Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][N:3]=1.Cl[C:12]1[N:17]=[N:16][C:15]([N:18]2[CH2:23][CH2:22][CH:21]([N:24]3[C:32]4[C:27](=[CH:28][CH:29]=[C:30]([F:33])[CH:31]=4)[CH2:26][CH2:25]3)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1>>[F:33][C:30]1[CH:31]=[C:32]2[C:27]([CH2:26][CH2:25][N:24]2[CH:21]2[CH2:22][CH2:23][N:18]([C:15]3[N:16]=[N:17][C:12]([C:5]4[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][CH:6]=4)=[CH:13][CH:14]=3)[CH2:19][CH2:20]2)=[CH:28][CH:29]=1
Reactant: Fc1ccc2c(c1)N(C1CCN(c3ccc(Cl)nn3)CC1)CC2
Reactant: Cc1ccc(B(O)O)cn1
Product: Cc1ccc(-c2ccc(N3CCC(N4CCc5ccc(F)cc54)CC3)nn2)cn1

Procedure:
The title compound was prepared following the procedure as described in Example 1, Method A, STEP4, reacting 2-methylpyridine-5-boronic acid and 1-(1-(6-chloropyridazin-3-yl)piperidin-4-yl)-6-fluoroindoline.
Reaction SMILES: [CH3:1][C:2]1[O:13][C:5]([CH:6](O)[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH:4][CH:3]=1.C(O)C[OH:16].O.C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH2:7]([CH:6]1[C:2]([OH:13])([CH3:1])[CH:3]=[CH:4][C:5]1=[O:16])[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCC(O)c1ccc(C)o1
Reactant: OCCO
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCCCC1C(=O)C=CC1(C)O
Yield: 84 %

Procedure:
In the same apparatus as in Example 1 5-methyl-α-n-pentyl-furfuryl alcohol (40 parts), ethylene glycol (20 parts) and a buffer solution prepared from water (1200 parts) and sodium acetate (0.5 part) and adjusted to pH 5.2 with acetic acid were charged, and the resultant mixture was stirred at 100° C. in a nitrogen stream for 20 hours. The reaction mixture was cooled and extracted with toluene. The extract was concentrated to give 2-n-pentyl-3-hydroxy-3-methyl-4-cyclopentenone in a yield of 84 %.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[S:22]([NH:25][C:26]2[CH:35]=[CH:34][C:33]3[CH2:32][CH2:31][CH2:30][CH2:29][C:28]=3[C:27]=2[C:36]([OH:38])=[O:37])(=[O:24])=[O:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si](C=[N+]=[N-])(C)(C)[CH3:40]>C1C=CC=CC=1.CO>[CH3:40][O:37][C:36]([C:27]1[C:28]2[CH2:29][CH2:30][CH2:31][CH2:32][C:33]=2[CH:34]=[CH:35][C:26]=1[NH:25][S:22]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[NH:15][CH2:14][CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1)(=[O:24])=[O:23])=[O:38]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2ccccc2S(=O)(=O)Nc2ccc3c(c2C(=O)O)CCCC3)CC1
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)c1c(NS(=O)(=O)c2ccccc2NCC2CCN(C(=O)OC(C)(C)C)CC2)ccc2c1CCCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of Example 396 (2.69 g, 5.0 mmol) in benzene (40 mL) and methanol (10 mL) was treated with TMSCHN2 (3.0 mL, 6.0 mmol, 2.0M solution in hexanes). The reaction was stirred at room temperature for 1 hour, then quenched with acetic acid, and diluted with ethyl acetate. The organic layer was washed with aqueous NaHCO3, dried (MgSO4), filtered, concentrated, and purified by column chromatography (25% ethyl acetate/hexanes) to provide the desired product. MS (ESI(+)) m/e 528 (M+H)+.
Reaction SMILES: CCN=C=NCCCN(C)C.[CH3:12][N:13]1[C:21]2[C:16](=[CH:17][C:18]([C:22]([F:25])([F:24])[F:23])=[CH:19][CH:20]=2)[C:15]([NH:26][CH2:27][C:28]([OH:30])=O)=[N:14]1.[C:31]([O:35][C:36]([N:38]1[CH2:41][CH:40]([NH2:42])[CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>>[C:31]([O:35][C:36]([N:38]1[CH2:41][CH:40]([NH:42][C:28](=[O:30])[CH2:27][NH:26][C:15]2[C:16]3[C:21](=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=3)[N:13]([CH3:12])[N:14]=2)[CH2:39]1)=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: Cn1nc(NCC(=O)O)c2cc(C(F)(F)F)ccc21
Agent: CCN=C=NCCCN(C)C
Product: Cn1nc(NCC(=O)NC2CN(C(=O)OC(C)(C)C)C2)c2cc(C(F)(F)F)ccc21

Procedure:
The title compound was prepared as white foam from EDCI coupling of (1-methyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetic acid (as prepared in the previous step) and 3-amino-azetidine-1-carboxylic acid tert-butyl ester using the procedure described in Step C of Example 1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[CH:22]1[CH2:27][CH2:26][N:25]([C:28](=[O:30])[CH3:29])[CH2:24][CH2:23]1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH:22]2[CH2:27][CH2:26][N:25]([C:28](=[O:30])[CH3:29])[CH2:24][CH2:23]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2O)CC1
Reactant: CC(=O)N1CCC(O)CC1
Product: CC(=O)N1CCC(Oc2ccccc2N2CCN(C(=O)OC(C)(C)C)CC2)CC1

Procedure:
The title compound was prepared by using Mitsunobu condition from 4-(2-hydroxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester and 1-(4-Hydroxy-piperidin-1-yl)-ethanone.
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[N:10]([CH2:14][C:15]([OH:17])=O)[CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].[C:18]([C:20]1[CH:28]=[CH:27][C:23]([CH2:24][CH2:25][NH2:26])=[CH:22][CH:21]=1)#[N:19]>>[C:18]([C:20]1[CH:28]=[CH:27][C:23]([CH2:24][CH2:25][NH:26][C:15](=[O:17])[CH2:14][N:10]2[C:11]3[C:12](=[O:13])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=3[N:8]=[CH:9]2)=[CH:22][CH:21]=1)#[N:19]
Reactant: N#Cc1ccc(CCN)cc1
Reactant: Cn1c(=O)c2c(ncn2CC(=O)O)n(C)c1=O
Product: Cn1c(=O)c2c(ncn2CC(=O)NCCc2ccc(C#N)cc2)n(C)c1=O
Yield: 21.2 %

Procedure:
Compound 409 (93 mg, 21%) was prepared from 101 (300 mg, 1.3 mmol) and 115 (175 mg, 1.2 mmol) according to General Procedure B. MS (APCI): m/z 367 [M+H]+. Anal. Calcd. for C18H18N6O3.0.04EtOAc.0.1H2O: C, 58.68; H, 5.02; N, 22.61; Found: C, 58.75; H, 5.01; N, 22.46.
Reaction SMILES: [OH:1][C:2]1([CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]2[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:5][NH:4][CH2:3]1.[F:20][C:21]1[C:22]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([I:38])=[CH:34][C:33]=2[F:39])=[C:23]([CH:27]=[CH:28][C:29]=1[F:30])[C:24](F)=[O:25].C(N(CC)C(C)C)(C)C>O1CCCC1>[C:15]([O:14][C:13](=[O:19])[NH:12][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]1[C:2]1([OH:1])[CH2:3][N:4]([C:24](=[O:25])[C:23]2[CH:27]=[CH:28][C:29]([F:30])=[C:21]([F:20])[C:22]=2[NH:31][C:32]2[CH:37]=[CH:36][C:35]([I:38])=[CH:34][C:33]=2[F:39])[CH2:5]1)([CH3:16])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)NC1CCCCC1C1(O)CNC1
Reactant: O=C(F)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCCCC1C1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Temperature: 50 °C
Reaction time: 0.75 h

Procedure:
To a solution of tert-butyl 2-(3-hydroxyazetidin-3-yl)cyclohexylcarbamate (181 mg, 0.669 mmol) and 3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzoyl fluoride (265 mg, 0.669 mmol), prepared using procedures similar to those described in Reference 1, in tetrahydrofuran (2.2 mL) was added N,N-diisopropylethylamine (110 μL) at room temperature. After an hour, the reaction mixture was heated to 50° C. and stirred for 45 minutes, at which time it was cooled to room temperature and evaporated. The residue was partitioned between ethyl acetate and 10% citric acid. The organic layer was washed with aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford tert-butyl-2-(1-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzoyl)-3-hydroxyazetidin-3-yl)cyclohexylcarbamate. This crude material was taken into the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.[Br:11][C:12]1[CH:13]=[C:14]([C:19]2[N:20]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=3[Cl:31])[CH:21]=[CH:22][N:23]=2)[C:15](Cl)=[N:16][CH:17]=1>O1CCOCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:15]2[C:14]([C:19]3[N:20]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=4[Cl:31])[CH:21]=[CH:22][N:23]=3)=[CH:13][C:12]([Br:11])=[CH:17][N:16]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CN)cc1
Reactant: Clc1cccc(-n2ccnc2-c2cc(Br)cnc2Cl)c1Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(CNc2ncc(Br)cc2-c2nccn2-c2cccc(Cl)c2Cl)cc1
Temperature: 100 °C

Procedure:
To a solution of excess (4-methoxyphenyl)methanamine (0.2 mL) in dioxane (2 mL)was added 5-bromo-2-chloro-3-(1-(2,3-dichlorophenyl)-1H-imidazol-2-yl)pyridine (0.089 g, 0.222 mmol). The mixture was heated at 100° C. for 16 hours in a sealed reaction vessel. The mixture was then cooled, diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, and the combined organics dried over sodium sulfate. After filtration and concentration, the residue was purified by flash chromatography (20% hexanes/methylene chloride to 25% ethyl acetate/methylene chloride to provide 0.065 g of N-(4-methoxybenzyl)-5-bromo-3-(1-(2,3-dichlorophenyl)-1H-imidazol-2-yl)pyridin-2-amine [LC-MS m/e=505.0 (M+H)]. Using the same procedure, N-(4-methoxybenzyl)-5-bromo-3-(1-(2,3-difluorophenyl)-1H-imidazol-2-yl)pyridin-2-amine and N-(4-methoxybenzyl)-5-bromo-3-(1-(3-chloro-2-fluorophenyl)-1H-imidazol-2-yl)pyridin-2-amine can be produced from 5-bromo-2-chloro-3-(1-(2,3-difluorophenyl)-1H-imidazol-2-yl)pyridine and 5-bromo-2-chloro-3-(1-(3-chloro-2-fluorophenyl)-1H-imidazol-2-yl)pyridine, respectively
Reaction SMILES: [OH:1][C:2]([CH2:10][O:11][Si:12]([CH2:17][CH3:18])([CH2:15][CH3:16])[CH2:13][CH3:14])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][C:4]#[CH:5].N1C=CN=C1.Cl[Si:25]([CH3:28])([CH3:27])[CH3:26]>CN(C)C=O>[CH2:13]([Si:12]([CH2:17][CH3:18])([CH2:15][CH3:16])[O:11][CH2:10][C:2]([O:1][Si:25]([CH3:28])([CH3:27])[CH3:26])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][C:4]#[CH:5])[CH3:14]
Reactant: C[Si](C)(C)Cl
Reactant: C#CCC(O)(CCCC)CO[Si](CC)(CC)CC
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C#CCC(CCCC)(CO[Si](CC)(CC)CC)O[Si](C)(C)C
Temperature: 0 °C

Procedure:
To a solution of the 4-hydroxy-4-triethylsilyloxymethyl-1-octyne (prepared in Example 3) and 23.9 g. of imidazole in 50 ml. of dimethylformamide at 0° C., is added with stirring, 21.2 g. of chlorotrimethylsilane. The mixture is stirred for 75 minutes, then poured into ice water and extracted with hexane. The hexane layer is washed with water, then saturated sodium bicarbonate solution, dried over magnesium sulfate and the hexane is removed. The residue is distilled. The fraction boiling at 133°-136° C. (1.2 mm.) is collected giving the desired product as a colorless liquid.
Reaction SMILES: [CH2:1]([C:11]1[C:18]2[S:17][C:16]3[C:19]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[C:20](C(O)=O)[S:21][C:15]=3[C:14]=2[S:13][C:12]=1C(O)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].N1C2C(=CC=CC=2)C=CC=1.C(=O)=O>[Cu].CCCCCC>[CH2:1]([C:11]1[C:18]2[S:17][C:16]3[C:19]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:20][S:21][C:15]=3[C:14]=2[S:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCc1c(C(=O)O)sc2c1sc1c(CCCCCCCCCC)c(C(=O)O)sc12
Agent: [Cu]
Agent: O=C=O
Solvent: CCCCCC
Solvent: c1ccc2ncccc2c1
Product: CCCCCCCCCCc1csc2c1sc1c(CCCCCCCCCC)csc12
Temperature: 255 °C
Yield: 44.6 %

Procedure:
Compound 68 (8.6 g, 0.016 mol), copper powder (0.7 g) and quinoline (50 mL) were combined and heated at 250-260° C. in a Woods-metal bath. When no further bubbles of carbon dioxide gas could be detected (about 2 hours), the mixture was cooled to room temperature and hexane (200 mL) was added. This mixture was washed repeatedly with HCl (1-2 M in water) to remove quinoline. The organic layer was dried over MgSO4 and concentrated by evaporation, and the residue was purified by column chromatography (SiO2/hexanes) to yield compound 63 (3.4 g, 47.4%). 1H NMR (CD2Cl2) δ 6.97 (s, 2H), 2.73 (t, 4H), 1.78 (m, 4H), 1.27 (m, 28H), 0.88 (t, 6H). 13C NMR: 141.89, 136.75, 130.99, 120.57, 32.33, 30.02, 29.79 (m, overlap), 29.74, 29.15, 23.10, 14.28.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:25]=[C:26]1[N:32]([CH:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C@@H:42]([C:54]([OH:56])=O)[CH2:43][C:44]3[CH:49]=[C:48]([CH3:50])[C:47]([OH:51])=[C:46]([O:52][CH3:53])[CH:45]=3)=[O:40])[CH2:35][CH2:34]2)[CH2:31][CH2:30][C:29]2[CH:57]=[CH:58][CH:59]=[CH:60][C:28]=2[NH:27]1.C(N(C(C)C)C(C)C)C.[O:70]1[CH2:75][CH2:74][CH:73]([N:76]2[CH2:81][CH2:80][NH:79][CH2:78][CH2:77]2)[CH2:72][CH2:71]1>CN(C=O)C>[O:25]=[C:26]1[N:32]([CH:33]2[CH2:34][CH2:35][N:36]([C:39]([O:41][C@H:42]([CH2:43][C:44]3[CH:49]=[C:48]([CH3:50])[C:47]([OH:51])=[C:46]([O:52][CH3:53])[CH:45]=3)[C:54](=[O:56])[N:79]3[CH2:78][CH2:77][N:76]([CH:73]4[CH2:74][CH2:75][O:70][CH2:71][CH2:72]4)[CH2:81][CH2:80]3)=[O:40])[CH2:37][CH2:38]2)[CH2:31][CH2:30][C:29]2[CH:57]=[CH:58][CH:59]=[CH:60][C:28]=2[NH:27]1
Reactant: C1CN(C2CCOCC2)CCN1
Reactant: COc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCOCC3)CC2)cc(C)c1O
Reaction time: 3 h

Procedure:
84 mg (0.22 mmol) HATU was added at RT under nitrogen to a solution of 100 mg (0.20 m mol) (R)-1-carboxy-2-(4-hydroxy-3-methoxy-5-methyl-phenyl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 110 μL (0.64 mmol) ethyldiisopropylamine and 59 mg (0.24 mmol) 1-(tetrahydropyran-4-yl)-piperazine (used as the bis-hydrochloride salt) in 5 mL DMF and the mixture was stirred for 3 h. The reaction mixture was evaporated down i.vac. at 50° C. and the crude product was purified by HPLC-MS; the fractions containing the product were combined and lyophilised.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH2:13])[C:6]([NH2:12])=[CH:7][CH:8]=2)[N:3]=1.[CH:14]([CH:16]=O)=O>C(O)C>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[CH:8]=[CH:7][C:6]3[N:12]=[CH:16][CH:14]=[N:13][C:5]=3[C:4]=2[N:3]=1
Reactant: O=CC=O
Reactant: Cc1ccc2ccc(N)c(N)c2n1
Solvent: CCO
Product: Cc1ccc2ccc3nccnc3c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.8 %

Procedure:
To a solution of 2-methylquinoline-7,8-diamine (255 mg, 1.48 mmol) in ethanol (3 mL) was added glyoxal (103 mg, 1.78 mmol). The mixture was stirred at room temperature for 2 h. The mixture was then concentrated to give 9-methylpyrido[2,3-f]quinoxaline as a yellow solid (300 mg). MS (ESI): m/z 196 (M+H)+.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.F[C:12]1[C:17]([C:18]2[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=3)[CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[N:19]=2)=[CH:16][C:15]([CH2:44][N:45]2[CH2:50][CH2:49][N:48]([S:51]([CH3:54])(=[O:53])=[O:52])[CH2:47][CH2:46]2)=[CH:14][N:13]=1.[NH2:55][C:56]1[CH:57]=[CH:58][C:59]([NH:62][C:63](=[O:69])[O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[N:60][CH:61]=1>C1COCC1>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][N:25]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[C:20]2[N:21]=[C:22]([CH3:24])[N:23]=[C:18]([C:17]3[C:12]([NH:55][C:56]4[CH:57]=[CH:58][C:59]([NH:62][C:63](=[O:69])[O:64][C:65]([CH3:67])([CH3:66])[CH3:68])=[N:60][CH:61]=4)=[N:13][CH:14]=[C:15]([CH2:44][N:45]4[CH2:50][CH2:49][N:48]([S:51]([CH3:54])(=[O:53])=[O:52])[CH2:47][CH2:46]4)[CH:16]=3)[N:19]=2)=[CH:28][CH:29]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3F)n2)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3Nc3ccc(NC(=O)OC(C)(C)C)nc3)n2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 46.3 %

Procedure:
LiHMDS (Aldrich) (2.44 mL, 2.44 mmol) was added dropwise at 0° C. to a stirred solution of 4-(2-fluoro-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.507 g, 0.815 mmol) and tert-butyl 5-aminopyridin-2-ylcarbamate (0.204 g, 0.976 mmol) in THF (2 mL). The dark red mixture was stirred at 0° C. for 2 h. More LiHMDS (1.6 mL, 1.6 mmol) was added dropwise at 0° C. and stirring was continued for another 30 min. The reaction was quenched by adding 0.3 mL of sat'd NH4Cl. The reaction mixture was partitioned between water (40 mL) and EtOAc (40 mL). The aqueous phase was extracted with EtOAc (2×30 mL). The combined organic layers were washed with saturated aqueous sodium chloride (40 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (100 g, eluent: iPrOH (w/10% NH4OH) in CHCl3 0%-10%) to give tert-butyl 5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-ylamino)pyridin-2-ylcarbamate (0.306 g, 46% yield). 1H NMR (400 MHz, CDCl3) δ 11.76 (s, 1H); 8.71 (d, J=2.54 Hz, 1H); 8.42 (d, J=2.35 Hz, 1H); 8.23 (d, J=2.35 Hz, 1H); 7.94 (dd, J=9.00, 2.54 Hz, 1H); 7.83 (d, J=9.00 Hz, 1H); 7.15-7.25 (m, 5H); 6.86 (dd, J=11.15, 8.61 Hz, 4H); 4.83 (d, J=10.17 Hz, 4H); 3.76-3.85 (m, 6H); 3.50 (s, 2H); 3.18 (br s., 4H); 2.71 (s, 3H); 2.59 (s, 3H); 2.55 (t, J=4.50 Hz, 4H); 1.53 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:5][C:6](=O)[C:7]=1[CH3:8])=[O:4].[CH3:10][NH:11][NH2:12]>C(O)C>[CH3:10][NH:11][N:12]1[C:3](=[O:4])[C:2]([CH3:1])=[C:7]([CH3:8])[C:6]1=[O:5]
Reactant: CNN
Reactant: CC1=C(C)C(=O)OC1=O
Solvent: CCO
Product: CNN1C(=O)C(C)=C(C)C1=O
Temperature: 70 °C
Reaction time: 3 h

Procedure:
2,3-Dimethylmaleic acid anhydride (3.5 g, 28 mM) was suspended in 50 ml of ethyl alcohol. To the dispersion was added methylhydrazine (1.28 g, 27.7 mM). After addition, the mixture was stirred at 70° C. for 3 hours. After ethanol was distilled away, the target compound was separated by chromatography from the reaction mixture.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:26]([O:28][CH3:29])=[O:27])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][NH:19][CH2:18][C:17]4[CH:22]=[CH:23][CH:24]=[CH:25][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:30][N:31]1[CH:35]=[C:34]([CH:36]=O)[CH:33]=[N:32]1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:26]([O:28][CH3:29])=[O:27])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][N:19]([CH2:36][C:34]4[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=4)[CH2:18][C:17]4[CH:22]=[CH:23][CH:24]=[CH:25][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cn1cc(C=O)cn1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCNCc1ccccc1-3
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCN(Cc1cnn(C)c1)Cc1ccccc1-3
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of methyl 14-cyclohexyl-5,6,7,8-tetrahydroindolo[2,1-a][2,5]-benzodiazocine-11-carboxylate (prepared as described in Example 48, Step 3) in MeOH (0.06 M), 1-methyl-1H-pyrazole-4-carbaldehyde (3 eq) was added and the pH adjusted to pH 4 with acetic acid. The solution was stirred at RT for 30 mins before addition of NaBH3CN (1.5 eq). The reaction was stirred at RT for 16 h. The reaction was quenched with saturated aqueous NaHCO3 and extracted with EtOAc (×2). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as a viscous oil (quantitative); MS (ES+) m/z 483 (M+H)+
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:24])[CH:3]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][C:26]1=[O:30]>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:25]3[CH2:29][CH2:28][CH2:27][C:26]3=[O:30])=[CH:3][C:4]=2[F:24])=[O:9])[CH2:11][CH2:12]1
Reactant: O=C1CCCN1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3F)CC2)c(C)c1

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (783 mg) described in Preparation Example 116 and pyrrolidin-2-one (0.16 mL) and by the reaction and treatment in the same manner as in Example 1, the title compound (313 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].O=S(Cl)Cl.[CH3:16]N(C=O)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:16])=[O:8]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc(Cl)ccc1I
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Cl)ccc1I
Temperature: 23 °C
Yield: 96 %

Procedure:
A solution of 5-chloro-2-iodobenzoic acid (3.0 g, 10.62 mmol), SOCl2 (12 mL) and DMF (0.6 mL) was gently warmed with a heat gun until the mixture became homogeneous (15 min). The solution was maintained at 23° C. for additional 30 min and then the solution was concentrated. MeOH (24 mL) was added to the crude residue and the solution was maintained at 23° C. for 30 min. The solution was concentrated and the residue was purified by flash chromatography on Biotage silica gel cartridge (cyclohexane to cyclohexane:EtOAc=85:15) to afford methyl 5-chloro-2-iodobenzoate (3.02 g, 10.20 mmol, 96%).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])[CH:14]=2)[CH2:9]1)(C)(C)C.Cl.[OH-].[Na+]>CO>[NH2:7][C@H:8]1[CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([C:18]([N:20]3[CH2:21][CH2:22][CH2:23][CH2:24]3)=[O:19])[CH:12]=[CH:11][C:10]=2[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2cc(C(=O)N3CCCC3)ccc2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N[C@H]1CCc2cc(C(=O)N3CCCC3)ccc2C1
Reaction time: 1 h

Procedure:
To a solution of [(S)-6-(pyrrolidine-1-carbonyl)-1,2,3,4-tetrahydronaphthalen-2-yl]carbamic acid tert-butyl ester (0.70 g) in MeOH (5 ml) was added concentrated hydrochloric acid (5 ml). After one hour, the mixture was basified with concentrated sodium hydroxide solution and extracted three times with DCM. The combined organic phases were dried over magnesium sulfate and concentrated. The product was thus obtained with the molecular weight of 244.34 (C15H20N2O); MS (ESI): 245 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](F)=[CH:7][CH:6]=1)[CH3:2].[NH:13]1[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([N:13]2[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(N2CCC(O)CC2)cc1
Temperature: 120 °C
Yield: 64.2 %

Procedure:
A mixture of 4-fluoro-benzoic acid ethyl ester (1.68 g, 10 mmoles), piperidin-4-ol (1.12 g, 11 mmoles) and anhydrous potassium carbonate (138 g, 10 mmoles) in DMSO (10 ml) was heated at 120° C. for 6 hours. After cooling, the mixture was poured into water and ice (500 ml) and extracted with ethyl acetate. The organic layer was washed with water and brine, dried and evaporated. The residue was purified by flash chromatography on silica gel using hexane/EtOAc (10/30) as eluent to give the title compound as a white solid (1.6 g, 64%).
Reaction SMILES: Cl.[C:2]1([N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)N)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN([CH:19]=[O:20])C>>[C:2]1([N:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:10]2[CH:15]=[CH:14][C:13]([CH:19]=[O:20])=[CH:12][CH:11]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN(c1ccccc1)c1ccccc1
Reactant: CN(C)C=O
Agent: Cl
Product: O=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Yield: 200 %

Procedure:
To a 300 ml four-neck flask were added 17.0 g (77 mmol) of 1,1-diphenylhydrazine hydrochloride obtained in Comparative Example 2, 21.1 g (77 mmol) of p-diphenylaminobenzaldehyde, and 70 g of DMF, followed by stirring at 40 to 45° C. for 3 hours. The reaction was traced by thin-layer chromatography. After, the completion of the reaction, 100 g of methanol was added and precipitated crystals were filtered off to obtain 32.3 g of p-diphenylaminobenzaldehyde=diphenylhydrazone. The yield was 95.4% based on the starting 1,1-diphenylhydrazine, the over all yield from the starting diphenylamine was 77.0%, and the purity determined by high-performance liquid chromatography was 98.2%.