Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[O:14]C=CC=2)=[CH:11][C:10]([C:18]([F:21])([F:20])[F:19])=[N:9]1.[O-:22]Cl=O.[Na+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]([OH:14])=[O:22])=[CH:11][C:10]([C:18]([F:21])([F:20])[F:19])=[N:9]1
Reactant: [O-][Cl+][O-]
Reactant: FC(F)(F)c1cc(-c2ccco2)n(-c2ccccc2Cl)n1
Agent: [Na+]
Solvent: CC#N
Product: O=C(O)c1cc(C(F)(F)F)nn1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 42 h

Procedure:
A 2 L flask was charged with 37.31 g of 1-(2-chlorophenyl)-5-furan-2-yl-3-trifluoromethyl-1H-pyrazole (119 mmol), 470 mL of acetonitrile, then a solution of NaH2PO4 (71.49 g in 174 mL of water) was added. The resulting solution was cooled to 0-30C in an ice bath and a NaClO2 solution (80%, 107.84 g in 391 mL of water) was added portionwise. The resulting solution was allowed to warm to room temperature where it remained for 42 h. The reaction was then concentrated in vacuo to remove acetonitrile. The residue was washed into a separatory funnel with 525 mL of 2.0 M NaOH and CH2Cl2. The CH2Cl2 was separated and was washed twice with 2.0 M NaOH. The NaOH washings were combined, acidified with concentrated HCl, and were extracted with CH2Cl2. The CH2Cl2 was then concentrated in vacuo and the crude acid was precipitated from CH2Cl2 with hexanes. 2-(2-chlorophenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid was recovered as a tan solid, yield: 20.1 g (58%); 1H NMR (400 MHz, DMSO-d6): δ 14.1 (s, 1H), 7.86-7.90 (m, 2H), 7.80 (dt, J=1.5, 7.5 Hz, 1H), 7.76 (s, 1H), 7.73 (dt, J=1.5, 7.5 Hz, 1H); MS (ES): 291 [M+H]+.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]([CH3:30])=[C:11]([CH3:29])[C:12]=1[C:13]([C:15]1[CH:20]=[C:19]([CH:21]([CH3:23])[CH3:22])[C:18]([O:24]C)=[C:17]([CH:26]([CH3:28])[CH3:27])[CH:16]=1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.C(Cl)Cl.C(=O)=O.CC(C)=O>C(Cl)Cl>[CH2:1]([C:8]1[O:9][C:10]([CH3:30])=[C:11]([CH3:29])[C:12]=1[C:13]([C:15]1[CH:16]=[C:17]([CH:26]([CH3:27])[CH3:28])[C:18]([OH:24])=[C:19]([CH:21]([CH3:23])[CH3:22])[CH:20]=1)=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(C(C)C)cc(C(=O)c2c(Cc3ccccc3)oc(C)c2C)cc1C(C)C
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: Cc1oc(Cc2ccccc2)c(C(=O)c2cc(C(C)C)c(O)c(C(C)C)c2)c1C
Reaction time: 1.5 h
Yield: 50.3 %

Procedure:
At −78° C., to a stirred solution of (2-benzyl-4,5-dimethyl-furan-3-yl)-(3,5-diisopropyl-4-methoxy-phenyl)-methanone (2.00 g, 4.94 mmol) in CH2Cl2 (16.6 mL) was added 1M boron tribromide/CH2Cl2 (10.4 mL). After the addition was complete, the dry ice/acetone bath was replaced with an ice bath and the reaction was stirred for 1.5 h. The reaction was quenched into crushed ice (18 g), diluted with H2O (20 mL) and extracted with ether. The combined ethereal extracts were washed with brine, dried (MgSO4) and concentrated. The crude product was purified on silica gel eluting with 15% acetone/hexane to give 0.97 g (50%) of the title compound as a white solid, mp 138° C.; 1H NMR (DMSO-d6) δ 1.14 (d, 12H), 1.80 (s, 3H), 2.19 (s, 3H), 3.34 [septet (under H2O peak), 2H], 3.84 (s, 2H), 7.04 (d, 2H), 7.17-7.25 (m, 3H), 7.44 (s, 2H), 9.11 (s, 1H). IR (KBr) 3400, 2950, 1580, 1320, 1200 cm−1. mass spectrum (EI), m/z 390 (M+). Anal. Calcd. for C26H30O3.0.2H2O: C, 79.24; H, 7.77; N, 0.12. Found: C, 79.27; H, 7.85; N, 0.12.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:11][CH:12]1[C:20]2[C:15](=[CH:16][C:17]([Br:21])=[CH:18][CH:19]=2)[CH2:14][CH2:13]1>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:11][CH:12]1[C:20]2[C:15](=[CH:16][C:17]([Br:21])=[CH:18][CH:19]=2)[CH2:14][CH2:13]1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: NC1CCc2cc(Br)ccc21
Product: Brc1ccc2c(c1)CCC2Nc1nc2ccccc2[nH]1

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and racemic 1-amino-5-bromoindane (prepared by Procedure B from 5-bromo-1-indanone) by Procedure A (30 min at 170° C.). The product was isolated by preparative LCMS to give the title compound as the free base and as a mixture of enantiomers (white solid, mp 242-243° C.). MS(ES+) m/z 328 ([M+1]+, 100). 1NMR (DMSO-d6) δ 1.92 (m, 1H), 2.50 (m, 1H), 2.83 (m, 1H), 2.95 (m, 1H), 5.35 (m, 1H), 6.82-7.02 (m, 3H), 7.12-7.35 (m, 4H), 7.46 (s, 1H), 10.7 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]=[CH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N(Br)C(=[O:17])C1.[OH-].[Na+]>O.FC(F)(F)C(O)=O>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]2[CH:12]([O:17]2)[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1=CCN(Cc2ccccc2)CC1
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(CN2CCC3OC3C2)cc1
Reaction time: 8 h
Yield: 3337.2 %

Procedure:
3.36 g of 1-benzyl-1,2,3,6-tetrahydropyridine (0.19 mmol) was dissolved in 35 mL of water containing 1.5 mL of trifluoroacetic acid (0.2 mmol). To that solution 5.87 g of NBS was added in small portions. After 4 hs reaction mixture was transferred to 50 mL of 20% NaOH solution and stirred overnight. On the morning reaction mixture was extracted with dichloromethane and combined organic fractions were dried over sodium sulfate and concentrated. The residue was purified on silica gel column using hexane-ethyl acetate 3:1 as eluent. Evaporation of solvent produced 1.2 g of 3-benzyl-7-oxa-3-azabicyclo[4.1.0]heptane as colorless oil.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].[O-]CC.[Na+].[C:10]([CH:12]([C:28](OCC)=[O:29])[CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1)#[N:11]>C(O)C>[NH2:4][C:3]1[NH:5][C:28](=[O:29])[C:12]([CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][CH:27]=2)=[C:10]([NH2:11])[N:2]=1
Reactant: CCOC(=O)c1ccc(OCCCC(C#N)C(=O)OCC)cc1
Reactant: N=C(N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1ccc(OCCCc2c(N)nc(N)[nH]c2=O)cc1
Yield: 92.9 %

Procedure:
Guanidine hydrochloride (4.18 g, 43.7 mmoles) was added to a solution of sodium ethoxide (65.6 mmoles) in ethanol (25 mL), and the mixture was treated with compound 1A (7.0 g, 21.9 mmoles) as a solution in ethanol (25 mL) and then refluxed for 7 hours. After cooling, the mixture was filtered, the solid residue was washed with 3 volumes (10 mL) of ethanol, and the combined filtrate and washings were treated with acetic acid to pH ~ 7.0. The filtrate was evaporated in vacuo to a viscous residue and treated with water (50 mL). Filtration gave a solid, which was washed with 3 volumes (10 mL) of water and dried at 50° C. in vacuo to give 6.76 g (93%) of compound 1B as a white solid. NMR (DMSO-d6) δ 1.28 (t, 3H, CH3 of ester), 1.75 (m, 2H, CH2 --CH2 -- CH2), 2.25 (t, 2H, CH2 --CH2CH2 --O), 3.97 (t, 2H, --CH2 --O), 4.25 (q, 2H, CH2 of ester), 5.7 (s, 2H, NH2), 5.93 (s, 2H, NH2), 6.98 (d, 2H, benzoate H's ortho to oxygen), 7.85 (d, 2H, benzoate H's ortho to carbonyl), 9.8 (br s, 1H, ring NH). The intermediate, compound 1B, was used in the next reaction without further purification.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[O:11]1[C:15]([C:16]2[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:14][N:13]=[CH:12]1>>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:22]([C:19]1[CH:20]=[CH:21][C:16]([C:15]3[O:11][CH:12]=[N:13][CH:14]=3)=[CH:17][CH:18]=1)(=[O:23])=[O:24])[CH:6]=[CH:5]2
Reactant: O=S(=O)(Cl)c1ccc(-c2cnco2)cc1
Reactant: Ic1ccc2[nH]ccc2c1
Product: O=S(=O)(c1ccc(-c2cnco2)cc1)n1ccc2cc(I)ccc21

Procedure:
This compound was prepared from 5-iodo-1H-indole and 4-oxazol-5-ylbenzene-sulfonyl-chloride by the method outlined under 1.a).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1Br)([CH3:4])([CH3:3])[CH3:2].[CH2:12]([NH:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH3:15].CC(C)([O-])C.[Na+]>>[CH2:12]([N:16]([CH2:17][CH2:18][CH2:19][CH3:20])[C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CC(C)(C)c1ccccc1Br
Reactant: CCCCNCCCC
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: CCCCN(CCCC)c1ccc(C(C)(C)C)cc1
Yield: 89.1 %

Procedure:
According to the general procedure B, 2-tert-butylbromobenzene (213 mg, 1.00 mmol) reacted with N,N-di-n-butylamine (130 mg, 1.00 mmol) using 1 mol % of catalyst and sodium tert-butoxide (115 mg, 1.20 mmol) at 60° C. to give the title compound (233 mg, 89%) as an oil: 1H-NMR (300 MHz, CDCl3): δ 7.25 (d, 2H, J=8.7 Hz), 6.62 (d, 2H, J=8.7 Hz), 3.25 (t, 4H, J=7.2 and 8.1 Hz), 1.58 (m, 4H), 1.35 (M, 4H), 1.30 (s, 9H), 0.97 (t, 6H, J=7.2 Hz). 13C{1H}-NMR (100 MHz, CDCl3): δ 146.01, 137.59, 125.92, 111.29, 50.84, 33.61, 31.56, 29.53, 20.39, 14.02. GC/MS(EI): m/z 261 (M+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH:15]=2)=[CH:2]1.CN(C)C=O.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:38][O:39][CH:40]1[CH2:44][CH2:43][N:42]([C:45]2[CH:46]=[C:47]([S:51](Cl)(=[O:53])=[O:52])[CH:48]=[CH:49][CH:50]=2)[CH2:41]1>O1CCCC1>[CH3:38][O:39][CH:40]1[CH2:44][CH2:43][N:42]([C:45]2[CH:46]=[C:47]([S:51]([N:1]3[C:9]4[C:4](=[N:5][CH:6]=[CH:7][CH:8]=4)[C:3]([C:10]4[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH:15]=4)=[CH:2]3)(=[O:53])=[O:52])[CH:48]=[CH:49][CH:50]=2)[CH2:41]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3cccnc23)CC1
Reactant: COC1CCN(c2cccc(S(=O)(=O)Cl)c2)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC1CCN(c2cccc(S(=O)(=O)n3cc(C4=CCN(C(=O)OC(C)(C)C)CC4)c4ncccc43)c2)C1
Temperature: 5 °C
Reaction time: 0.33 h

Procedure:
Into a 1-Neck round-bottom flask tert-butyl 4-(1H-pyrrolo[3,2-b]pyridin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate (100 mg, 0.000334 mol) was stirred in tetrahydrofuran (3 mL, 0.04 mol) and N,N-dimethylformamide (3 mL, 0.04 mol) at 5° C. and 1.0 M of sodium bis(trimethylsilyl)amide in tetrahydrofuran (0.50 mL) was added. The reaction was stirred for 20 minutes at 5° C. 3-(3-Methoxypyrrolidin-1-yl)benzenesulfonyl chloride (138 mg, 0.000501 mol) in tetrahydrofuran (3 mL, 0.04 mol) was added by syringe at 5° C. and the reaction was stirred for 30 minutes. The reaction was extracted with ethyl acetate and was washed with water and brine. The solvent was rotovaped.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[N:12]([CH2:15][CH2:16][CH2:17][F:18])[N:11]=[N:10]1.Cl[CH2:20][C:21]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:22]=1[O:23][CH:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:18][CH2:17][CH2:16][CH2:15][N:12]1[C:13](=[O:14])[N:9]([C:3]2[CH:4]=[CH:5][C:6]([O:8][CH2:20][C:21]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:22]=3[O:23][CH:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26])=[CH:7][C:2]=2[F:1])[N:10]=[N:11]1
Reactant: O=c1n(CCCF)nnn1-c1ccc(O)cc1F
Reactant: COC(=O)C(C)Oc1cc(C)ccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1cc(C)ccc1COc1ccc(-n2nnn(CCCF)c2=O)c(F)c1
Yield: 27.5 %

Procedure:
By the method Example 1, Step I, 0.85 g (0.0033 mole) of 1-(2-fluoro-4-hydroxyphenyl)-1,4-dihydro-4-(3-fluoropropyl)-5H-tetrazol-5-one and 1.21 g (0.0050 mole) of methyl 2-(2-chloromethyl-5-methylphenoxy)propionate (Example 1, Step H) were reacted in the presence of 0.70 g (0.0050 mole) of anhydrous potassium carbonate in 60 mL of N,N-dimethylformamide, yielding 0.42 g of methyl 2-[2-[4-[1,4-dihydro-4-(3-fluoropropyl)-5H-tetrazol-5-on-1-yl]-3-fluorophenoxymethyl]-5-methylphenoxy]propionate as an oil. The NMR spectrum was consistent with the proposed structure. NMR: 1.64 (d, 3H, JHH =8 Hz); 2.2-2.4 (m, 2H); 2,32 (s, 3H); 3.72 (s, 3H); 4.18 (t, 2H, JHH =8 Hz); 4.50-4.64 (dt, 2H, JHH =8 Hz, JHF =45 Hz); 4.84 (q, 1H, JHH =8 Hz), 5.20 (q, 2H, JHH =8 Hz); 6.58-7.40 (m, 6H).
Reaction SMILES: Cl[O-].[O:3]=[C:4]([O-])[C@@H:5]([C@H:7]([C@@H:9]([C@@H:11](CO)[OH:12])[OH:10])[OH:8])[OH:6]>>[O:3]=[CH:4][C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6]
Reactant: O=C([O-])[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [O-]Cl
Product: O=C[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 0.5 h

Procedure:
The hypochlorite solution is metered into the warm gluconate solution at a rate such that the addition is complete within a period of about 10-60 minutes, preferably about 30 minutes. The hypochlorite solution can, of course, also be metered in over a longer period, and this may be unavoidable in the case of very large batches. However, as a rule, the addition is effected in as short a time as possible. Thereafter, the mixture is stirred for a further brief period until the excess hypochlorite has disappeared. D-arabinose may then be isolated in a conventional manner. The yield of D-arabinose is about 70-75%, relative to the starting D-glucose, and this is achieved even when the crude fermentation solution from oxidation of D-glucose is employed.
Reaction SMILES: [CH3:1][C:2]([S@@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[Si:8]([O:15][CH2:16][CH:17]=O)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]>S([O-])([O-])(=O)=O.[Cu+2].C(Cl)Cl>[Si:8]([O:15][CH2:16]/[CH:17]=[N:7]/[S:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)S(=O)/N=C/CO[Si](C)(C)C(C)(C)C
Yield: 115.5 %

Procedure:
A three necked round bottom flask fitted with a mechanical stirrer, nitrogen inlet and temperature probe was charged with (S)-(−)-2-Methyl-2-Propanesulfinamide (113 g, 0.929 mol) and DCM (2.0 L) at RT (endotherm to 9° C.). Copper(II) Sulfate (309 g, 1.94 mol) was then added followed by (tert-butyldimethylsilyl-oxy)acetaldehyde (150 g, 0.774 mol). After 36 hours the reaction was filtered through a plug of Celite, plug rinsed with DCM (3×200 mL), and concentrated to provide 248 g of the title compound as a light yellow syrup (87 wt %). 1H NMR (CDCl3) δ 8.08 (1H, s), 4.56 (2H, s), 1.22 (9H, s), 0.95 (9H, s), 0.12 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)[CH3:9])=[CH:4][C:3]=1[N+:15]([O-:17])=O.O.[NH2:19][NH2:20].Cl>C(O)CCC>[ClH:1].[N:10]1([CH:8]([C:5]2[CH:6]=[CH:7][C:2]3[N:20]=[N:19][N:15]([OH:17])[C:3]=3[CH:4]=2)[CH3:9])[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: NN
Reactant: CC(c1ccc(Cl)c([N+](=O)[O-])c1)n1ccnc1
Agent: Cl
Solvent: CCCCO
Solvent: O
Product: CC(c1ccc2nnn(O)c2c1)n1ccnc1
Reaction time: 12 h
Yield: 99 %

Procedure:
A mixture of 4.3 parts of 1-[1-(4-chloro-3-nitrophenyl)ethyl]-1H-imidazole, 3.42 parts of hydrazine monohydrate and 40 parts of 1-butanol was stirred for 12 hours at reflux temperature. After cooling, 3.4 parts of a hydrochloric acid solution 10N were added. The separated organic layer was evaporated. The residue was stirred in ethyl acetate. The product was filtered off and dried, yielding 4.5 parts (99.0%) of 6-[1-(1H-imidazol-1-yl)ethyl]-1H-benzotriazol-1-ol monohydrochloride (compound 149).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[F:11].[CH3:13][S:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1)(=[O:16])=[O:15]>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:21][C:20]2[CH:19]=[CH:18][C:17]([S:14]([CH3:13])(=[O:16])=[O:15])=[CH:24][CH:23]=2)=[CH:6][C:5]=1[F:11]
Reactant: CS(=O)(=O)c1ccc(CCl)cc1
Reactant: COC(=O)c1ccc(O)cc1F
Product: COC(=O)c1ccc(OCc2ccc(S(C)(=O)=O)cc2)cc1F

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure E except KI (1.0 eq.) is also added from 2-fluoro-4-hydroxy-benzoic acid methyl ester [CAS 197507-22-5] and 4-methylsulfonylbenzyl chloride. 1H NMR (DMSO) 8.0 (d, 2H), 7.9 (t, 1H), 7.7 (d, 2H), 7.1 (dd, 1H), 7.0 (dd, 1H), 5.4 (s, 2H), 3.8 (s, 3H), 3.3 (s, 3H)
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][CH2:23][CH2:24][N:25]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>C(O)C>[NH2:25][CH2:24][CH2:23][CH2:22][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:2]1=[O:1]
Reactant: O=C1c2ccccc2C(=O)N1CCCN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a suspension of 2-[3-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)propyl]-1H-isoindole-1,3(2H)-dione (1.25 g, 2.70 mmol) in ethanol (25 mL) was added hydrazine monohydrate (0.70 mL, 8.2 mmol). The reaction mixture was stirred at ambient temperature for 3 days, over which time a precipitate was deposited. The solid was collected by filtration and purified by column chromatography and eluted with ethyl acetate/methanol/7 N methanolic ammonia (10/1/0.2) to afford 1′-(3-aminopropyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one as a yellow oil: MS (ES+) m/z 336.9 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH3:18][O:19][C:20]1[CH:29]=[C:28]2[C:23]([C:24](=[O:38])[CH:25]([C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[CH2:26][S:27]2)=[CH:22][CH:21]=1.O>O1CCCC1>[O:9]1[CH2:10][CH2:11][O:12][CH:8]1[C:4]1[CH:3]=[C:2]([C:24]2([OH:38])[C:23]3[C:28](=[CH:29][C:20]([O:19][CH3:18])=[CH:21][CH:22]=3)[S:27][CH2:26][CH:25]2[C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(C2OCCO2)c1
Reactant: COc1ccc(C2CSc3cc(OC)ccc3C2=O)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C2CSc3cc(OC)ccc3C2(O)c2cccc(C3OCCO3)c2)cc1
Reaction time: 0.83 h
Yield: 50 %

Procedure:
To a solution of 2-(3-bromophenyl)-1,3-dioxolane (3.04 g, 13.28 mmol) in dry tetrahydrofuran (35 ml) was added n-butyl lithium (8.37 ml, 13.316 mmol, 1.59 mol/l tetrahydrofuran solution) dropwise as −78° C. over 10 minutes and stirred for 50 minutes at the same temperature. Then to the reaction mixture was added 7-methoxy-3-(4-methoxyphenyl)thiochroman-4-one (2 g, 6.658 mmol) dissolved in tetrahydrofiuran at the same temperature over 10 minutes. The reaction mixture was stirred for 6 h at −78° C. and followed at −10C for 2 h. When the reaction was completed, water was added to the reaction solution which was then extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified with column chromatography (n-hexane:ethyl acetate=8:1 to 7:3) to give 1.50 g (yield: 50%) of the title compound as a colorless oil. In this reaction, 0.77 g (38%) of the unreacted starting compound was recovered.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[N:10]1([C:16](=[O:19])[CH2:17][CH3:18])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+].Cl>O.CN(C=O)C>[C:16]([N:10]1[CH2:15][CH2:14][N:13]([C:2]2[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=2)[CH2:12][CH2:11]1)(=[O:19])[CH2:17][CH3:18]
Reactant: CCC(=O)N1CCNCC1
Reactant: O=Cc1cccc(Br)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(=O)N1CCN(c2cccc(C=O)n2)CC1
Temperature: 120 °C
Yield: 30.8 %

Procedure:
To a high-pressure tube was added 6-bromopicolinaldehyde (1, 2.00 g, 10.7 mmol), 1-(piperazin-1-yl)propan-1-one (18, 3.82 g, 26.9 mmol), potassium carbonate (6.69 g, 48.4 mmol) and anhydrous DMF (12 mL). The tube was sealed and the reaction mixture was heated at 120° C. for 17 h. The reaction suspension was poured into water (100 mL) and the mixture was brought to pH 7 using 2 N aq. HCl (20 mL). The solution was extracted with CH2Cl2 (3×100 mL), washed with brine (300 mL), dried over Na2SO4, filtered and concentrated to a brown oil. The product was purified by silica gel chromatography eluting with 0-5% CH3OH in CH2Cl2 to afford the title compound (0.815 g, 31%) as an orange solid: 1H NMR (500 MHz, CDCl3) δ 9.89 (s, 1H), 7.68 (t, J=8.0 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 3.84-3.73 (m, 2H), 3.68-3.59 (m, 2H), 2.40 (q, J=7.5 Hz, 2H), 1.19 (t, J=7.5 Hz, 3H).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[Cl:11][C:12]1[N:21]=[C:20]2[C:15]([CH:16]=[CH:17][C:18]([N:22]3[CH:30]([OH:31])[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]3=[O:32])=[N:19]2)=[CH:14][CH:13]=1>N1C=CC=CC=1>[Cl:11][C:12]1[N:21]=[C:20]2[C:15]([CH:16]=[CH:17][C:18]([N:22]3[CH:30]([O:31][C:2]([O:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)=[O:3])[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]3=[O:32])=[N:19]2)=[CH:14][CH:13]=1
Reactant: O=C1c2ccccc2C(O)N1c1ccc2ccc(Cl)nc2n1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Product: O=C(Oc1ccccc1)OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Temperature: 20 °C
Reaction time: 3 h
Yield: 80.7 %

Procedure:
Phenyl chloroformate (126 g.) is added to a suspension of 2-(7-chloro-1,8-naphthyridin-2-yl)-3-hydroxyisoindolin-1-one (86.5 g.) in pyridine (980 cc.), whilst keeping the temperature at about 25° C. The reaction mixture is stirred for 3 hours at a temperature of about 20° C., after which it is poured into ice-water (9,000 cc.). The product which crystallises is filtered off, washed with water (6 × 500 cc.) and then with acetonitrile (3 × 200 cc.). After drying, 2-(7-chloro-1,8-naphthyridin-2-yl)-3-phenoxycarbonyloxy-isoindolin-1-one (96.7 g.), melting at 235° C. with decomposition, is obtained.
Reaction SMILES: [Br-].[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH:12]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:13].[Li]CCCC.[CH3:38][CH:39]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH:40]=O>>[CH3:40][CH:39]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH:38]=[C:12]([C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:2]=1)[CH3:13]
Reactant: CCCCCCCCCC(C)C=O
Reactant: CC(c1ccc2ccccc2c1)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Product: CCCCCCCCCC(C)C=C(C)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 22.6 %

Procedure:
Starting from (1-(2-naphthyl)ethyltriphenylphosphonium bromide (6.40 g, 12.9 mmol, 1.0 equiv.), n-BuLi (1.6 M in hexanes, 8.0 mL, 12.9 mmol, 1.0 equiv.) and 2-methylundecanal (3.56 g, 19.3 mmol, 1.5 equiv.), and after stirring the mixture at 25° C. for 3 h, 0.94 g (23%) of the title compound as a colorless oil was obtained after purification by flash chromatography on SiO2 (cyclohexane).
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>O.ClCCl>[F:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([C:4]2[CH:5]=[CH:6][C:1]([O:7][CH3:8])=[CH:2][CH:3]=2)=[O:15])=[CH:12][CH:11]=1
Reactant: COc1ccccc1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(=O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
Anisole (27.5 grams), 4-fluorobenzoyl chloride (35 grams) and dichloromethane (250 mL) were combined in a reaction flask. Aluminum chloride (30.8 grams) was added to the reaction mixture slowly over 20 minutes. Stirred the reaction mixture at room temperature for two hours and then poured it into a mixture of 70 mL concentrated HCl and 500 mL of water. The layers were phase separated and the aqueous layer was extracted with 2 portions of dichloromethane (300 mL each). The organic portions were combined and washed with saturated aqueous sodium bicarbonate (400 mL). The organic layer was dried over anhydrous sodium sulfate and evaporated to yielding 48.0 grams of 4-fluoro-4′-methoxy-benzophenone as a white solid. This material was not purified further but was used directly in the next step.