Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][S:14]2=[O:22])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(OCC)C>CC(O)C.O1CCOCC1>[NH:8]1[CH2:13][CH2:12][C:11]2([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][S:14]2=[O:22])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)c1ccccc1CS2=O
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)O
Solvent: C1COCCO1
Product: O=S1Cc2ccccc2C12CCNCC2
Reaction time: 4 h

Procedure:
42.0 g (0.13 mole) of 1'-t-butoxycarbonylspiro[benzo[c]thiophene-1(3H),4'-piperidine]-2-oxide [prepared as described in step (b) above] were dissolved in 420 ml of 2-propanol, and 150 ml of a 4 N solution of hydrogen chloride in dioxane was added thereto, whilst ice-cooling. The mixture was then stirred for 4 hours. At the end of this time, 200 ml of diethyl ether were added to the mixture, and the mixture was allowed to stand for 1 hour, whilst ice-cooling. The precipitated crystals were then collected by filtration. The crystals were dissolved in 200 ml of a 5% w/v aqueous solution of sodium hydroxide. The product was extracted with methylene chloride, and the organic extract was dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, to give 21.7 of the title compound as a white amorphous product.
Reaction SMILES: [CH3:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[C:7]([C:12](O)=[O:13])=[CH:6][N:5]([CH3:15])[C:4]=2[CH:3]=1.C([N:18](CC)CC)C.ClC(OCC)=O.N>O1CCCC1>[CH3:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[C:7]([C:12]([NH2:18])=[O:13])=[CH:6][N:5]([CH3:15])[C:4]=2[CH:3]=1
Reactant: CCN(CC)CC
Reactant: Cc1cc2c(s1)c(=O)c(C(=O)O)cn2C
Agent: CCOC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: Cc1cc2c(s1)c(=O)c(C(N)=O)cn2C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxylic acid (1.27 g), triethylamine (0.6 ml) and dry tetrahydrofuran (120 ml) was stirred at ambient temperature for 30 minutes. The mixture was cooled to 0° and a solution of ethyl chloroformate (0.6 ml) in dry tetrahydrofuran (10 ml) was added during 3 minutes, before being allowed to warm to ambient temperature. Stirring was continued for 18 hours and a further quantity of ethyl chloroformate (0.3 ml) was added at ambient temperature. After stirring for a further 2 hours, the mixture was cooled to 5° and aqueous ammonia (specific gravity 0.880, 10 ml) was added. The mixture was stirred for 20 minutes and the solid was collected, washed with water (50 ml) and dried to give a second sample of crude 2,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide. The two samples of the carboxamide from (e) and (f) were combined and crystallised from industrial methylated spirit to give pure novel compound 2,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide, m.p. 328°-330°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([NH2:11])[C:3]=1[NH2:12].[C:13](O)(=O)[CH3:14]>>[Br:1][C:2]1[C:3]2[N:12]=[C:13]([CH3:14])[NH:11][C:4]=2[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: CC(=O)O
Reactant: Nc1cc([N+](=O)[O-])cc(Br)c1N
Product: Cc1nc2c(Br)cc([N+](=O)[O-])cc2[nH]1
Yield: 56.6 %

Procedure:
A mixture of 3-bromo-5-nitrobenzene-1,2-diamine (90 g, 389 mmol) in acetic acid (800 mL) was stirred under reflux for 18 h. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to give the product (56 g, 56.6%) as a brown solid; LC/MS: MS (ES+) m/e 256 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 2.60 (s, 3H), 8.20 (d, J=1.8 Hz, 3H), 8.34 (d, J=1.8 Hz, 2H), 13.25 (s, br, 1H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])([O-])=O.[Na+].[Na+].CCOCC>C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[C:9]1([C:2]2[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1ccc(Br)s1
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2ccccc2)s1
Reaction time: 0.08 h
Yield: 91.9 %

Procedure:
5-Bromothiophene-2-carboxaldehyde (10 g, 5.2 mmol) is added to a solution of tetrakis(triphenylphosphine)palladium(O) (180 mg, 0.16 mmol) in degassed THF (10 mL). The resulting solution is stirred for 5 minutes. A solution of phenylboronic acid (760 mg, 6.2 mmol) in THF (10 mL) is added followed by aqueous Na2CO3 (2M, 5.2 mL). The mixture is heated at reflux for 24 hours. The reaction mixture is allowed to cool, poured into ether, and washed twice with water. The ether layer is dried over Na2SO4 and concentrated in vacuo. The crude product is purified by flash column chromatography (1:1 hexanes:CH2Cl2) to yield the desired product (900 mg, 91%). 1H NMR (300 MHz, CDCl3) δ 7.38-7.45, 7.65-7.68, 7.73, 9.88.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:13])=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9]C)=O.O[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]>>[Cl:1][C:2]1[C:3]([F:13])=[CH:4][C:5]([O:12][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[C:6]([CH2:7][OH:9])[CH:11]=1
Reactant: COC(=O)c1cc(Cl)c(F)cc1O
Reactant: CC(C)(C)OC(=O)NCCCCCO
Product: CC(C)(C)OC(=O)NCCCCCOc1cc(F)c(Cl)cc1CO

Procedure:
Intermediate I-30 was prepared from methyl 5-chloro-4-fluoro-2-hydroxybenzoate and tert-butyl 5-hydroxypentylcarbamate analogously to Examples 27-28.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:21][CH2:20][N:8]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]([C:16]([O:18][CH3:19])=[O:17])[C:14]=4[CH:15]=[C:7]3[C:6]=2[N:22]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[O:31][C:32]3[CH:42]=[C:41]([N:43]([CH3:48])[S:44]([CH3:47])(=[O:46])=[O:45])[C:40](B4OC(C)(C)C(C)(C)O4)=[CH:39][C:33]=3[C:34]=2[C:35]([NH:37][CH3:38])=[O:36])=[CH:26][CH:25]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[O:31][C:32]3[CH:42]=[C:41]([N:43]([CH3:48])[S:44]([CH3:47])(=[O:45])=[O:46])[C:40]([C:2]4[CH:3]=[CH:4][C:5]5[O:21][CH2:20][N:8]6[C:9]7[CH:10]=[CH:11][CH:12]=[C:13]([C:16]([O:18][CH3:19])=[O:17])[C:14]=7[CH:15]=[C:7]6[C:6]=5[N:22]=4)=[CH:39][C:33]=3[C:34]=2[C:35](=[O:36])[NH:37][CH3:38])=[CH:26][CH:25]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: COC(=O)c1cccc2c1cc1n2COc2ccc(Cl)nc2-1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(C(=O)OC)cccc5n3CO4)cc12
Temperature: 100 °C
Yield: 84 %

Procedure:
To a degassed solution of methyl 2-chloro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole-11-carboxylate (40 mg, 0.13 mmol) and 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (50 mg, 0.10 mmol) in 1,4-dioxane (3 mL), Pd2(dba)3 (10 mg), X-Phos (10 mg) and K3PO4 (60 mg, 0.23 mmol) were added under N2. The mixture was heated to 100° C. for 2 hours. The reaction mixture was cooled to RT, filtered and washed with EtOAc. The filtrate was washed with H2O, brine, dried over Na2SO4. After concentrated, the resulting residue was purified using column chromatography (dichloromethane:MeOH=100:1) to provide the product of methyl 2-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole-11-carboxylate (55 mg, yield: 84%). MS (M+H)+: 655.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(O)C.Cl>CO.C(Cl)(Cl)Cl>[CH2:22]([NH:29][CH2:19][CH:17]([OH:18])[CH2:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([C:6]2[C:5]3[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)=[CH:14][CH:13]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCc1ccccc1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: OC(CNCc1ccccc1)COc1ccc(-c2noc3cc(F)ccc23)cc1
Yield: 33.9 %

Procedure:
Combine (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole (29) (500 mg, 1.75 mmol), benzylamine (755 mg, 7.05 mmol), ethanol (5.0 ml) and heat (˜80° C.) for 18.5 hours. At room temperature the reaction solidified. Dissolve reaction mixture with chloroform and concentrate (in vacuo). Purify the compound by column chromatography (silica) eluting with 10% ethanol in chloroform to obtain a white solid. Dissolve the free base in hot methanol and add ethereal HCl to a pH ˜2-3. Concentrate the reaction mixture (in vacuo) and recrystallize (methanol) the salt and dry (60° C., 1.0 mm Hg) to give the title compound as white solid (233 mg, 46% Yield). mp=251-253° C. Microanalysis (C, H, N) is consistent with the final, desired compound. [α]22D=+9.17, c (MeOH)=0.60.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:34][C:35]1[CH:36]=[C:37]([S:42](Cl)(=[O:44])=[O:43])[CH:38]=[C:39]([CH3:41])[CH:40]=1.O>ClCCl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([S:42]([C:37]4[CH:38]=[C:39]([CH3:41])[CH:40]=[C:35]([CH3:34])[CH:36]=4)(=[O:44])=[O:43])[C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:25])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: Cc1cc(C)cc(S(=O)(=O)Cl)c1
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C)cc(S(=O)(=O)n2c(=O)n(-c3ccc(C(C)(C)C#N)cc3)c3c4cc(Br)ccc4ncc32)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 1, 50 mg, 0.12 mmol) and triethylamine (24.4 mg (0.36 mmol) in dichloromethane (6 ml) was added 3,5-dimethylbenzene-1-sulfonyl chloride (0.18 mmol) at 0° C. The reaction was stirred at RT for 3 hours. The reaction mixture was poured into cold water and organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound. Yield: 25 mg (33.33%); 1H NMR (CDCl3, 300 MHz): δ 9.58 (s, 1H), 7.957-7.987 (d, 1H, J=9 Hz), 7.79 (s, 2H), 7.699-7.727 (d, 2H, J=8.4 Hz), 7.605-7.642 (dd, 1H, J=9 Hz, 2.1 Hz), 7.425-7.453 (d, 2H, J=8.4 Hz), 7.29 (s, 1H), 6.96 (d, 1H, J=1.8 Hz), 2.36 (s, 6H), 1.79 (s, 6H); MS: m/z 575 (M+).
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][C:4]([C:7]([CH2:9][NH2:10])=[O:8])=[CH:3]1.C(=O)(O)[O-].[Na+].[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20]>>[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([NH:10][CH2:9][C:7]([C:4]1[CH:5]=[CH:6][S:2][CH:3]=1)=[O:8])=[O:20]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: NCC(=O)c1ccsc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(CNC(=O)c1ccccc1Cl)c1ccsc1
Yield: 95.7 %

Procedure:
7.5 g of N-[(3-thienylcarbonyl)methyl]amine hydrochloride, 10.0 g of sodium bicarbonate and 8.86 g of 2-chlorobenzoyl chloride are treated in the same manner as described in Preparation 1-(3). 11.3 g of N-(2-chlorobenzoyl)-N-[(3-thienylcarbonyl)methyl]amine are thereby obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([S:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CC(C)=O.[B-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu+]>[Cl:1][C:2]1[CH:10]=[C:9]([S:11][CH3:12])[CH:8]=[CH:7][C:3]=1[CH:4]=[O:5]
Reactant: CSc1ccc(C(=O)Cl)c(Cl)c1
Agent: [Cu+]
Agent: [B-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)=O
Product: CSc1ccc(C=O)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
A mixture of 2-chloro-4-(methylsulphenyl)-benzoyl chloride (1.0 g), triphenyl phosphine (2.47 g) and bis(triphenylphosphine)copper (I) borohydride (1.0 g) in acetone was stirred at 0° C. for 1 hour. Further his (triphenylphosphine)copper (I) borohydride (1.5 g) was added and the mixture was stirred for 2 hours. The mixture was filtered and the filtrate was evaporated to dryness. The residue was dissolved in chloroform and treated with copper (I) bromide (2.1 g). The filtrate was evaporated to dryness and the residue was purified by chromotography eluted with a mixture of ethyl acetate and hexane to give 2-chloro-4-(methylsulphenyl)benzaldehyde (0.83 g) as an off-white solid, m.p. 76°-77° C.
Reaction SMILES: [Br:1][C:2]1[C:17]([CH3:18])=[CH:16][C:5]([O:6][C@@H:7]2[CH2:10][C@H:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH2:8]2)=[CH:4][C:3]=1[CH3:19].[H-].[Na+].I[CH3:23]>CN(C)C(=O)C>[Br:1][C:2]1[C:17]([CH3:18])=[CH:16][C:5]([O:6][C@@H:7]2[CH2:8][C@H:9]([N:11]([CH3:23])[S:12]([CH3:15])(=[O:14])=[O:13])[CH2:10]2)=[CH:4][C:3]=1[CH3:19]
Reactant: CI
Reactant: Cc1cc(O[C@H]2C[C@@H](NS(C)(=O)=O)C2)cc(C)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(O[C@H]2C[C@@H](N(C)S(C)(=O)=O)C2)cc(C)c1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-(cis-3-(4-bromo-3,5-dimethylphenoxy)cyclobutyl)methanesulfonamide (130 mg) and sodium hydride (16 mg) are stirred in N,N-dimethylacetamide (2 mL) for 10 minutes. Iodomethane (0.1 mL) is added and the mixture is stirred at ambient temperature overnight. After cooling to ambient temperature, the mixture is concentrated, partitioned between ethyl acetate and water. The organic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate gradient of increasing polarity) to give the title compound. Yield: 110 mg.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[C:10](=[O:21])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18].B(Br)(Br)Br.O>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[C:10](=[O:21])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)CCCCCCC(=O)c1cc(C)ccc1OC
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: COC(=O)CCCCCCC(=O)c1cc(C)ccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.7 %

Procedure:
Methyl 8-(2-methoxy-5-methyl-phenyl)-8-oxo-octanoate (992 mg) was dissolved in methylene chloride (30 ml) to prepare a solution. 1 M boron tribromide (5.0 ml) was added at −78° C. to the solution, and the mixture was stirred at room temperature for 30 min. Water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography using acetone-hexane to give methyl 8-(2-hydroxy-5-methyl-phenyl)-8-oxo-octanoate (271 mg, yield 29%).
Reaction SMILES: [OH-].[Li+].[OH:3][C:4]1[C:5]([C:23]([O:25]C)=[O:24])=[N:6][C:7]([CH2:11][C:12]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:8][C:9]=1[OH:10]>O.O1CCCC1>[OH:3][C:4]1[C:9](=[O:10])[NH:8][C:7]([CH2:11][C:12]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:14][CH2:15][CH2:16]2)=[N:6][C:5]=1[C:23]([OH:25])=[O:24]
Reactant: COC(=O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1nc(CC2(c3ccccc3)CCCC2)[nH]c(=O)c1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 35.7 %

Procedure:
A solution of lithium hydroxide (7.66 mg, 320 μmol) in water (1.00 ml) was added to a stirred mixture of methyl 5,6-dihydroxy-2-((1-phenylcyclopentyl)methyl)pyrimidine-4-carboxylate (0.035 g, 107 μmol) in tetrahydrofuran (THF) (4 ml). The mixture was stirred at RT for 72 h and then quenched with amberlyst (H+) IE resin, filtered and evaporated to dryness. The residue was triturated with EtOAc and dried under vacuum to give the title product as a white solid (0.012 g; 32%). LCMS: m/z=315 (MH+).
Reaction SMILES: C(OC([N:8]([CH2:32][C:33]1[CH:51]=[CH:50][C:36]([C:37]([O:39][CH2:40][O:41]/[N:42]=[N+:43](\[O-:49])/[N:44]([CH2:47][CH3:48])[CH2:45][CH3:46])=[O:38])=[CH:35][CH:34]=1)[S:9]([C:12]1[CH:17]=[C:16]([C:18](=[O:30])[NH:19][N:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][CH:21]2[CH3:29])[CH:15]=[CH:14][C:13]=1[Cl:31])(=[O:11])=[O:10])=O)(C)(C)C.Cl>O1CCOCC1>[Cl:31][C:13]1[CH:14]=[CH:15][C:16]([C:18](=[O:30])[NH:19][N:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][CH:21]2[CH3:29])=[CH:17][C:12]=1[S:9]([NH:8][CH2:32][C:33]1[CH:34]=[CH:35][C:36]([C:37]([O:39][CH2:40][O:41]/[N:42]=[N+:43](\[O-:49])/[N:44]([CH2:45][CH3:46])[CH2:47][CH3:48])=[O:38])=[CH:50][CH:51]=1)(=[O:11])=[O:10]
Reactant: CCN(CC)/[N+]([O-])=N/OCOC(=O)c1ccc(CN(C(=O)OC(C)(C)C)S(=O)(=O)c2cc(C(=O)NN3c4ccccc4CC3C)ccc2Cl)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCN(CC)/[N+]([O-])=N/OCOC(=O)c1ccc(CNS(=O)(=O)c2cc(C(=O)NN3c4ccccc4CC3C)ccc2Cl)cc1
Temperature: 25 °C

Procedure:
Dissolve the compound obtained in Step C (4.74×10−4 mol) in 1,4-dioxane (5 ml). Place the solution under stirring at ambient temperature and then add 10 ml of a 4N solution of HCl in 1,4-dioxane. The initially yellowish reaction mixture becomes darker and darker until it is virtually black. After stirring for 2 days at ambient temperature, the reaction mixture is evaporated to dryness under reduced pressure. The black residue obtained is chromatographed on a silica column using as eluant a 50/50 n-heptane/ethyl acetate mixture.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[N:8][NH:7][C:6]=2[CH:10]=1.[OH-].[Na+].[Cl:13][CH2:14][CH2:15][CH2:16]Br>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:13][CH2:14][CH2:15][CH2:16][N:7]1[C:6]2[CH:10]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[N:9]=[N:8]1
Reactant: Fc1ccc2nn[nH]c2c1
Reactant: ClCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Product: Fc1ccc2nnn(CCCCl)c2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 32.3 %

Procedure:
6-fluoro-1H-benzotriazole (13.7 g, 0.10 mol) is dissolved into 100 ml of 30% wt. sodium hydroxide, 3-chlorobromopropane (31.4 g, 0.10 mol), tetrabutyl ammonium bromide (0.8 g) are added, and mixed for 5 min. The reaction solution is gradually heated to 60° C., stirred for reaction for 2 hours. Post treatment was performed based on common method one for synthesis. The solution was separated and purified by HPLC to produce 6.9 g of 1-(3-chloropropyl)-6-fluoro-1H-benzotriazole, with a yield of 32.3%.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][C@H:7]([CH:9]([CH3:11])[CH3:10])[N:6]([C:12]2[CH:17]=[CH:16][N:15]3[N:18]=[CH:19][C:20]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5[N:31]=[CH:30][N:29]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[N:28]=5)=[CH:23][CH:22]=4)=[C:14]3[N:13]=2)[C:5]1=[O:40].[CH3:41][C:42]1[CH:47]=[CH:46][C:45]([S:48](Cl)(=[O:50])=[O:49])=[CH:44][CH:43]=1>N1C=CC=CC=1>[CH3:41][C:42]1[CH:47]=[CH:46][C:45]([S:48]([O:1][CH2:2][CH2:3][N:4]2[CH2:8][C@H:7]([CH:9]([CH3:11])[CH3:10])[N:6]([C:12]3[CH:17]=[CH:16][N:15]4[N:18]=[CH:19][C:20]([C:21]5[CH:22]=[CH:23][C:24]([C:27]6[N:31]=[CH:30][N:29]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:37])([CH3:39])[CH3:38])[N:28]=6)=[CH:25][CH:26]=5)=[C:14]4[N:13]=3)[C:5]2=[O:40])(=[O:50])=[O:49])=[CH:44][CH:43]=1
Reactant: CC(C)[C@H]1CN(CCO)C(=O)N1c1ccn2ncc(-c3ccc(-c4ncn(COCC[Si](C)(C)C)n4)cc3)c2n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCN2C[C@H](C(C)C)N(c3ccn4ncc(-c5ccc(-c6ncn(COCC[Si](C)(C)C)n6)cc5)c4n3)C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
To a solution of (S)-1-(2-hydroxyethyl)-4-isopropyl-3-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)imidazolidin-2-one (Example 25, Step 6; 0.160 g, 0.284 mmol) in pyridine was added 4-methylbenzene-1-sulfonyl chloride (0.136 g, 0.711 mmol) and the reaction stirred overnight at ambient temperature. The reaction was next concentrated in vacuo and the reaction chromatographed using EtOAc as eluent to yield (S)-2-(4-isopropyl-2-oxo-3-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)imidazolidin-1-yl)ethyl 4-methylbenzenesulfonate (0.14 g, 68.7%).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]([O:20]C)=[O:19])=[N:10]2)=[C:4]([F:22])[CH:3]=1.[OH-].[Na+].Cl>CCO>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]([OH:20])=[O:19])=[N:10]2)=[C:4]([F:22])[CH:3]=1
Reactant: COC(=O)c1nn(-c2cc(F)c(Br)cc2F)cc(OC)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cn(-c2cc(F)c(Br)cc2F)nc(C(=O)O)c1=O
Yield: 101.8 %

Procedure:
A solution of methyl 1-(4-bromo-2,5-difluorophenyl)-5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate (25 g, 68 mmol) and 2 M NaOH aqueous solution (68 mL) in EtOH (68 mL) was stirred at room temperature overnight. The solvent was removed by evaporation and resulting aqueous solution was acidified by 6 M HCl aqueous solution (12 mL). The precipitate was collected by filtration and azeotroped with toluene to give the title compound (25 g, 100% yield) as a brown solid: LC-MS (ESI) m/z 376 [M+H]+.
Reaction SMILES: [Cl:1]/[CH:2]=[CH:3]/[CH2:4][O:5][C:6]1[C:14]2[S:13][C:12]([CH3:15])=[N:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[CH:16]1[C:26]2[CH2:25][CH2:24][C:23]3[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=3[CH:21]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[C:20]=2[CH:19]=[CH:18][CH:17]=1.Cl[CH2:38]/C=C/CCl>>[CH:27]1[C:23]2[CH2:24][CH2:25][C:26]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[CH:21]([N:31]3[CH2:32][CH2:33][N:34]([CH2:38]/[CH:2]=[CH:3]/[CH2:4][O:5][C:6]4[C:14]5[S:13][C:12]([CH3:15])=[N:11][C:10]=5[CH:9]=[CH:8][CH:7]=4)[CH2:35][CH2:36]3)[C:22]=2[CH:30]=[CH:29][CH:28]=1.[Cl:1]/[CH:2]=[CH:3]/[CH2:4][O:5][C:6]1[C:14]2[S:13][C:12]([CH3:15])=[N:11][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc2c(c1)CCc1ccccc1C2N1CCNCC1
Reactant: ClC/C=C/CCl
Agent: Cc1nc2cccc(OC/C=C/Cl)c2s1
Product: Cc1nc2cccc(OC/C=C/CN3CCN(C4c5ccccc5CCc5ccccc54)CC3)c2s1

Procedure:
The title compound was prepared according to Method GA from trans-7-(3-chloro-allyloxy)-2-methyl-benzothiazole and 1-(10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5-yl)piperazine. mp 151-152° C.; LSIMS m/z 496. The trans-7-(3-chloroallyloxy)-2-methyl-benzothiazole was prepared by Method IV with trans-1,4-dichloro-2-butene as the alkylating agent.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:31]=[CH:32][CH:33]=1)[C:7]([C:9]1[CH:10]=[CH:11][C:12]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[C:13]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH:14]=1)=O)([OH:3])=[O:2].Cl.[NH2:35][OH:36]>>[C:1]([C:4]1[CH:5]=[C:6]([C:7](=[N:35][OH:36])[C:9]2[CH:10]=[CH:11][C:12]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[C:13]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH:14]=2)[CH:31]=[CH:32][CH:33]=1)([OH:3])=[O:2]
Reactant: CCCCCCCCCCOc1ccc(C(=O)c2cccc(C(=O)O)c2)cc1CCC(=O)O
Reactant: NO
Agent: Cl
Product: CCCCCCCCCCOc1ccc(C(=NO)c2cccc(C(=O)O)c2)cc1CCC(=O)O
Yield: 81 %

Procedure:
The title product was also prepared in 81% yield directly from 5-(3-carboxybenzoyl)-2-(decyloxy)benzenepropanoic acid upon treatment with hydroxylamine hydrochloride according to the procedure of Example 51.