Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[C:4]([O:11][CH3:12])[CH:3]=1.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=1[F:30])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[C:24]2[CH:25]=[CH:26][C:21]([O:20][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[C:22]([F:30])[CH:23]=2)=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Reactant: COc1cc(Br)cc2[nH]ncc12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(Br)cc2c1cnn2-c1ccc(OCc2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 120 h
Yield: 65.4 %

Procedure:
To a solution of 6-bromo-4-(methyloxy)-1H-indazole (1.0 g, 4.40 mmol) in dichloromethane (50 mL) was added 4-benzyloxy-3-fluorobenzeneboronic acid (2.16 g, 8.80 mmol), pyridine (0.71 mL, 8.79 mmol), copper acetate (1.2 g, 6.62 mmol) and powdered 4A molecular sieves (2 g). The reaction mixture was stirred at room temperature in the presence of air for 5 days. Celite was added to the mixture and stirred for 10 mins then the mixture was filtered through a pad of celite and then the filtrate was washed with dichloromethane, then washed with water, dried over magnesium sulphate, filtered and concentrated. The product was purified by silica gel chromatography eluting with 5-30% ethyl acetate in hexane to yield the title compound (D9) (1.23 g).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][N:17]([CH3:20])[CH:18]=O>>[C:1]1([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[CH:16]2[N:8]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH2:7][CH2:18][N:17]2[C:20]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)C=O
Reactant: c1ccc(-c2cc3ccccc3[nH]2)cc1
Product: c1ccc(-c2[nH]c3ccccc3c2C2N(c3ccccc3)CCN2c2ccccc2)cc1

Procedure:
4.44 parts by weight of bis-[1,3-diphenyl-imidazolidin-(2)-ylidene] and 3.86 parts by weight of 2-phenylindole in 20 parts by volume of dimethylformamide are heated under nitrogen for 5 hours to boiling point. A little unreacted bis-[ 1,3-diphenyl-imidazolidin-(2)-ylidene] is filtered off while still warm, the solvent is removed partly in vacuo and 2-(2-phenylindol-3-yl)-1,3-diphenyl-imidazolidine is obtained in the form of colourless crystals melting at 237°-238° C (from toluene) ##STR15##
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[C:16]([F:19])[CH:15]=[CH:14][CH:13]=3)[C:5]([CH:8]=[CH2:9])=[N:6][CH:7]=1.[ClH:20].O1CCOCC1>>[Br:1][C:2]1[CH:3]=[C:4]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[C:16]([F:19])[CH:15]=[CH:14][CH:13]=3)[C:5]([CH2:8][CH2:9][Cl:20])=[N:6][CH:7]=1
Reactant: Cl
Reactant: C=Cc1ncc(Br)cc1-c1cc2c(F)cccc2[nH]1
Solvent: C1COCCO1
Product: Fc1cccc2[nH]c(-c3cc(Br)cnc3CCCl)cc12
Yield: 90 %

Procedure:
A solution of 2-(5-bromo-2-vinylpyridin-3-yl)-4-fluoro-1H-indole (800 mg, 2.52 mmol) in 20 mL of HCl/1,4-dioxane (4 mol/L) was heated at 80° C. for 2 hours and then the mixture was concentrated in vacuo to give the crude 2-(5-bromo-2-(2-chloroethyl)pyridin-3-yl)-4-fluoro-1H-indole (800 mg, yield: 90%) which was used directly in the next step without further purification. 1H-NMR (CDCl3, 400 MHz) δ 8.76 (s, 1H), 8.66 (s, 1H), 7.93 (s, 1H), 7.14˜7.22 (m, 2H), 6.73˜6.86 (m, 1H), 6.72 (s, 1H), 4.07˜4.10 (m, 2H), 3.35˜3.36 (m, 2H). MS (M+H)+: 353/355.
Reaction SMILES: Cl.[CH:2]1([N:7]2[C:11]3=[N:12][C:13]([C:17]4[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=4)=[N:14][C:15](=[O:16])[C:10]3=[C:9]([CH2:24][CH3:25])[NH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:26][S:27](Cl)(=[O:29])=[O:28].O>N1C=CC=CC=1>[CH4:2].[CH:2]1([N:7]2[C:11]3=[N:12][C:13]([C:17]4[CH:18]=[CH:19][C:20]([NH:23][S:27]([CH3:26])(=[O:29])=[O:28])=[CH:21][CH:22]=4)=[N:14][C:15](=[O:16])[C:10]3=[C:9]([CH2:24][CH3:25])[NH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CS(=O)(=O)Cl
Reactant: CCc1[nH]n(C2CCCC2)c2nc(-c3ccc(N)cc3)nc(=O)c1-2
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: C
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3ccc(NS(C)(=O)=O)cc3)nc(=O)c1-2
Temperature: 25 °C
Reaction time: 48 h
Yield: 143.6 %

Procedure:
To a mixture of 1-cyclopentyl-3-ethyl-6-(4-aminophenyl)pyrazolo[3,4-d]pyrimidin-4-one hydrochloride 1/3 hydrate (0.61 g, 1.7 mmol) in dry pyridine (20 ml) in an ice bath was added methanesulfonyl chloride (0.49 g, 4.25 mmol). The reaction mixture was stirred at room temperature for about two days, the solvent was stripped to dryness and the residue was treated with water. The product was collected by filtration and recrystallized from ethanol, after DARCO® treatment, to afford 0.49 g (72%) of 1-cyclopentyl-3-ethyl-6-[4-(methylsulfonylamino)phenyl]pyrazolo[3,4-d]pyrimidin-4-one, m.p. 325° C. (dec.).
Reaction SMILES: [C:1]1([C:7](=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][Cl:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([NH:19][CH2:20][CH3:21])[CH3:18]>>[ClH:9].[CH2:17]([N:19]([CH2:8][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:20][CH3:21])[CH3:18]
Reactant: ClCC(=Cc1ccccc1)c1ccccc1
Reactant: CCNCC
Product: CCN(CC)CC(=Cc1ccccc1)c1ccccc1
Product: Cl
Reaction time: 24 h

Procedure:
A solution consisting of 4 parts of 2,3-diphenylallyl chloride dissolved in 7.12 parts of diethylamine is allowed to stand at 65° for about 24 hours. Then the excess diethylamine is removed under nitrogen and the oil and solid which remain are covered with n-hexane. The solid is separated by filtration and the filtrate is acidified by adding isopropanolic hydrochloric acid. The oil which separates is then isolated by decantation and crystallized from isopropanol-ethyl ether to yield pure N,N-diethyl-2,3-diphenylallylamine hydrochloride, melting at about 190° and displaying maxima in the nuclear magnetic resonance spectrum at about 70, 76, 82, 162-190, 242, 246 and 422-436 Hertz. That compound is represented by the following structural formula ##STR4##
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH2:9][CH2:8][N:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]1=[O:18])=[O:4].[I-:19].[Na+]>CC(C)=O>[I:19][CH2:2][C:3]([N:5]1[CH2:9][CH2:8][N:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]1=[O:18])=[O:4]
Reactant: [I-]
Reactant: CC(C)(C)OC(=O)NN1CCN(C(=O)CBr)C1=O
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NN1CCN(C(=O)CI)C1=O

Procedure:
N-[3-(Bromoacetyl)-2-oxo-1-imidazolidinyl]carbamic acid, 1,1-dimethylethyl ester (20.9 g, 65 mmol) was dissolved in acetone (250 ml) containing sodium iodide (10.5 g, 70 mmol). The solution was stirred at reflux for three hours and filtered hot through Celite. The solution was evaporated in vacuo to give the title compound as a light yellow solid, 23.9 g.
Reaction SMILES: C1COCC1.[Cl:6][C:7]1[CH:8]=[C:9]([CH2:23][CH2:24][NH:25][C:26](=[O:29])[CH2:27][CH3:28])[CH:10]=[C:11]([CH2:14][O:15][Si](C(C)(C)C)(C)C)[C:12]=1[Cl:13].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CCOCC>[Cl:6][C:7]1[CH:8]=[C:9]([CH2:23][CH2:24][NH:25][C:26](=[O:29])[CH2:27][CH3:28])[CH:10]=[C:11]([CH2:14][OH:15])[C:12]=1[Cl:13]
Reactant: CCC(=O)NCCc1cc(Cl)c(Cl)c(CO[Si](C)(C)C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(=O)NCCc1cc(Cl)c(Cl)c(CO)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a THF (0.12 M) solution of N-{2-[3,4-dichloro-5-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)phenyl]ethyl}propanamide (1 eq.) from the previous step was added TBAF (1.0 M THF solution, 1.1 eq.). The resulting solution was stirred at RT for 2 h. The now orange solution was diluted with ether and quenched with 1 N aq. NaOH. The aqueous layer was separated and back-extracted with ether. The combined organic extracts were washed further with water and brine, dried over Na2SO4 and filtered. Concentration of the filtrate in vacuo afforded the crude title compound as a pale yellow oil.
Reaction SMILES: [ClH:1].[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([NH2:9])=[NH:8].Br.CC1SC(C(OC(C)C)=O)=CC=1[C:23]1[N:24]=[C:25]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[S:26][CH:27]=1.[C:35]1(NC(N)=S)C=CC=CC=1>>[ClH:1].[CH3:35][C:6]1[S:2][C:3]([C:7]([NH2:9])=[NH:8])=[CH:4][C:5]=1[C:23]1[N:24]=[C:25]([NH:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[S:26][CH:27]=1
Reactant: NC(=S)Nc1ccccc1
Reactant: Cc1sc(C(=O)OC(C)C)cc1-c1csc(Nc2ccccc2)n1
Reactant: N=C(N)c1cccs1
Agent: Br
Agent: Cl
Product: Cc1sc(C(=N)N)cc1-c1csc(Nc2ccccc2)n1
Yield: 28 %

Procedure:
5-Methyl-4-[2-phenylamino)(1,3-thiazol-4-yl)]thiophene-2-carboxamidine hydrochloride: Isopropyl 5-methyl-4-[2-(phenylamino)(1,3-thiazol-4-yl)]-thiophene-2-carboxylate hydrobromide (74 mg, 0.16 mmol) was treated with phenylthiourea (24.3 mg) as described in Example 154, step (b) to give 15 mg (28% yield) (of 5-methyl-4-[2-(phenylamino)(1,3-thiazol-4-yl)]thiophene-2-carboxamidine hydrochloride, which was further purified by recrystallization from methanol-water. 1H NMR (DMSO-d6, 300 MHz) δ 2.79 (s, 3H), 6.96 (t, 1H, J=7.2 Hz), 7.09 (s, 1H), 7.33 (t, 2H, J=7.5 Hz), 7.71 (d, 2H, J=7.7 Hz), 8.39 (s, 1H), 8.95 (bs, 2H), 9.33 (bs, 2H), 10.37 (s, 1H); Mass Spectrum (ESI) m/z calcd. for C15H14N4S3, 314.4 (M+H), found 315.2.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9]([CH3:26])=[N:10][N:11]([CH:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[CH:12]=2)=[CH:4][C:3]=1[C:27]1[O:28][C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=1.C(O)(C(F)(F)F)=O>ClCCl.C(#N)C>[O:28]1[C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=[C:27]1[C:3]1[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([C:8]2[C:9]([CH3:26])=[N:10][N:11]([CH:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)[CH:12]=2)[CH:4]=1
Reactant: Cc1nn(C2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1cnc(N)c(-c2nc3ccccc3o2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Cc1nn(C2CCNCC2)cc1-c1cnc(N)c(-c2nc3ccccc3o2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.5 %

Procedure:
To a solution of tert-butyl 4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-3-methyl-pyrazol-1-yl]piperidine-1-carboxylate (500 mg) in dichloromethane (3 ml) was added TFA (1 ml). The solution was stirred at 25° C. for 2 hours. The mixture was evaporated to dryness, then the residue was diluted in dichloromethane and ammonia in methanol 7N was added. After removal of solvents, the crude product was purified by flash chromatography on silica gel eluting with 10% methanol in dichloromethane followed by 10 to 25% methanolic ammonia (7 N) in dichloromethane. The solvent was evaporated to dryness to afford a solid which was stirred in acetonitrile overnight, filtered and dried to afford 3-(1,3-benzoxazol-2-yl)-5-[3-methyl-1-(4-piperidyl)pyrazol-4-yl]pyridin-2-amine (290 mg) as a solid; NMR Spectrum: (DMSOd6) 1.77 (dd, 1H), 1.82 (dd, 1H), 1.93-1.99 (m, 2H), 2.12 (bs, 1H), 2.32 (s, 3H), 2.58 (ddd, 1H), 3.01-3.07 (m, 2H), 4.06-4.25 (m, 1H), 7.41-7.48 (m, 2H), 7.64 (bs, 2H), 7.80 (dd, 1H), 7.84 (dd, 1H), 8.04 (s, 1H), 8.28 (d, 1H), 8.35 (d, 1H); Mass spectrum: M+H+: 375
Reaction SMILES: Cl[CH:2]=[CH:3][C:4]#[C:5][Si:6]([CH3:9])([CH3:8])[CH3:7].C(NCC)C.[C:15]1([O:21][C:22]([N:24]2[CH:37]([C:38]#[CH:39])[C:36]34[O:40][C:31]3([C:32](=[O:41])[CH2:33][CH2:34][CH2:35]4)[C:30]3[CH:29]=[CH:28][C:27]([O:42][C:43](=[O:48])[C:44]([CH3:47])([CH3:46])[CH3:45])=[CH:26][C:25]2=3)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[C:15]1([O:21][C:22]([N:24]2[CH:37]([C:38]#[C:39]/[CH:2]=[CH:3]\[C:4]#[C:5][Si:6]([CH3:9])([CH3:8])[CH3:7])[C:36]34[O:40][C:31]3([C:32](=[O:41])[CH2:33][CH2:34][CH2:35]4)[C:30]3[CH:29]=[CH:28][C:27]([O:42][C:43](=[O:48])[C:44]([CH3:46])([CH3:45])[CH3:47])=[CH:26][C:25]2=3)=[O:23])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C[Si](C)(C)C#CC=CCl
Reactant: C#CC1N(C(=O)Oc2ccccc2)c2cc(OC(=O)C(C)(C)C)ccc2C23OC12CCCC3=O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: c1ccccc1
Product: CC(C)(C)C(=O)Oc1ccc2c(c1)N(C(=O)Oc1ccccc1)C(C#C/C=C\C#C[Si](C)(C)C)C13CCCC(=O)C21O3
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32 %

Procedure:
A mixture of Pd(PPh3)4 (185 mg, 0.16 mmol), 1-chloro-4-(trimethylsilyl)-but-1-en-3-yne (0.776 g, 4.89 mmol), and diethylamine (0.51 mL, 4.93 mmol) in degassed benzene (5 mL) was stirred at 25° C. for 15 minutes. The resultant solution was added to a mixture of Compound 230 (1.50 g, 3.26 mmol) and CuI (124 mg, 0.65 mmol) in degassed benzene (15 mL) via a syringe followed by stirring at 25° C. for one hour. The reaction mixture was quenched by saturated aqueous NH4Cl, extracted with ethyl ether (80 mL), washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. Purification of the residue by flash column chromatography (silica gel, 25 percent ethyl ether in petroleum ether) provided a solid product Compound 231 (0.606 g, 32 percent): Rf =0.43 (silica, 50 percent ethyl ether in petroleum ether); IR (CHCl3) νmax 2964, 1721, 1494, 1378, 1305, 1270, 1253, 1202, 1181, 1122, 846 cm-1 ; 1H NMR (300 MHz, CDCl3) δ 8.40 (d, J=8.7 Hz, 1 H, H1), 7.44-7.10 (m, 6 H, H4 and aromatic), 6.99 (dd, J=8.7, 2.4 Hz, 1 H, H2), 5.98 (d, J=1.5 Hz, 1 H, H6), 5.84 (d, J=11.1 Hz, 1 H, olefinic), 5.69 (br d, J=11.1 Hz, 1 H, olefinic), 2.81-2.66 (m, 2 H, H9), 2.41-2.26 (m, 2 H, H7), 2.10-1.86 (m, 2 H, H8), 1.33 (s, 9 H, COC(CH3)3), 0.22 (s, 9 H, SiC(CH3)3); MS (FAB+) m/e (rel intensity) 582 (M+H, 100), 525 (13), 460 (48), 406 (8), 360 (6), 320 (8), 279 (25), 246 (5);HRMS for C34H36NO6Si (M+H), calcd 582.2312, found 582.2322.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@:5]1([NH:10]C(OC(C)(C)C)=O)[CH2:7][C@H:6]1[CH:8]=[CH2:9])=[O:4].[ClH:18].CO>O1CCOCC1>[ClH:18].[CH3:1][O:2][C:3]([C@@:5]1([NH2:10])[CH2:7][C@H:6]1[CH:8]=[CH2:9])=[O:4]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)OC
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C=C[C@@H]1C[C@]1(N)C(=O)OC
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 76 %

Procedure:
Compound 20a (39.96 g, 165.7 mmol) was dissolved in dioxane (25 mL) and the solution added dropwise with stirring to 4 N HCl in dioxane (Aldrich, 250 mL). After 45 min, TLC analysis indicated complete deprotection. Volatiles were removed under reduced pressure, and the residue co-evaporated twice with MeOH (2×100 mL). Ether (300 mL) and MeOH (10 mL) were added to the brown, oily residue and the mixture stirred overnight at room temperature resulting in the precipitation of a semi-solid. Additional MeOH (15 mL) was added and stirring continued for 6 h, at which point a yellowish solid was collected by filtration. The product was washed with 5% MeOH in ether (50 mL) and ether (2×50 mL), and dried in vacuo to give compound 20b as a yellowish solid (22.60 g, 76% yield). Filtrates (including washings) were evaporated in vacuum to give additional 20b as a brown oil (7.82 g, 26% yield). Both fractions were pure enough for use in the synthesis of HCV protease inhibitors: [α]D25 +38.2° (c 1.0, MeOH).
Reaction SMILES: [Br:1][C:2]1[O:6][CH:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.C(N(CC)CC)C.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][C:20]=1[N:26]1[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1>S(Cl)(Cl)=O>[Br:1][C:2]1[O:6][CH:5]=[C:4]([C:7]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[C:20]([N:26]3[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]3)[CH:21]=2)=[O:9])[CH:3]=1
Reactant: O=C(O)c1coc(Br)c1
Reactant: COc1ccc(N)cc1N1CCN(C)CC1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: COc1ccc(NC(=O)c2coc(Br)c2)cc1N1CCN(C)CC1
Reaction time: 18 h

Procedure:
5-Bromo-3-furancarboxylic acid (0.302;1.58 mmol) was heated at reflux in thionyl chloride (8 ml) for 30 minutes, cooled, evaporated in vacuo and the residue azeotroped with toluene. The residue was redissolved in CH2Cl2 (10 ml) and treated with dry triethylamine (0.22 ml; 1.58 mmol) and 4-methoxy-3-(4-methyl-1-piperazinyl)benzenamine (0.35 g;1.58 mmol). The solution was stirred under Ar (18 hours), evaporated in vacuo and partitioned satd. K2CO3 (aq)/EtOAc. The organic phases were combined, dried over Na2SO4, filtered and the filtrate evaporated in vacuo to a brown gum. The gum was purified by flash silica-gel chromatography and eluted with 3%MeOH/CHCl3 to yield the title compound as a tan solid after trituration with Et2O (0.3 g;48%), mp=185°-187° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([F:25])[CH:19]=1>O1CCCC1>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:2]=2[OH:1])=[C:20]([F:25])[CH:19]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: COc1ccc(C(=O)O)c(O)c1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2ccc(Cl)cc2F)c(O)c1

Procedure:
To a solution of 2-hydroxy-4-methoxybenzoic acid (1.68 g, 10 mmole) in tetrahydrofuran (40 mL) was added thionyl chloride (2.5 mL, 35 mmole) and refluxed 3 hr. The mixture was steamed (110° C.) by Dean-Stark. The residue was directly reacted with 4-chloro-2-fluorobenzenamine (1.1 mL, 10 mmole) in THF (40 mL) for 14 hr. The reaction mixture was concentrated and extracted with ethyl acetate, dried over anhydrous magnesium sulfate. Recrystallization of desired products from hot dichloromethane afforded the compound.
Reaction SMILES: [CH:1]1[CH2:8][CH2:7][CH:6]=[CH:5][CH2:4][CH2:3][CH:2]=1.CC(O)C>[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Rh].[Rh].[Rh].[Rh].CC(C)=O>[CH:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH2:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1=CCCC=CCC1
Agent: [Rh]
Agent: [C-]#[O+]
Solvent: CC(C)O
Solvent: CC(C)=O
Product: C1=CCCCCCC1
Product: C1CCCCCCC1
Reaction time: 0.17 h

Procedure:
0.3 ml of 1,5-cyclooctadiene, 32 ml of 2-propanol, 8 ml of acetone and 3 mg of tetrarhodiumdodecacarbonyl [Rh4 (CO)12 ] were fed into the same quartz cell as that used in the Example 1. Nitrogen gas was bubbled through the contents under stirring for 10 minutes and thereafter, the irradiation of the cell with light was started. The stirring was conducted with a magnetic stirrer. The reaction cell was put in a quartz-window thermostatic chamber to keep the reaction temperature at 20° C. In the irradiation, the rays which were emitted from a 500-W high-pressure mercury lamp set on an irradiation apparatus as an outer light source and passed through a filter UV-25, mfd. by Toshiba Corporation, were used. After the irradiation had been conducted for 5.5 hours in such a manner, the reaction solution was analyzed by gas chromatography. Cyclooctene was obtained in a yield of 79% with the formation of cyclooctane in a yield of 16%. 5% of unreacted 1,5-cyclooctadiene remained.
Reaction SMILES: [NH2:1][C:2]1[S:12][C:5]2[CH2:6][N:7]([CH2:10][CH3:11])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:13]([NH2:15])=[O:14].[O-:16][C:17]#[N:18].[Na+]>C(O)(=O)C.O>[CH2:10]([N:7]1[CH2:8][CH2:9][C:4]2[C:3]([C:13]([NH2:15])=[O:14])=[C:2]([NH:1][C:17]([NH2:18])=[O:16])[S:12][C:5]=2[CH2:6]1)[CH3:11]
Reactant: CCN1CCc2c(sc(N)c2C(N)=O)C1
Reactant: N#C[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCN1CCc2c(sc(NC(N)=O)c2C(N)=O)C1
Reaction time: 2 h
Yield: 23.3 %

Procedure:
To a stirred mixture of compound F4 (451 mg, 2.00 mmol) in acetic acid (6 mL) at room temperature was added a solution of sodium cyanate (169 mg, 2.60 mmol) in water (2.5 mL) dropwise over 2 min. After addition, the reaction mixture was stirred for another 2 h and then concentrated under reduced pressure. The resulting residue was mixed with saturated aqueous sodium bicarbonate (50 mL) and extracted with methylene chloride (3×150 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel eluting with methanol/methylene chloride (15:85) to afford compound M1 as a yellow solid (125 mg, 23%): 1H NMR (300 MHz, DMSO-d6) δ 10.45 (s, 1H), 7.31 (bs, 1H), 6.77 (bs, 3H), 3.41 (s, 2H), 2.73 (d, J=4.8 Hz, 2H), 2.63 (d, J=4.8 Hz, 2H), 2.50-2.45 (m, 2H), 1.06 (t, J=7.0 Hz, 3H). MS (M+H) 269.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[S:11]([NH2:14])(=[O:13])=[O:12].CO.[H][H]>[Pd].O1CCCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[S:11]([NH2:14])(=[O:12])=[O:13]
Reactant: [H][H]
Reactant: Nc1ccc([N+](=O)[O-])cc1S(N)(=O)=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(N)c(S(N)(=O)=O)c1
Temperature: 23 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
2-Amino-5-nitro-benzenesulfonamide (5.00 kg, 23.0 mol), methanol (65 L), tetrahydrofuran (65 L), and 10% palladium on carbon (250 g) were charged to an autoclave. The mixture was cycled with nitrogen and hydrogen purges (3×), and the mixture was then stirred under hydrogen (50 psi) at 23° C. overnight. The catalyst was removed by filtration and the filtrate was then concentrated in vacuo to give a brown solid. The solid was further dried in vacuo at 45° C. to afford the desired product, 2,5-diamino-benzenesulfonamide (4.21 kg, 22.4 mol, 98%), as a solid. 1H NMR (400 MHz, DMSO-d6) δ: 4.54 (2H, bs), 4.98 (2H, bs), 6.55-6.60 (2H, m), 6.87 (1H, d, J=2.2 Hz), 6.99 (2H, bs). LC-MS (ESI) calcd for C6H9N3O2S 187.04, found 188.3 [M+H+].
Reaction SMILES: ClC1C=CC=[C:4]([C:8]([O:10]O)=O)C=1.CC1(C)CO[CH:16]([CH:19]([C@@H:21]2[C@:38]3([CH3:39])[C@H:24]([C@H:25]4[C@H:35]([CH2:36][CH2:37]3)[C@:33]3([CH3:34])[C:28](=[CH:29][C:30](=[O:41])[C@@H:31]5[O:40][C@@H:32]53)C=C4)[CH2:23][CH2:22]2)C)OC1>C(Cl)(Cl)Cl>[O:40]1[C:31]2=[C:32]3[C@:33]([CH3:34])([CH2:28][CH2:29][C:30]2=[O:41])[C@@H:35]2[C@H:25]([C@H:24]4[C@:38]([CH3:39])([CH2:37][CH2:36]2)[C@@H:21]([CH2:19][CH3:16])[CH2:22][CH2:23]4)[C@@H:4]2[O:10][C@:8]123
Reactant: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC[C@H]1CC[C@H]2[C@@H]3[C@@H]4O[C@]45OC4=C5[C@](C)(CCC4=O)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 72 h
Yield: 76 %

Procedure:
A solution of 0.664 g (3.85 mmoles) of m-chloroperbenzoic acid in 50 ml of chloroform was mixed with a solution of 0.328 g (0.769 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregna-4,6-dien-3-one in 10 ml of chloroform and the resulting mixture was stirred at room temperature for 3 days. The reaction mixture was filtered and the precipitate was washed with chloroform. The filtrate and the washings were combined, diluted with chloroform and washed successively with aqueous potassium iodide solution and aqueous sodium chloride solution. Finally the organic layer was dried over magnesium sulfate and the solvent was then distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane: 1:10, v/v) to recover 0.258 g of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α;6α,7α-diepoxypregn-4-en-3-one (yield: 76%).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10].O=S(Cl)[Cl:15]>C(Cl)Cl>[ClH:15].[Cl:15][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10]
Reactant: O=S(Cl)Cl
Reactant: OCc1cnccc1C(F)(F)F
Solvent: ClCCl
Product: Cl
Product: FC(F)(F)c1ccncc1CCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3-hydroxymethyl-4-trifluoromethylpyridine (1.11 g, 6.27 mmol) from step 1 above in CH2Cl2 (20 mL) at 0° C. was added SOCl2 (0.89 g, 7.5 nmuol) in CH2Cl2 (10 mL). The mixture was allowed to warm to room temperature and stirred for 1 h, and the solvent and excess SOCl2 were evaporated under reduced pressure. The residue was concentrated from cyclohexane (3-) to give 3-chloromethyl-4-trifluoromethylpyridine hydrochloride as a solid which was used in the next step without purification (TLC: Rf = 0.75 (1:1 hexane:EtOAc)).