Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:25]=[CH:24][C:15]([C:16]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:17])=[CH:14][CH:13]=2)=[N:2]1.OO.S([O-])(O)=[O:29].[Na+]>CO>[OH:29][N:21]1[CH2:22][CH2:23][N:18]([C:16](=[O:17])[C:15]2[CH:14]=[CH:13][C:12](/[CH:11]=[CH:10]/[C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][N:2]=3)=[CH:25][CH:24]=2)[CH2:19][CH2:20]1
Reactant: O=C(c1ccc(/C=C/c2n[nH]c3ccccc23)cc1)N1CCNCC1
Reactant: O=S([O-])O
Agent: OO
Agent: [Na+]
Solvent: CO
Product: O=C(c1ccc(/C=C/c2n[nH]c3ccccc23)cc1)N1CCN(O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 17 %

Procedure:
Compound 18 (0.35 g, 1.1 mmol) was dissolved in methanol (2.1 mL) and was added with a 31% hydrogen peroxide solution (0.13 g, 1.1 mmol), followed by stirring at room temperature for 1 hour. The reaction mixture was added with sodium hydrogen sulfite (0.1 g, 0.96 mmol), and then the deposited crystals were removed by filtration after confirming the disappearance of hydrogen peroxide using a potassium iodide-starch paper. The solvent of the filtrate was evaporated under reduced pressure, the crude product was purified by preparative silica gel chromatography [amino-modified chemically bound silica gel Chromatorex (registered trademark) NH, Fuji Silysia Chemical Ltd., methanol/chloroform=1/91 to obtain Compound 147 (57 mg, 15%).
Reaction SMILES: Br[CH2:2][C:3]1([CH3:26])[CH:7]([C:8]([O:10][CH3:11])=[O:9])[N:6]2[C:12](=[O:25])[CH:13]([NH:14][C:15](=[O:24])[CH2:16][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C@H:5]2[S:4]1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>F[B-](F)(F)F.[Ag+].C(Cl)Cl>[NH:27]([CH2:2][C:3]1([CH3:26])[CH:7]([C:8]([O:10][CH3:11])=[O:9])[N:6]2[C:12](=[O:25])[CH:13]([NH:14][C:15](=[O:24])[CH2:16][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C@H:5]2[S:4]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)C1N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1(C)CBr
Reactant: Nc1ccccc1
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC(=O)C1N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1(C)CNc1ccccc1
Yield: 45.3 %

Procedure:
By treating in the similar manner as described in Example 16 using methyl 2-bromomethyl-2-methyl-6-(2-phenoxyacetamido)penam-3-carboxylate (0.88 g), aniline (0.28 g), silver fluoroborate (0.43 g) and methylene chloride (15 ml), there was obtained oily methyl 2-anilinomethyl-2-methyl-6-(2-phenoxyacetamido)-penam-3-carboxylate (0.41 g) from the fractions of the third to seventh.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)/[CH:27]=[C:28](/[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=1)\[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=2)=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)/C=C(\CBr)Oc1cccc(Cl)c1
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(Cl)c2)=CC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 35.1 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (786 mg, 0.004 mol) in N,N-dimethylformamide (10 mL) was added N,N-diisopropylethylamine (2.58 g, 0.020 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with (E)-4-bromo-3-(3-chloro-phenoxy)-but-2-enoic acid ethyl ester (1.30 g, 0.004 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (silica gel (100-200 mesh)) afforded (S)-2-[4-(3-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionic acid methyl ester (530 mg, 33%) as a yellow oil.
Reaction SMILES: [OH:1][CH:2]([CH2:17][OH:18])[CH2:3][N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[N:7]=[CH:6][C:5]1=[O:16].[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[Si:19]([O:18][CH2:17][CH:2]([OH:1])[CH2:3][N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[N:7]=[CH:6][C:5]1=[O:16])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: COc1ccc2ncc(=O)n(CC(O)CO)c2c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2ncc(=O)n(CC(O)CO[Si](C)(C)C(C)(C)C)c2c1
Reaction time: 12 h

Procedure:
1-(2,3-Dihydroxypropyl)-7-methoxyquinoxalin-2(1H)-one (3.06 g, 12.22 mmol) was dissolved in dichloromethane (75 ml). To the solution, tert-butyldimethylsilyl chloride (2.03 g, 13.44 mmol), triethylamine (2.21 ml, 15.89 mmol) and 4-dimethylamino pyridine (299 mg, 2.44 mmol) were added under cooling on ice, and the reaction mixture was stirred for 12 hours while the temperature was rising to room temperature. The reaction solution was diluted with dichloromethane, washed with water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol) to yield 5.29 g (quantitative) of the title compound in the form of a dark orange oily product.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1I)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[B:22](OC(C)C)([O:27]C(C)C)[O:23]C(C)C.Cl>C1COCC1>[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[B:22]([OH:27])[OH:23])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Clc1ccc(OCc2ccccc2)c(I)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cc(Cl)ccc1OCc1ccccc1
Temperature: -78 °C
Yield: 52.6 %

Procedure:
Butyllithium (11.5 ml, 28.7 mmol, 2.5 M) was added, under nitrogen, over 10 minutes, to a solution of 2-benzyloxy-5-chloro-iodobenzene (9 g, 26.2 mmol) in THF (40 ml) at −100° C. The reaction mixture was then warmed up at −78° C. and stirred for 1 hour (at −78° C.) before triisopropyl borate (18 ml, 78.4 mmol) was added over 10 minutes. The reaction mixture was then warmed to room temperature before a solution of HCl (60 ml, 1M) was added. The mixture was vigorously stirred for 1½ hours. The organic phase was separated, washed sequentially with water and brine, dried (MgSO4) filtered and concentrated. The residue was triturated with a 30% solution of ether in iso-hexane and filtered to give the title compound (3.62 g, 53%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[C:7]([C@H:20]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:6]([CH3:31])=[CH:5]2.[C:32]([Sn](CCCC)(CCCC)CCCC)#[C:33][CH3:34].C([O-])(O)=O.[Na+].C(N(CC)CC)C>[Pd+2]>[C:27]([O:26][C@@H:20]([C:7]1[C:6]([CH3:31])=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:32]#[C:33][CH3:34])[CH:3]=2)[C:8]=1[O:12][S:13]([C:16]([F:19])([F:17])[F:18])(=[O:15])=[O:14])[C:21]([O:23][CH2:24][CH3:25])=[O:22])([CH3:28])([CH3:29])[CH3:30]
Reactant: CC#C[Sn](CCCC)(CCCC)CCCC
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2cc(Br)ccc2c1OS(=O)(=O)C(F)(F)F
Agent: [Pd+2]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CC#Cc1ccc2c(OS(=O)(=O)C(F)(F)F)c([C@H](OC(C)(C)C)C(=O)OCC)c(C)cc2c1
Temperature: 120 °C

Procedure:
A Smith process vial was charged (S)-ethyl 2-(6-bromo-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-tert-butoxyacetate (55 mg, 0.104 mmol), (1-Propynyl)tributylstannane (35 μL, 0.115 mmol), Chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II) (8 mg, 0.01 mmol), NaHCO3 (4 mg, 0.05 mmol), triethylamine (44 μL, 0.3 mmol) and flushed with nitrogen. DMF (2.0 mL) was added and mixture sparged with nitrogen for 10 minutes and then heated in microwave at 120° C. for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with brine, dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give (S)-ethyl 2-tert-butoxy-2-(3-methyl-6-(prop-1-ynyl)-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate. 1H NMR (400 MHz, CDCl3): δ 7.94 (d, J=4.4 Hz, 1H), 7.80 (s, 1H), 7.56 (s, 1H), 7.50 (d, J=4.6 Hz, 1H), 5.63 (s, 1H), 4.08 (m, 2H), 2.52 (s, 3H), 2.08 (s, 3H), 1.21 (s, 9H), 1.18 (t, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[N:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][C:30](O)=[O:31])[CH2:24][CH2:23]1>>[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[N:22]1[CH2:23][CH2:24][N:25]([CH2:28][CH2:29][C:30]([O:1][CH2:2][C:3]2[CH:12]=[C:11]3[C:6]([CH2:7][CH2:8][C:9](=[O:13])[NH:10]3)=[CH:5][CH:4]=2)=[O:31])[CH2:26][CH2:27]1
Reactant: O=C(O)CCN1CCN(c2cccc(Cl)c2Cl)CC1
Reactant: O=C1CCc2ccc(CO)cc2N1
Product: O=C1CCc2ccc(COC(=O)CCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1

Procedure:
(2-Oxo-1,2,3,4-tetrahydroquinolin-7-yl)methyl 3-(4-(2,3-dichlorophenyl)piperazin-1-yl)propanoate (38b) (Scheme 7) was prepared from the carbinol 37 and the carboxylic acid 18b according to the protocol described for the compound 38a (Example 55). Colorless oil, 0.39 g (99%). 1H NMR (400 MHz, CDCl3): δ 2.55-2.60 (m, 4H); 2.62 (broad s, 4H); 2.78 (t, J=7.6 Hz, 2H); 2.93 (t, J=7.6 Hz, 2H); 3.00 (broad s, 4H); 5.05 (s, 2H); 6.83 (s, 1H); 6.90-6.93 (m, 1H); 6.98 (dd, J=1.2, 7.6 Hz, 1H); 7.09-7.13 (m, 3H); 9.22 (broad s, 1H). MS (ESI): m/z=462.10 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16][CH2:15]1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[C:32]([CH:35]=O)[S:33][CH:34]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[CH2:6]([N:7]([CH2:35][C:32]1[S:33][CH:34]=[C:30]([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:14]2[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16][CH2:15]2)[CH:31]=1)[CH2:8][CH3:4])[CH3:5]
Reactant: NC(=O)c1cc(Br)cc2c(C3CCS(=O)(=O)CC3)c[nH]c12
Reactant: CC1(C)OB(c2csc(C=O)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCN(CC)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCS(=O)(=O)CC4)c3c2)cs1
Temperature: 150 °C
Yield: 6.4 %

Procedure:
To 5-bromo-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-indole-7-carboxamide (400 mg, 1.08 mmol) in dioxane and water (4 mL/1 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thiophenecarbaldehyde (462 mg, 1.94 mmol), Pd(PPh3)4 (100 mg) and K2CO3 (447 mg, 3.24 mmol). The reaction mixture was heated at 150° C. for 20 minutes by microwave irradiation. The organic phase was concentrated and redissolved in DMSO (10 mL). The resulting solution was split to eight. NaBH3CN (30 mg), ZnCl2 (30 mg) and N-ethylethanamine (50 mg) were added. The mixture was heated to 100° C. for 30 minutes which was then filtered and purified by HPLC with TFA to afford the title compound (16 mg).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1)(=O)=O.[P:16]([O-:21])([O:19][CH3:20])[O:17][CH3:18].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:13][C:9]1[CH:8]=[C:7]([P:16](=[O:21])([O:19][CH3:20])[O:17][CH3:18])[CH:12]=[CH:11][CH:10]=1
Reactant: O=S(=O)(Oc1cccc(Cl)c1)C(F)(F)F
Reactant: COP([O-])OC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COP(=O)(OC)c1cccc(Cl)c1
Temperature: 160 °C

Procedure:
This reaction was performed using a PersonalChemistry™ microwave instrument set at normal absorbance, fixed hold time and 30 sec pre-stirring. A 10-mL reaction vial was charged with 3-chlorophenyl trifluoromethanesulfonate (0.60 g, 2.30 mmol), dimethyl phosphite (0.42 mL, 4.58 mmol) and triethylamine (0.64 mL, 4.59 mmol) in toluene (4 mL). Nitrogen was bubbled through the stirred solution for 5 min, the tetrakis(triphenylphosphine)palladium(0) (0.1 g) was added, the solution was covered with a blanket of nitrogen and sealed. The reaction mixture was heated 11 min at 160° C., then cooled to room temperature and diluted with ethyl acetate. The yellow solution washed successively with water (3×) and brine. The organic solution was dried over sodium sulfate, filtered and the solvent was removed by rotary evaporation under reduced pressure. Pure dimethyl (3-chlorophenyl)phosphonate was obtained as a colorless oil (0.27 g, 57%) by chromatography over silica gel using ethyl acetate-hexane (gradient: 5% ethyl acetate to 100%). 1H NMR (300 MHz, CDCl3) δ 7.77 (br d, J=13.7 Hz, 1H), 7.68 (ddt, J=13.0, 7.5, 1.4 Hz, 1H), 7.53 (dquint., J=8.0, 1.1 Hz, 1H), 7.38-7.45 (m, 1H), 3.79 (s, 3H), 3.75 (s, 3H) ppm; MS [M+H]+ 221, [2M+H]+ 441
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:29])[CH2:14][NH:15][C:16]2[C:20]3[CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=[CH:24][C:19]=3[O:18][N:17]=2)[CH2:9]1.[CH2:30]([CH:32]1[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1)[CH3:31]>>[CH2:30]([CH:32]1[CH2:37][CH2:36][CH:35]([N:8]2[CH2:11][CH:10]([NH:12][C:13](=[O:29])[CH2:14][NH:15][C:16]3[C:20]4[CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=[CH:24][C:19]=4[O:18][N:17]=3)[CH2:9]2)[CH2:34][CH2:33]1)[CH3:31]
Reactant: O=C(CNc1noc2ccc(C(F)(F)F)cc12)NC1CNC1
Reactant: CCC1CCC(=O)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCC1CCC(N2CC(NC(=O)CNc3noc4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
The title compound was prepared as a white solid from reaction of (N-Azetidin-3-yl-2-(5-trifluoromethyl-benzo[d]isoxazol-3-ylamino)-acetamide TFA salt (as prepared in Example 1, Step D) and 4-ethyl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][C:7]2[C:11](=[O:12])[N:10]([C:13]3[S:14][C:15]([C:19]([O:21]C)=[O:20])=[C:16]([CH3:18])[N:17]=3)[NH:9][C:8]=2[CH3:23])=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCCC1.O>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][C:7]2[C:11](=[O:12])[N:10]([C:13]3[S:14][C:15]([C:19]([OH:21])=[O:20])=[C:16]([CH3:18])[N:17]=3)[NH:9][C:8]=2[CH3:23])=[CH:4][CH:3]=1
Reactant: COC(=O)c1sc(-n2[nH]c(C)c(Cc3ccc(Cl)cc3)c2=O)nc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(-n2[nH]c(C)c(Cc3ccc(Cl)cc3)c2=O)sc1C(=O)O
Yield: 53 %

Procedure:
To a solution of methyl 2-(4-(4-chlorobenzyl)-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-4-methylthiazole-5-carboxylate (0.22 g, 0.57 mmol) in a mixture of tetrahydrofuran (8 mL) and water (2 mL) was added lithium hydroxide monohydrate (0.12 g, 2.88 mmol). The reaction mixture was heated to reflux for 3 hours. The solvent was removed in vacuo, and the residue was neutralized to pH 4˜5 with 10% hydrochloric acid. The resulting precipitate was collected by filtration and dried to afford the title compound in 53% yield (0.11 g): 1H NMR (300 MHz, DMSO-d6) δ 12.29 (br s, 1H), 7.27 (d, J=8.5 Hz, 2H), 7.21 (d, J=8.5 Hz, 2H), 3.52 (s, 2H), 2.56 (s, 3H), 2.14 (s, 3H); MS (ES+) m/z 364.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([Cl:12])[C:5]=2[N:6]=1.[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[Cl:1][C:2]1[S:3][C:4]2[C:10]([N+:13]([O-:15])=[O:14])=[C:9]([F:11])[CH:8]=[C:7]([Cl:12])[C:5]=2[N:6]=1
Reactant: Fc1cc(Cl)c2nc(Cl)sc2c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1c(F)cc(Cl)c2nc(Cl)sc12
Temperature: 0 °C
Reaction time: 3 h

Procedure:
23.7 g 2,4-Dichloro-6-fluorobenzothiazole was dissolved in 100 ml concentrated sulfuric acid and the solution cooled to 0° C. To this was added very slowly, dropwise, a cooled solution of 14 ml concentrated sulfuric acid and 14 ml 100% nitric acid. The mixture was stirred for 3 hours, poured into 500 ml ice water, the resulting crystals filtered off, washed with water until neutral and dried in vacuo. Yield: 22.7 g=79% of theory m.p.: 110°-112° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].[NH3:19]>C(O)C>[NH2:19][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17]
Reactant: CC1CC(=O)NN=C1c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: N
Solvent: CCO
Product: CC1CC(=O)NN=C1c1ccc(N)c([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
A mixture of 5 g of 6-(4-chloro-3-nitrophenyl)-5-methyl-2,3,4,5-tetrahydropyridazin-3-one, 50 ml of 25% aqueous NH3 solution and 50 ml of ethanol is heated at 100° for 16 hours. The mixture is poured into ice water and extracted with methylene dichloride, the phases are separated and the organic phase is dried over sodium sulfate and evaporated to give 6-(4-amino-3-nitrophenyl)-5-methyl-2,3,4,5-tetrahydropyridazin-3-one, m.p. 234°-238°.
Reaction SMILES: [CH3:1][C@H:2]1[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[CH2:9]([C:12]1[C:20]2[O:19][N:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[C:16]=2[CH:15]=[CH:14][C:13]=1[O:25][CH2:26][CH2:27][CH2:28]Br)[CH2:10][CH3:11]>>[CH3:1][C@H:2]1[NH:6][C:5](=[O:7])[N:4]([CH2:28][CH2:27][CH2:26][O:25][C:13]2[CH:14]=[CH:15][C:16]3[C:17]([C:21]([F:23])([F:24])[F:22])=[N:18][O:19][C:20]=3[C:12]=2[CH2:9][CH2:10][CH3:11])[C:3]1=[O:8]
Reactant: C[C@H]1NC(=O)NC1=O
Reactant: CCCc1c(OCCCBr)ccc2c(C(F)(F)F)noc12
Product: CCCc1c(OCCCN2C(=O)N[C@H](C)C2=O)ccc2c(C(F)(F)F)noc12

Procedure:
5(R)-Methyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione was prepared as for Example 10 from 5(R)-methylimidazolidine-2,4-dione and the bromide from Example 7. After aqueous work-up and silica gel chromatography, the title compound was obtained.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:18]=[CH:19][C:20]([O:24][CH3:25])=[C:21]([NH2:23])[CH:22]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>>[CH:12]1[C:8]2[CH2:9][CH2:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6](=[CH:16][C:17]3[CH:18]=[CH:19][C:20]([O:24][CH3:25])=[C:21]([NH:23][S:27]([CH3:26])(=[O:29])=[O:28])[CH:22]=3)[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: COc1ccc(C=C2c3ccccc3CCc3ccccc32)cc1N
Reactant: CS(=O)(=O)Cl
Product: COc1ccc(C=C2c3ccccc3CCc3ccccc32)cc1NS(C)(=O)=O
Yield: 77 %

Procedure:
Following procedures essentially as described in Example 90-, 5-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-2-methoxy-phenylamine and methanesulfonyl chloride gives the title compound in 77% yield as a tan foam, mp 192.1° C. 1H NMR (CDCl3) δ 2.74 (s, 3H), 2.80-4.61 (br m, 4H), 4.81 (s, 3H), 6.67-7.50 (m, 13H); MS (ES) 423 (M+NH4), 404 (M−H). HPLC shows 100% purity.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([CH2:6][C:7]([CH3:13])([CH3:12])[CH2:8]2)=[C:4]([CH3:14])[CH:3]=1.[CH3:15][O:16]C(Cl)Cl>ClCCl.Cl[Ti](Cl)(Cl)Cl>[Cl:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([CH2:6][C:7]([CH3:12])([CH3:13])[CH2:8]2)=[C:4]([CH3:14])[C:3]=1[CH:15]=[O:16]
Reactant: COC(Cl)Cl
Reactant: Cc1cc(Cl)c(C)c2c1CC(C)(C)C2
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1c(Cl)c(C=O)c(C)c2c1CC(C)(C)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
To a solution of 19.8 g of the 6-chloro-2,2,4,7-tetramethylindane in 100 ml of dry dichloromethane was continuously added 13 ml of α,α-dichloromethyl methyl ether and 12.4 ml of TiCl4 at 0° C. The reaction mixture was stirred at room temperature for 2 hours, quenched with 200 ml of water, and separated the organic layer. The aqueous layer was extracted with dichloromethane. The combined organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography to afford 21.8 g of the title compound as yellow solid.
Reaction SMILES: [C:1]([CH:4]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][NH:5]1)([OH:3])=[O:2].[C:14](Cl)(=[O:23])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>[OH-].[Na+]>[C:14]([N:5]1[CH:4]([C:1]([OH:3])=[O:2])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:23]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)C1Cc2ccccc2CN1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C1Cc2ccccc2CN1C(=O)OCc1ccccc1

Procedure:
188 g (1.05 moles) of 3-carboxy-1,2,3,4-tetrahydroisoquinoline are added to 1,050 ml of 1N NaOH at 0°, and 160 ml of benzyl chlorocarbonate and a further 1,050 ml of 1N NaOH are then simultaneously added dropwise at this temperature, while stirring. The mixture is then stirred for 2 hours at room temperature and extracted three times with ether, and the alkaline/aqueous phase is acidified to pH 1 with concentrated HCl. The oil which separates out is extracted with ethyl acetate. The ethyl acetate solution is washed with water until the water phase has a pH of 3.0. After the ethyl acetate solution has been dried over sodium sulfate, the product crystallizes from this solution after concentration and trituration. 1.5 liters of diisopropyl ether are added to the suspension of crystals, and the latter is stirred for one hour at room temperature, and filtered under suction. The product is dried over phosphorus pentoxide in a high vacuum.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13](OS(C(F)(F)F)(=O)=O)[C:12]([C:27]2[N:28]([CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[N:29]=[CH:30][CH:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:45](B1OC(C)(C)C(C)(C)O1)=[CH2:46].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:41]([O:40][C:38]([N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH:45]=[CH2:46])[C:12]([C:27]2[N:28]([CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[N:29]=[CH:30][CH:31]=2)=[CH:11][CH:10]=1)=[O:39])([CH3:43])([CH3:44])[CH3:42]
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc(-c2ccnn2C2CCCCO2)c1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: C=Cc1c(-c2ccnn2C2CCCCO2)ccc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1C(=O)OC
Temperature: 80 °C

Procedure:
A mixture of methyl 6-[bis-(tert-butoxycarbonyl)amino]-3-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-2-trifluoromethanesulfonyloxybenzoate (Intermediate 11, 4.35 g), vinylboronic acid pinacol ester (1.9 mL), bis(triphenylphosphine)palladium (II) dichloride (0.255 g) and cesium carbonate (7.1 g) in dioxane (300 mL) and water (47 mL) was de-gassed and purged with nitrogen. The mixture was then heated to 80° C. for 4 hours. After cooling, the mixture was diluted with ether and the organic layer was separated, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-60% to give methyl 6-[bis-(tert-butoxycarbonyl)amino]-3-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-2-vinylbenzoate (2.84 g) as a gum.