Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.C([Mg]Br)C.[CH3:16][N:17]1[C:25]2[C:20](=[CH:21][C:22]([CH:26]=[O:27])=[CH:23][CH:24]=2)[CH:19]=[N:18]1>C1COCC1>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([CH:26]([C:22]3[CH:21]=[C:20]4[C:25](=[CH:24][CH:23]=3)[N:17]([CH3:16])[N:18]=[CH:19]4)[OH:27])=[CH:3][N:4]=2)[N:7]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: Cn1ncc2cc(C=O)ccc21
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: Cn1ncc2cc(C(O)c3cnc4ccc(Cl)nn34)ccc21
Temperature: -10 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
To a solution of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (232.0 mg, 1.00 mmol) in 5 mL THF, was added ethylmagnesium bromide (1.50 mL, 1.50 mmol) at −10° C. After stirring at −10° C. for 1 hour, 1-methyl-1H-indazole-5-carbaldehyde (240.0 mg, 1.50 mmol) was added. The mixture was allowed to warm to room temperature slowly and stirred for additional 2 hours. The reaction was quenched with Sat. NH4Cl solution and concentrated under reduced pressure. The residue was diluted with water, and extracted with EtOAc twice. The organic layers were combined, dried over Na2SO4 and concentrated. The crude product was washed with DCM to give the title compound as a white solid (230 mg, 70%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.21 (d, 1H), 8.02 (s, 1H), 7.81 (s, 1H), 7.59 (d, 1H), 7.56 (s, 1H), 7.49 (d, 1H), 7.35 (d, 1H), 6.29 (d, 1H), 6.21 (d, 1H), 4.02 (s, 3H). LCMS (method A): [MH]+=314, tR=4.44 min
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][N:17]=[C:16]2[NH:25][C:26]1[S:27][C:28]2[CH:34]=[C:33]([NH2:35])[CH:32]=[CH:31][C:29]=2[N:30]=1>O>[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][N:17]=[C:16]2[NH:25][C:26]1[S:27][C:28]2[CH:34]=[C:33]([NH:35][C:9]([NH:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[O:10])[CH:32]=[CH:31][C:29]=2[N:30]=1
Reactant: COc1cc2ncnc(Nc3nc4ccc(N)cc4s3)c2cc1OC
Reactant: O=C=Nc1cccc(F)c1
Solvent: O
Product: COc1cc2ncnc(Nc3nc4ccc(NC(=O)Nc5cccc(F)c5)cc4s3)c2cc1OC

Procedure:
1-[2-(6,7-Dimethoxyquinazolin-4-ylamino)benzothiazol-6-yl]-3-(3-fluorophenyl)urea was prepared from 3-fluorophenyl isocyanate (13 μL, 0.113 mmol) and N2-(6,7-dimethoxyquinazolin-4-yl)benzothiazole-2,6-diamine (40 mg, 0.113 mmol) according to GP 3. The mixture was poured into water (20 mL) and the resulting precipitate was purified by pTLC (dichloromethane:methanol=9:1) to obtain a yellow solid (14 mg, 29 μmol, 26%). LC/ESI-MS: m/z=491 [M+H]+; m/z=489 [M−H]−; Rt=3.27 min.
Reaction SMILES: [C:1]([O:9]C)(=[O:8])[CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5].[C:11]([Si:15]([CH3:26])([CH3:25])[O:16][CH:17]1[CH2:22][CH2:21][CH:20]([CH:23]=O)[CH2:19][CH2:18]1)([CH3:14])([CH3:13])[CH3:12].CC(C)([O-])C.[K+].C(O)(C)(C)C.Cl>>[CH3:7][O:6][C:4](=[O:5])[C:3](=[CH:23][CH:20]1[CH2:19][CH2:18][CH:17]([O:16][Si:15]([C:11]([CH3:12])([CH3:14])[CH3:13])([CH3:26])[CH3:25])[CH2:22][CH2:21]1)[CH2:2][C:1]([OH:9])=[O:8]
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(C=O)CC1
Reactant: COC(=O)CCC(=O)OC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: COC(=O)C(=CC1CCC(O[Si](C)(C)C(C)(C)C)CC1)CC(=O)O
Temperature: 50 °C
Yield: 38.3 %

Procedure:
A solution of dimethyl succinate (730 mg, 5.0 mmol) and 4-(tert-butyl-dimethyl-silanyloxy)-cyclohexanecarbaldehyde (1.00 g, 4.1 mmol) was added over 25 min to a 1.0 M solution of potassium tert-butoxide in tert-butanol (4.4 mL. 4.4 mmol). The reaction mixture was heated at 50° C. for 50 min, cooled to RT and concentrated under vacuum. The residue was dissolved in water (25 mL) and washed with EtOAc (2×10 mL). The aqueous layer was acidified with 6 N HCl (2.0 mL, 12 mmol) and extracted with EtOAc (2×20 mL), dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (25% EtOAc/DCM) to give the title compound (560 mg) as a mixture of olefin isomers (˜1:1) and a mixture of cis and trans isomers at the cyclohexyl ring (˜1:1). 1H NMR (CDCl3, 400 mHz) δ (ppm) olefin peaks at 6.88 (d, J=10.2 Hz) 6.77 (d, J=10.0 Hz) CHOTBS peaks at 3.96 ppm (br s) (cis isomer, hydrogen equitorial, 3.55 (m) (trans isomer, hydrogen axial).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][OH:14])=O)(C)(C)C.[F:15][C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1O>C1COCC1>[F:15][C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[O:14][CH2:13][C@@H:9]1[CH2:10][CH2:11][CH2:12][NH:8]1
Reactant: Oc1cccc(F)c1F
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Solvent: C1CCOC1
Product: Fc1cccc(OC[C@@H]2CCCN2)c1F
Reaction time: 40 h

Procedure:
A 4.03 g (20 mmol) sample of (S)-1-t-butoxycarbonyl-2-pyrrolidinemethanol (from Example 3a above) and 3.90 g (30 mmol) of 2,3-difluorophenol (Aldrich) were added to a complex of TPP and TBAD, (prepared as in Example 5b above, 30 mmol of each) in 150 mL of THF. The reaction was stirred for 40 hr, and the solvents were removed under vacuum. Hexane was added to the residue, and the crude product was collected by filtration. The product was washed with hexane and 10% NaOH, then purified by flash chromatography on silica gel, eluting with CHCl3. Removal of the solvent gave 7.5 g of the title compound.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C@H:12]3[C@@:14]4([C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[NH:16][C:15]4=[O:23])[CH2:13]3)=[CH:9][CH:10]=2)[NH:5][N:4]=1)=[CH2:2].Br[C:25]1[C:26]([CH3:31])=[N:27][CH:28]=[CH:29][CH:30]=1.CCN(C(C)C)C(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:31][C:26]1[N:27]=[CH:28][C:29](/[CH:2]=[CH:1]/[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C@H:12]4[C@@:14]5([C:22]6[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=6)[NH:16][C:15]5=[O:23])[CH2:13]4)=[CH:9][CH:10]=3)[NH:5][N:4]=2)=[CH:30][CH:25]=1
Reactant: C=Cc1n[nH]c2cc([C@@H]3C[C@@]34C(=O)Nc3ccccc34)ccc12
Reactant: Cc1ncccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(/C=C/c2n[nH]c3cc([C@@H]4C[C@@]45C(=O)Nc4ccccc45)ccc23)cn1
Yield: 31.9 %

Procedure:
To a mixture of (1R*,2S*)-2-(3-vinyl-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-one (60.2 mg, 0.2 mmol) and 3-bromo-2-methylpyridine (34.4 mg, 0.2 mmol) in DMF (1.5 mL) was added iPr2NEt (0.07 mL), followed by Pd(OAc)2 (2.2 mg, 0.01 mmol) and P(o-tol)3 (6.7 mg, 0.022 mmol). The resulting mixture was purged with argon, and then microwaved 2 h at 125° C. Purification by prep-HPLC gave the title compound as a light yellow solid (25 mg, 25%). NMR indicated 6% of the branched isomer. 1H NMR (400 MHz, CD3OD) δ 8.90 (s, 1H), 7.74 (dd, J=8.4 Hz, 1.6 Hz, 1H), 8.02 (d, J=8.4 Hz, 1H), 7.87 (d, J=8.4 Hz, 1H), 7.78 (d, J=16.8 Hz, 1H), 7.55 (d, J=16.8 Hz, 1H), 7.49 (s, 1H), 7.07-7.00 (m, 2H), 6.94 (d, J=8.0 Hz, 1H), 6.55 (t, J=7.6 Hz, 1H), 5.97 (d, J=7.6 Hz, 1H), 3.34 (t, J=8.4 Hz, 1H, partially overlapping with MeOH residue), 2.78 (s, 3H), 2.23 (dd, J=7.6 Hz, J=4.8 Hz, 1H), 2.18 (dd, J=8.8 Hz, J=4.8 Hz, 1H); MS ESI 393.1 [M+H]+, calcd for [C25H20N4O+H]+ 393.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH:28]1[CH2:33][CH:34]([CH2:37][OH:38])[CH2:35][OH:36]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH:28]2[CH2:33][CH:34]([CH2:37][OH:38])[CH2:35][OH:36])[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1
Reactant: OCC(CO)CC1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Product: CCOC(=O)C1=C(CN2CCOCC2CC(CO)CO)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 44.3 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.34 g, 0.68 mmol) was reacted with 2-(morpholin-3-ylmethyl)propane-1,3-diol (0.12 g, 0.68 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a yellow solid (0.18 g, 44%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[N:31]1([CH2:6][CH2:7][C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[N:18]=[CH:19][C:20]([C:23]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[O:24])=[CH:21][CH:22]=4)=[CH:13][C:11]=3[CH:12]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1
Reactant: C1CCNCC1
Product: O=C(c1ccc(-c2ccc3oc(CCN4CCCCC4)cc3c2)nc1)N1CCOCC1

Procedure:
The product from Example 44E and piperidine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ8.70 (m, 1H), 8.22 (d, J=1.8 Hz, 1H), 7.95 (m, 3H), 7.58 (d, J=8.7 Hz, 1H), 6.82 (s, 1H), 3.3-3.8 (m, 12H), 3.05 (m, 2H), 1.5-2.0 (m, 8H); MS (DCI) m/z 420 (M+H)+;
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:18][CH2:19][CH2:20][CH:21]1[O:23][CH2:22]1>>[OH:23][CH:21]([CH2:20][CH2:19][CH3:18])[CH2:22][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4][CH3:5])=[CH:15][CH:16]=2)([CH3:10])[CH3:9])=[CH:6][CH:7]=1
Reactant: CCCC1CO1
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Product: CCCC(O)COc1ccc(C(C)(C)c2ccc(OCC(O)CCC)cc2)cc1

Procedure:
Bis-phenol A, that is 2,2-di(p-hydroxy-phenyl-)propane, was reacted in known manner with an excess of pentene - 1,2-oxide. The product, the mixture of diastereisomers, 2,2-bis-(p-(β-hydroxy-pentoxy-)phenyl)propane was obtained as a yellow-brown, semisolid mass, which was obtained as a colorless substance by distillation b.p.:192°-210° C/O .005 mm. The OH-equivalent was 207.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH:20]=[C:19]([O:22][Si](C)(C)C)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>C(#N)C.C(OCC)(=O)C>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH:18]([Br:8])[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CC=C(O[Si](C)(C)C)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(=O)C(Br)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
NBS (1.4 g) was added to a solution of 1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-4-(trimethylsilyloxy)pyridine (2 g) in acetonitrile and the mixture was stirred at room temperature for 30 minutes. The solution was diluted with ethyl acetate(50 ml) and washed with water (50 ml), sodium bicarbonate solution (50 ml) and brine (50 ml), dried (MgSO4) and evaporated to give the title compound as a colourless solid (1.8 g).
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:20])=[CH:9][C:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12](=[O:17])[C:11]=2[C:18]=1[CH3:19])=[O:5]>C1COCC1.CCCCCC>[CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:20])=[CH:9][C:10]2[O:14][C:13]([CH3:15])([CH3:16])[CH:12]([OH:17])[C:11]=2[C:18]=1[CH3:19])=[O:5]
Reactant: Cc1cc2c(c(C)c1NC(=O)CC(C)(C)C)C(=O)C(C)(C)O2
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc2c(c(C)c1NC(=O)CC(C)(C)C)C(O)C(C)(C)O2
Yield: 82 %

Procedure:
Using 3,3-dimethyl-N-(2,2,4,6-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)butanamide obtained in Reference Example 342, the title compound was synthesized in the same manner as in Example 234. Yield: 82%. Melting point: 217-218° C. (THF-hexane).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[NH2:12][C:13]1[N:18]=[C:17]([CH3:19])[C:16](/[CH:20]=[CH:21]/[C:22](OCC)=[O:23])=[C:15]([NH:27][C@@H:28]2[CH2:32][CH2:31][O:30][CH2:29]2)[N:14]=1>O>[NH2:12][C:13]1[N:18]=[C:17]([CH3:19])[C:16]2[CH:20]=[CH:21][C:22](=[O:23])[N:27]([C@@H:28]3[CH2:32][CH2:31][O:30][CH2:29]3)[C:15]=2[N:14]=1
Reactant: CCOC(=O)/C=C/c1c(C)nc(N)nc1N[C@@H]1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: Cc1nc(N)nc2c1ccc(=O)n2[C@@H]1CCOC1
Temperature: 170 °C
Reaction time: 24 h
Yield: 48.2 %

Procedure:
To a flask were added DBU (20 mL) and (R,E)-ethyl 3-(2-amino-4-methyl-6-(tetrahydrofuran-3-ylamino)pyrimidin-5-yl)acrylate (3.9 g, 13.4 mmol). The reaction mixture was stirred at 170° C. for 24 h under nitrogen. The mixture was allowed to cool to room temperature and was diluted with water. The aqueous layer was extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine, separated and dried with MgSO4. The mixture was purified by chromatography to give (R)-2-amino-4-methyl-8-(tetrahydrofuran-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (1.59 g, 48% yield); MS (EI) for C12H14N4O2: 247.1 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][C:17](F)=[CH:18][C:19]=3[C:11]=2[C:10](C)(C)[CH2:9][N:8]([C:23](=[O:31])[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH:7]=1)=[O:5])[CH3:2].C([O:34]C(C1C2NC3C=CC(N)=CC=3C=2C(C)(C)CN(C(=O)C2C=CC(F)=CC=2)C=1)=O)C.[H+].[B-](F)(F)(F)F.O>CC#N>[CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[C:15]([OH:34])=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[CH2:10][CH2:9][N:8]([C:23](=[O:31])[C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(C)(C)c2c1[nH]c1ccc(F)cc21
Reactant: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(C)(C)c2c1[nH]c1ccc(N)cc21
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1c(O)cccc21
Temperature: 10 °C
Reaction time: 0.33 h

Procedure:
For the preparation of 9-fluoro-3-(4-fluoro-benzoyl)-1,1-dimethyl-1,2,3,6-tetrahydro-azepino[4,5-b]indole-5-carboxylic acid ethyl ester, to a stirred solution of 9-amino-3-(4-fluoro-benzoyl)-1,1-dimethyl-1,2,3,6-tetrahydro-azepino[4,5-b]indole-5-carboxylic acid ethyl ester (Example 41C) (0.024 g, 0.055 mmol) in 1.0 mL of MeCN was added 11 μL of 48% HBF4 water solution at ±10° C. under N2 for 10 minutes. 9 μL of tBuONO (90%, 0.066 mmol) was added to the reaction mixture and stirred at ±10° C. for 20 minutes. The reaction mixture was warmed to room temperature for 1 hour and monitored by LC-MS. The solvents were removed in vacuo, and the residue was washed with Et2O/hexane (1:1) once and benzene twice. After having dried in high vacuo for several hours, a brown solid was obtained. The solid in 1.5 mL of xylenes was heated at 145° C. reflux under N2 for 1 hour and then concentrated. The crude product was purified by flash chromatograph on silica gel, eluting with EtOAc-hexane (0-30%) to yield the title compound (0.012 g) as a light yellow solid. 1H-NMR (CDCl3): δ10.68 (1H, s), 7.83 (1H, s), 7.62 (2H, m), 7.44 (1H, dd), 7.29 (1H, m), 7.13 (2H, m), 6.93 (1H, m), 4.23 (2H, q), 1.56 (6H, s), 1.22 (3H, t). MS (ESI): 425 (MH+).
Reaction SMILES: O=[C:2]1[C:6]2[S:7][CH:8]=[CH:9][C:5]=2[S:4](=[O:11])(=[O:10])[NH:3]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:13].[ClH:26]>N1C=CC=CC=1>[ClH:26].[S:4]1(=[O:11])(=[O:10])[C:5]2[CH:9]=[CH:8][S:7][C:6]=2[C:2](=[S:13])[NH:3]1
Reactant: O=C1NS(=O)(=O)c2ccsc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: Cl
Solvent: c1ccncc1
Product: O=S1(=O)NC(=S)c2sccc21
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of 15.2 g (0.08 mole) of 2,3-dihydro-3-oxothieno[2,3-d]isothiazole 1,1-dioxide (U.S. Pat. No. 4,028,373) in 200 ml of dry pyridine at 80° C. was added 15.2 g of phosphorus pentasulfide over a period of 10 minutes. The reaction mixture was stirred for a period of 45 minutes at this temperature and was then poured into 500 ml of ice water. The reaction mixture was acidified with conc. hydrochloric acid solution to pH 1. The resulting precipitate was collected on a filter and was dissolved in 20% sodium bicarbonate solution then filtered. The filtrate upon acidification with conc. hydrochloric acid gave 7.6 g of thieno[2,3-d]isothiazole-3(2H)-thione 1,1-dioxide, m.p. 185°-187° C. A second treatment of the precipitate which did not dissolve with 20% sodium bicarbonate followed by acidification gave an additional 3.7 g of product, m.p. 186°-189° C. The two crops of product were combined giving 11.3 g (69%).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6].[N+:7]([O-])([OH:9])=[O:8]>>[N+:7]([CH2:1][CH:2]=[CH:3][CH2:4][CH2:5][CH3:6])([O-:9])=[O:8]
Reactant: C=CCCCC
Reactant: O=[N+]([O-])O
Product: CCCC=CC[N+](=O)[O-]
Temperature: 40 °C
Yield: 20.5 %

Procedure:
1-Hexene (125 mL, 1.0 mole) and concentrated nitric acid (90 mL, 2.0 moles) were mixed at room temperature. With rapid stirring the solution was heated to 40° C. for 41/2 hours. With continued stirring the solution was cooled to room temperature and the organic layer separated. It was washed with a saturated sodium chloride solution then dried over magnesium sulfate. After filtering, vacuum distillation removed unreacted 1-hexene leaving one product, 1-nitro-2-hexene in 20.5% yield. This desired product was confirmed by IR and gas chromatography (GC) analysis.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][C:8]=2[CH:17]=1)([O-])=O>CO.[Ni]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][C:8]=2[CH:17]=1
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2o1
Agent: [Ni]
Solvent: CO
Product: CCOC(=O)c1cc2cc(N)ccc2o1

Procedure:
A solution of 2.3 g of ethyl 5-nitrobenzofuran-2-carboxylate in 60 ml of methanol is hydrogenated in the presence of Raney nickel. The catalyst is filtered off and the solution is concentrated. After customary working up, ethyl 5-aminobenzofuran-2-carboxylate, Rf 0.1 (dichloromethane/ethanol 9.5:0.5) obtained; hydrochloride m.p. 246°-248°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:11])[C:9]=1[OH:10])[CH:5]=[O:6].Br[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:11])[C:9]=1[O:10][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)[CH:5]=[O:6]
Reactant: O=Cc1cc(Br)c(O)c(Br)c1
Reactant: COc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Product: COc1cccc(COc2c(Br)cc(C=O)cc2Br)c1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
A mixture of 3,5-dibromo-4-hydroxybenzaldehyde (0.28 g), 1-bromomethyl-3-methoxybenzene (0.15 mL), potassium carbonate (0.29 g) and potassium iodide (42 mg) in 10 mL absolute ethanol was stirred at 80° C. for 2 days. The reaction mixture was concentrated and the title compound was obtained as a off-white solid after flash column chromatography (silica gel, heptane/ethyl acetate (3/7, v/v)), Rf=0.51).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[NH:6][N:5]=1)([O-:3])=[O:2].Cl.[CH3:13][NH:14][O:15][CH3:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl>[CH3:16][O:15][N:14]([CH3:13])[C:9]([C:7]1[NH:6][N:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=1)=[O:11]
Reactant: O=C(O)c1cc([N+](=O)[O-])n[nH]1
Reactant: CNOC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cc([N+](=O)[O-])n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
A 500-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 3-nitro-1H-pyrazole-5-carboxylic acid (15.7 g, 1.0 eq., 100 mmol), N,O-dimethylhydroxylamine hydrochloride (19.5 g, 2.0 eq., 200 mmol), HATU (76.0 g, 2.0 eq., 200 mmol), triethylamine (40.4 g, 4.0 eq., 400 mmol), and dichloromethane (300 mL). The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. The resulting residue was purified by silica-gel column chromatography eluting with 100:1 dichloromethane/methanol to afford 150a (16.0 g, 80%) as a white solid. MS-ESI: [M+H]+ 201.1
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=2C)=[O:9])[CH:3]=1.ClC1N=CN=C(C(NC2C=CC(O)=CC=2)=O)C=1.C(N(C(C)C)C(C)C)C.[NH2:45][C:46]1[C:47]([CH3:52])=[CH:48][CH:49]=[CH:50][CH:51]=1>C(O)C>[OH:17][C:14]1[CH:13]=[CH:12][C:11]([NH:10][C:8]([C:4]2[CH:3]=[C:2]([NH:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[CH3:52])[N:7]=[CH:6][N:5]=2)=[O:9])=[CH:16][CH:15]=1
Reactant: Cc1cc(O)ccc1NC(=O)c1cc(Cl)ncn1
Reactant: Cc1ccccc1N
Agent: O=C(Nc1ccc(O)cc1)c1cc(Cl)ncn1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1Nc1cc(C(=O)Nc2ccc(O)cc2)ncn1
Temperature: 160 °C

Procedure:
A solution of 6-chloro-N-(4-hydroxy-2-methylphenyl)pyrimidine-4-carboxamide, Intermediate 7 (50.0 mg; 0.20 mmol) in ethanol (3 mL) was treated with N-ethyldiisopropylamine (69 μl; 0.4 mmol) and o-toluidine (Fluka, 21.5 μl; 0.20 mmol). The reaction mixture was heated at 160° C. for 3 hours under microwave irradiation. The solvents were removed in vacuo, EtOAc was added and the organic phase was washed with a citric acid solution, dried over magnesium sulfate then evaporated in vacuo. The crude product was purified by column chromatography (silica), eluting with cyclohexane containing an increasing amount of EtOAc. The title compound was obtained as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.[NH:15]1[CH2:20][CH2:19][S:18][CH2:17][CH2:16]1.C([O-])([O-])=O.[Cs+].[Cs+]>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].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[N+:12]([C:4]1[CH:3]=[C:2]([N:15]2[CH2:20][CH2:19][S:18][CH2:17][CH2:16]2)[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(Br)cc(C(F)(F)F)c1
Reactant: C1CSCCN1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cc(N2CCSCC2)cc(C(F)(F)F)c1
Yield: 56 %

Procedure:
Add 1-bromo-3-nitro-5-(trifluoromethyl)benzene (500 mg, 2.9 mmol), thiomorpholine (455 mg, 4.4 mmol), Cs2CO3 (2.86 g, 8.8 mmol), BINAP (55 mg, 0.09 mmol) and Pd2(dba)3 (54 mg, 0.06 mmol) under N2 to 1,4-dioxane (10 mL), stir the reaction under N2 at 100° C. for 16 hrs. TLC (100% PE) shows the reaction is complete. Cool the reaction to room temperature, filter and concentrate the filtrate under reduced pressure to get crude product. Purification by chromatography (silica gel, 100% PE) affords the target compound (475 mg, 55%). MS: (M+1): 293.1.