Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[N:22]=[CH:21][C:20]([CH2:23][N:24]2[CH:28]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:26]([CH:35]=O)=[CH:25]2)=[CH:19][CH:18]=1.C(OP([CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])(OCC)=O)C.O>CN(C)C=O>[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[N:22]=[CH:21][C:20]([CH2:23][N:24]2[CH:28]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:26](/[CH:35]=[CH:45]/[C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:25]2)=[CH:19][CH:18]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(C=O)c(-c3ccccc3)c2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)nc2)cc1-c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Sodium hydride (60%, oily, 190 mg) was added to a solution of 1-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethyl]-4-phenyl-3-pyrrolecarbaldehyde (1.05 g) and ethyl diethylphosphonoacetate (1.05 g) in N,N-dimethylformamide (50 ml) at 0° C., and the mixture was stirred at 0° C. for 2 hours. The reaction mixture was poured into water, and the precipitated crystals were collected by filtration to obtain ethyl(E)-3-[1-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethyl]-4-phenyl-3-pyrrolyl]propenoate. The crystals were dissolved in ethanol (80 ml), and hydrogenated on 5% palladium-carbon (800 mg) at room temperature under a normal pressure. The catalyst was filtered, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[1-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethyl]-4-phenyl-3-pyrrolyl]propionate (1.05 g, yield: 86%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume 5 ratio).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.[C:11](#[N:14])[CH:12]=[CH2:13].C[O-].[Na+]>CO.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.[F:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]([CH2:13][CH2:12][C:11]#[N:14])[C:7]#[N:8])=[CH:4][CH:3]=1
Reactant: C=CC#N
Agent: C[O-]
Agent: N#CCc1ccc(F)cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: N#CCCC(C#N)c1ccc(F)cc1
Reaction time: 2 h

Procedure:
Twenty-five g of 4-fluorobenzylcyanide is mixed with approximately 3.5 ml of freshly distilled acrylonitrile in a suitable reaction vessel. To this stirred mixture is added dropwise a solution of 80 mg of sodium methoxide in 1 ml of methanol. When about half of the sodium methoxide is added, there is an exothermic reaction. After all the sodium methoxide is added, the mixture is kept on a steam-bath for 2 hours and is then dissolved in toluene and washed with water. The toluene is removed by evaporation and the residue is separated into its components by fractional distillation to give 18 g of 4-fluorobenzylcyanide, and 2 g of 2-(4-fluorophenyl)glutaronitrile, bp 118°-122° C. at 0.03 mm.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.Br[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=1>>[OH:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:23][CH2:24][CH2:25][O:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:35])[F:36])[CH:28]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1
Reactant: FC(F)(F)c1cccc(OCCCBr)c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOc3cccc(C(F)(F)F)c3)cc2)C(O)C1

Procedure:
Analogously to Method I, 0.750 g of tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and 0.924 g of 1-(3-bromopropoxy)-3-trifluoromethylbenzene are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.28 (1:1 EtOAc-heptane); Rt=5.43.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)C.[CH3:8][C:9]([CH3:17])([C:11]([CH:13]1[CH2:16][CH2:15][CH2:14]1)=[O:12])[CH3:10].O>CS(C)=O.O1CCCC1>[C:9]([C:11]1([CH:13]2[CH2:16][CH2:15][CH2:14]2)[CH2:4][O:12]1)([CH3:17])([CH3:10])[CH3:8]
Reactant: C[S+](C)C
Reactant: CC(C)(C)C(=O)C1CCC1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC(C)(C)C1(C2CCC2)CO1
Temperature: 60 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
A suspension of sodium hydride (from 1.68 gms of petrol-washed 80% oil dispersion) in dimethylsulphoxide (40 mls) was stirred at 60° C. for 11/2 hours under a nitrogen atmosphere. The solution was cooled to 20° C., diluted with dry tetrahydrofuran (40 ml) and cooled to -5° C. A slurry of trimethylsulphonium iodide (11.42 gms) in dimethyl sulphoxide (30 mls) was added followed, after 10 minutes stirring, by a solution of the product of Stage 1 (4.9 g) in Tetrahydrofuran (30 mls). The mixture was stirred for 2 hours at -5° C., stood overnight at 20° C., and poured into water and extracted with petrol (30°-40° C.). The extracts were washed with brine, dried and evaporated to give 4.67 gms of yellow product. Gas chromatography showed 75% of a major component. The product was used without further purification.
Reaction SMILES: [CH2:1]=[C:2]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH2:7]2)[C:4](=[O:10])[O:3]1.[CH3:11][CH2:12][N:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15].[C-]#N.[K+]>C(#N)C>[CH2:12]([NH+:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH3:11].[OH:3][C:2]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH2:7]2)[C:4](=[O:10])[CH:1]=1
Reactant: C=C1OC(=O)C2CCC1C2
Reactant: CCN(C(C)C)C(C)C
Agent: [C-]#N
Agent: [K+]
Solvent: CC#N
Product: CC[NH+](C(C)C)C(C)C
Product: O=C1C=C(O)C2CCC1C2

Procedure:
Analogously to Example P3, 1.38 g (10 mmol) of 4-methylene-3-oxabicyclo[3.2.1]octan-2-one is stirred for a period of 12 hours in the presence of 1.29 g (10 mmol) of Hünig's base and 0.13 g of potassium cyanide in 10 ml of acetonitrile. Solid components (potassium salts) are filtered off and the filtrate is evaporated to dryness to yield the ethyldiisopropyl-ammonium salt of 4-hydroxybicyclo[3.2.1]oct-3-en-2-one in the form of a resin.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:17](Cl)(=O)[C:18](Cl)=O.[CH2:23]([C:30]1(C)[CH:34](C)[CH:33]=[CH:32][S:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O>[CH2:23]([C:30]1[S:31][C:17]([CH3:18])=[C:33]([CH3:32])[C:34]=1[C:9]([C:8]1[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:7]=1)=[O:11])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC1C=CSC1(C)Cc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(C(=O)O)cc1C1CCCC1
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)c2c(Cc3ccccc3)sc(C)c2C)cc1C1CCCC1
Yield: 52.3 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 2 using 3-cyclopentyl-p-anisic acid (5.0 g, 22.7 mmol, RN-59216-82-9), oxalyl chloride (2.4 mL, 27.2 mmol), N,N-dimethylformamide (2 drops) tin(IV) chloride (2.9 mL, 25.0 mmol) and 2-benzyl-2,3-dimethylthiophene (5.1 g, 25.0 mmol). Purification on silica gel eluting 5% EtOAc/pet. ether gave 4.8 g (52%) of the title compound as an amber oil. (DMSO-d6) δ 7.61-7.54 (m, 2H), 7.24-7.14 (m, 3H), 7.08-7.02 (m, 3H), 3.87 (s, 3H), 3.84 (s, 2H), 3.42-3.30 (m, 1H), 2.26 (s, 3H), 2.00-1.85 (m, 2H), 1.81 (s, 3H), 1.74-1.58 (m, 4H), 1.48-1.36 (m, 2H). mass spectrum (EI) m/z 404 (M+). Anal. Calc. for C26H28O2S: C, 77.19, H, 6.98, N, 0.00. Found: C, 76.26, H, 7.24, N, 0.04.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([N:21]4[N:25]=[N:24][C:23]([CH2:26][CH3:27])=[N:22]4)[C@@H:18]([OH:28])[C@H:17]3[OH:29])=[C:9]([NH:30][CH2:31][CH:32]([C:40]3[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=3)[C:33]3[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=3)[N:8]=2)[CH2:3]1.[ClH:47].C1(C(C2C=CC=CC=2)CNC2N=C(N3CC[C@@H](N[C:72]([NH:74][CH2:75][C:76]4[CH:81]=[CH:80][CH:79]=[CH:78][N:77]=4)=[O:73])C3)N=C3C=2N=CN3[C@@H]2C[C@H](N3N=NC(CC)=N3)[C@@H](O)[C@H]2O)C=CC=CC=1>>[ClH:47].[OH:46][C:43]1[CH:44]=[CH:45][C:40]([CH:32]([C:33]2[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=2)[CH2:31][NH:30][C:9]2[N:8]=[C:7]([N:4]3[CH2:5][CH2:6][C@@H:2]([NH:1][C:72]([NH:74][CH2:75][C:76]4[CH:81]=[CH:80][CH:79]=[CH:78][N:77]=4)=[O:73])[CH2:3]3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[C@@H:16]2[CH2:20][C@H:19]([N:21]3[N:25]=[N:24][C:23]([CH2:26][CH3:27])=[N:22]3)[C@@H:18]([OH:28])[C@H:17]2[OH:29])=[CH:41][CH:42]=1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)NCc6ccccn6)C5)nc43)[C@H](O)[C@@H]2O)n1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccc(O)cc5)c5ccc(O)cc5)nc(N5CC[C@@H](N)C5)nc43)[C@H](O)[C@@H]2O)n1
Agent: Cl
Product: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccc(O)cc5)c5ccc(O)cc5)nc(N5CC[C@@H](NC(=O)NCc6ccccn6)C5)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
This compound is prepared from (1R,2S,3R,5S)-3-{2-((R)-3-amino-pyrrolidin-1-yl)-6-[2,2-bis-(4-hydroxy-phenyl)-ethylamino]-purin-9-yl}-5-(5-ethyl-tetrazol-2-yl)-cyclopentane-1,2-diol (Example 106) using a procedure analogous to that of 1-((R)-1-{6-(2,2-diphenyl-ethylamino)-9-[(1R,2S,3R,4S)-4-(5-ethyl-tetrazol-2-yl)-2,3-dihydroxy-cyclopentyl]-9H-purin-2-yl}-pyrrolidin-3-yl)-3-pyridin-2-ylmethyl-urea hydrochloride (Example 113). MS (ES+) m/e 762.53 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:14]=[CH:15][C:16](=O)[NH:17][N:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][CH3:12].[Cl-:20].[Cl-].[Cl-].[P+3]=O>>[Cl:20][C:16]1[N:17]=[N:18][C:13]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH2:10][CH2:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:14][CH:15]=1
Reactant: CCCOc1ccc(-c2ccc(=O)[nH]n2)cc1OC
Reactant: [Cl-]
Agent: O=[P+3]
Product: CCCOc1ccc(-c2ccc(Cl)nn2)cc1OC

Procedure:
29.9 g of 6-(3-methoxy-4-n-propoxyphenyl)-3[2H]pyridazinone are introduced in portions into 65 ml of phosphorus oxide-trichloride, with stirring, and the mixture is then stirred at 100° for 1 hour. The reaction mixture is concentrated to half in vacuo and poured onto ice, with thorough stirring. The crystals which deposit are filtered off with suction, washed with water and dried in vacuo. 31.6 g of 3-chloro-6-(3-methoxy-4-n-propoxyphenyl)pyridazine are obtained.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([Cl:19])=[CH:13][C:12]=2[F:20])[CH2:7][C@@H:6]1[CH3:21])=[O:4].[NH:22]1[C:26]2=[N:27][CH:28]=[CH:29][CH:30]=[C:25]2[CH:24]=[N:23]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Cl:19][C:14]1[C:15]([O:17][CH3:18])=[CH:16][C:11]([N:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:22]3[C:26]4=[N:27][CH:28]=[CH:29][CH:30]=[C:25]4[CH:24]=[N:23]3)[C@@H:6]([CH3:21])[CH2:7]2)=[C:12]([F:20])[CH:13]=1.[Cl:19][C:14]1[C:15]([O:17][CH3:18])=[CH:16][C:11]([N:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:23]3[CH:24]=[C:25]4[C:26]([N:27]=[CH:28][CH:29]=[CH:30]4)=[N:22]3)[C@@H:6]([CH3:21])[CH2:7]2)=[C:12]([F:20])[CH:13]=1
Reactant: c1cnc2[nH]ncc2c1
Reactant: COc1cc(N2CCN(C(=O)CCl)[C@@H](C)C2)c(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(N2CCN(C(=O)Cn3cc4cccnc4n3)[C@@H](C)C2)c(F)cc1Cl
Product: COc1cc(N2CCN(C(=O)Cn3ncc4cccnc43)[C@@H](C)C2)c(F)cc1Cl
Temperature: 80 °C

Procedure:
2-Chloro-1-[4-(4-chloro-2-fluoro-5-methoxyphenyl)-2-(S)-methylpiperazin-1-yl]ethanone (arylpiperazine) (4.81 g, 14.32 mmol, 1 equiv), 1H-pyrazolo[3,4-b]pyridine (2.27 g, 17.18 mmol, 1.2 equiv), and potassium carbonate (20.00 g, 143.2 mmol, 10 equiv) were dissolved in dimethylformamide (DMF) (10 mL) and heated at 80° C. for 1 hour, then cooled to room temperature. The resultant mixture was diluted with ethyl acetate (300 mL), and washed with water (3×150 mL) and brine (100 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo to provide a crude residue. The crude residue was purified by flash chromatography (silica, 100% ethyl acetate with 1% triethylamine to 100% acetone with 1% triethylamine) provided 1-[4-(4-Chloro-2-fluoro-5-methoxyphenyl)-2-(S)-methylpiperazin-1-yl]-2-pyrazolo[3,4-b]pyridine-1-ylethanone (2.3 g) and 1-[4-(4-chloro-2-fluoro-5-methoxyphenyl)-2-(S)-methylpiperazin-1-yl]-2-pyrazolo[3,4-b]pyridine-2-ylethanone (2.5 g).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]([C:20]3[S:24][C:23]([NH:25][C:26]4[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=4)=[N:22][C:21]=3[NH2:38])[S:18][CH:19]=2)[CH:12]=[CH:13][CH:14]=1.N1C=CC=CC=1.CN(C=O)C>C1COCC1>[NH2:38][C:21]1[N:22]=[C:23]([NH:25][C:26]2[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=2)[S:24][C:20]=1[C:17]1[S:18][CH:19]=[C:15]([C:11]2[CH:10]=[C:9]([NH:8][C:1](=[O:3])[CH3:2])[CH:14]=[CH:13][CH:12]=2)[N:16]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(Nc2nc(N)c(-c3nc(-c4cccc(N)c4)cs3)s2)cc(OC)c1OC
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc(Nc2nc(N)c(-c3nc(-c4cccc(NC(C)=O)c4)cs3)s2)cc(OC)c1OC
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
Acetic anhydride (21.3 μL, 0.2250 mmol) was added to a solution of 4-(3-aminophenyl)-N2′-(3,4,5-trimethoxyphenyl)-[2,5′]bithiazolyl-2′,4′-diamine (50.0 mg, 0.1125 mmol), prepared as described in Example C(1), dissolved in pyridine (28.5 μL, 0.352 mmol), DMF (70 μL), and THF (700 μL) at −15° C. (bath temperature). After 30 minutes, the reaction was quenched with MeOH (0.5 mL), concentrated, and purified by preparative C-18 reverse-phase HPLC (gradient elution, 95% H2O/0.1% TFA/CH3CN to 5% H2O/0.1% TFA/CH3CN), giving 46 mg (82% yield) of N-{3-[4′-amino-2′-(3,4,5-trimethoxy-phenylamino)-[2,5′]bithiazolyl-4-yl]-phenyl}acetamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5](O)=O.C(N(CC)CC)C.ClC(OC[CH:24]([CH3:26])C)=O.C[NH:28][C:29](=[S:32])[NH:30][NH2:31]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[N:28]([CH2:24][CH3:26])[C:29]([SH:32])=[N:30][N:31]=2)[CH:8]=[C:9]([Cl:11])[CH:10]=1
Reactant: CC(C)COC(=O)Cl
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1
Reactant: CNC(=S)NN
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCn1c(S)nnc1-c1cc(Cl)cc(Cl)c1
Temperature: 70 °C
Reaction time: 0.75 h
Yield: 8.5 %

Procedure:
3,5-Dichloro-benzoic acid (382 mg, 2 mmol) was mixed with triethylamine (606 mg, 3 mmol) in THF (6 ml) at 10° C. Then isobutyl chloroformate (300 mg, 2.2 mmol) was added dropwise and stirred for 45 min. To the reaction mixture, 4-methyl-3-thiosemicarbazide (238.4 mg, 2 mmol) was added. After being stirred at room temperature for 10 min, the reaction mixture was heated to 70° C. overnight. Standard work-up. The product was purified by column chromatography with 25˜30% ethyl acetate in hexanes to give 46.4 mg (8.5%) of 5-(3,5-dichloro-phenyl)-4-ethyl-4H-[1,2,4]triazole-3-thiol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([CH2:14][C:15](O)=O)(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N:18]1[C:22]2[CH:23]=[CH:24][C:25]([C:27]([NH:29][NH2:30])=O)=[CH:26][C:21]=2[NH:20][CH:19]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1.O=P(Cl)(Cl)Cl>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([CH2:14][C:15]2[S:40][C:27]([C:25]3[CH:24]=[CH:23][C:22]4[NH:18][CH:19]=[N:20][C:21]=4[CH:26]=3)=[N:29][N:30]=2)(=[O:12])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccc(S(=O)(=O)CC(=O)O)cc1OC
Reactant: NNC(=O)c1ccc2nc[nH]c2c1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(S(=O)(=O)Cc2nnc(-c3ccc4[nH]cnc4c3)s2)cc1OC

Procedure:
The compound was synthesized starting from (3,4-dimethoxyphenylsulfonyl)acetic acid (261 mg; 1 mmol), benzimidazol-5-carbohydrazide (176 mg; 1 mmol), Lawesson's reagent (606 mg; 1.5 mmol) and POCl3 (0.137 ml; 1.5 mmol) as described in method 3 but purified by flash chromatography on silica using a CHCl3/MeOH gradient; yield: 0.026 g (6.3%); MS m/z: 417.2 [M+H]hu +; 1H-NMR (DMSO d6, 400 MHz): δ 3.76 (s, 3H); 3.81 (s, 3H); 5.38 (s, 2H); 7.13 (d, 1H3J=8.7 Hz); 7.30 (d, 1H, 4J=2.1 Hz); 7.36 (dd, 1H, 4J=2.1 Hz, 3J=8.7 Hz); 7.69-7.71 (m, 1H); 7.78-7.80 (m, 1H); 8.16 (br s, 1H); 8.35 (s, 1H); 12.76 (br s, 1H); HPLC (METHOD [A]): rt 10.63 min (97.8%)
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:12]=[C:11]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[N:10]([CH3:27])[N:9]=1)(=[O:3])[CH3:2].[I:28]N1C(=O)CCC1=O.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C.O.[Cl-].[Na+].O>[C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12]([I:28])=[C:11]([NH:13][S:14]([C:17]2[CH:18]=[CH:19][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:21][CH:22]=2)(=[O:15])=[O:16])[N:10]([CH3:27])[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCOc1cc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n(C)n1
Reactant: O=C1CCC(=O)N1I
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)OCCOc1nn(C)c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 2-{[5-({[4-(tert-butyl)phenyl]sulfonyl}amino)-1-methyl-1H-pyrazol-3-yl)oxy}ethyl acetate (Preparation 8) (1.15 g) in solution in tetrahydrofuran (200 ml) was added portionwise N-iodosuccinimide (18 g), at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction was then diluted with ethyl acetate (150 ml), water (50 ml) and brine (50 ml). A 1M solution of sodium metabisulphite (100 ml) was added and the organic layer separated. The organics were washed successively with a diluted solution of sodium metabisulphite (100 ml) and then brine (50 ml). The solution was dried on magnesium sulfate, filtered and concentrated under reduced pressure to yield the desired product as an off pink solid (33.6 g)
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][C:3]#[CH:4].[H-].[Na+].Cl[C:9]1[N:14]=[CH:13][CH:12]=[CH:11][N:10]=1>COCCOC.O1CCCC1.O>[CH2:1]([O:5][C:9]1[N:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH2:2][C:3]#[CH:4]
Reactant: C#CCCO
Reactant: Clc1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: C1CCOC1
Solvent: O
Product: C#CCCOc1ncccn1
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of but-3-yn-1-ol (4.59 g, 65.5 mmol) in 1,2-dimethoxyethane (120 mL) was added 60% sodium hydride (2.45 g, 61.1 mmol) under ice-cooling, and the mixture was stirred for 1 hr. A solution of 2-chloropyrimidine (5.00 g, 43.7 mmol) in tetrahydrofuran (30 mL) was added thereto, and the mixture was stirred at room temperature for 4 hr. The reaction solution was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80→60/40) to give the title compound (5.18 g, yield 80%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:16]2[CH2:17][CH2:18][CH2:19][CH2:20][C:21](=[O:22])[C:15]2=[CH:14][CH:13]=1)(=[O:10])=[O:9].[CH3:28]O>[Pd]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([O:22][CH3:28])[C:15]2=[CH:14][CH:13]=1)(=[O:10])=[O:9].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:15]2=[CH:14][CH:13]=1)(=[O:10])=[O:9]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1CCCCC2=O
Reactant: CO
Agent: [Pd]
Product: COC(=O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1CCCCC2
Product: COC(=O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1CCCCC2OC

Procedure:
A solution of Example 510F (3.47 g, 8.87 mmol) in 100:1 methanol/concentrated HCl (152 mL) was added to 10% Pd/C (700 mg). The resulting suspension was reacted under 60 psi H2 at 50° C. for 16 hours and filtered. The filtrate was concentrated and purified by flash chromatography to provide Example 510G (methyl 2-{[(2-fluorophenyl)sulfonyl]amino}-5-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulene-1-carboxylate) (1.16 g, 32%) and Example 510H (methyl 2-{[(2-fluorophenyl)sulfonyl]amino}-6,7,8,9-tetrahydro-5H-benzo[7]annulene-1-carboxylate) (1.05 g, 31%). Example 510G: MS (ESI(+)) m/e 408 (M+H)+, 425 (M+NH4)+; MS (ESI(−)) m/e 406 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 10.00 (br s, 1H), 7.69 (m, 2H), 7.42 (t, 1H), 7.31 (t, 1H), 7.28 (d, 1H), 7.00 (d, 1H), 4.37 (d, 1H), 3.65 (s, 3H), 3.21 (s, 3H), 2.70 (m, 1H), 2.49 (m, 1H), 1.61 (m, 2H), 1.59 (m, 3H), 1.37 (m, 1H). Example 510H: MS (ESI(+)) m/e 378 (M+H)+, 395 (M+NH4)+, 400 (M+Na)+; MS (ESI(−)) m/e 376 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 9.86 (br s, 1H), 7.61 (m, 2H), 7.35 (dd, 1H), 7.24 (td, 1H), 7.06 (d, 1H), 6.81 (d, 1H), 3.58 (s, 3H), 2.67 (t, 2H), 2.50 (m, 2H), 1.65 (m, 2H), 1.42 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][N:24]4[CH2:28][CH2:27][NH:26][C:25]4=[O:29])=[N:21][CH:22]=3)[C:9]=2[F:30])[CH:5]=[CH:6][CH:7]=1.[CH2:31]1COCC1.[H-].[Na+].CI>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][N:24]4[CH2:28][CH2:27][N:26]([CH3:31])[C:25]4=[O:29])=[N:21][CH:22]=3)[C:9]=2[F:30])[CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: COc1ccc(Cc2ccc(CN3CCNC3=O)nc2)c(F)c1-c1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COc1ccc(Cc2ccc(CN3CCN(C)C3=O)nc2)c(F)c1-c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Into an 8 mL vial was added P-374 (21 mg, 0.05 mmol), THF (1 mL) and the solution was cooled to 0° C. Sodium hydride (3 mg, 0.076 mmol) was added and after 15 minutes at room temperature, methyl iodide (6 uL, 0.101 mmoL) was added. The reaction was stirred for 30 minutes at room temperature and then 1 mL of water was added. The THF was evaporated and the product was extracted with ethyl acetate and concentrated. The residue was passed through a silica gel plug eluting with methanol, which afforded P-375 (18.1 mg, 82%) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) 8.42 (d, J=1.6 Hz, 1H), 7.60 (dd, J=2.0, 7.9 Hz, 1H), 7.50-7.39 (m, 2H), 7.37 (s, 1H), 7.34 (t, J=8.7 Hz, 1H), 7.28 (d, J=6.4 Hz, 1H), 7.19 (d, J=8.1 Hz, 1H), 6.94 (d, J=8.5 Hz, 1H), 4.31 (s, 2H), 3.95 (s, 2H), 3.72 (s, 3H), 3.24 (s, 4H), 2.67 (s, 3H) ppm. LC/MS=97.8%, 440.1 (APCI+).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[C:17]([CH2:18][C:19]([OH:21])=[O:20])=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH3:22][C:23]1([CH3:30])[O:27][CH:26]([CH2:28]O)[CH2:25][O:24]1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:1]1([C:7]2[O:8][C:9]3[C:17]([CH2:18][C:19]([O:21][CH2:28][CH:26]4[CH2:25][O:24][C:23]([CH3:30])([CH3:22])[O:27]4)=[O:20])=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: O=C(O)Cc1cccc2c(=O)cc(C3=CCCCC3)oc12
Reactant: CC1(C)OCC(CO)O1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC1(C)OCC(COC(=O)Cc2cccc3c(=O)cc(C4=CCCCC4)oc23)O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
[2-(1-Cyclohexenyl)-4-oxo-4H-[1]-benzopyran-8-yl]acetic acid (2.84 g), 2,2-dimethyl-1,3-dioxolan-4-methanol (3.96 g) and dicyclohexylcarbodiimide (2.28 g) were added to dichloromethane (30 ml) with ice cooling and then the mixture was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (2.65 g), yield 67%, m.p. 104°-105° C. (recrystallized from ethyl acetate).