Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.[Li].[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([CH3:20])[C:16]([O:18][CH3:19])=[O:17].[F:21]N(S(C1C=CC=CC=1)(=O)=O)S(C1C=CC=CC=1)(=O)=O>O1CCCC1>[F:21][C:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][N:9]=1)([CH3:20])[C:16]([O:18][CH3:19])=[O:17]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: COC(=O)C(C)c1ccccn1
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C(C)(F)c1ccccn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 78 %

Procedure:
To a stirred, cooled (−78° C.) solution of 5.00 mL (10.0 mmol) of a 2.0 M solution of lithium diisopropylamine in tetrahydrofuran under an atmosphere of nitrogen was added a solution of 1.5 g (9.1 mmol) of methyl 2-pyridin-2-yl-propanoate in 4.0 mL of anhydrous THF. The reaction mixture was allowed to stir for 10 min then warmed to 0° C. over 30 min. The mixture was then re-cooled to −78° C. and a solution of 3.70 g (11.8 mmol) of N-fluoro-N-(phenylsulfonyl)benzenesulfonamide in 4.0 mL THF was added. The resulting mixture was allowed to warm to ambient temperature and stir for 2 h. The reaction was quenched with 50 mL of a saturated ammonium chloride solution and then extracted with diethyl ether (3×50 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated in vacuo. The crude residue was purified by silica gel chromatography eluting with a 0-40% ethyl acetate in hexanes gradient to afford the title compound as a dark oil (1.3 g, 78%). LC-MS: m/z (E/S) 184 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH:4]([C:6]1[CH:24]=[CH:23][C:9]2[C:10]3(OCC[O:19]3)[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH:13]=[CH:14][C:8]=2[CH:7]=1)[CH3:5].CC(C)=O>O>[CH3:1][O:2][C:3](=[O:25])[CH:4]([C:6]1[CH:24]=[CH:23][C:9]2[C:10](=[O:19])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH:13]=[CH:14][C:8]=2[CH:7]=1)[CH3:5]
Reactant: COC(=O)C(C)c1ccc2c(c1)C=Cc1ccccc1C21OCCO1
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)C(C)c1ccc2c(=O)c3ccccc3ccc2c1
Yield: 75 %

Procedure:
1.0 Gm. of 2-(5,5-ethylenedioxy-5H-dibenzo[a,d] cyclohepten-2-yl)propionic acid methyl ester is dissolved in 10 ml. of acetone and to the solution is added 5 ml. of N-hydrochloric acid. The mixture is refluxed for one hour, then cooled, diluted with water, and extracted with ethyl acetate. The extract is washed with aqueous sodium carbonate and water, then dried and evaporated to afford a 75% yield of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)propionic acid methyl ester, as an oil which slowly crystallized, m.p. 37°-39°C., NMR: δCDCl 3 1.55(d), 3.67(s), 3.83(g), 7.04(s) ppm. Use of 2-(5,5-ethylenedioxy-5H-dibenzo[a,d] cyclohepten-2-yl)acetic acid methyl ester gives a similar yield of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)acetic acid methyl ester, m.p. 67°-69°C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:19])([CH:16](O)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.CS(Cl)(=O)=O>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH:16]([CH3:17])[O:19]1
Reactant: CC(O)C(O)(Cn1cncn1)c1ccc(F)cc1F
Agent: CS(=O)(=O)Cl
Product: CC1OC1(Cn1cncn1)c1ccc(F)cc1F

Procedure:
In a manner like that described in Reference Example 25, (2RS,3SR)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2,3-butanediol (1.1 g) obtained in Reference Example 42 was allowed to react with methanesulfonyl chloride (0.35 ml), followed by treatment with a 28% sodium methylate methanol solution to afford (2RS,3RS)-2-(2,4-difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyl oxirane. The product was purified by means of a silica gel column chromatography (ethyl acetate: methylene chloride=4:1) to give a yellow oily product (0.8 g).
Reaction SMILES: [C:1]([N:4]1[C@@H:12]([C:13]([O-:15])=O)[CH2:11][C:10](=[O:16])[C:9]2[CH:17]=[CH:18][CH:19]=[CH:20][C:8]=2[N:7]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:28])[C:6](=[O:29])[C@@H:5]1[CH2:30][C:31]12[CH2:40][CH:35]3[CH2:36][CH:37]([CH2:39][CH:33]([CH2:34]3)[CH2:32]1)[CH2:38]2)(=[O:3])[CH3:2].C([N:44]1[C@H:52]([C:53]([O-:55])=[O:54])CC(=O)C2C=CC=CC=2N(CC2C=CC=CC=2)C(=O)[C@H]1CC12CC3CC(CC(C3)C1)C2)(=O)C>>[C:1]([N:4]1[C@@H:12]([C:13]([NH:44][CH2:52][C:53]([OH:55])=[O:54])=[O:15])[CH2:11][C:10](=[O:16])[C:9]2[CH:17]=[CH:18][CH:19]=[CH:20][C:8]=2[N:7]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:28])[C:6](=[O:29])[C@@H:5]1[CH2:30][C:31]12[CH2:40][CH:35]3[CH2:36][CH:37]([CH2:39][CH:33]([CH2:34]3)[CH2:32]1)[CH2:38]2)(=[O:3])[CH3:2]
Reactant: CC(=O)N1[C@@H](C(=O)[O-])CC(=O)c2ccccc2N(Cc2ccccc2F)C(=O)[C@@H]1CC12CC3CC(CC(C3)C1)C2
Reactant: CC(=O)N1[C@H](CC23CC4CC(CC(C4)C2)C3)C(=O)N(Cc2ccccc2)c2ccccc2C(=O)C[C@H]1C(=O)[O-]
Product: CC(=O)N1[C@@H](C(=O)NCC(=O)O)CC(=O)c2ccccc2N(Cc2ccccc2F)C(=O)[C@@H]1CC12CC3CC(CC(C3)C1)C2

Procedure:
The compound was prepared by an identical route to that used to prepare example 22 except that (3S,5R)-4-acetyl-3-(1-adamantyl)methyl-1-(2-fluorobenzyl)-2,7-dioxo-2,3,4,5,6,7-hexahydro-1H-1,4-benzodiazonine-5-carboxylate was used in step a in place of (3R,5S)-4-acetyl-3-(1-adamantyl)methyl-1-benzyl-2,7-dioxo-2,3,4,5,6,7-hexahydro-1H-1,4-benzodiazonine-5-carboxylate
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[CH3:20]C([N-]C(C)C)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[CH:10]([CH3:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)c2ccccc21
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1CN(C(=O)OC(C)(C)C)c2ccccc2C1=O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 23 %

Procedure:
To a solution of 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-4-quinolinone (structure 68A of Scheme LI, where R1-2 =H) (EXAMPLE 325) (500 mg, 0.002 mol) in THF (5 mL) at -78° C. was added 2.0M LDA in THF (1.01 mL, 0.002 mol). The reaction mixture was stirred at -78° C. for 15 min and iodomethylane (126 mL, 0.002 mol) was added all at once. The temperature was raised to 0° C. and the resulting mixture stirred for 4 h. The reaction was then quenched with sat'd NH4Cl (5 mL), extracted with ethyl acetate (2×10 mL), dried (Na2SO4) and concentrated in vacuo to a solid residue that was subjected to flash column chromatography (silica gel, hexanes/ethyl acetate, 95:5) to give 117 mg (23%) of 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-3-methyl-4-quinolinone (structure 69A of Scheme LI, where R1-2 =H, R3 =methyl), 128 mg (23%) of 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-3,3-dimethyl-4-quinolinone (structure 70A of Scheme LII, where R1-2 =H, R3-4 =methyl) and 200 mg (40%) of recovered starting material. Data for 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-3-methyl-4-quinolinone: 1 H NMR (400 MHz, CDCl3) 7.99 (dd, J=7.9, 1.7, 1H), 7.77 (d, J=8.4, 1H), 7.48 (ddd, J=7.3, 7.3, 1.7, 1H), 7.13 (dd, J=7.4, 1.0, 1H), 4.32 (dd, J=13.4, 4.4, 1H), 3.69 (dd, J=13.3, 9.8, 1H), 2.76 (ddd, J=9.8, 7.0, 4.4, 1H), 1.56 (s, 9H), 1.24 (d, J=7.0, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:26])[C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:15][C:14]=2[F:25])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=1.C(C1C=C(NC(C2C=CC(N3CCN(C4C=CC(C(O)=O)=CC=4)CC3)=C(F)C=2)=O)C=CC=1)(C)(C)C>>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:20][CH2:21][N:22]([C:28]4[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=4)[CH2:23][CH2:24]3)=[CH:15][C:14]=2[F:25])=[O:26])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCNCC3)cc2F)c1
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)c(F)c2)c1
Product: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)cc2F)c1

Procedure:
4-{4-[4-(3-tert-Butyl-phenylcarbamoyl)-3-fluoro-phenyl]-piperazin-1-yl}-benzoic acid was synthesized by the coupling of N-(3-tert-butyl-phenyl)-2-fluoro-4-piperazin-1-yl-benzamide and 4-bromo benzoic acid in a manner similar to the one described in the synthesis of 4-{4-[4-(3-tert-butyl-phenylcarbamoyl)-2-fluoro-phenyl]-piperazin-1-yl}-benzoic acid above. LCMS calcd for C28H30FN3O3 (m/e) 475, obsd 476 (M+H).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl.C(N(CC)CC)C.CCOC(C)=O>[C:13]([N:1]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1CCCNc2ccccc21
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C1CCCN(C(=O)c2ccccc2)c2ccccc21
Yield: 55.7 %

Procedure:
1,2,3,4-Tetrahydro-benzo[b]azepin-5-one from Example E5.5 (480 mg, 2.98 mmol) was dissolved in a mixture of dichloromethane (30 ml) and triethylamine (1.3 ml). Benzoyl chloride (0.46 g, 3.28 mmol) was added and the reaction mixture was heated for at reflux for 2 h. The mixture was cooled and reduced in vacuo. The residue was dissolved in EtOAc and washed with 1M KHSO4 (aq), water and brine. The organic layer was dried, filtered and reduced in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 50% EtOAc: 50% hexane) to yield the title compound (440 mg, 56%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([NH:12][C:13](=[N:22]Cl)[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[CH:5]=1.C([O-])(O)=O.[Na+]>CO>[CH3:1][O:2][C:3]([C:4]1[C:5]2[N:22]=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])[NH:12][C:6]=2[C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)=[O:24]
Reactant: COC(=O)c1ccc(OC)c(NC(=NCl)c2ccc(Cl)cc2Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(OC)c2[nH]c(-c3ccc(Cl)cc3Cl)nc12
Temperature: 25 °C
Yield: 53 %

Procedure:
3-[(2,4-dichloro-N-chloro-benzimidoyl)-amino]-4-methoxy-benzoic acid methyl ester (4 g, 10.32 mmol) obtained in step 1 was dissolved in 50 ml of 50% methanol and NaHCO3 (2.19 g, 20.64 mmol) was added dropwise thereto at room temperature and refluxed for 5 min. The resulting solution was cooled to room temperature, extracted with ethyl acetate, and the extract was concentrated under a reduced pressure. The resulting residue was purified by recrystallization from ethyl acetate/hexane to obtain the title compound (3.2 g, 5.47 mmol) in a yield of 88%.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:7])=[CH:5][CH:6]=1.Cl[CH:9]([O:11]C)Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[S:3][C:4]([Cl:7])=[CH:5][C:6]=1[CH:9]=[O:11]
Reactant: COC(Cl)Cl
Reactant: Clc1ccc(Cl)s1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: O=Cc1cc(Cl)sc1Cl
Reaction time: 0.83 h
Yield: 97.2 %

Procedure:
To a solution of 2,5-dichlorothiophene (100.0 g) and dichloromethylmethylether (165.3 g) in dichloromethane (800 ml) was added dropwise a solution of titanium tetrachloride (272.7 g) in dichloromethane (160 ml) at −10 to −15° C. taking 50 minutes, and at the same temperature, the mixture was stirred for 30 minutes. The reaction solution was poured into ice, and the organic layer was washed with water, sodium hydrogen carbonate solution, water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated to give 2,5-dichloro-3-formylthiophene (115.0 g) as oil. To a mixture of acetone (1000 ml), sodium hydroxide (28.6 g) and water (1200 ml) was added at 0° C. a solution of 2,5-dichloro-3-formylthiophene (58.6 g) in acetone (200 ml) for 1.5 hours, and the mixture was stirred at the same temperature for 1 hour. Under reduced pressure, acetone was evaporated, and the crystals were filtered, washed with water and dried to give 4-(2,5-dichlorothiophen-3-yl)-3-buten-2-one (136.6 g). To a solution of 20% sodium ethoxide in ethanol (211 g) was added diethyl malonate (99.3 g) at room temperature, and then 4-(2,5-dichlorothiophen-3-yl)-3-buten-2-one (136.6 g) little by little. The mixture was stirred at room temperature for 30 minutes, heated for 2 hours while stirring, and cooled. The solvent was evaporated, and to the residue was added water. The aqueous layer was washed with ethyl acetate and concentrated, to which was added 2M sodium hydroxide (340 ml). The mixture was stirred at 100° C. for 2 hours and cooled. To the mixture was added 2.5M sulfuric acid (340 ml) for 15 minutes, and the mixture was stirred at 100° C. for 1.5 hours. The mixture was cooled, and precipitated crystals were filtered and washed with ethyl acetate-isopropylether (1:4) and isopropylether to give 5-(2,5-dichlorothiophen-3-yl)cyclohexane-1,3-dione (78.9 g) as colorless crystals.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([CH2:11][O:12][C:13]2[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15]([OH:17])=O)[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2].[C:22]1([NH:28][C:29](=[O:32])[NH:30][NH2:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC(=CC1=2)Cl)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([CH2:11][O:12][C:13]2[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15]([NH:31][NH:30][C:29]([NH:28][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:32])=[O:17])[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: NNC(=O)Nc1ccccc1
Reactant: CC(=O)Nc1cc(COc2ccccc2C(=O)O)ccn1
Agent: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1cc(COc2ccccc2C(=O)NNC(=O)Nc2ccccc2)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.1 %

Procedure:
To a solution of 2-(2-acetamidopyridin-4-yl)methoxybenzoic acid (500 mg, 1.8 mmol; Reference Compound 3-(1)), 4-phenylsemicarbazide (265 mg, 1.8 mmol) and diisopropylethylamine (450 μL, 2.6 mmol) in N,N-dimethylformamide (5.0 mL) was added HCTU (940 mg, 2.3 mmol) under ice-cooling, and then the mixture was stirred for 8 hours at room temperature. The reaction solution was diluted with ethyl acetate (20 mL). To the solution was added a 0.1 M aqueous sodium hydroxide solution (20 mL). The ethyl acetate layer was washed with a saturated brine solution, dried over anhydrous sodium sulfate, and concentrated under a reduced pressure to dryness, and ethanol was added to the residue. The precipitated solid was filtered off and dried under a reduced pressure to give 250 mg (46%) of the titled compound as colorless solid.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14](S(C4C=CC=CC=4)(=O)=O)[C:15]([C:17]4[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH:22]=4)=[CH:16][C:9]=23)[C:5]([C:39]2[CH:44]=[CH:43][C:42]([NH:45][C:46]([NH:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)=[O:47])=[CH:41][CH:40]=2)=[N:4]1)[CH3:2].[OH-].[Na+]>CO>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH:22]=4)=[CH:16][C:9]=23)[C:5]([C:39]2[CH:40]=[CH:41][C:42]([NH:45][C:46]([NH:48][C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)=[O:47])=[CH:43][CH:44]=2)=[N:4]1)[CH3:2]
Reactant: CCn1cc(-c2ccnc3c2cc(C2=CCN(C(=O)OC(C)(C)C)CC2)n3S(=O)(=O)c2ccccc2)c(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCn1cc(-c2ccnc3[nH]c(C4=CCN(C(=O)OC(C)(C)C)CC4)cc23)c(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Temperature: 25 °C

Procedure:
To a solution of 1,1-dimethylethyl 4-[4-[1-ethyl-3-(4-{[(phenylamino)carbonyl]amino}phenyl)-1H-pyrazol-4-yl]-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-3,6-dihydro-1(2H)-pyridinecarboxylate (0.38 mmol) in methanol (3.8 mL) was added 6N sodium hydroxide (1.14 mmol). The reaction mixture was refluxed for 5 h, cooled to room temperature and concentrated under reduced pressure. The solid residue was suspended in water, stirred vigorously and collected by filtration to give the title compound as an orange solid which was used without further purification (95%). Alternatively, the solid residue was purified by Gilson reverse phase HPLC to afford the title compound. ESMS [M+H]+: 604.4
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:13][CH:7]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[C:10]=2[O:9][C:8]1([CH3:12])[CH3:11]
Reactant: CC1(C)Cc2cccc(Br)c2O1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)Oc2c(Br)cccc2C1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A stirring mixture of 7.0 grams (0.031 mole) of 7-bromo-2,3-dihydro-2,2-dimethylbenzofuran and 5.5 grams (0.031 mole) of N-bromosuccinimide in 150 mL of carbon tetrachloride is heated to reflux while irradiating with a sun lamp. The refluxing reaction mixture is stirred for about three hours, then it is cooled to ambient temperature. After this time the reaction mixture is washed with two 50 mL portions of aqueous 5% sodium bicarbonate solution, and one 50 mL portion of water. The organic layer is dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure, yielding 3,7-dibromo-2,3-dihydro-2,2-dimethylbenzofuran.
Reaction SMILES: [N:1]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5][CH:4]([C:7]([O:9]C)=O)[CH2:3][CH2:2]1.[Cl:18][CH2:19]I.C[Li]>C1COCC1>[Cl:18][CH2:19][C:7]([CH:4]1[CH2:3][CH2:2][N:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5]1)=[O:9]
Reactant: ClCI
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li]C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)CCl)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 1-tert-butyl 4-methyl piperidine-1,4-dicarboxylate (3.6 g, 14.9 mmol) in THF (100 mL) was cooled to −78° C. under nitrogen and then charged with neat chloroiodomethane (1.8 mL, 24.7 mmol). A solution of methyllithium (16.5 mL, 1.5 M in Et2O) was added dropwise. The reaction was stirred for 60 min at −78° C. and then quenched with half-saturated NH4Cl. After warming to room temperature, the mixture was extracted twice with EtOAc. The organic phases were combined, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to yield impure tert-butyl 4-(2-chloroacetyl)piperidine-1-carboxylate as a dark oil. Key non-solvent resonances in 1H-NMR (400 MHz, d6-DMSO) δ=4.68 (s, 2H), 4.1-3.8 (m, 4H), 2.75 (m, 1H), 1.8 (m, 1H), 1.7-1.5 (m, 2H), 1.4 (s, 9H), 1.4-1.2 (m, 2H).
Reaction SMILES: [F:1][CH:2]([F:28])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([O:25][CH2:26][CH3:27])[CH:16]=2)[CH:4]=1.[NH2:29][C:30]1[CH:31]=[C:32]([S:36]([NH:39][CH:40]2[CH2:42][CH2:41]2)(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=1>>[CH:40]1([NH:39][S:36]([C:32]2[CH:31]=[C:30]([NH:29][C:12]([C:11]3[CH:10]=[N:9][N:8]4[C:3]([CH:2]([F:1])[F:28])=[CH:4][C:5]([C:15]5[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[C:17]([O:25][CH2:26][CH3:27])[CH:16]=5)=[N:6][C:7]=34)=[O:14])[CH:35]=[CH:34][CH:33]=2)(=[O:38])=[O:37])[CH2:42][CH2:41]1
Reactant: Nc1cccc(S(=O)(=O)NC2CC2)c1
Reactant: CCOc1cc(-c2cc(C(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Product: CCOc1cc(-c2cc(C(F)F)n3ncc(C(=O)Nc4cccc(S(=O)(=O)NC5CC5)c4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(3-ethoxy-4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.12) and 3-amino-N-cyclopropyl-benzenesulfonamide [CAS 459434-39-0] according to general procedure II. Yellow solid. MS (ISP) 594.1 [(M−H)−]; mp 213° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[C:3]=1[CH3:9].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][OH:19])=[CH:14][CH:13]=1.[H-].[Na+].O>CN(C=O)C.[Cl-].[Na+].O.CCCCCCC.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:19][CH2:18][C:15]2[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)[C:3]=1[CH3:9]
Reactant: Cc1c(F)cccc1Br
Reactant: COc1ccc(CO)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCCCCCC
Product: COc1ccc(COc2cccc(Br)c2C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.9 %

Procedure:
1-Bromo-3-fluoro-2-methylbenzene (388 mg, 2.05 mmol), and (4-methoxyphenyl)methanol (0.511 mL, 4 mmol) were dissolved in DMF (5 mL) in a microwave vessel. Sodium hydride as a 60% dispersion in mineral oil (164 mg, 4.0 mmol) was added portionwise under a flow of nitrogen over 10 min. The reaction vessel was then sealed and heated at 180° C. for 900s. The crude reaction mixture was poured onto 1:1 water:brine (6 mL) and DCM (10 mL). The biphasic mixture was stirred at ambient temperature for 1 h and then the organic and aqueous layers were separated. The combined organics were dried over Na2SO4 and concentrated in vacuo. The crude material was then purified by chromatography on silica gel. Elution with 5:95 ethyl acetate:heptane afforded 1-bromo-3-(4-methoxybenzyloxy)-2-methylbenzene (289 mg, 0.9 mmol, 46%).
Reaction SMILES: B(Cl)(Cl)Cl.C[O:6][C:7]1[CH:11]=[CH:10][S:9][C:8]=1[C:12](=[O:17])[CH:13]=[C:14]([CH3:16])[CH3:15].[K+].[Br-]>ClCCl>[OH:6][C:7]1[CH:11]=[CH:10][S:9][C:8]=1[C:12](=[O:17])[CH:13]=[C:14]([CH3:15])[CH3:16]
Reactant: COc1ccsc1C(=O)C=C(C)C
Agent: ClB(Cl)Cl
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)=CC(=O)c1sccc1O
Temperature: 0 °C

Procedure:
A solution of boron trichloride, (1.0M in dichloromethane, 800 mL, 0.80 mol) was slowly added to a solution of 3-methoxy-2-(3-methyl-1-oxo-2-buten-1-yl) thiophene (52.3 g, 0.27 mol) in dichloromethane (400 mL) at -10° C. to 5° C. The resultant solution was stirred an additional 1.5 h at -5° C. Ice water was added slowly with rapid stirring. The organic layer was separated, dried over sodium sulfate, and eluted through a pad of silica gel. The solvent was evaporated in vacuo and the resultant oil was crystallized from hexanes at -70° C. to give the product, 40.0 g (82%), as a yellow solid: mp 32-33° C.; IR (KBr): 1641, 1581 and 1541 cm-1 ; MS: m/z 183 (MH+); 1H NMR (CDCl3): δ2.00 (d, J=1.1 Hz, 3H), 2.30 (d, J=1.0 Hz, 3H), 6.25 (m, 1H), 6.75 (d, J=5.3 Hz, 1H), 7.37 (d, J=5.3 Hz, 1H) and 12.14 (s, exchanges with D2O, 1H).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[N:29]1[CH2:36][C@H:35]2[NH:37][CH2:38][C@@H:30]1[CH2:31][CH:32]=[CH:33][CH2:34]2.CCN(C(C)C)C(C)C>C(O)C>[CH:9]1[C:10]2[NH:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]=2[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:37]2[CH2:38][CH:30]3[N:29]([C:20]4[CH:21]=[CH:22][C:23]5[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH:19]=4)[CH2:36][CH:35]2[CH2:34][CH:33]=[CH:32][CH2:31]3)=[CH:7][CH:8]=1
Reactant: c1ccc2c(c1)[nH]c1cccc(OC[C@@H]3CO3)c12
Reactant: C1=CC[C@H]2CN[C@@H](C1)CN2c1ccc2ccccc2c1
Agent: C1=C\C[C@H]2CN[C@@H](C/1)CN2c1ccc2ccccc2c1
Agent: O[C@H](COc1cccc2[nH]c3ccccc3c12)CN1CC2C/C=C\CC1CN2c1ccc2ccccc2c1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O[C@H](COc1cccc2[nH]c3ccccc3c12)CN1CC2CC=CCC1CN2c1ccc2ccccc2c1
Temperature: 95 °C

Procedure:
(S)-4-Oxiranylmethoxy-9H-carbazole (18.5 mg, 0.077 mmol) and Z-(1S,6S)-7-naphthalen-2-yl-7,9-diaza-bicyclo[4.2.2]dec-3-ene (20 mg, 0.189 mmol) were placed in a μW tube with ethanol (3 ml), DIPEA (15 μL, 0.086 mmol) and heated to 95° C. for 900 sec. The solvent was evaporated and the residue was purified via silica chromatography (30% Ethyl acetate/heptane) to yield the title compound as a residue.