Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH:22]=O)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:24][CH:25]([CH3:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][NH:24][CH:25]([CH3:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CC(C)N
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C=O)ccc3c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCOC(=O)CC(C)NCc1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
6-(trans-4-tert-butylcyclohexyloxy)-2-naphthaldehyde (30 mg, 0.097 mmol), ethyl 3-aminobutanoate (CAS no. 5303-65-1) (19 mg, 0.145 mmol), and acetic acid (17 mg, 0.291 mmol) were dissolved in dichloroethane (2 mL). The mixture was stirred at r.t. for 10 min under nitrogen atmosphere. Then NaBH(OAc)3 (41 mg, 0.194 mmol) was added to the mixture and the mixture was stirred at r.t. for 15 h. Then saturated NaHCO3 was added to the mixture to adjust the pH to 8. The mixture was extracted with ethyl acetate and the organic layer was purified by silica gel column chromatography using dichloromethane:methanol 10:1 to give produce ethyl 3-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)butanoate (40 mg, 88%) as a slight yellow solid. ESI-MS: 426.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.70-7.65 (m, 3H), 7.41 (d, 1H), 7.13-7.09 (m, 2H), 4.28-4.23 (m, 1H), 4.12 (q, 2H), 3.98-3.88 (m, 2H), 3.22-3.18 (m, 1H), 2.53-2.42 (m, 2H), 2.28-2.25 (m, 2H), 1.90-1.87 (m, 2H), 1.45-1.42 (m, 2H), 1.26-1.09 (m, 9H), 0.90 (s, 9H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:8]=1[CH2:9][OH:10].C(N(CC)CC)C>ClCCl>[Cl:6][C:7]1[CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:12]=[CH:11][C:8]=1[CH2:9][O:10][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccc(C(F)(F)F)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccc(C(F)(F)F)cc1Cl
Reaction time: 0.5 h

Procedure:
Methanesulfonyl chloride (1.1 ml) was added dropwise to a solution of 2-chloro-4-(trifluoromethyl)benzyl alcohol (2.64 g) and anhydrous triethylamine (2.3 ml) in anhydrous dichloromethane (30 ml) in a nitrogen stream under ice-cooling and the mixture was stirred for 30 minutes under the same conditions. The reaction mixture was successively washed with water, aqueous sodium hydrogencarbonate, and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate. The filtrate was concentrated to give 2-chloro-1-((methanesulfonyloxy)methyl)-4-(trifluoromethyl)benzene as white crystals (3.62 g).
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[C:18]([OH:25])[CH:17]=1.C(=O)(O)[O-].[Na+].[CH2:31](I)[CH3:32]>CN(C)C=O>[CH2:31]([O:21][C:20](=[O:22])[C:19]1[CH:23]=[CH:24][C:16]([O:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([OH:8])[C:2]=2[OH:1])=[CH:17][C:18]=1[OH:25])[CH3:32]
Reactant: O=C(O)c1ccc(OCCCCCCc2cccc(O)c2O)cc1O
Reactant: CCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCCCCCCc2cccc(O)c2O)cc1O
Reaction time: 6 h
Yield: 74 %

Procedure:
A mixture of 1.0 g (2.9 mmole) of 4-[6-(2,3-dihydroxyphenyl)hexyloxy]-2-hydroxybenzoic acid, 0.295 g (3.5 mmole) of sodium bicarbonate and 2.4 mL (29 mmole) of ethyl iodide in 10 ml of anhydrous dimethylformamide was stirred at 50° for 6 hours. The solvent was removed on the oil pump and the residue was treated with sodium bicarbonate solution. The product was extracted with ethyl acetate and the dried extract was concentrated at reduced pressure to a solid. Recrystallization from ether-hexane gave 0.8 g, mp 63°-68°, (74% yield) of 4-[6-(2,3-dihydroxyphenyl)hexyloxy]-2-hydroxybenzoic acid ethyl ester.
Reaction SMILES: [CH:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC([NH:23][CH2:24][C:25]1[CH:26]=[C:27]([CH2:33][CH:34]([O:40][CH:41]([CH3:43])[CH3:42])[C:35]([O:37]CC)=[O:36])[CH:28]=[CH:29][C:30]=1[O:31][CH3:32])=O)(C)(C)C>>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH:23][CH2:24][C:25]3[CH:26]=[C:27]([CH2:33][CH:34]([O:40][CH:41]([CH3:43])[CH3:42])[C:35]([OH:37])=[O:36])[CH:28]=[CH:29][C:30]=3[O:31][CH3:32])=[O:13])=[CH:14][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1ccc(C2CCCCC2)cc1
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CNC(=O)OC(C)(C)C)c1)OC(C)C
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1CNC(=O)c1ccc(C2CCCCC2)cc1

Procedure:
Using 4-cyclohexylbenzoic acid and ethyl 3-[3-([(tert-butoxycarbonyl)amino]methyl)-4-methoxyphenyl)-2-isopropoxypropanoate, 3-(3-[(4-cyclohexylbenzoyl)amino)methyl-4-methoxyphenyl)-2-isopropoxypropanoic acid was obtained in the same method as in Example 38).
Reaction SMILES: Br[CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[NH:12]1[CH:16]=[CH:15][N:14]=[CH:13]1.C(C(CC)(CC)CN)C.C(OCC)(=O)C>O>[N:12]1([CH:2]([CH3:11])[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:4])[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: c1c[nH]cn1
Reactant: CC(Br)C(=O)c1ccccc1
Agent: CCC(CC)(CC)CN
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C(=O)c1ccccc1)n1ccnc1
Temperature: 25 °C
Yield: 65 %

Procedure:
A mixture of 2-bromopropiophenone (21.3 g, 0.1M), imidazole (20.4 g, 0.3M), triethylethylamine (30.3 g, 0.3M) and ethyl acetate (300 ml) was refluxed overnight, cooled to room temperature and treated with water. The organic phase was separated, dried over MgSO4 and evaporated to give 2-(imidazol-1-yl)propiophenone as a viscous oil (12.95 g,
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3[C:13]([O:29][CH3:30])=[N:14][NH:15][C:16]=3[NH:17][S:18]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:11][C:6]=2[O:5][CH2:4]1.[CH3:31][O:32][CH2:33]Br.[Cl-].[NH4+]>O1CCCC1>[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3[C:13]([O:29][CH3:30])=[N:14][NH:15][C:16]=3[N:17]([CH2:31][O:32][CH3:33])[S:18]([CH2:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)(=[O:20])=[O:19])=[CH:11][C:6]=2[O:5][CH2:4]1
Reactant: COCBr
Reactant: COc1n[nH]c(NS(=O)(=O)CCc2ccccc2)c1-c1ccc2c(c1)OCO2
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCN(c1[nH]nc(OC)c1-c1ccc2c(c1)OCO2)S(=O)(=O)CCc1ccccc1
Reaction time: 0.17 h

Procedure:
Sodium hydride (60% dispersion in oil, 5 mg) was added at room temperature under an atmosphere of nitrogen to a solution of N-[4-(1,3-benzodioxol-5-yl)-3-methoxy-1H-pyrazol-5-yl]-2-phenyl-1-ethanesulfonamide (Preparation 56) in anhydrous tetrahydrofuran (2.5 ml). After 10 minutes, bromomethyl methyl ether (12 μl) was added and the reaction was stirred overnight. An aqueous saturated solution of ammonium chloride (4 ml) was added and the mixture was extracted with ethyl acetate (3×6 ml). The combined organic fractions were washed with brine (6 ml), dried over sodium sulfate and concentrated under reduced pressure. The oily residue was purified by column chromatography (Sep-Pak)™ eluted with hexane:ethyl acetate (4:1) then with hexane:ethyl acetate (1:1) to yield the title compound as a white solid (40 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:44])([CH3:43])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH2:40][NH2:41])=[CH:30][CH:29]=2)[C:17]1=[O:42])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C([O-])=O.[N-:52]=[C:53]=[O:54]>>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:44])([CH3:43])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH2:40][NH:41][C:53]([NH2:52])=[O:54])=[CH:32][CH:33]=2)[C:17]1=[O:42])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3CN)cc2)C1=O
Reactant: [N-]=C=O
Agent: O=C([O-])C(F)(F)F
Product: CC(C)(NC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3CNC(N)=O)cc2)C1=O

Procedure:
Prepared from 2-benzyloxycarbonylamino-2-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-(aminomethyl)[1,1'-biphenyl]-4-yl]-methyl]-1H-benzazepin-3(R)-yl]propanamide, trifluoroacetate (Example 36, Step A) and trimefflylsilyl isocyanate according to the procedure described in Example 37, Step A. 1H NMR (200 MHz, CD3OD): δ 1.40 (s, 6H), 1.82 (m, 1H), 2.15-2.60 (m, 3H), 4.12 (s, 2H), 4.32 (m, 1H), 4.85 (d, 15 Hz, 1H), 5.00 (s, 2H), 5.32 (d, 15 Hz, 1H), 7.05-7.43 (m, 17H). FAB-MS: calculated for C37H39N5O5 633; found 644(M+H, 100%).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.I[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O[Na])(C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C(C)=CC=CC=1>[C:15]1([C:10]2[C:11]3[NH:12][C:13]4[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=4)[C:6]=3[CH:7]=[CH:8][CH:9]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: Ic1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)O[Na]
Solvent: Cc1ccccc1C
Product: c1ccc(-c2cccc3c2[nH]c2ccccc23)cc1
Yield: 84.1 %

Procedure:
Ina stream of argon, 670 g of carbazole, 850 kg of iodobenzene, 20 L of xylene, 460 g of t-BuONa, and palladium acetate (Pd(OAc)2) were added, and then the mixture was refluxed for 8 hours. Impurities were filtrated, and then the filtrate was concentrated under reduced pressure and washed with hexane. After that, the washed product was dried. As a result, 820 g of phenylcarbazole were obtained as a white powder. In a stream of argon, 24 g of phenylcarbazole, 8.3 g of potassium iodide, 10.7 g of potassium iodate, 500 mL of ethanol, and 8 mL of sulfuric acid were added into a 1,000-mL three-necked flask, and then the mixture was stirred at 75° C. for 2 hours. After that, the reaction product was injected into ice water, and then the mixture was extracted with ethyl acetate and water. After having been washed with water, the extract was subjected to column chromatography with silica gel. As a result, 67 g of a white powder were obtained. A reaction was performed in the same manner as in the synthesis of Intermediate 1 except that 9-phenylcarbazole was used instead of 4-bromobiphenyl. As a result, 22.3 g of a white powder were obtained. FD-MS analysis identified the powder as Intermediate 11.
Reaction SMILES: [H][H].[C:3]1([CH:9]([CH3:11])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C1C=CC=CC=1>[C:3]1([CH:9]([CH3:11])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:4]=[CH:3][CH3:8]
Reactant: [H][H]
Solvent: CC(C)c1ccccc1
Solvent: c1ccccc1
Product: C=CC

Procedure:
A stainless steel reaction tube with a glass-coated inside was filled with 0.1 g of a carrier molded into 0.5 to 1.0 mm in size, and a pretreatment was carried out in a stream of gaseous hydrogen of 80 ml/min in rate for three hours. 1 μl of cumene was injected into the tube at a reaction temperature of 200° C. to obtain the cracking ratios (mol %) of cumene to propylene and benzene.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.C([O:16]P(OCCCC)(OCCCC)=O)CCC>OS(O)(=O)=O>[C:2]1([CH:1]=[O:16])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2ccccc12
Reactant: CCCCOP(=O)(OCCCC)OCCCC
Agent: O=S(=O)(O)O
Product: O=Cc1cccc2ccccc12
Yield: 25.7 %

Procedure:
The same reaction was tried in a modified cell, without the crank 23. 2 g (14 mmol) of 1-methylnaphthalene in 3 g of tributylphosphate was allowed to react for 40 hours with electrochemically produced Co(III) sulphate at 40°-45° C. The electrolyte solution was composed of 0.12M Co(II) sulphate in 2M H2SO4. The current was 200 mA. The organic material isolated from this run was placed on a silica gel column, which was eluted with a solution of 5% ether in petroleum ether (bp=60°-80° C.). The initial band consisted of 860 mg (6 mmol, 43%) of starting material. The second band yielded 447 mg (2.9 mmol) of 1-naphthaldehyde. The aldehyde yield was 36% based on consumed starting material. The aldehyde yield was 36% based on consumed starting material. The infrared spectrum of the product was identical to that of an authentic sample.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:28]=[CH:27][C:13]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)=[O:15])=[CH:12][C:11]=2[NH:29][C:30]2[C:31]3[CH:39]=[CH:38][CH:37]=[N:36][C:32]=3[N:33]=[CH:34][N:35]=2)=[CH:5][CH:4]=1.C(C1C=CC2C(NC3C=C(C=CC=3SC3C=CC(OC)=CC=3)C(NC3C=CC(C)=CC=3)=O)=NC=NC=2N=1)(C)C>>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:28]=[CH:27][C:13]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:25])[F:26])[CH:18]=3)=[O:15])=[CH:12][C:11]=2[NH:29][C:30]2[C:31]3[CH:39]=[CH:38][CH:37]=[N:36][C:32]=3[N:33]=[CH:34][N:35]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Sc2ccc(C(=O)Nc3cccc(C(F)(F)F)c3)cc2Nc2ncnc3ncccc23)cc1
Agent: COc1ccc(Sc2ccc(C(=O)Nc3ccc(C)cc3)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1ccc(Sc2ccc(O)cc2)c(Nc2ncnc3ncccc23)c1

Procedure:
The product from Example 260C was reacted according to the procedure from Example 150 substituting the product from Example 260C for the product from Example 138 to provide a residue which was purified by trituration from methanol to provide the title compound as an off white solid (33.3 mg, 90%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 11.74 (s, 1 H), 10.54 (s, 1 H), 10.01 (s, 1 H), 9.19 (s, 1 H), 9.11 (d, J=7.35 Hz, 1 H), 8.90 (s, 1 H), 8.19 (s, 1 H), 7.86-8.08 (m, 4 H), 7.60 (t, J=7.91 Hz, 1 H), 7.46 (d, J=7.72 Hz, 1 H), 7.24-7.38 (m, 2 H), 7.03 (d, J=8.46 Hz, 1 H), 6.73-6.91 (m, 2 H); MS (ESI+) m/z 534.1 (M+H)+, (ESI−) m/z 532.2 (M−H)−.
Reaction SMILES: [CH2:1]([CH:3]([CH2:7][CH3:8])[C:4]([NH2:6])=[O:5])[CH3:2].[C:9]([O:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=O)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:20][CH:19]=1)(=[O:14])[CH2:10][C:11]([O-:13])=[O:12]>C(O)C.[C].[Pd]>[CH2:1]([CH:3]([CH2:7][CH3:8])[C:4]([NH2:6])=[O:5])[CH3:2].[C:9]([O:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:20][CH:19]=1)(=[O:14])[CH2:10][C:11]([O-:13])=[O:12]
Reactant: CCCCCCCC(=O)c1ccc(CCOC(=O)CC(=O)[O-])cc1
Agent: [Pd]
Agent: CCC(CC)C(N)=O
Solvent: CCO
Product: CCCCCCCCc1ccc(CCOC(=O)CC(=O)[O-])cc1

Procedure:
Diethyl acetamide-2-(4-octanoyl phenyl)ethyl malonate prepared in the step J (923 g) was stirred in ethanol (10 L) under atmosphere of hydrogen in the presence of 5% palladium carbon (138 g) overnight. The catalyst was removed by filtration, and the filtrate was concentrated. The residue was recrystallized from hexane to obtain diethyl acetamide-2(4-octyl phenyl)ethyl malonate (670 g) in the form of colorless crystal.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[O:12][N:11]=[C:10]2[C:15]2[C:19]([NH:20][CH2:21][CH2:22][O:23]C)=[N:18][O:17][N:16]=2)[CH:5]=[CH:6][C:7]=1[F:8].B(Br)(Br)Br>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[O:12][N:11]=[C:10]2[C:15]2[C:19]([NH:20][CH2:21][CH2:22][OH:23])=[N:18][O:17][N:16]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=c1onc(-c2nonc2NCCO)n1-c1ccc(F)c(Br)c1
Temperature: -10 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
4-(3-Bromo-4-fluorophenyl)-3-{4-[(2-methoxyethyl)amino]-1,2,5-oxadiazol-3-yl}-1,2,4-oxadiazol-5(4H)-one (78.4 g, 0.196 mol) was dissolved in dichloromethane (600 mL). At −67° C. boron tribromide (37 mL, 0.392 mol) was added over 15 min. The reaction was warmed up to −10° C. in 30 min. LCMS indicated reaction completed. The reaction was stirred at room temperature for 1 hour. At 0-5° C. the reaction was slowly quenched with saturated sodium bicarbonate solution (1.5 L) over 30 min. The reaction temperature rose to 25° C. The reaction was extracted with ethyl acetate (2×500 mL, first extraction organic layer is on the bottom and second extraction organic lager is on the top). The combined organic layers were dried over sodium sulfate and concentrated to give the desired product (75 g, 99%) as a crude brown solid. LCMS for C12H10BrFN5O4 (M+H)+: m/z=386.0, 388.0. 1H NMR (400 MHz, DMSO-d6): δ 8.08 (dd, J=6.2, 2.5 Hz, 1H), 7.70 (m, 1H), 7.68 (t, J=8.7 Hz, 1H), 6.33 (t, J=5.6 Hz, 1H), 4.85 (t, J=5.0 Hz, 1H), 3.56 (dd, J=10.6, 5.6 Hz, 2H), 3.29 (dd, J=11.5, 5.9 Hz, 2H).
Reaction SMILES: C([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][NH:14][C:15](=[O:16])[C:10]=2[CH2:9]1)C1C=CC=CC=1.C(N(CC)CC)C.C(O)=O>CO.[OH-].[Pd+2].[OH-]>[N:12]1[C:11]2[CH2:17][CH2:18][NH:8][CH2:9][C:10]=2[C:15](=[O:16])[NH:14][CH:13]=1
Reactant: O=c1[nH]cnc2c1CN(Cc1ccccc1)CC2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O=CO
Product: O=c1[nH]cnc2c1CNCC2
Temperature: 60 °C

Procedure:
A mixture of 6-benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one (Intermediate 1, 18.0 g, 0.0738 mol), triethylamine (48 mL, 0.34 mol), palladium hydroxide (10 g, 0.07 mol) in methanol (242 mL) was heated to 60° C. Formic acid (7.6 mL, 0.20 mol) was added dropwise to the mixture over a 15 minute period. The mixture was heated at 65° C. for three hours, allowed to cool, and filtered over Celite. The filtrate was concentrated under vacuum to yield the title compound as a yellow solid which was used as such for the next step (9.62 g, 77.6%). MS: 152.2 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21](Cl)=[N:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][O-:24].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([O:24][CH3:23])=[N:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2nccnc2Cl)CC1
Agent: [Na+]
Solvent: CO
Product: COc1nccnc1NCC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
4[(3-Chloro-pyrazin-2-ylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (3.0 g, 0.0092 mol) and 0.5M sodium methoxide in methanol (40 mL) were heated under nitrogen at 75° C. for 18 h. The reaction was concentrated in vacuo, diluted with methylene chloride (100 mL) and washed with water (pH=9, adjusted with NaOH). The organic extract was dried over sodium sulfate filtered and concentrated to give the title compound. M.S. (M+1): 323.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1.BrN1C(=O)CCC1=O.C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])O.[Na+]>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][N:3]=1
Reactant: OCc1ccnc(Br)c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)N1Br
Solvent: c1ccccc1
Product: O=Cc1ccnc(Br)c1
Yield: 87.6 %

Procedure:
A mixture of 21.0 g of 2-bromo-4-pyridinemethanol, 32.3 g of N-bromosuccinimide and 23.1 g of anhydrous sodium carbonate was suspended in 600 ml of benzene, and heated under reflux (bath temperature 110° to 120° C.) for 4 hours. The mixture was cooled over an ice bath, and a saturated aqueous solution of sodium hydrogen carbonate was added to adjust its pH to 9 to 10. The insoluble matter was removed by filtration (by washing with ethyl acetate). The organic layer was separated, washed with a 10% aqueous solution of sodium thiosulfate and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. The solvent was evaporated to give 18.2 g (yield 88%) of 2-bromo-4-pyridinecarboxaldehyde.
Reaction SMILES: [C:1]([OH:6])(=O)[CH2:2][CH2:3][CH3:4].[Cl:7][S:8]([N:11]=C=O)(=[O:10])=[O:9]>C1C=CC=CC=1>[C:1]([NH:11][S:8]([Cl:7])(=[O:10])=[O:9])(=[O:6])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)O
Reactant: O=C=NS(=O)(=O)Cl
Solvent: c1ccccc1
Product: CCCC(=O)NS(=O)(=O)Cl
Yield: 99.7 %

Procedure:
n-Butanoic acid (0.881 g, 10 mmol) was added slowly dropwise to chlorosulfonyl isocyanate (1.42 g, 10 mmol), with ice/water bath cooling as required to maintain gentle gas evolution. After the addition was complete, the residue was taken up in benzene (10 mL) and the mixture concentrated in vacuo to provide the title compound (1.85 g, quantitative) as a crystalline, hygroscopic solid.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([NH:24][C:25]4[C:30]([N+:31]([O-])=O)=[CH:29][N:28]=[C:27]5[N:34]([S:37]([C:40]6[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=6)(=[O:39])=[O:38])[CH:35]=[CH:36][C:26]=45)[CH2:19]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C1COCC1>[Pd].CCO>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([NH:24][C:25]4[C:30]([NH2:31])=[CH:29][N:28]=[C:27]5[N:34]([S:37]([C:40]6[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=6)(=[O:39])=[O:38])[CH:35]=[CH:36][C:26]=45)[CH2:19]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)N1CCCC(Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCCN(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Temperature: 50 °C
Reaction time: 6 h
Yield: 85.1 %

Procedure:
A suspension of 3-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (7.09 g, 11.4 mmol) and palladium on carbon (2.1 g, 10%, wet, Degussa, E101 NE/W) in a 4:1 mixture of THF and EtOH (100 ml) was stirred under a hydrogen atmosphere (2 balloons) at 50° C. for 6 h. The reaction mixture was cooled to 25° C. and was filtered through Celite. The Celite was washed with THF (2×25 ml), and the combined filtrate and washings were concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (gradient: 0 to 7% CH3OH in CH2Cl2) gave 3-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (5.76 g, 85%, purple foam) still containing some impurities. This material was used in the next step below without additional purification or characterization.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=2)[NH:8][N:7]=1)=[O:5])[CH3:2].N1C=CN=C1.[CH3:21][C:22]([Si:25](Cl)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:24])[CH3:23].C(=O)([O-])O.[Na+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][Si:25]([C:22]([CH3:24])([CH3:23])[CH3:21])([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:12][CH:13]=2)[NH:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1n[nH]c2cc(O)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCOC(=O)c1n[nH]c2cc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl6-hydroxyindazole-3-carboxylate (1.457 g) which can be prepared according to the method described in Reference example 17, etc. was dissolved in dehydrated DMF (15.6 mL; manufactured by Kanto Chemical Co., Inc.), added with imidazole (1.425 g; manufactured by Tokyo Chemical Industry, Co., Ltd.) and TBDPSCl (4.06 mL), followed by stirring overnight at room temperature. The reaction solution was poured to a saturated aqueous solution of sodium hydrogen carbonate and extracted twice with ethyl acetate. The organic layer was washed with brine and insoluble matters were filtered using Celite. The organic layer was washed twice with water and dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by column chromatography (“COLUMN-A”; n-hexane:ethyl acetate=81:19→60:40) to obtain the title compound (1.467 g).