cc3n[nH]c(=O)c4ccccc34)ccc1F)CC2
Reaction time: 12 h
Yield: 34 %

Procedure:
Methyl 7-[2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carboxylate 3 (30 mg, 0.057 mmol) was dissolved in 1.5 mL of a mixed solvent of tetrahydrofuran, methanol and water (V N N=1:1:1), followed by addition of sodium hydroxide (10 mg, 0.25 mmol). After stirring for 12 hours, concentrated hydrochloric acid was added dropwise to the reaction mixture until the pH was 2. The reaction mixture was extracted with dichloromethane (15 mL×2). The organic phase was combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 7-[2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoyl]-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-1-carboxylic acid 8 (10 mg, yield 34.4%) as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([OH:14])=O)[C:6]3[CH2:15][CH2:16][N:17]([CH3:19])[CH2:18][C:5]=3[C:4]=2[CH:3]=1.C(Cl)(=O)C(Cl)=O.[C:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:28])[CH3:27]>ClCCl>[C:26]([N:29]1[CH2:34][CH2:33][N:32]([C:12](=[O:14])[CH2:11][N:7]2[C:8]3[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=3[C:5]3[CH2:18][N:17]([CH3:19])[CH2:16][CH2:15][C:6]2=3)[CH2:31][CH2:30]1)(=[O:28])[CH3:27]
Reactant: CN1CCc2c(c3cc(Cl)ccc3n2CC(=O)O)C1
Reactant: CC(=O)N1CCNCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC(=O)N1CCN(C(=O)Cn2c3c(c4cc(Cl)ccc42)CN(C)CC3)CC1
Reaction time: 3 h
Yield: 12 %

Procedure:
A mixture of 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)acetic acid (125 mg, 0.45 mmol) and oxalyl chloride (2 ml) in dichloromethane (6.0 ml) was stirred at 25 deg C. for 3 h. The reaction mixture was concentrated to dryness. The resulting crude was dissolved in dichloromethane (6.0 ml) and DMAP (64 mg, 052 mmol) was added followed by addition of acetyl piperazine (56 mg, 0.43 mmol). The resulting mixture was stirred at 25 deg C. for 14 h. The solvent was removed in vacuo and purified by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL) to obtain 20 mg of 1-(4-Acetyl-piperazin-1-yl)-2-(8-chloro-2-methyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-ethanone as trifluoroacetic acid salt.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([OH:14])=O)[CH:3]=1.[C:15]1([C:21]2[CH:25]=[C:24]([CH2:26][N:27]3[CH2:32][CH2:31][CH:30]([CH2:33][NH2:34])[CH2:29][CH2:28]3)[O:23][N:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([NH:34][CH2:33][CH:30]2[CH2:29][CH2:28][N:27]([CH2:26][C:24]3[O:23][N:22]=[C:21]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:25]=3)[CH2:32][CH2:31]2)=[O:14])[CH:3]=1
Reactant: Nc1cc(C(=O)O)nc2ccccc12
Reactant: NCC1CCN(Cc2cc(-c3ccccc3)no2)CC1
Product: Nc1cc(C(=O)NCC2CCN(Cc3cc(-c4ccccc4)no3)CC2)nc2ccccc12

Procedure:
According to the same procedure described in Example 225, using the compound prepared in Example 275 instead of 4-amino-5-cyano-6-ethoxypicolinic acid, and using 1-{1-[(3-phenyl-5-isoxazolyl)methyl]-4-piperidinyl}methanaminethe compound prepared in Example 9 instead of tert-butyl 4-(aminomethyl)piperidine-1-carboxylate the title compound having the following physical data was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:14]2[C:16]3=[C:17]4[C:7]([CH:8]=[CH:9][CH:10]=[C:11]4[CH:12]=[CH:13]2)=[C:6](C#CCO)[CH:5]=[C:4]3C=1C.[OH-].[Na+].[C:25]1(C)C=CC=C[CH:26]=1>>[C:6]1([C:25]#[CH:26])[C:5]2[C:12]3=[C:13]4[C:14](=[CH:16][CH:4]=2)[CH:15]=[CH:2][CH:1]=[C:8]4[CH:9]=[CH:10][C:11]3=[CH:17][CH:7]=1
Reactant: Cc1ccccc1
Reactant: Cc1cc2ccc3cccc4c(C#CCO)cc(c1C)c2c34
Agent: [Na+]
Agent: [OH-]
Product: C#Cc1ccc2ccc3cccc4ccc1c2c34
Temperature: 120 °C
Yield: 58 %

Procedure:
1.5 g (5.28 mmol) of Dimethylhydroxymethyl-9-pyrenylacetylene and 222 mg (5.54 mmol) of NaOH (KISHIDA CHEMICAL CO., Ltd., 0.7 mm granular, 98%) were placed in a 50 mL two-neck flask equipped with a reflux condenser and the air inside the flask was replaced with Ar. 26 mL of toluene was added thereto and the mixture was refluxed at 120° C. for 0.67 hour. Toluene was added to the reaction mixture and the mixture was washed with a saturated aqueous ammonium chloride solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure by an evaporator. The crude reaction product was purified by column chromatography (Hexane/AcOEt=10/1) using silica gel to give 1-pyrenylethyne as an orange-color solid (0.69 g, yield: 58%).