Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:31])[CH:3]1[CH:20]2[C:7]([OH:25])([C:8]([OH:24])=[C:9]3[CH:18]([CH2:19]2)[S:17][C:16]2[C:11](=[C:12]([OH:22])[CH:13]=[CH:14][C:15]=2Cl)[C:10]3=[O:23])[C:6](=[O:26])[C:5]([C:27]([NH2:29])=[O:28])=[C:4]1[OH:30].C(N(CC)CC)C>CO>[CH3:31][N:2]([C@@H:3]1[C:4](=[O:30])[C:5]([C:27]([NH2:29])=[O:28])=[C:6]([OH:26])[C@:7]2([OH:25])[C@H:20]1[CH2:19][C@@H:18]1[S:17][C:16]3[C:11](=[C:12]([OH:22])[CH:13]=[CH:14][CH:15]=3)[C:10]([OH:23])=[C:9]1[C:8]2=[O:24])[CH3:1]
Reactant: CN(C)C1C(O)=C(C(N)=O)C(=O)C2(O)C(O)=C3C(=O)c4c(O)ccc(Cl)c4SC3CC12
Solvent: CCN(CC)CC
Solvent: CO
Product: CN(C)[C@@H]1C(=O)C(C(N)=O)=C(O)[C@@]2(O)C(=O)C3=C(O)c4c(O)cccc4S[C@H]3C[C@@H]12

Procedure:
467 mg of 7-chloro-6-thiatetracycline in 25 ml of methanol are hydrogenated in the presence of 101 mg of triethylamine on 200 mg of 10% Pd-on-charcoal at 20° and normal pressure to give 6-thiatetracycline.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH:13]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14][CH2:15][S:16][CH3:17].OOS([O-])=O.[K+].[OH2:32].C[OH:34]>>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][CH:13]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])[CH2:14][CH2:15][S:16]([CH3:17])(=[O:34])=[O:32]
Reactant: O
Reactant: CO
Reactant: CSCCC(CN1C(=O)c2ccccc2C1=O)NC(=O)OC(C)(C)C
Agent: O=S([O-])OO
Agent: [K+]
Product: CC(C)(C)OC(=O)NC(CCS(C)(=O)=O)CN1C(=O)c2ccccc2C1=O
Reaction time: 3 h

Procedure:
To a solution of tert-butyl [1-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-(methylsulfanyl)butan-2-yl]carbamate (29 g, 80 mmol) in methanol (700 mL) was added Oxone (148 g, 0.241 mol) and water (700 mL) at room temperature. After 3 hours, the reaction mixture was quenched with 20% aqueous sodium bisulfate solution, diluted with water, and extracted with DCM. The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl [1-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-(methylsulfonyl)butan-2-yl]carbamate which was used in the next step without purification. MS ESI calc'd. for C18H25N2O6S [M+H]+ 397. found 397. 1H NMR (400 MHz, CD3OD) δ 7.87-7.82 (m, 4H), 4.05-3.95 (m, 1H), 3.77-3.75 (m, 2H), 3.25-3.10 (m, 2H), 3.00 (s, 3H), 2.11-1.89 (m, 2H), 1.24 (s, 9H).
Reaction SMILES: CC#N.[CH3:4][O:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:29][Si:30]([CH2:33][CH2:34][O:35][CH2:36]Cl)([CH3:32])[CH3:31]>C(OCC)(=O)C>[CH3:4][O:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13](=[O:21])[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:36][O:35][CH2:34][CH2:33][Si:30]([CH3:32])([CH3:31])[CH3:29])=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccccc1C(=O)c1ccc(O)cc1
Reactant: C[Si](C)(C)CCOCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1ccccc1C(=O)c1ccc(OCOCC[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 68 %

Procedure:
Dry CH3CN (50 mL) was added to 2-(4-hydroxybenzoyl)benzoic acid methyl ester (3.65 g, 15 mmol) followed by cesium carbonate (5.4 g, 16.5 mmol) and trimethylsilylethoxymethylchloride (2.9 mL, 16.5 mmol). The system was stirred at room temperature under nitrogen for 24 h and monitored by TLC. Removal of the solvent gave a light yellow oil that was taken up into ethyl acetate (100 mL), washed with water (3×50 mL), brine (40 mL) and dried with MgSO4. The solvent was removed and the crude product was purified by flash column chromatography (5:95 EtOAc:petrol) to give 2-[4-(2-trimethylsilanylethoxymethoxy)benzoyl]benzoic acid methyl ester as a yellow oil (3.94 g, 10.2 mmol, 67%); Rf 0.79 (40:60 EtOAc:petrol). λmax (CH3OH)/nm 282, Abs 1.072. IR: 2939, 1720, 1666, 1589, 1489 cm−1. 1H NMR: (300 MHz, CDCl3) δ 0.00 (s, 9H, Si—(CH3)3), 0.94 (m, 2H, R—O—CH2—CH2—Si), 3.66 (s, 3H, COOCH3), 3.75 (m, 2H, O—CH2—CH2—Si), 5.27 (s, 2H, O—CH2—O), 7.05 (m, 2H, Ar—H), 7.37 (m, 1H, Ar—H), 7.53-7.66 (dtd, 2H, J=22.6, 7.4, 1.4 Hz, Ar—H), 7.72 (m, 2H, Ar—H), 8.05 (m, 1H, Ar—H). 13C NMR: (75 MHz, d6-DMSO) δ −2, 16.8, 51.5, 65.3, 91.5, 115.1, 127, 128, 129, 129.2, 129.6, 130.4, 132, 140.7, 160.2, 165.2, 194. LC/MS-ES+ m/z 163.2, 297.1, 387.1 [MH+], 409 [MNa+]. HRMS (EI) m/z Calcd. for C21H26O5Si: 386.1549. Found 386.1562.
Reaction SMILES: [Sm:1].[C:2](=[O:5])([OH:4])[O-:3].[NH4+]>[N+]([O-])(O)=O>[C:2](=[O:3])([O-:5])[O-:4].[Sm+3:1].[C:2](=[O:3])([O-:5])[O-:4].[C:2](=[O:3])([O-:5])[O-:4].[Sm+3:1]
Reactant: [Sm]
Reactant: O=C([O-])O
Agent: [NH4+]
Solvent: O=[N+]([O-])O
Product: O=C([O-])[O-]
Product: [Sm+3]

Procedure:
In the preparative method, 10 liters of a solution containing 19.8 g/l samarium in dilute nitric acid are charged to the vessel. The solution pH is adjusted to about 3 with ammonium bicarbonate, heat is applied to obtain a solution temperature of about 60° C., and about 200 grams of samarium carbonate are added. The impeller is started and a 2M solution of ammonium bicarbonate is pumped through the distributor, at a rate of about 49 ml/minute, until a pH of about 6 is obtained. The addition of ammonium bicarbonate is stopped and, under continued vessel agitation, the vessel is drained to leave a total slurry volume of about 5 liters. Agitation is stopped, the crystals are allowed to settle, and clear solution is decanted to leave a proper amount of crystals for the next batch preparation. After adjusting the pH of slurry in the vessel to a value less than about 5, samarium solution for the next batch is added. All batches after the first are precipitated at a temperature of 40° C.
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2[N:10]=[C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:12]=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1.[I:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[S:32])=[CH:26][CH:25]=1.C(N(CC)CC)C>>[I:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([N:17]2[CH2:18][CH2:19][N:14]([C:11]3[N:12]=[CH:13][C:8]4[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4][N:3]([CH2:2][CH3:1])[C:9]=4[N:10]=3)[CH2:15][CH2:16]2)=[S:32])=[CH:26][CH:25]=1
Reactant: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCNCC3)nc21
Reactant: S=C=Nc1ccc(I)cc1
Solvent: CCN(CC)CC
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(C(=S)Nc4ccc(I)cc4)CC3)nc21

Procedure:
Pipemidic acid (25 mg, 0.0824 mmol), 4-iodophenyl isothiocyanate (21.5 mg, 0.0824 mmol) and triethylamine (23 μL, 0.165 mmol) were used. Purification on silica yielded compound 3 in Table 1, below (36 mg, 77%). 1H NMR (300 MHz, CDCl3) δ 9.32 (s, 1H), 8.66 (s, 1H), 7.66 (d, J=6.94 Hz, 1H), 7.37 (s, 1H), 7.27 (s, 1H), 7.00 (d, J=7.44 Hz, 1H), 4.33 (q, J=6.90 Hz, 2H), 4.21-3.99 (m, 8H), 1.49 (t, J=7.14 Hz, 3H) ppm.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=3)[CH:19]=[CH:20][CH:21]=1)[C:10]([CH3:33])([CH3:32])[CH2:9]2)=[O:5])C.O.[OH-].[Li+].Cl>CO.O1CCCC1.O>[C:28]([C:25]1[CH:24]=[CH:23][C:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([CH:11]3[C:10]([CH3:33])([CH3:32])[CH2:9][C:8]4[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=4)[NH:12]3)[CH:17]=2)=[CH:27][CH:26]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(-c3ccc(C(C)(C)C)cc3)c1)N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)c1ccc(-c2cccc(C3Nc4ccc(C(=O)O)cc4CC3(C)C)c2)cc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 69.1 %

Procedure:
A mixture of 2-(4′-tert-butyl-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.28 g, 0.63 mmol) in methanol (7 mL) and tetrahydrofuran (5 mL), lithium hydroxide hydrate (0.27 g, 6.3 mmol) in water (0.5 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(4′-tert-butyl-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (0.18 g, 70%) as a white solid which was used for next step without further purification: LC/MS m/e calcd for C28H31NO2 (M+H)+: 414.6, observed: 414.1;
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[C:10](=[O:11])[CH2:9][CH:8]([CH3:12])[CH2:7][C:5]=2[N:6]=1.C1C(=O)N(Br)C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1CCN2C(=NCCC2)CC1.Cl>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:1][C:2]1[S:3][C:4]2[C:10]([OH:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:5]=2[N:6]=1
Reactant: CC1CC(=O)c2sc(Br)nc2C1
Agent: Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: Cc1cc(O)c2sc(Br)nc2c1
Temperature: 90 °C
Yield: 71 %

Procedure:
To a solution of 26 (7.38 g, 30.0 mmol) in CCl4 (90 mL) was added NBS (5.61 g, 31.5 mmol) and dibenzoyl peroxide (727 mg, 3.0 mmol). The reaction was heated at 90° C. in a sealed reaction vessel for about 4 h. Then DBU (6.73 mL, 45.0 mmol) in CH2Cl2 (15 mL) was added. The mixture was heated a reflux for 30 min, then a 1 M HCl solution was added. The layers were separated, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with a brine solution. The organic layer was then dried, filtered, and concentrated in vacuo. The crude product was adsorbed on ˜30 g of silica then run through a plug of silica with 40% EtOAc/hexanes to give 5.2 g of 27. 1H-NMR: 400 MHz, (CD3OH) δ: 7.25 (s, 1H), 6.69 (s, 1H), 2.40 (s, 3H). LCMS-ESI+: calc'd for C8H7BrNOS: 243.9 (M+H+); Found: 244.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:28])([CH2:25][CH:26]=[CH2:27])[CH2:9][CH2:10][NH:11][CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.Cl[C:30](Cl)([O:32]C(=O)OC(Cl)(Cl)Cl)Cl.C1CCN2C(=NCCC2)CC1>C1COCC1.N1C=CC=CC=1>[CH2:25]([C:8]1([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[O:28][C:30](=[O:32])[N:11]([CH2:12][CH:13]2[CH2:14][CH2:15][N:16]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:17][CH2:18]2)[CH2:10][CH2:9]1)[CH:26]=[CH2:27]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C=CCC(O)(CCNCC1CCN(c2ccccc2)CC1)c1ccc(F)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: C=CCC1(c2ccc(F)cc2)CCN(CC2CCN(c3ccccc3)CC2)C(=O)O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 20.6 %

Procedure:
3-(4-fluorophenyl)-1-((1-phenylpiperidin-4-yl)methylamino)hex-5-en-3-ol (120 mg, 0.314 mmol) was dissolved in THF (30 mL) and pyridine (c.a. 500 μL, excess). A solution of triphosgene (60 mg, excess) in THF (5 mL) was added slowly in 4 batches. After stirring 4 h at rt, DBU (94 μL, 2 equiv.) was added and the mixture was heated to reflux for overnight. There was still a lot of starting material on LC-MS spectra. The mixture was concentrated, redissolved in EtOAc (40 mL), washed with 5% aq HCl (2×8 mL), brine (8 mL), and dried over Na2SO4. After filtration and concentration, the residue was purified by prep HPLC to afford 6-allyl-6-(4-fluorophenyl)-3-((1-phenylpiperidin-4-yl)methyl)-1,3-oxazinan-2-one (17 mg, 13%). LC-MS Method 1 tR=1.32 min, m/z=409 (M+1); 1H NMR (CD3OD) 7.62-7.53 (m, 4H), 7.39 (m, 2H), 7.13 (t, 2H), 5.67 (m, 1H), 5.04 (dd, 2H), 3.05 (m, 2H), 2.63 (d, 2H), 2.57 (d, 1H), 2.32 (m, 1H), 2.06 (m, 1H).
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][C:3]1[CH:12]=[CH:11][C:8]([O:9][CH3:10])=[C:5]([O:6][CH3:7])[CH:4]=1.[CH3:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[CH:17]1[O:19][CH2:18]1>C1C=CC=CC=1.CCCCCC>[CH3:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[CH:17]([OH:19])[CH2:18][NH:13][CH2:1][CH2:2][C:3]1[CH:12]=[CH:11][C:8]([O:9][CH3:10])=[C:5]([O:6][CH3:7])[CH:4]=1
Reactant: Cc1ccccc1C1CO1
Reactant: COc1ccc(CCN)cc1OC
Solvent: c1ccccc1
Solvent: CCCCCC
Product: COc1ccc(CCNCC(O)c2ccccc2C)cc1OC
Yield: 36.2 %

Procedure:
Homoveratrylamine (13.6 g, 0.0753 mole) and o-methylstyrene oxide (10.1 g, 0.0753 mole) were stirred at 100° under argon for 16 hours and then diluted with benzene and hexane and cooled in ice. The solid which precipitated was filtered and recrystallized from benzene-hexane to give 8.6 g (36%) of 2-methyl-α-[N-(3,4-dimethoxyphenethyl)aminomethyl]benzyl alcohol, mp 91°-94°.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[CH3:15][N:16]1[C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=[N:17]1.C(N(CC)CC)C.C(OCC)(=O)C>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:21]([C:20]1[N:16]([CH3:15])[N:17]=[CH:18][CH:19]=1)=[O:22]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: Cn1nccc1C(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1nccc1C(=O)NCCc1c[nH]c2ccc(Cl)cc12
Yield: 85.6 %

Procedure:
This compound was obtained following Method B starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.0443 g, 0.188 mmol), 1-methyl-1H-pyrazole-5-carbonyl chloride (0.028 g; 0.188 mmol), and triethylamine (0.066 mL; 0.470 mmol) in dichloromethane (3 mL). Flash chromatography on silica gel eluting with 2 to 16% of ethyl acetate in dichloromethane gave 0.0487 g (86%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1-methyl-1H-pyrazole-5-carboxamide as a solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:9]2[N:10]=[C:11]([NH:13][C:14](=[O:22])[C:15]3[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=3)[S:12][C:8]=2[C:7]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:36](OC(=O)C)(=[O:38])[CH3:37].C(=O)(O)[O-].[Na+]>C1COCC1.O>[C:36]([N:26]1[CH2:27][CH2:28][CH:23]([C:7]2[C:8]3[S:12][C:11]([NH:13][C:14](=[O:22])[C:15]4[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=4)=[N:10][C:9]=3[C:4]([O:3][CH3:2])=[CH:5][CH:6]=2)[CH2:24][CH2:25]1)(=[O:38])[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(C2CCNCC2)c2sc(NC(=O)c3ccnc(C)c3)nc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C2CCN(C(C)=O)CC2)c2sc(NC(=O)c3ccnc(C)c3)nc12
Reaction time: 1 h
Yield: 74.2 %

Procedure:
To a solution of 0.75 g (0.165 mMol) N-(4-methoxy-7-piperidin-4-yl-benzothiazol-2-yl)-2-methyl-isonicotinamide hydrochloride (1:2) in 4 ml THF were added 0.05 ml triethyl amine. At 0° C. 0.019 ml (0.2 mMol) acetic anhydride was added dropwise and stirred for 1 h. Then a mixture of 5 ml sat. aqueous sodium bicarbonate and 10 ml water were added. A precipitation formed, which was filtered. The residue on the filter was triturated in water. Upon isolation and drying in vacuo one obtained 0.052 g (74%) N-[7-(1-acetyl-piperidin-4-yl)-4-methoxy-benzothiazol-2-yl]-2-methyl-isonicotinamide as a white solid. F.p.: 213-215° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([CH3:22])[C:16]([CH2:23]/[CH:24]=[CH:25]/[OH:26])=[C:15]2[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1.C(N(CC)CC)C>ClCCl>[Cl:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([CH3:22])[C:16](/[CH:23]=[CH:24]/[CH:25]=[O:26])=[C:15]2[C:27]1[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=1
Reactant: Cc1nc2ccc(Cl)cc2c(-c2ccc(F)cc2)c1C/C=C/O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1nc2ccc(Cl)cc2c(-c2ccc(F)cc2)c1/C=C/C=O

Procedure:
A solution of oxalyl chloride (2.28 mL, 1.3 equivalents) in 100 mL of dichloromethane was cooled to -78° C. under a nitrogen atmosphere. A solution of dimethylsulfoxide (3.67 mL, 2.6 equivalents) in 75 mL of dichloromethane was added dropwise with stirring. Five minutes after addition was complete, a solution of (E)-3-[6-chloro-4-(4-fluorophenyl)-2-methyl-3-quinolyl]-propenol (6.59 g) in 75 mL of dichloromethane was added dropwise. This solution was stirred at -78° C. for three-quarters of an hour and then 1mL (5.0 equivalents) of triethylamine was added.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([NH:10][CH:11]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[C:12]2[C:13]([C:24](O)=[O:25])=[N:14][N:15]([CH:21]3[CH2:23][CH2:22]3)[C:16]=2[C:17]([F:20])([F:19])[F:18])[CH:3]=1>C(Cl)Cl>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([N:10]2[CH:11]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[C:12]3[C:13](=[N:14][N:15]([CH:21]4[CH2:22][CH2:23]4)[C:16]=3[C:17]([F:20])([F:18])[F:19])[C:24]2=[O:25])[CH:3]=1
Reactant: Cn1cc(NC(c2ccc(Cl)cc2)c2c(C(=O)O)nn(C3CC3)c2C(F)(F)F)cc(Cl)c1=O
Solvent: ClCCl
Product: Cn1cc(N2C(=O)c3nn(C4CC4)c(C(F)(F)F)c3C2c2ccc(Cl)cc2)cc(Cl)c1=O

Procedure:
The title compound was prepared in analogy to the procedure described in Example 1 using 4-(((5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)amino)(4-chlorophenyl)methyl)-1-cyclopropyl-5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (Step 40.4) at RT for 30 min. tR: 1.12 min (LC-MS 2); ESI-MS: 483 [M+H]+ (LC-MS 2); Rf=0.69 (CH2Cl2/5% MeOH/1% ammonia); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.11-1.22 (m, 2H) 1.22-1.38 (m, 2H) 3.41 (s, 3H) 3.86-4.00 (m, 1H) 6.36 (s, 1H) 7.26 (m, J=8.6 Hz, 2H) 7.36 (m, J=8.6 Hz, 2H) 7.90 (d, J=2.7 Hz, 1H) 7.87 (d, J=2.7 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([S:11](=[O:15])(=[O:14])[CH2:12][CH2:13][N:7]3[C@H:6]3[CH2:16][CH2:17][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][C@@H:5]23)[CH:10]=1.[F:27][C:28]([F:41])([F:40])[C:29]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:30]=1B(O)O>>[CH3:36][O:35][C:33]1[CH:32]=[CH:31][C:30]([C:2]2[CH:3]=[C:4]3[C:8]4=[C:9]([S:11](=[O:15])(=[O:14])[CH2:12][CH2:13][N:7]4[C@H:6]4[CH2:16][CH2:17][N:18]([C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH2:19][C@@H:5]34)[CH:10]=2)=[C:29]([C:28]([F:27])([F:40])[F:41])[CH:34]=1
Reactant: COc1ccc(B(O)O)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CCS3(=O)=O
Product: COc1ccc(-c2cc3c4c(c2)S(=O)(=O)CCN4[C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]32)c(C(F)(F)F)c1
Yield: 74.2 %

Procedure:
The bromo-indoline (0.6 mmol), boronic acid (0.8 mmol) and barium hydroxide (1 mmol) were stirred into a solution of water (4 mL) and DME (8 mL), then heated at 60° C. while bubbling through a stream of Argon gas for 20 min. The reaction mixture was then cooled to room temperature and Pd(PPh3)2Cl2 (0.03 mmol) and PPh3 (0.09 mmol) were quickly added and refluxing resumed for 4 hours. When the reaction was completed as shown by TLC, ethyl acetate (10 mL) was added and the mixture was filtered through a Celite bed. Organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure. This residue was purified on a flash column eluting with 10% EtOAc/Hexanes to give the desired product in 60-95% yield. tert-butyl(6bR,10aS)-5-[4-methoxy-2-(trifluoromethyl)phenyl]-1,2,6b,9,10,10a-hexahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole-8(7H)-carboxylate 3,3-dioxide (135 mg, 74%) was prepared via coupling of the tert-butyl(6bR,10aS)-5-bromo-1,2,6b,9,10,10a-hexahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole-8(7H)-carboxylate 3,3-dioxide (150 mg, 0.338 mmol) with 2-trifluoromethyl-4-methoxyphenyl boronic acid (112 mg, 0.507 mmol) using the general procedure described above.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:14][C:13]([CH2:15][CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[C:44]([N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)(=[O:46])[CH3:45]>CN(C=O)C>[C:44]([N:47]1[CH2:52][CH2:51][N:50]([C:17](=[O:19])[CH2:16][CH2:15][C:13]2[S:14][C:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:21])[F:20])=[CH:9][CH:8]=3)=[CH:11][CH:12]=2)[CH2:49][CH2:48]1)(=[O:46])[CH3:45]
Reactant: O=C(O)CCc1ccc(-c2ccc(OC(F)(F)F)cc2)s1
Reactant: CC(=O)N1CCNCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(C(=O)CCc2ccc(-c3ccc(OC(F)(F)F)cc3)s2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
50 mg (0.16 mmol) of 3-[5-(4-trifluoromethoxy-phenyl) -thiophen-2-yl]-propionic acid, 0.182 g (1.58 mmol) of NEM and 57 mg (0.17 mmol) of TOTU were dissolved in 2 ml of DMF and stirred at room temperature for 15 min. 22 mg (0.17 mmol) of 1-acetyl-piperazine were added, and the reaction mixture was stirred at room temperature for 16 h. After evaporation, the product was purified by preparative RP HPLC eluting with a gradient of 0 to 100% acetonitrile in water (+0.01% TFA). After lyophilization, the product was obtained as a solid. Yield: 17 mg.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6]([OH:9])=[N:7][CH:8]=1.C([O-])(=O)C.[Na+].[Br:17]Br>C(O)(=O)C>[Br:17][C:5]1[C:6]([OH:9])=[N:7][CH:8]=[C:3]([C:2]([F:1])([F:10])[F:11])[CH:4]=1
Reactant: Oc1ccc(C(F)(F)F)cn1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Oc1ncc(C(F)(F)F)cc1Br
Temperature: 80 °C
Yield: 100.6 %

Procedure:
To a solution of 5-(trifluoromethyl)pyridin-2-ol (10.52 g, 62 mmol) and sodium acetate (5.29 g, 64 mmol) in glacial acetic acid (38 mL) was added bromine (3.36 mL, 65 mmol) at room temperature. The white cloudy solution slowly turned into a clear brown solution, which was heated at 80° C. for 2.5 h. The mixture was allowed to cool to room temperature and then evaporated under reduced pressure. The residue was neutralized with saturated NaHCO3 solution to pH=8. The resulting solution was extracted with EtOAc three times. The combined extracts were dried over MgSO4, filtered, and evaporated in vacuo to yield 15.1 g (99.8%) of the crude product (15.1 g, 98.8%) as a white solid. LC-MS calculated for C6H3BrF3NO: (M+H)+241.9; found 241.9/243.9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[NH:10][S:9]2(=[O:18])=[O:17])=[C:4]([F:19])[CH:3]=1.O[CH2:21][CH2:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[C:32]([O:31][C:29](=[O:30])[NH2:26])([CH3:35])([CH3:34])[CH3:33].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]([CH2:21][CH2:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[S:9]2(=[O:17])=[O:18])=[C:4]([F:19])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reactant: O=S1(=O)Nc2ccccc2N1c1ccc(Cl)cc1F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(N)=O
Product: O=S1(=O)N(CCC2CCNCC2)c2ccccc2N1c1ccc(Cl)cc1F

Procedure:
To a stirring solution of 1-(4-chloro-2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (100 mg, 0.335 mmol), tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (147 uL, 0.67 mmol), and triphenylphosphine (176 mg, 0.67 mmol) in anhydrous tetrahydrofuran was added diisopropylazodicarboxylate (130 uL, 0.67 mmol) and the solution stirred, capped, at room temperature for 18 hr. The reaction mixture was concentrated then loaded directly onto silica gel and purified via Isco chromatography (Redisep, silica, gradient 0-35% ethyl acetate in hexane to afford 1-(4-chloro-2-fluorophenyl)-3-(2-piperidin-4-ylethyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide carbamic acid tert-butyl ester as an orange colored wax. This material was dissolved in diethyl ether and methanol and 2N HCl in diethyl ether was added a precipitate formed. The mixture was filtered to afford impure product. This material was dissolved in DMSO and purified by Gilson RP-HPLC (YMC CombiPrep ProC18 50×20 mm I.D. column, S-5□m, 12 nm. Flow rate 20 mL/min. Gradient: 10/90 Acetonitrile/Water to 100% acetonitrile over 10 minutes then hold for three minutes at 100% acetonitrile and ramp back to 10/90 acetonitrile/water over two minutes) to give 0.089 g of 1-(4-chloro-2-fluorophenyl)-3-(2-piperidin-4-ylethyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide as an orange solid.