Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:22]=[C:23]([CH2:26]O)[S:24][CH:25]=4)[N:17]=3)[S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[NH:53]1[CH2:56][CH:55]([C:57]([O:59][CH2:60][CH3:61])=[O:58])[CH2:54]1.C(N(CC)C(C)C)(C)C>>[C:1]1([C:7]2[CH:8]=[C:9]([C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:22]=[C:23]([CH2:26][N:53]5[CH2:56][CH:55]([C:57]([O:59][CH2:60][CH3:61])=[O:58])[CH2:54]5)[S:24][CH:25]=4)[N:17]=3)[S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C1CNC1
Reactant: OCc1cc(-c2noc(-c3cc(-c4ccccc4)c(C(F)(F)F)s3)n2)cs1
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CN(Cc2cc(-c3noc(-c4cc(-c5ccccc5)c(C(F)(F)F)s4)n3)cs2)C1

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 1 (1f) using (4-{5-[4-phenyl-5-(trifluoromethyl)-2-thienyl]-1,2,4-oxadiazol-3-yl}-2-thienyl)methanol (0.10 g, 0.25 mmol) that was obtained in Example 3 (3c), carbon tetrabromide (0.17 g, 0.50 mmol), triphenylphosphine (0.13 g, 0.50 mmol), ethyl 3-azetidinecarboxylate hydrochloride (62 mg, 0.38 mmol), and N,N-diisopropylethylamine (0.11 ml, 0.63 mmol). Subsequently, the crude product of the title compound thus obtained was purified by thin layer chromatography on a silica gel plate using a mixed solvent of ethyl acetate and hexane (2:3) as the developing solvent to afford the title compound (73 mg) in a yield of 56% as a white crystalline solid.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[Br:5][CH:6]([F:12])[C:7](OCC)=[O:8]>C(O)C.C(O)CO>[CH:1]([NH:4][C:7](=[O:8])[CH:6]([Br:5])[F:12])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(F)Br
Reactant: CC(C)N
Solvent: OCCO
Solvent: CCO
Product: CC(C)NC(=O)C(F)Br
Reaction time: 2 h

Procedure:
A solution of 14.8 grams (0.25 mole) isopropyl amine in 25 milliliters ethanol was added dropwise to a solution of ethyl bromofluoroacetate, 40 grams (0.22 mole), and 5 drops ethylene glycol in 100 milliliters ethyl alcohol at 10°-15° C. The solution was stirred at 10°-20° C. for 2 hours and was then stored at -15° C. for 3 days. At this time, the solution was evaporated to leave a liquid, 41.8 grams, nD30 1,4629, identified by infrared spectroscopy as the title compound.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1.[N+:16]([CH3:19])([O-:18])=[O:17].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][C:8]1[CH:15]=[CH:14][C:11](/[CH:12]=[CH:19]/[N+:16]([O-:18])=[O:17])=[CH:10][CH:9]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(CCc2ccco2)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1ccc(CCc2ccco2)cc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
To an acetic acid (5 mL) solution of 4-(2-furan-2-yl-ethyl)-benzaldehyde (480 mg, 2.4 mmol) described in Manufacturing Example 80-1-4 were added nitromethane (732 mg, 12 mmol) and ammonium acetate (370 mg, 4.8 mmol) under nitrogen atmosphere at room temperature, which was stirred for 2 hours at 120° C. The reaction mixture was partitioned into water and ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure to obtain the title compound (554 mg, 95%) as a crude product.
Reaction SMILES: Cl.[CH2:2]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:21])=[C:11]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:12]=2[F:14])[C:7](=[O:22])[C:6]([C:23]([OH:25])=[O:24])=[CH:5]1)[CH3:3].C(N(CC)CC)C.[N+:33]([C:36]1[CH:43]=[CH:42][C:39]([CH2:40]Br)=[CH:38][CH:37]=1)([O-:35])=[O:34]>CN(C)C=O>[CH2:2]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:21])=[C:11]([N:15]3[CH2:16][CH2:17][N:18]([CH2:40][C:39]4[CH:42]=[CH:43][C:36]([N+:33]([O-:35])=[O:34])=[CH:37][CH:38]=4)[CH2:19][CH2:20]3)[C:12]=2[F:14])[C:7](=[O:22])[C:6]([C:23]([OH:25])=[O:24])=[CH:5]1)[CH3:3]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)c(F)c21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(Cc4ccc([N+](=O)[O-])cc4)CC3)c(F)c21
Temperature: 90 °C
Reaction time: 10.5 h
Yield: 81.5 %

Procedure:
A mixture of 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)quinoline-3-carboxylic acid hydrochloride (6.7 g), triethylamine (5.45 g), p-nitrobenzylbromide (5.8 g) and dimethylformamide (200 ml) was stirred at 90° C. for 10.5 hrs. The solvent was evaporated off and the residue was treated with water. The solid was filtered, washed with water, dried, and recrystallized from a mixture of dimethylformamide and ethanol to give 6.9 g of 1-ethyl-6,8-difluoro-1,4-dihydro-7-[4-(p-nitrobenzyl)-1-piperazinyl]-4-oxoquinoline-3-carboxylic acid. mp: 241°-242° C.
Reaction SMILES: C(N)CCCCCCCCCCCCCCCC.[CH:19]1([N:25]=[C:26]=[N:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.N(C(OC(C)(C)C)=O)(CC(O)=[O:38])C>C(Cl)(Cl)Cl>[C:26]([NH:25][CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1)([NH:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:38]
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCCCCCCCCCCCCCCCCN
Solvent: ClC(Cl)Cl
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
C17BocSar1 : the product C17BocSar1 is obtained by coupling heptadecylamine with BocSar1 in the presence of dicyclohexylcarbodiimide (DCCI). 3.78 g (0.02 mole) of BocSar and 2.06 g (0.01 mole) of DCCI are mixed cold (at 0° C.) in 100 ml of chloroform. A copious precipitate of dicyclohexylurea (DCU) is formed. The mixture is left for 30 minutes at 0° C., with agitation, and 2.55 g (0.01 mole) of heptadecylamine are added. The reaction is left to proceed for 20 hours. The precipitate is filtered off and washed, the filtrate is recovered, the chloroform is evaporated off, the residue is taken up in 50 ml of THF, the mixture is cooled to 0° C. and filtered to remove the maximum amount of dicyclohexylurea, and the precipitate is washed with the minimum amount of cold THF.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].[N:18]1[CH:23]=[C:22](B(O)O)[CH:21]=[N:20][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.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>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:22]1[CH:23]=[N:18][CH:19]=[N:20][CH:21]=1)[CH:9]=2)=[O:4]
Reactant: OB(O)c1cncnc1
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2sc1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1c(O)c2ccc(-c3cncnc3)cc2sc1=O
Yield: 35.9 %

Procedure:
To a mixture of 7-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (Example 5 e) (220 mg, 0.70 mmol) in dimethoxyethane (DME) (3.1 mL) was added pyrimidine-5-yl boronic acid (104 mg, 0.84 mmol), Pd(PPh3)4 solid (65 mg, 0.08 mmol) and then 2M aqueous Na2CO3 solution (0.86 mL). The resulting mixture was purged with nitrogen gas for 1 min and heated to reflux for 2 h. After cooling, the reaction mixture was diluted with water (80 mL), acidified using 1 N HCl to pH 3-4 and extracted with EtOAc. The two phases were filtered through a pad of Celite® to form two clear layers. The organic layer was separated, washed with brine, dried over MgSO4, filtered and concentrated. The crude product was triturated with MeOH (10 mL) and the solid collected, rinsed with MeOH (2 mL) and dried in vacuo to provide 4-hydroxy-2-oxo-7-pyrimidin-5-yl-2H-thiochromene-3-carboxylic acid methyl ester (79 mg). MS ESI(−) m/e: 313.09 (M−1).
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[Cl:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]([N:18]2[CH2:23][CH2:22][N:21]([S:24]([CH2:27][CH:28]([NH:37][OH:38])[C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=3)(=[O:26])=[O:25])[CH2:20][CH2:19]2)[CH:13]=1>O1CCCC1>[Cl:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]([N:18]2[CH2:23][CH2:22][N:21]([S:24]([CH2:27][CH:28]([N:37]([OH:38])[CH:5]=[O:7])[C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=3)(=[O:25])=[O:26])[CH2:20][CH2:19]2)[CH:13]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=S(=O)(CC(NO)c1ccc(Cl)c(Cl)c1)N1CCN(c2cc(Cl)ncn2)CC1
Solvent: O=CO
Solvent: C1CCOC1
Product: O=CN(O)C(CS(=O)(=O)N1CCN(c2cc(Cl)ncn2)CC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Acetic anhydride (0.23 ml) was added directly to formic acid (0.9 ml. The solution was stirred at room temperature for 30 minutes and then added a solution of N-[2-{[4-(6-chloropyrimidin-4-yl)tetrahydropyrazin-1-yl]sulfonyl}-1-(3,4-dichlorophenyl)ethyl]hydroxylamine (0.227 g) in tetrahydrofuran (5 ml). The solution was stirred at room temperature for 18 hours. The solution was evaporated (water-bath temperature 30° C.) and the residual gum was purified by chromatography using a 10 g silica isolute eluting with CH2Cl2-3% Methanol/CH12Cl2 to give N-[2-{[4-(6-chloropyrimidin-4-yl)piperazino]sulfonyl}-1-(3,4-dichlorophenyl)ethyl]-N-hydroxyformamide (0.178 g), 98-101° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Cl[C:17]1[N:22]=[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]2)[CH:20]=[C:19]([CH3:30])[N:18]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:17]2[N:22]=[C:21]([N:23]3[CH2:24][CH2:25][CH:26]([OH:29])[CH2:27][CH2:28]3)[CH:20]=[C:19]([CH3:30])[N:18]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: Cc1cc(N2CCC(O)CC2)nc(Cl)n1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2nc(C)cc(N3CCC(O)CC3)n2)ccc1-n1cnc(C)c1
Yield: 82 %

Procedure:
The title compound was prepared from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (41 mg, 0.20 mmol) and 1-(2-chloro-6-methyl-pyrimidin-4-yl)-piperidin-4-ol (50 mg, 0.22 mmol) in analogous manner as described in example 90. It was obtained in 82% yield as a light brown solid. MS ISP (m/e): 395.2 (100) [(M+H)+]; 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.23 (s, 1H), 7.96 (s, 1H), 7.63 (s, 1H), 7.18 (m, 2H), 7.01 (s, 1H), 6.22 (s, 1H), 4.75 (d, 1H), 4.03 (br m, 2H), 3.78 (s, 3H), 3.75 (m, 1H), 3.23 (m, 2H), 2.20 (s, 3H), 2.14 (s, 3H), 1.76 (m, 2H), 1.32 (m, 2H).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[C:17]([OH:21])([CH3:20])([CH3:19])[CH3:18].C(OC(C)C)(C)C>[Zn]>[C:17]([O:21][C:3](=[O:2])[CH2:4][NH:5][C:6]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:7])([CH3:20])([CH3:19])[CH3:18]
Reactant: COC(=O)CNC(=O)OCc1ccccc1
Reactant: CC(C)(C)O
Agent: [Zn]
Solvent: CC(C)OC(C)C
Product: CC(C)(C)OC(=O)CNC(=O)OCc1ccccc1
Yield: 83.8 %

Procedure:
Under a nitrogen atmosphere, a mixture of carbobenzyloxyglycine methyl ester (3.0 mmol), t-butanol (3.6 mmol), a zinc cluster Zn4O (OCOCF3)6 (0.0375 mmol), and diisopropyl ether (5.0 ml) was refluxed for 18 hours. As a result, carbobenzyloxyglycine t-butyl ester was obtained in a yield of 83.8%.
Reaction SMILES: CN(C=O)C.[CH2:6]([NH2:8])[CH3:7].[CH:9]1([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([C:22]2[N:23]=[C:24]([C@@H:27]3[CH:32]4[O:33][C@@H:29]([CH2:30][CH2:31]4)[C@@H:28]3[CH2:34][C:35]3[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=3[CH2:42][CH2:43][C:44]([OH:46])=O)[O:25][CH:26]=2)=[O:21])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.Cl.CN(C)CCCN=C=NCC>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH:9]1([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([C:22]2[N:23]=[C:24]([CH:27]3[CH:28]([CH2:34][C:35]4[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=4[CH2:42][CH2:43][C:44](=[O:46])[NH:8][CH2:6][CH3:7])[CH:29]4[O:33][CH:32]3[CH2:31][CH2:30]4)[O:25][CH:26]=2)=[O:21])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CCN
Reactant: O=C(O)CCc1ccc(F)cc1C[C@H]1[C@@H]2CCC(O2)[C@H]1c1nc(C(=O)NCCCCC2CCCCC2)co1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCNC(=O)CCc1ccc(F)cc1CC1C2CCC(O2)C1c1nc(C(=O)NCCCCC2CCCCC2)co1
Reaction time: 23 h
Yield: 20.8 %

Procedure:
DMF (0.22 mL) and ethyl amine (77 μL, 0.15 mmol) were added to 3-(2-{(1S,2R,3S)-3-[4-(4-Cyclohexyl-butylcarbamoyl)-oxazol-2yl]-7-oxa-bicyclo[2.2.1]hept-2-ylmethyl}-4-fluoro-phenyl)-propionic acid (1) (28 mg, 0.053 mmol), EDCI [1-(3-dimehylaminopropyl)-3-ethylcarbodiimide hydrochloride] (17 mg, 0.089 mmol) and DMAP (8 mg, 0.065 mmol). The solution was stirred for 23 h and then was diluted with 15 mL ethyl acetate and washed with HCl (1 M, 3×15 mL). The ethyl acetate solution was then dried (Na2SO4), filtered and evaporated. Flash chromatography on silica gel (ethyl acetate) gave a mixture of the starting acid and the product amide. Purification by preparative thin layer chromatography (4% methanol/dichloromethane) gave the title amide (6 mg, 0.011 mmol, 20%). 1H NMR (300 MHz, ppm) δ 8.06 (s, 1 H) 7.1–7.0 (m, 2 H) 6.8–6.7 (m, 2 H) 5.43 (br s, 1 H) 4.97 (d, J=4.4 Hz, 1 H) 4.82 (d, J=4.4 Hz, 1 H) 3.4–3.3 (m, 3 H) 3.3–3.2 (m, 2 H) 2.9–2.8 (m, 2 H) 2.6–2.5 (m, 1 H) 2.3–2.1 (m, 4 H) 1.8–0.8 (m, 24 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[NH:14][C:13]([CH2:17][CH2:18][CH2:19][CH3:20])=[N:12]1.[C:21]([NH:25][S:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]1[CH:40]=[CH:39][C:38]([CH2:41]Br)=[CH:37][CH:36]=1)(=[O:28])=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[N:14]([CH2:41][C:38]2[CH:39]=[CH:40][C:35]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[S:26](=[O:28])(=[O:27])[NH:25][C:21]([CH3:22])([CH3:24])[CH3:23])=[CH:36][CH:37]=2)[C:13]([CH2:17][CH2:18][CH2:19][CH3:20])=[N:12]1
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Br)c(=O)[nH]1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(CBr)cc1
Product: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Br)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Yield: 92 %

Procedure:
The alkylation of 2-(2-bromo-5-nitrophenyl)-5-n-butyl-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step A) with [2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl bromide (from Example 7) was carried out according to the procedure of Example 8, Step A, to give a 92% yield of the title compound as a yellow solid, mp 126°-128° C.; homogeneous by TLC in 98:2 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 642, 644 (M+1)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=O)=[CH:2]1.[CH2:12]([C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][NH:24][C:23]2[CH:25]=[CH:26][C:20]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:21][CH:22]=2)=[CH:2]1
Reactant: CCCCCCCCc1ccc(N)cc1
Reactant: O=Cc1c[nH]c2ccccc12
Product: CCCCCCCCc1ccc(NCc2c[nH]c3ccccc23)cc1
Yield: 52.6 %

Procedure:
By the reaction and treatment in the same manner as in Preparation Example 1 using 1H-indole-3-aldehyde (1.5 g) and 4-octylaniline (2.1 g) as starting materials, [(1H-indol-3-yl)methyl](4-octylphenyl)amine (1.8 g) was obtained.
Reaction SMILES: C(N1C(C2SC3CCO[C:15]4C=C(C5CN(C(C)(C)C#N)C5)C=[CH:19][C:16]=4[C:17]=3[N:18]=2)=NC=N1)(C)C.OC(C(F)(F)F)=O.[CH:39]([N:42]1[C:46]([C:47]2[S:48][C:49]3[CH2:50][CH2:51][O:52][C:53]4[CH:60]=[C:59]([CH:61]5[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]5)[CH:58]=[CH:57][C:54]=4[C:55]=3[N:56]=2)=[N:45][CH:44]=[N:43]1)([CH3:41])[CH3:40]>>[CH:39]([N:42]1[C:46]([C:47]2[S:48][C:49]3[CH2:50][CH2:51][O:52][C:53]4[CH:60]=[C:59]([CH:61]5[CH2:66][CH2:65][N:64]([C:16]([CH3:19])([CH3:15])[C:17]#[N:18])[CH2:63][CH2:62]5)[CH:58]=[CH:57][C:54]=4[C:55]=3[N:56]=2)=[N:45][CH:44]=[N:43]1)([CH3:41])[CH3:40]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(C(C)(C)C#N)C3)ccc1-2
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CCNCC3)ccc1-2
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CCN(C(C)(C)C#N)CC3)ccc1-2

Procedure:
The title compound was prepared by a similar procedure to 2-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-2-methyl-propionitrile using 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt to give 2-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-piperidin-1-yl}-2-methyl-propionitrile isolated as an orange oil (346 mg) as a roughly 1:1 mixture with 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene and was used without further purification. LCMS: RT=4.71 min, [M+H]+=463
Reaction SMILES: I[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:11][CH2:12][CH2:13][O:14][CH3:15])=[CH:4][CH:3]=1.[Li]CCCC.[CH3:21][C:22]([CH3:52])([CH2:48][CH2:49][CH2:50][CH3:51])[C:23]([NH:25][CH2:26][C@@H:27]1[O:31][C:30]([CH3:33])([CH3:32])[N:29]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C@H:28]1[CH2:41][C@H:42]([CH:46]=[O:47])[CH:43]([CH3:45])[CH3:44])=[O:24].[NH4+].[Cl-]>C1COCC1>[CH3:52][C:22]([CH3:21])([CH2:48][CH2:49][CH2:50][CH3:51])[C:23]([NH:25][CH2:26][C@@H:27]1[O:31][C:30]([CH3:32])([CH3:33])[N:29]([C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])[C@H:28]1[CH2:41][C@H:42]([CH:46]([OH:47])[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:11][CH2:12][CH2:13][O:14][CH3:15])=[CH:4][CH:3]=1)[CH:43]([CH3:44])[CH3:45])=[O:24]
Reactant: COCCCn1ncc2ccc(I)cc21
Reactant: CCCCC(C)(C)C(=O)NC[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1C[C@H](C=O)C(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCC(C)(C)C(=O)NC[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1C[C@@H](C(C)C)C(O)c1ccc2cnn(CCCOC)c2c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 19.9 %

Procedure:
To a solution of 6-iodo-1-(3-methoxypropyl)-1H-indazole (1.1 g, 3.48 mmol) in anhydrous THF (15 mL) at −78° C. under N2 was added dropwise n-BuLi (2.5 M in hexanes, 1.4 mL, 3.5 mmol). After stirring at −78° C. for 2 h, the reaction mixture was added through a cannula to a solution of (4S,5S)-tert-butyl 5-((2,2-dimethylhexanamido)methyl)-4-((S)-2-formyl-3-methylbutyl)-2,2-dimethyloxazolidine-3-carboxylate (160 mg, 0.35 mmol) in anhydrous THF (10 mL) at −78° C. The mixture was stirred at this temperature for 2 h, allowed to warm to rt and stirred overnight. Satd aq NH4Cl (25 mL) was added and the mixture was extracted with EtOAc (3×15 mL). The combined organic extracts were washed with brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel to give (4S,5S)-tert-butyl 5-((2,2-dimethylhexanamido)methyl)-4-((S)-2-(hydroxy(1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-3-methylbutyl)-2,2-dimethyloxazolidine-3-carboxylate (45 mg, 20% yield). MS: 645 (M++1)
Reaction SMILES: [BH4-].[Na+].O.[F:4][C:5]1([F:23])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]=2[C:6]1([F:22])[F:21]>C(O)(C)C>[F:4][C:5]1([F:23])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]([OH:16])[C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]=2[C:6]1([F:21])[F:22]
Reactant: O=C1c2ccccc2C(F)(F)C(F)(F)c2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: OC1c2ccccc2C(F)(F)C(F)(F)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 190 mg. (0.005 mole) of sodium borohydride in 1 ml. of water is added dropwise to a stirred solution of 830 mg. (0.00296 mole) of 10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cyclohepten-5-one in 10 ml. of isopropyl alcohol. After stirring the mixture for 3 hours at room temperature and 30 minutes at reflux, the isopropyl alcohol is evaporated under reduced pressure. The residue is partitioned between benzene and water and the benzene extract is separated, washed, and dried. Evaporation under reduced pressure leaves the product as the residual pale yellow oil. A sample for analysis is evaporatively distilled at 80° C. and 0.1 mm.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=4)[CH:15]=3)[N:10]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[C:29]([NH:36][C@@H:37]1[CH2:41][CH2:40][NH:39][CH2:38]1)([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>CS(C)=O>[CH3:22][N:20]1[CH:21]=[C:17]([C:14]2[CH:15]=[C:16]3[C:8]([C:6]4[N:7]=[C:2]([N:39]5[CH2:40][CH2:41][C@@H:37]([NH:36][C:29](=[O:30])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:38]5)[CH:3]=[CH:4][CH:5]=4)=[N:9][N:10]([CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][O:24]4)[C:11]3=[CH:12][N:13]=2)[CH:18]=[N:19]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: Cn1cc(-c2cc3c(-c4cccc(F)n4)nn(C4CCCCO4)c3cn2)cn1
Solvent: CS(C)=O
Product: Cn1cc(-c2cc3c(-c4cccc(N5CC[C@@H](NC(=O)OC(C)(C)C)C5)n4)nn(C4CCCCO4)c3cn2)cn1
Temperature: 95 °C
Reaction time: 72 h
Yield: 86.7 %

Procedure:
A mixture of 3-(6-fluoropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine (50.0 mg, 0.13 mmol) and (R)-3-(Boc-amino)pyrrolidine (246.1 mg, 1.32 mmol) in DMSO (2.6 mL) in a sealed tube was stirred at 95° C. under N2 for 3 days. The cooled reaction mixture was diluted into 1:1 ether-ethyl acetate. The organic layer was washed with 10% aqueous citric acid until pH ˜4 to 5, water and brine, dried over Na2SO4, filtered, and evaporated in vacuo. The crude product was purified using flash chromatography (Si-PPC gradient elution, solvent: 0-20% methanol in ethyl acetate) to give tert-butyl (3R)-1-(6-(5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)pyrrolidin-3-ylcarbamate as a foam (61.4 mg, 85.3%). 1H NMR (400 MHz, CDCl3) δ 1H NMR (400 MHz, CDCl3) δ 9.11 (s, 1H), 8.79 (s, 1H), 8.05 (broad s, 1H), 7.97 (s, 1H), 7.62-7.50 (m, 2H), 6.37 (d, J=7.9 Hz, 1H), 5.86 (dd, J=8.5, 2.2 Hz, 1H), 4.79 (s, 1H), 4.44 (s, 1H), 4.07-3.95 (m, 4H), 3.92-3.84 (m, 1H), 3.84-3.69 (m, 3H), 3.63-3.51 (m, 1H), 2.64-2.49 (m, 1H), 2.37 (td, J=13.6, 7.7 Hz, 1H), 2.17 (d, J=9.8 Hz, 2H), 2.11-2.01 (m, 1H), 1.89-1.68 (m, 3H), 1.46 (s, 9H). LC/MS: m/z 545.3 [M+1].
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH3:9].[P:10]([O:17]CC)([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:12]([O:11][P:10]([C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH3:9])(=[O:17])[O:14][CH2:15][CH3:16])[CH3:13]
Reactant: CCOP(OCC)OCC
Reactant: Cc1ccc(I)c(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Product: CCOP(=O)(OCC)c1ccc(C)cc1C
Temperature: 25 °C
Yield: 84 %

Procedure:
4-Iodo-m-xylene (4.31 mmol), triethyl phosphite (6.03 mmol) and palladium acetate (0.43 mmol) were mixed together in acetonitrile (10 ml), in a microwave tube. The vessel was sealed and placed in a microwave to react at 160° C., for 45 minutes. After cooling to room temperature, acetonitrile was removed. The crude material was purified by silica gel chromatography (eluent: stepwise gradient of ethyl acetate (0-30%) in petroleum ether) to yield Intermediate I.1 as an oil (84%). Intermediate 1.1 was characterized by the following spectroscopic data: 1H NMR (CDCl3, 400 MHz) δ (ppm) 1.32 (t, J=8.0 Hz, 6H), 2.35 (s, 3H), 2.53 (s, 3H), 4.07-4.14 (m, 4H), 7.07-7.08 (m, 2H), 7.77-7.83 (m, 1H); 31P NMR (CDCl3, 162 MHz) δ (ppm) 20.15 (s, 1P); and MS (ESI, EI+) m/z=243 (MH+).