Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[N+](C(C)C)([O-])=[O:3].[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[C:11]([F:17])[CH:10]=1>C(O)C>[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:3])=[C:11]([F:17])[CH:10]=1
Reactant: Fc1cc(Br)ccc1CBr
Reactant: CC(C)[N+](=O)[O-]
Agent: [Na]
Solvent: CCO
Product: O=Cc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium (317 mg) was dissolved in ethanol (30 ml), then 2-nitropropane (1.24 ml) was added. To the mixture 4-bromo-2-fluorobenzyl bromide (3.55 g) in ethanol (10 ml) was added. The reaction mixture was stirred at room temperature for 3 hours, and insoluble materials were filtered off. The filtrate was concentrated and the residue was dissolved in diethyl ether and water. The organic layer was washed with 1N sodium hydroxide and water, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel column eluting with a mixture of hexane and ethyl acetate (20:1) to give 4-bromo-2-fluorobenzaldehyde (2.28 g) as solid.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH3:17])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:19][CH2:20][CH3:21])([CH:10]2[OH:18])[CH2:8][CH2:7][C:6](=[O:22])[CH:5]=1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.CCOCC.O>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH3:17])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:19][CH2:20][CH3:21])([C:10]2=[O:18])[CH2:8][CH2:7][C:6](=[O:22])[CH:5]=1
Reactant: CCCC12CCC(=O)C=C1c1c(cc(OC)c(Cl)c1Cl)C2O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: CC(C)=O
Solvent: O
Product: CCCC12CCC(=O)C=C1c1c(cc(OC)c(Cl)c1Cl)C2=O
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5,6-dichloro-9-hydroxy-7-methoxy-9a-propyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (3.03 g, 0.089 mol) in a mixture of acetone (75 ml), ether (75 ml) and water (7 ml) cooled to 5° C. was added Jones reagent (3.4 ml, 2.67N). The reaction mixture was stirred for 1/2 hour at 5° C. then for 11/2 hours at 25° C. The reaction mixture was diluted with ether and H2O, the ether layer washed with NaHCO3, dried over MgSO4, evaporated and chromatographed on silica gel eluting with ethyl acetate-hexane (1:1.5) to give 5,6-dichloro-7-methoxy-9a-propyl-1,2,9,9a-tetrahydro-3H-fluoren-3,9-dione which melts at 167°-9° C.
Reaction SMILES: Cl[C:2]1([C:15]([NH2:17])=[O:16])[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]3OCO[C:8]3=[CH:9]2)=[N:4][CH2:3]1.[NH2:18][C:19]1[C:20]([CH3:27])=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][OH:23].C(O)(=O)C>CN(C=O)C.O>[OH:23][CH2:22][C:21]1[C:20]([CH3:27])=[C:19]([CH:26]=[CH:25][CH:24]=1)[NH:18][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:15]([NH2:17])=[O:16]
Reactant: NC(=O)C1(Cl)C=c2cc3c(cc2=NC1)OCO3
Reactant: Cc1c(N)cccc1CO
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cc1c(CO)cccc1Nc1c(C(N)=O)cnc2ccccc12
Yield: 87.5 %

Procedure:
A mixture of 3-Chloro-6,7-methylenedioxy-3-quinolinecarboxamide (106 mg, 0.42 mmol); 3-amino-2-methylbenzylalcohol (72 mg, 0.52 mmol) and acetic acid (100 μL) in DMF (2 ml) was heated at 100° C. for 6 h. After cooling, the mixture was diluted with water (20 ml) and washed twice with ethyl acetate. The aqueous phase was made alkaline with 1 M NaOH and the resulting precipitate was collected by filtration, washed with water and dried to give the title compound (113 mg, 75%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][Si:9]([C:12]#[CH:13])([CH3:11])[CH3:10].C(N(CC)CC)C>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:8][Si:9]([CH3:11])([CH3:10])[C:12]#[C:13][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccccc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of iodobenzene (1 mmole) in DME (5 mL) was treated with trimethylsilylacetylene (2 mmole), Pd(PPh3)2Cl2 (0.035 mmole), CuI (0.08 mmole) and triethylamine (4 mmole), and the resulting reaction mixture was stirred under nitrogen at room temperature for 5 h. Evaporation followed by chromatography gave 1-trimethylsilyl-2-phenylacetylene as a solid.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1)=O.P([Cl:34])(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.C(N(CC)CC)C.C(#N)C>C(OCC)(=O)C>[C:6]1([N:5]=[C:3]([Cl:34])[C:2]([F:17])([F:16])[F:1])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Reactant: O=C(Nc1cccc2ccccc12)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: FC(F)(F)C(Cl)=Nc1cccc2ccccc12
Temperature: 82 °C
Yield: 86.4 %

Procedure:
Five grams (20.9 mmol) of 2,2,2-trifluoro-N-(naphthalen-1-yl)acetamide, 11.23 g (41.8 mmol) of diphenyl chlorophosphate, 4.22 g (41.8 mmol) of triethylamine, and 20 ml of acetonitrile were introduced into a 50 ml flask and reacted for 15 hours while being refluxed (82° C.). After the reaction, the reaction solution was cooled to room temperature, 15 ml of ethyl acetate was added thereto, and the precipitate was then filtered off. The filtrate was subjected to solvent removal by evaporation, and the crude product thus obtained was purified by column chromatography (silica gel, ethyl acetate:hexane=3:7), resulting in 4.65 g of N-(naphthalen-1-yl)-2,2,2-trifluoroacetimidoyl chloride as a yellow oil (yield: 86.2%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:9])=[N+:6]([O-])[CH:7]=1.C[Si]([C:14]#[N:15])(C)C.C(N(CC)CC)C>C(#N)C>[Br:1][C:2]1[C:7]([C:14]#[N:15])=[N:6][C:5]([Cl:9])=[CH:4][CH:3]=1
Reactant: [O-][n+]1cc(Br)ccc1Cl
Reactant: C[Si](C)(C)C#N
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1nc(Cl)ccc1Br
Temperature: 100 °C

Procedure:
To a solution of 5-bromo-2-chloropyridine 1-oxide (from step 1) (1.0 eq.) in acetonitrile (0.2 M) was added trimethylsilyl cyanide (TMSCN) (4.0 eq.) and triethylamine (3.0 eq.). The reaction was heated at 100° C. overnight. After cooling to room temperature, the solvent was concentrated en vacuo, and the residue was purified by a COMBIFLASH® system (ISCO) using 0-40% ethyl acetate in hexane to give 3-bromo-6-chloropicolinonitrile.
Reaction SMILES: C([O:4][CH2:5][C@:6]1([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:10][C@@H:9]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[C@H:8]([O:20]C(=O)C)[C@@H:7]1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=O)C.C[O-].[Na+].Cl>CO>[CH2:25]([O:24][C@@H:7]1[C@@:6]([CH2:5][OH:4])([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:10][C@@H:9]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[C@@H:8]1[OH:20])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(=O)OC[C@]1(COCc2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)[C@H](OC(C)=O)[C@@H]1OCc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1cn([C@@H]2O[C@](CO)(COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H]2O)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of nucleoside 34 (553 mg, 1.05 mmol) in methanol (5.5 cm3) was added sodium methoxide (287 mg, 5.25 mmol). The reaction mixture was stirred at room temperature for 10 min, then neutralised with dilute hydrochloric acid. The solvent was partly evaporated and extraction was performed with dichloromethane (2×20 cm3). The combined organic phase was washed with saturated aqueous sodium hydrogencarbonate (3×20 cm3) and was dried (Na2SO4). The solvent was removed under reduced pressure to give 35 as a white solid material (476 mg, 97%). δH (CDCl3) 7.47 (1H, d, J 1.0 6-H), 7.36-7.22 (10H, m, Bn), 6.07 (1H, d, J 3.8, 1′-H), 4.87 (1H, d, J 11.7, Bn), 4.55 (1H, d, J 11.7, Bn), 4.50-4.32 (4H, m, Bn, 2′-H, 3′-H), 3.84-3.53 (4H, m, 5′-Ha, 5′-Hb, 1″-Ha, 1″-Hb), 1.50 (3H, d, J 1.1, CH3). δC (CDCl3) 164.3 (C-4), 151.3 (C-2), 137.6 (C-6) 136.4, 136.3, 128.8, 128.6, 128.4, 128.3, 127,9 (Bn), 111.1 (C-5), 91.1, 91.0, 88.1 (C-1′, C-3′, C-4′), 77.4 (C-2′), 74.8, 73.8, 71.4, 63,2 (Bn, C-5′, C-1″), 12.0 (CH3). FAB-MS m/z 491 [M+Na]+. Found: C, 63.4; H, 6.0; N, 5.5: C25H28N2O7, 1/4H2O requires C, 63.5; H, 6.1; N, 5.9%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:10][OH:11])[CH:2]=1.[I:18][CH2:19][CH2:20][CH3:21]>C(#N)C>[I-:18].[OH:11][N:10]=[C:9]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:8][CH2:7][C:3]1[CH:2]=[N+:1]([CH2:19][CH2:20][CH3:21])[CH:6]=[CH:5][CH:4]=1
Reactant: ON=C(CCc1cccnc1)c1ccccc1
Reactant: CCCI
Solvent: CC#N
Product: CCC[n+]1cccc(CCC(=NO)c2ccccc2)c1
Product: [I-]
Yield: 101.7 %

Procedure:
To a solution of 3-(3-pyridinyl)-1-phenylpropan-1-one oxime (4.79 g, 0.021 mol) in acetonitrile (50 mL) was added 1-iodopropane (3.10 mL, 0.032 mol). The mixture was then refluxed for 12 hours. Solvent was removed to dryness under vacuum to give a dark brown oil (8.46 g, 100%). The crude product was used in the next step without further purification.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][C:6]([N:9]1[C:13]([OH:14])=[C:12]([C:15](=[O:35])[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[C:18]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[C:17]=2[CH3:34])[CH:11]=[N:10]1)([CH3:8])[CH3:7].C(N(CC)CC)C>ClCCl>[CH3:8][C:6]([N:9]1[C:13]([O:14][C:1](=[O:3])[CH3:2])=[C:12]([C:15](=[O:35])[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[C:18]([C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)[C:17]=2[CH3:34])[CH:11]=[N:10]1)([CH3:5])[CH3:7]
Reactant: CC(=O)Cl
Reactant: COc1ccc(-c2c(S(C)(=O)=O)ccc(C(=O)c3cnn(C(C)(C)C)c3O)c2C)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-c2c(S(C)(=O)=O)ccc(C(=O)c3cnn(C(C)(C)C)c3OC(C)=O)c2C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 0.25 mL of acetyl chloride in 3 mL of dry dichloromethane was added slowly under nitrogen at 0° C. with stirring to a solution of 1.5 g (3.4 mmol) of 1-(1,1-dimethylethyl)-5-hydroxy-4-(2-methyl-4-methylsulfonyl-3-(4-methoxyphenyl)benzoyl)pyrazole and 0.52 mL of triethylamine in about 20 mL of dry dichloromethane. The mixture was allowed to warm to ambient temperature and stir for 2 hours and was then diluted with dichloromethane. The resulting solution was extracted with saturated aqueous sodium bicarbonate solution and with water, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure. The residual yellow oil was chromatographed on silica gel eluting with a 50:50 mixture of ethyl acetate and hexane. The product fractions were combined and concentrated by evaporation under reduced pressure to obtain 1.03 g (62 percent of theory) of the title compound as a white powder melting at 160-163° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=[CH:12][C:4]=2[O:3]1.[H-].[Na+].I[CH:21]([CH3:23])[CH3:22].O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:17])[C:7](=[O:8])[N:6]([CH:21]([CH3:23])[CH3:22])[C:5]2[CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=[CH:12][C:4]=2[O:3]1
Reactant: COC(=O)c1ccc2c(c1)NC(=O)C(C)(C)O2
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)N(C(C)C)C(=O)C(C)(C)O2
Temperature: 60 °C
Reaction time: 2 h
Yield: 31.1 %

Procedure:
To a solution of 2,2-dimethyl-6-methoxycarbonyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (3.0 g) in dimethylformamide (60 ml) were added 60% sodium hydride (in oil) (0.61 g) and 2-iodopropane (2.38 g) and the mixture was stirred at 60° C. for 2 hours. Water was added to the reaction solution and extraction with ethyl acetate was conducted. The solvent was distilled off under reduced pressure and the resulting residue was subjected to purification by column chromatography using ethyl acetate/hexane [1:4 (v/v)] to give 2,2-dimethyl-6-methoxycarbonyl-4-(2-propyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (1.1 g).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].N12CCCN=C1CCCCC2.CN(C)C=O.[CH2:29]([C:33]1[N:34]=[C:35]([CH3:63])[N:36]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][N:58]=2)[C:37](=[O:56])[C:38]=1[CH2:39][C:40]1[CH:41]=[CH:42][C:43]([C:46]2[CH:55]=[CH:54][CH:53]=[CH:52][C:47]=2[C:48](=[N:50][OH:51])[NH2:49])=[N:44][CH:45]=1)[CH2:30][CH2:31][CH3:32]>O>[CH2:29]([C:33]1[N:34]=[C:35]([CH3:63])[N:36]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][N:58]=2)[C:37](=[O:56])[C:38]=1[CH2:39][C:40]1[CH:41]=[CH:42][C:43]([C:46]2[CH:55]=[CH:54][CH:53]=[CH:52][C:47]=2[C:48]2[NH:49][C:1](=[O:2])[O:51][N:50]=2)=[N:44][CH:45]=1)[CH2:30][CH2:31][CH3:32]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCCCc1nc(C)n(-c2ccccn2)c(=O)c1Cc1ccc(-c2ccccc2C(N)=NO)nc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CCCCc1nc(C)n(-c2ccccn2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.2 %

Procedure:
Process 3: 1,1′-Carbonyldiimidazole (490 mg, 3.02 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (460 mg, 3.02 mmol) were added to dimethylformamide solution (25 mL) of 2-{5-{[4-butyl-2-methyl-6-oxo-1-(pyridin-2-yl)-1,6-dihydropyrimidin-5-yl]methyl}pyridin-2-yl}-N′-hydroxybenzimidamide (430 mg, 0.918 mmol) and stirred for 3 hours at room temperature. Once the reaction is completed, the reaction mixture was added water and extracted with ethyl acetate. The organic layer was combined, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residues were purified by silica gel column chromatography (ethyl acetate) to give 3-{2-{5-{[4-butyl-2-methyl-6-oxo-1-(pyridin-2-yl)-1,6-dihydropyrimidin-5-yl]methyl}pyridin-2-yl}phenyl}-1,2,4-oxadiazol-5(4H)-one (160 mg, 35%, two step yield) as weak yellow oil.
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:34]([C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[NH:42][C:41](=[O:46])[CH2:40]2)([OH:36])=O.[NH:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1.C(N(CC)CC)C>ClCCl>[N:47]1([C:34]([C:37]2[CH:38]=[C:39]3[C:43](=[CH:44][CH:45]=2)[NH:42][C:41](=[O:46])[CH2:40]3)=[O:36])[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1
Reactant: O=C1Cc2cc(C(=O)O)ccc2N1
Reactant: C1COCCN1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1Cc2cc(C(=O)N3CCOCC3)ccc2N1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
PyBOP (3.5 g, 6.72 mmol) was added to a mixture of 5-carboxy-2-oxindole (1 g, 5.6 mmol), morpholine (0.5 mL, 6.2 mmol) and triethylamine (2.0 mL, 14 mmol) in dichloromethane. After stirring at room temperature for 4 hours, the reaction was diluted with more dichloromethane, washed with saturated sodium bicarbonate and brine, dried and concentrated. The residue was purified by column chromatography to give 5-(morpholine-4-carbonyl)-1,3-dihydro-indol-2-one.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:20]3[C:19]([CH3:21])=[C:18]([CH2:22][N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[S:17][C:16]=3[C:15]([Br:28])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[C:4]([Br:29])[C:3]=1[OH:30].O[C@@H:32]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:33]([O:35]C)=[O:34]>C(#N)C>[Br:29][C:4]1[CH:5]=[C:6]([C:8]2[C:20]3[C:19]([CH3:21])=[C:18]([CH2:22][N:23]([CH2:24][CH3:25])[CH2:26][CH3:27])[S:17][C:16]=3[C:15]([Br:28])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:7]=[C:2]([Br:1])[C:3]=1[O:30][C@H:32]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:33]([OH:35])=[O:34]
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Reactant: CCN(CC)Cc1sc2c(Br)c3ccccc3c(-c3cc(Br)c(O)c(Br)c3)c2c1C
Solvent: CC#N
Product: CCN(CC)Cc1sc2c(Br)c3ccccc3c(-c3cc(Br)c(O[C@H](Cc4ccccc4)C(=O)O)c(Br)c3)c2c1C

Procedure:
Prepared from 2,6-dibromo-4-(9-bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-phenol (Example 18) and (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (Example 25) according to the procedure of Example 30. White solid: NMR (DMSO-d6); δ 13.3 (broad band, 1H), 8.20 (d, J=8 Hz, 1H), 7.70(s, 2H), 7.66 (ddd, J=8, 7, 1 Hz, 1H), 7.51(ddd, J=8, 7, 1 Hz, 1H), 7.40-7.25(m, 6H), 5.21(t, J=7 Hz, 1H), 3.75(s, 2H), 3.32(dd, J=4, 3 Hz, 2H), 2.55 (q, J=7 Hz, 4H), 1.63(s, 3H), 1.02 (t, J=7 Hz, 6H) MS [(+)FAB]: [M+H]+ @ m/z 758, 3bromine isotope pattern, 758(25%), 760(80%), 762(75%), 764(35%), 689(100%); Anal HPLC, Primesphere 5C-18 column, eluent 62% acetonitrile for 15 minutes indicated 97.8% purity; High Resolution MS (FAB)+ve: Calculated Sample Mass: 759.95556 for formula C33H31NO3Br3 as [M+H], Measured Mass 759.97370 mass deviation: 18.14 mmu.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH2:28][C:29]([NH2:31])=[O:30])[C:17]([C:32]([F:35])([F:34])[F:33])=[CH:16][N:15]=3)=[C:9]([O:36][C:37]([F:40])([F:39])[F:38])[CH:8]=2)[CH2:3][CH2:2]1.C=O.[C:43](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(Cl)Cl>[CH3:43][N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH2:28][C:29]([NH2:31])=[O:30])[C:17]([C:32]([F:34])([F:35])[F:33])=[CH:16][N:15]=3)=[C:9]([O:36][C:37]([F:38])([F:40])[F:39])[CH:8]=2)[CH2:3][CH2:2]1
Reactant: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCNCC3)cc2OC(F)(F)F)ncc1C(F)(F)F
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CN1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)c(OC(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.2 %

Procedure:
To a suspension of 2-(2-(2-(2-((4-(piperidin-4-yl)-2-(trifluoromethoxy)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (10) (0.039 g, 0.069 mmol) in anhydrous methanol (4 mL) was added a 37% aq. solution of formaldehyde (0.020 mL, 0.28 mmol) under an atmosphere of nitrogen followed by sodium triacetoxyborohydride (0.073 g, 0.34 mmol). The reaction was stirred at room temperature for 3 hours. The volatiles were then removed in vacuo and the residue was diluted with EtOAc (50 mL) and sat. aq. NaHCO3 (30 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×30 mL), the combined organic layers were washed with brine (40 mL), dried (MgSO4), filtered and concentrated in vacuo to give a gum which was taken up in DCM (˜10 mL) and methanol (˜1 mL) and concentrated in vacuo. The process was repeated with only DCM twice. The resulting gum was then suspended in diethyl ether (5 mL) and the solvent was removed in vacuo. The procedure was repeated to give the title compound (11) (0.037 g, 93% yield) as a white fluffy solid: 1H NMR (400 MHz, d6-DMSO) δ 9.79 (s, 1H), 8.59 (s, 1H), 7.60 (d, J=8.3 Hz, 1H), 7.39 (s, 1H), 7.28 (dd, J=8.4, 1.9 Hz, 1H), 7.26-7.23 (m, 1H), 7.23-7.19 (m, 1H), 7.18-7.08 (m, 3H), 6.89 (s, 1H), 3.45 (s, 2H), 3.08-2.93 (m, 4H), 2.90-2.83 (m, 2H), 2.57-2.52 (m, 1H, obscured by residual solvent signal), 2.19 (s, 3H), 1.96 (td, J=11.5, 2.0 Hz, 2H), 1.80-1.72 (m, 2H), 1.65 (ddd, J=24.6, 12.4, 3.7 Hz, 2H). LCMS Method C: rt 5.11 min; m/z 582.1 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:3]1.[Li]CCCC.[CH2:18]([C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=[O:24])[CH3:19].[Cl-].[NH4+]>C1COCC1>[CH2:18]([C:20]1[CH:21]=[C:22]([CH:23]([C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:5]=2)[OH:24])[CH:25]=[CH:26][CH:27]=1)[CH3:19]
Reactant: Cn1cnc(-c2ccccc2)n1
Reactant: CCc1cccc(C=O)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCc1cccc(C(O)c2nc(-c3ccccc3)nn2C)c1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 79.5 %

Procedure:
To a solution of 1-methyl-3-phenyl-1H-1,2,4-triazole (284 mg, 1.8 mmol, see J. Chem. Soc., 1954, 3319-3322) in THF (112 mL) at −78° C. was added BuLi (1.15 mL, 1.6 M in hexanes, 1.8 mmol). The reaction was stirred for 5 minutes at -78° C. and a solution of intermediate 370.1 (200 mg, 1.5 mmol) in THF (2 mL) was added dropwise. The mixture was warmed to ambient temperature over 2 h. Ammonium chloride (80 mg) was added to the mixture and it was concentrated. Purification of the crude material afforded 350 mg of intermediate 370.2 as a white solid. LCMS 294.2 (M+H)+.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH2:10][C@H:9]1[C:24]([OH:26])=O)=[O:7])(C)(C)C.[C:27]1([CH:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)C(Cl)=O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[S:43]1[CH:47]=[CH:46][CH:45]=[C:44]1[CH2:48][NH2:49]>>[C:37]1([CH:33]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[CH2:10][C@H:9]2[C:24]([NH:49][CH2:48][C:44]2[S:43][CH:47]=[CH:46][CH:45]=2)=[O:26])=[O:7])[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: NCc1cccs1
Reactant: COc1ccc(CON=C2C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C2)cc1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: COc1ccc(CON=C2C[C@@H](C(=O)NCc3cccs3)N(C(=O)C(c3ccccc3)c3ccccc3)C2)cc1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylic acid, diphenylacetyl chloride, and 2-thienylmethylamine the title compound was obtained in 63% purity by LC/MS. MS(ESI+): m/z=554.4.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:13](=O)[C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:11]([OH:12])=[C:6]2[CH:5]=[N:4]1)[CH3:2].Cl.[NH2:24]O>N1C=CC=CC=1>[CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]3[C:13]([C:14]4[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=4)=[N:24][O:12][C:11]3=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc2c(O)c(C(=O)c3ccc(OC)cc3)cnc21
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CCn1ncc2c3onc(-c4ccc(OC)cc4)c3cnc21

Procedure:
1-Ethyl-4-hydroxy-5-(4-methoxybenzoyl)-1H-pyrazolo[3,4-b]pyridine (3.60 g) was refluxed overnight in 30 ml of pyridine containing 4.0 g of hydroxylamine hydrochloride. At the end of this time the pyridine was evaporated and the residue triturated with 5% hydrochloric acid. The product obtained in this manner was chromatographed over silica gel (5% methanol/dichloromethane) to remove a fluorescent impurity. Combination of the appropriate fractions and recrystallization from dichloromethane/hexane gave 2.95 g of pure product, mp 156°-157° C.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([OH:14])=[C:10]([Br:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[O:15]1[C:19]2([CH2:24][CH2:23][C:22]([CH2:25]O)=[CH:21][CH2:20]2)[O:18][CH2:17][CH2:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C(OCC)(=O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:14][CH2:25][C:22]3[CH2:23][CH2:24][C:19]4([O:15][CH2:16][CH2:17][O:18]4)[CH2:20][CH:21]=3)=[C:10]([Br:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2cc(O)c(Br)cc21
Reactant: OCC1=CCC2(CC1)OCCO2
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)N1CCc2cc(OCC3=CCC4(CC3)OCCO4)c(Br)cc21
Reaction time: 1 h
Yield: 180.6 %

Procedure:
1-Acetyl-6-bromo-2,3-dihydro-1H-indol-5-ol (Tetrahedron 1973, 29, 1115) (1.10 g, 4.3 mmol), 1,4-dioxaspiro[4,5]dec-7-ene-8-methanol (D11, 0.88 g, 5.2 mmol) and triphenylphosphine (1.36 g, 5.2 mmol) were stirred under Ar in dry THF (50 ml) as diethyl azodicarboxylate (0.82 ml, 5.2 mmol) was added dropwise. The mixture was stirred for 1 h, diluted with ethyl acetate (100 ml), washed with brine, dried (Na2SO4) and evaporated to give a dark oil. Chromatography on silica gel, eluting with 0-5% methanol/dichloromethane, gave the title compound (3.17 g) contaminated by substantial amounts of triphenylphosphine and diethyl azodicarboxylate-derived residues (NMR).