Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:8]([CH:9]=[C:10]3[C:15]=1[N:14]=[C:13]([C:16]1[N:17]([C:25]4[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][N:26]=4)[N:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[O:12][C:11]3=[O:32])=[N:7][CH:6]=[CH:5][N:4]=2.[CH:33]1([CH2:36][NH2:37])[CH2:35][CH2:34]1>C1COCC1>[CH:33]1([CH2:36][NH:37][C:11]([C:10]2[CH:9]=[C:8]3[C:3](=[C:2]([Cl:1])[C:15]=2[NH:14][C:13]([C:16]2[N:17]([C:25]4[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][N:26]=4)[N:18]=[C:19]([C:21]([F:23])([F:24])[F:22])[CH:20]=2)=[O:12])[N:4]=[CH:5][CH:6]=[N:7]3)=[O:32])[CH2:35][CH2:34]1
Reactant: O=c1oc(-c2cc(C(F)(F)F)nn2-c2ncccc2Cl)nc2c(Cl)c3nccnc3cc12
Reactant: NCC1CC1
Solvent: C1CCOC1
Product: O=C(NCC1CC1)c1cc2nccnc2c(Cl)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reaction time: 8 h
Yield: 74 %

Procedure:
0.55 g (1.15 mol) 9-chloro-2-[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-3-oxa-1,5,8-triaza-anthracen-4-one and 0.5 ml C-cyclopropylmethylamine is dissolved in 15 ml THF and stirred for 8 hours. After evaporation, the residue is crystallised in diethyl ether to give 0.47 g (74%) of the title compound. m.p.: 180-183° C.
Reaction SMILES: C(OC([N:8]1[CH2:22][CH2:21][C:12]2=[C:13](Cl)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=O)(C)(C)C.FC(F)(F)C(O)=O.[NH:30]1[CH2:33][CH:32]([C:34]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)=[O:35])[CH2:31]1>>[CH3:43][O:42][C:39]1[CH:40]=[CH:41][C:36]([C:34]([CH:32]2[CH2:31][N:30]([C:13]3[N:14]4[C:18]([N:19]=[C:11]5[CH2:10][CH2:9][NH:8][CH2:22][CH2:21][C:12]=35)=[CH:17][CH:16]=[N:15]4)[CH2:33]2)=[O:35])=[CH:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(Cl)c2CC1
Reactant: COc1ccc(C(=O)C2CNC2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(=O)C2CN(c3c4c(nc5ccnn35)CCNCC4)C2)cc1

Procedure:
The product was prepared using 10-chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester in route 1 (step e and f), in step e (route 1) azetidin-3-yl-(4-methoxy-phenyl)-methanone trifluoroacetate was used as the amine.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>>[O:8]=[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:15]([C:11]1[S:10][CH:14]=[CH:13][CH:12]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)Cc1cccs1
Product: CCOC(=O)C(C(=O)c1ccccc1)c1cccs1

Procedure:
From benzoyl chloride and ethyl 2-(thiophene-2-yl)acetate, the title compound was prepared using a similar method to the one described in Example 1.14, Step A to give a clear oil. 1H NMR (400 M Hz, CDCl3) δ ppm 1.22 (t, J=7.07 Hz, 3H), 4.16-4.26 (m, 2H), 5.88 (s, 1H), 6.96-7.02 (m, 1H), 7.07 (d, J=3.03 Hz, 1H), 7.31 (dd, J=5.18, 1.14 Hz, 1H), 7.46 (t, J=7.71 Hz, 2H), 7.57 (t, J=7.33 Hz, 1H), 7.98-8.02 (m, 2H).
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])C.[K+].[CH3:7][O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][C:14]2=O.[Cl-].[NH4+]>O1CCCC1>[C:5]1(=[C:14]2[C:15]3[C:10](=[C:9]([O:8][CH3:7])[CH:18]=[CH:17][CH:16]=3)[CH2:11][CH2:12][CH2:13]2)[CH2:2][CH2:1]1
Reactant: CC(C)(C)[O-]
Reactant: COc1cccc2c1CCCC2=O
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cccc2c1CCCC2=C1CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.6 %

Procedure:
Under ice-cooling, to an anhydrous tetrahydrofuran (200 ml) solution of (3-bromopropyl)triphenylphosphinium bromide (19.8 g), potassium t-butoxide (9.58 g) was added, followed by stirring at room temperature for 1.5 hours. To the reaction mixture, 5-methoxy-1-tetralone (5.0 g) was added, followed by stirring at room temperature for 5 hours. The reaction mixture was poured into a saturated aqueous ammonium chloride solution. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saturated saline, dried with anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to thereby obtain the title compound (5.66 g) having the following physical data.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[NH:8][C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[CH:22]1([CH2:27][CH2:28]Br)[CH2:26][CH2:25][CH:24]=[CH:23]1>>[CH:22]1([CH2:27][CH2:28][N:8]2[C:9]([C:10](=[O:19])[C:11]3[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:21])[NH:6][C:7]2=[O:20])[CH2:26][CH2:25][CH:24]=[CH:23]1
Reactant: Cc1cc(C)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: BrCCC1C=CCC1
Product: Cc1cc(C)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2CCC2C=CCC2)c1
Yield: 32.3 %

Procedure:
5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 2-(cyclopent-2-en-1-yl)ethyl bromide were reacted by the same method with example 40 to obtain the titled compound (123 mg).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:16][C:15]3[CH:17]=[C:18]([C:21]4[CH:22]=[C:23]([N+:28]([O-])=O)[C:24]([NH2:27])=[N:25][CH:26]=4)[CH:19]=[CH:20][C:14]=3[O:13][CH2:12][CH2:11]2)=[O:9])[CH2:4][CH2:3]1.C([O-])=O.[NH4+]>[Pd].C(O)C>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:16][C:15]3[CH:17]=[C:18]([C:21]4[CH:22]=[C:23]([NH2:28])[C:24]([NH2:27])=[N:25][CH:26]=4)[CH:19]=[CH:20][C:14]=3[O:13][CH2:12][CH2:11]2)=[O:9])[CH2:4][CH2:3]1
Reactant: CC1CCN(C(=O)N2CCOc3ccc(-c4cnc(N)c([N+](=O)[O-])c4)cc3C2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC1CCN(C(=O)N2CCOc3ccc(-c4cnc(N)c(N)c4)cc3C2)CC1
Yield: 73.2 %

Procedure:
To a slurry of 5-{-4-[(4-methylpiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}-3-nitropyridin-2-amine (1.0 g, 2.4 mmol), 10% Pd—C (0.1 g) and ethanol (15 mL) was added ammonium formate (1.5 g, 24 mmol) portionwise over 1 hour. The reaction mixture was stirred for an additional hour and the catalyst was removed by filtration. Concentration of the filtrate followed by purification by silica gel column chromatography (0-5% methanol in dichloromethane) provided 5-{4-[(4-methylpiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}pyridine-2,3-diamine (0.67 g, 72% yield) as a pale yellow foam. MS (EI) for C21H27N5O2: 382 (MH+)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=1.[N-:16]=[N+:17]=[N-:18].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[NH:18][N:17]=[N:16][N:15]=2)[CH:9]=1
Reactant: N#Cc1cccc(-c2ccccc2Br)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Brc1ccccc1-c1cccc(-c2nnn[nH]2)c1
Temperature: 90 °C

Procedure:
A mixture of 2′-bromo-biphenyl-3-carbonitrile (200 mg, 0.77 mmol), sodium azide (66 mg, 1.01 mmol) and triethylamine hydrochloride (139 mg, 1.01 mmol) in toluene (2 ml) was heated at 90° C. for 24 hours. A further portion of sodium azide (66 mg, 1.01 mmol) and triethylamine hydrochloride (139 mg, 1.01 mmol) was added and heated for a further 24 hours. After cooling, the mixture was extracted with water (3×2 ml). The combined extracts were acidified and the precipitate filtered off and dried. (163 mg, 70%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl[CH2:12][CH2:13][OH:14].C(=O)([O-])[O-].[K+].[K+].C>C(C(C)=O)C.CO>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:12][CH2:13][OH:14])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CO
Product: O=[N+]([O-])c1cccc(OCCO)c1
Reaction time: 8 h

Procedure:
A mixture of m-nitrophenol (28 g, 0.2 mole), 2-chloroethanol (53.6 ml, 0.8 mole), and potassium carbonate (110.4 g, 0.8 mole) in 300 ml methyl ethyl ketone was kept at reflux temperature with stirring overnight. The solid was filtered and dissolved in water. The filtrate was concentrated and some solid was crystallized from 2-propanol/isopropyl ether. This light-brown solid was collected and weighed 22.78 g(62%). The mother liquor was concentrated and redissolved in toluene/ethyl acetate and extracted with the above aqueous solution. The aqueous layer was further extracted with fresh toluene/ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, filtered, and concentrated to give a second crop of 6.46 g (17.6%). The second crop was dissolved in methanol, stirred with charcoal, filtered, evaporated, and crystallized from 2-propanol/isopropyl ether to give a pure sample. The sample was dried under vacuum at room temperature overnight, mp 85°-86° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([OH:20])=O)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[C:21]([C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1)#[N:22]>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:20])[NH:27][C:26]3[CH:28]=[CH:29][C:23]([C:21]#[N:22])=[CH:24][CH:25]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: N#Cc1ccc(N)cc1
Product: N#Cc1ccc(NC(=O)CC2CCc3cc(Br)cc4[nH]c(=O)c(=O)n2c34)cc1
Yield: 41 %

Procedure:
A procedure similar to that described in Example 52 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (170 mg, 0.5 mmol) and p-cyanoaniline (60 mg, 0.51 mmol) to give 90 mg of the title compound (41%): mp>270° C.; 1H NMR (270 MHz, DMSO-d6) δ12.06 (s, 1H), 10.44 (s, 1H), 7.77 (d, 2H, J=9.2 Hz), 7.74 (d, 2H, J=9.2 Hz), 7.23 (bs, 1H), 7.17 (bs, 1H), 5.18~5.26 (m, 1H), 3.03 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.83 (dm, 1H, J=17.1Hz), 2.65(d, 2H, J=7.6Hz),2.11 (dm, 1H, J=13.5Hz), 1.83~1.96 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[CH:15]1[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[Na].[Cl-].[NH4+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[CH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([OH:21])[CH2:16]1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: CC(C)(C)OC(=O)c1ccc(C2CCCC(=O)C2)c(Cl)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(C2CCCC(O)C2)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a mixture of tert-butyl 3-chloro-4-(3-oxocyclohexyl)benzoate in anhydrous methanol (50 mL) was added sodium borobydride (1.04 g, 27.40 mmol) at 0° C. The reaction mixture was stirred for 1 hour at 0° C., after which saturated ammonium chloride solution (10 mL) was added. All volatiles were evaporated under reduced pressure, and the residue was partitioned between ethyl acetate (200 mL) and water (20 mL). The organic phase was washed with brine (10 mL), dried over sodium sulfate, and filtered. Concentration under reduced pressure gave a residue which was purified by silica gel column chromatography using 0-40% ethyl acetate in hexanes as eluent to afford the title compound as colorless oil (2.24 g, 53%): 1H NMR (300 MHz, CDCl3) δ 7.94-7.92 (m, 1H), 7.84-7.79 (m, 1H), 7.32-7.27 (m, 1H), 3.85-3.69 (m, 1H), 3.16-3.03 (m, 1H), 2.19-2.04 (m, 2H), 1.96-1.77 (m, 2H), 1.63-1.18 (m, 14H); MS (ES+) m/z 255.2, 257.1 (M−55).
Reaction SMILES: C(O[C:4]([C:6]1[C:11]([NH:12][C:13]2[CH:14]=[N:15][CH:16]=[N:17][CH:18]=2)=[CH:10][CH:9]=[C:8]([CH3:19])[N:7]=1)=[O:5])C.[NH2:20][C:21]1[S:22][C:23]([CH3:26])=[CH:24][N:25]=1>>[CH3:26][C:23]1[S:22][C:21]([NH:20][C:4]([C:6]2[C:11]([NH:12][C:13]3[CH:18]=[N:17][CH:16]=[N:15][CH:14]=3)=[CH:10][CH:9]=[C:8]([CH3:19])[N:7]=2)=[O:5])=[N:25][CH:24]=1
Reactant: Cc1cnc(N)s1
Reactant: CCOC(=O)c1nc(C)ccc1Nc1cncnc1
Product: Cc1ccc(Nc2cncnc2)c(C(=O)Nc2ncc(C)s2)n1

Procedure:
The title compound, was prepared in accordance with the general method of Example 78, step 2 from 6-Methyl-3-(pyrimidin-5-ylamino)-pyridine-2-carboxylic acid ethyl ester and 2-Amino-5-methylthiazole to yield the final compound as a yellow crystalline solid, MS (ISP): m/e=327.1 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:22]([OH:24])=O)[CH2:13][S:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(C)C(C)=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[C:22](=[O:24])[NH:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[S:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1SC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: Cc1ccccc1C
Product: O=C(NC1CSc2ccccc2NC1=O)OCc1ccccc1
Yield: 71.7 %

Procedure:
17.8 g of N-benzyloxycarbonyl-S-(2-aminophenyl)cysteine was dissolved in 250 ml of xylene and the resulting solution was heated under reflux for 4 hours. After the solvent was distilled off under reduced pressure, ether was added to the residue. The precipitated crystals were separated to obtain 12.1 g of the desired compound, or 3-benzyloxycarbonylamino-2,3-dihydro-1,5-benzothiazepin-4(5H)-one. Its melting point was 149°-151° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[C:23]1([C:29]2[CH:33]=[C:32]([NH:34][C:35](=O)[O:36]C3C=CC=CC=3)[O:31][N:30]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([NH:19][C:35]([NH:34][C:32]2[O:31][N:30]=[C:29]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:33]=2)=[O:36])[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: O=C(Nc1cc(-c2ccccc2)no1)Oc1ccccc1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(-c5ccccc5)no4)c3)c2cc1OC
Yield: 44 %

Procedure:
The title compound was prepared according to the procedure described in Example 113C, by using compound 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (90 mg, 0.3 mmol) and compound phenyl 3-phenylisoxazol-5-ylcarbamate from the previous step (126 mg, 0.45 mmol) to afford 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-phenylisoxazol-5-yl)urea as a white solid (63.34 mg, 44%). 1H NMR (300 MHz, DMSO-d6) δ 10.4 (s, 1H), 9.14 (s, 1H), 8.5 (s, 1H), 7.83 (d, 2H), 7.83-7.48 (m, 7H), 7.42 (d, 1H), 7.00 (d, 1H), 6.56 (s, 1H), 4.00 (s, 6H); LC-MS (ESI) m/z 484 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)([CH3:3])=[CH2:2].[Cl:10]N1C(=O)CCC1=O.C(Cl)(Cl)(Cl)Cl>CCCCCC>[Cl:10][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)=[CH2:3]
Reactant: C=C(C)c1ccccn1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCCCCC
Solvent: ClC(Cl)(Cl)Cl
Product: C=C(CCl)c1ccccn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 19.4 %

Procedure:
A mixture of 4.0 g of 2-isopropenylpyridine, 4.5 g of N-chlorosuccinimide and 8 ml of carbon tetrachloride was stirred at 150° to 160° C. for 20 minutes. After the reaction mixture was cooled to room temperature, n-hexane was added thereto to remove the insoluble matter through filtration. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluted with n-hexane-ethyl acetate 20:1) to obtain 1.0 g of the objective compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:19]3[N:18]=[N:17][N:16]([CH2:20][C:21]4[C:29]5[C:24](=[N:25][CH:26]=[CH:27][CH:28]=5)[NH:23][N:22]=4)[C:15]=3[CH:14]=[CH:13][C:12]=2[Cl:30])[CH:9]=1)[C:5]#N.[H-].[H-].[H-].[H-].[Li+].[Al+3].C1C[O:40]CC1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:19]3[N:18]=[N:17][N:16]([CH2:20][C:21]4[C:29]5[C:24](=[N:25][CH:26]=[CH:27][CH:28]=5)[NH:23][N:22]=4)[C:15]=3[CH:14]=[CH:13][C:12]=2[Cl:30])[CH:9]=1)[CH:5]=[O:40]
Reactant: C1CCOC1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3c2nnn3Cc2n[nH]c3ncccc23)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: O=Cc1cc(Cl)cc(Oc2c(Cl)ccc3c2nnn3Cc2n[nH]c3ncccc23)c1
Reaction time: 0.5 h

Procedure:
To 3-chloro-5-{[5-chloro-1-(1H-pyrazolo[3,4-b]pyridin-3-ylmethyl)-1H-1,2,3-benzotriazol-4-yl]oxy}benzonitrile (10 mg, 0.023 mmol) dissolved in dry THF (0.5 mL) at 0° C. was added LAH solution 1M in THF (0.046 mL, 0.046 mmol). After 30 minutes, the reaction was quenched with EtOAc (2 mL) at 0° C., followed by addition of saturated aqueous Na2SO4 (0.25 mL), and then after 5 minutes by addition of water (0.5 mL). This mixture was allowed to stir for 5 minutes after which time solid Na2SO4 was added to the reaction mixture. The dried mixture was then filtered and solvent removed under reduced pressure. The resulting residue was purified by reverse phase chromatography eluting with 30-95% MeCN/H2O+0.1% TFA. Product fractions were lyophilized to afford the title compound. 1H NMR (DMSO-d6) δ 9.90 (s, 1H), 8.52 (d, J=3.5 Hz), 8.10 (d, J=7.5 Hz), 7.90 (d, J=8.9 Hz, 1H), 7.80 (d, J=8.9 Hz, 1H), 7.72 (m, 1H), 7.30 (m, 1H), 7.20 (dd, J=8.1 Hz, J=4.6 Hz, 1H), 6.40 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH2:16][CH:17]=[C:18]([Cl:20])[CH3:19])([CH2:13][CH2:14][CH3:15])[C:8]2=[O:12])=[CH:4][C:3]=1[CH:21]([CH2:25][C:26]([OH:28])=[O:27])C(O)=O.Cl>[Cu].N1C2C(=CC=CC=2)C=CC=1>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH2:16][CH:17]=[C:18]([Cl:20])[CH3:19])([CH2:13][CH2:14][CH3:15])[C:8]2=[O:12])=[CH:4][C:3]=1[CH2:21][CH2:25][C:26]([OH:28])=[O:27]
Reactant: CCCC1(CC=C(C)Cl)Cc2cc(C(CC(=O)O)C(=O)O)c(Cl)c(Cl)c2C1=O
Agent: [Cu]
Agent: Cl
Solvent: c1ccc2ncccc2c1
Product: CCCC1(CC=C(C)Cl)Cc2cc(CCC(=O)O)c(Cl)c(Cl)c2C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.3 %

Procedure:
[6,7-Dichloro-2-(3-chloro-2-butenyl)-2,3-dihydro-1-oxo-2-propyl-1H-inden-5-yl]succinic acid (7.9 g, 0.01764 mole) was combined with quinoline (70 ml) and copper powder (2.9 g), stirred under N2 at 130°-135° C. (internal) in an oil bath for 1/2 hour. The mixture was poured into ice water, acidified with hydrochloric acid and extracted with methylene chloride. The organic extracts were washed with dilute HCl, H2O, dried over MgSO4 and concentrated under vacuum. The residue was chromatographed on silica eluting with methylene chloride, tetrahydrofuran, acetic acid (100:1:1) to obtain 7 g of the product as an oil.
Reaction SMILES: [CH:1]([C:3]1[CH:29]=[CH:28][C:6]([C:7]([NH:9][C:10]2[CH:27]=[CH:26][C:13]([C:14]([N:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18][CH2:17]3)=[O:15])=[CH:12][CH:11]=2)=[O:8])=[CH:5][CH:4]=1)=[O:2].[BH4-].[Na+].O>CO>[OH:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[CH:27]=[CH:26][C:13]([C:14]([N:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18][CH2:17]3)=[O:15])=[CH:12][CH:11]=2)=[O:8])=[CH:28][CH:29]=1
Reactant: O=Cc1ccc(C(=O)Nc2ccc(C(=O)N3CCCc4ccccc43)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(Nc1ccc(C(=O)N2CCCc3ccccc32)cc1)c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.7 %

Procedure:
To a solution of 1-[4-(4-formylbenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline (0.3 g) in methanol (10 ml) is added gradually sodium borohydride (59 mg) under ice-cooling and the mixture is stirred at room temperature for 2 hours. Water is added to the mixture and the solvent is distilled off under reduced pressure. The resulting residue is extracted with dichloromethane, washed with water, and dried over magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=50:1), and recrystallized from methanol to give 1-[4-(4-hydroxymethylbenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline (165 mg) as white powder, m.p. 224.5-225.5° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[NH2:6].[Cl:16][CH2:17][CH2:18][C:19]([N:21]=[C:22]=[O:23])=[O:20]>C1(C)C=CC=CC=1>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[C:5]([NH:6][C:22]([NH:21][C:19](=[O:20])[CH2:18][CH2:17][Cl:16])=[O:23])[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1
Reactant: O=C=NC(=O)CCCl
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Product: O=C(CCCl)NC(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
11.45 g (0.05 mol) of 3,5-bis-trifluoromethylaniline were dissolved in 80 ml of dry toluene, and 6.7 g (0.05 mol) of β-chloropropionyl isocyanate in 20 ml of dry toluene were added. The mixture was stirred at 60° C. for 1 hour, the solvent was distilled off in vacuo and the residue was taken up in petroleum ether. The crystalline product was filtered off and dried. 14.5 g (80.5% of theory) of N-(3,5-bis-trifluoromethyl-phenyl)-N'-(β-chloropropionyl)-urea, which melts at 175° C., were obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH:13]=[N:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][CH:7]([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:6]1)=[O:4].O.[OH-].[Li+].Cl>C1COCC1.O>[CH2:16]([O:15][N:14]=[CH:13][C:5]1([C:3]([OH:4])=[O:2])[CH2:8][CH:7]([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:6]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCCCC1CC(C=NOCc2ccccc2)(C(=O)OC)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCC1CC(C=NOCc2ccccc2)(C(=O)O)C1
Temperature: 90 °C

Procedure:
A mixture of 1-(benzyloxyimino-methyl)-3-butyl-cyclobutanecarboxylic acid methyl ester (7.23 g, 23.8 mmol) and lithium hydroxide monohydrate (10 g, 238 mmol) in THF (100 mL) and water (50 mL) was heated at 90° C. for 18 h. The reaction mixture was acidified to pH 3 with 6N aqueous HCl and was extracted with dichloromethane (75 mL×6). The combined organic layers were dried (MgSO4) and were evaporated in vacuo to yield the title compound as a pale yellow oil. (6.33 g, 92%). MH+290.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH:16]([OH:19])([CH3:18])[CH3:17].[CH3:20][O:21][C:22](=[O:30])[C:23]1[CH:28]=[C:27](O)[CH:26]=[N:25][CH:24]=1.C1C=CC=CC=1>C(Cl)(Cl)Cl.Cl[Cu]>[CH:16]([O:19][C:27]1[CH:26]=[N:25][CH:24]=[C:23]([CH:28]=1)[C:22]([O:21][CH3:20])=[O:30])([CH3:18])[CH3:17]
Reactant: CC(C)O
Reactant: COC(=O)c1cncc(O)c1
Agent: Cl[Cu]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cncc(OC(C)C)c1
Temperature: 105 °C
Reaction time: 13 h
Yield: 46.8 %

Procedure:
A solution of 677 mg (3.28 mmol) of dicyclohexylcarbodiimide (DCC), 0.3 mL (3.92 mmol) of isopropanol, and 7.7 mg (0.078 mmol) of CuCl was heated at 60° C. After 13 h, 460 mg (3.0 mmol) of 5-hydroxynicotinic acid methyl ester and 10 mL of benzene were added and heated at 105° C. for 24.5 h. The mixture was diluted with chloroform and filtered. The organic layer was washed with 15 mL of sat. NaHCO3, water, and brine and dried over Na2SO4. Purification by flash silica gel chromatography (100% CHCl3) provided 274 mg of methyl 5-isopropoxynicotinate as a yellow oil in 47% yield.