Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:25])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH3:23])[CH:17]=2)=[CH:11][C:10]=1[CH3:24])(C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C.[F:37][C:38]([F:48])([F:47])[C:39]1[CH:46]=[CH:45][C:42]([CH2:43]Br)=[CH:41][CH:40]=1>O>[CH3:24][C:10]1[CH:11]=[C:12]([S:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:43][C:42]3[CH:41]=[CH:40][C:39]([C:38]([F:37])([F:47])[F:48])=[CH:46][CH:45]=3)=[C:18]([CH3:23])[CH:17]=2)[CH:13]=[CH:14][C:9]=1[O:8][CH2:7][C:6]([OH:5])=[O:25]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: Cc1cc(Sc2ccc(OCC(=O)OC(C)(C)C)c(C)c2)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Sc2ccc(OCc3ccc(C(F)(F)F)cc3)c(C)c2)ccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.9 %

Procedure:
An oven-dried 100 mL round-bottomed flask was charged with compound 1.1 (400 mg, 1.1 mmol), finely powdered Cs2CO3 (405 mg, 1.2 mmol), and anhydrous DMF (2 mL). 4-(Trifluoromethyl)benzyl bromide (298 mg, 1.1 mmol, Aldrich) was added, and the reaction was stirred vigorously overnight at room temperature. The reaction mixture was poured into 60 mL of water and extracted with 3×20 mL of methylene chloride. The combined organics were washed with 2×50 mL of water, dried over Na2SO4, and concentrated to a slightly yellow oil (422 mg). This crude material was dissolved in methylene chloride (2.5 mL), and trifluoroacetic acid (1.2 mL) was slowly added. The reaction was stirred for 4 h, after which the volatile components were removed in vacuo to reveal a crude pink oil. The crude pink oil was purified using flash chromatography (SiO2 gel 60, eluted with 60% EtOAc/hexanes), and the resulting white solid was recrystallized from methylene chloride/hexanes to give fine white crystals (213 mg). MS ESI m/e: 461.1 (M−H). 1H NMR (400 MHz) (CDCl3) δ 7.65 (2H, d, J=8.4 Hz); 7.54 (2H, d, J=8.4 Hz); 7.20 (1H, s); 7.17-7.14 (2H, d, m); 7.10 (11H, dd, J=13.0, 2.4 Hz); 6.77 (1H, d, J=8.4 Hz); 6.65 (1H, d, J=8.4 Hz); 5.12 (2H, s); 4.66 (2H, s); 2.25 (3H, s); 2.24 (3H, s).
Reaction SMILES: [N:1]1([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([O:10]CC)=[O:9])[CH2:3][CH2:2]1.[Li+].[OH-]>C1COCC1.O>[CH2:16]([O:15][C:13]([N:1]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1)=[O:14])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)C1CCCN(C(=O)OCc2ccccc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1CCCN(C(=O)OCc2ccccc2)CC1
Yield: 81.8 %

Procedure:
To a stirred solution of 1-benzyl 4-ethyl azepane-1,4-dicarboxylate (500 mg, 1.64 mmol) in THF (3 ml) was added LiOH (96 mmol, 2.30 mmol) dissolved in water (3 ml). After 16 hours the mixture was concentrated, diluted with dichloromethane (30 ml), washed with 1M aq. HCl (15 ml), water (15 ml), dried (MgSO4), filtered and concentrated giving the title product as colourless oil (372 mg, 82%) that was used without and further purification.
Reaction SMILES: [CH:1]1([O:6][C:7](=[O:33])[C@H:8]([NH:15]C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)[CH2:9][S:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.N1CCCCC1>CC#N>[CH:1]1([O:6][C:7](=[O:33])[C@H:8]([NH2:15])[CH2:9][S:10][C:11]([CH3:12])([CH3:13])[CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)SC[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC1CCCC1
Solvent: CC#N
Solvent: C1CCNCC1
Product: CC(C)(C)SC[C@@H](N)C(=O)OC1CCCC1
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
(S)-3-tert-Butylsulfanyl-2-(9H-fluoren-9-ylmethoxycarbonylamino)-propionic acid cyclopentyl ester (1.63 g, 3.50 mmol) was dissolved in a CH3CN (25 ml) at 0° C. Piperidine (21 ml) was added to the solution. After stirring for 30 minutes, the solvent was removed in vacuo to give a residue. Purification by column chromatography (EtOAc eluent) gave the product as a colourless oil (628 mg, 73% yield). 1H NMR (300 MHz, CDCl3), δ: 1.30 (9H, s, (CH3)3), 1.55-1.95 (8H, m, CH2×4), 2.75 (1H, dd, CH, J=7.2, 12.3 Hz), 2.95 (1H, dd, CH, J=4.8, 12.3 Hz), 5.25 (1H, m, CH).
Reaction SMILES: N.CC(C)([O-:5])C.[K+].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17].C(OO)(C)(C)C>C1COCC1>[OH:5][C:14]1[CH:15]=[C:10]([O:9][CH3:8])[C:11]([N+:16]([O-:18])=[O:17])=[CH:12][N:13]=1
Reactant: CC(C)(C)[O-]
Reactant: COc1ccncc1[N+](=O)[O-]
Agent: CC(C)(C)OO
Agent: N
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cc(O)ncc1[N+](=O)[O-]
Temperature: -35 °C
Reaction time: 2 h
Yield: 50.8 %

Procedure:
THF (100 mL) was cooled to −78° C. and anhydrous NH3 (−200 mL) was condensed into the THF. Potassium t-butoxide (45.5 g, 405 mmol) was added and the mixture was allowed to warm to ˜−35° C. 4-Methoxy-3-nitropyridine (25.0 g, 162 mmol) was cooled to 0° C. in THF (200 mL) and a solution of t-BuOOH (5 M in decane, 34 mL, 170 mmol) was added over 10 min. This solution was then added dropwise to the KOt-Bu solution over 1 h, then stirred for 2 h at −35° C. and then carefully quenched with ˜50 mL of sat. NH4Cl solution. The mixture was allowed to vent and warm to rt overnight, then the organics were concentrated and the residue made acidic with NH4Cl solution and filtered. The solid was washed with cold H2O and dried to give the title compound as a tan solid (14.0 g, 51%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[O:10])[CH:5]=[N:6][C:7]=1[CH3:8].[H-].[Na+].[F:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27]Br>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:27][C:26]3[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=3[F:24])[CH:12]=2)=[O:10])[CH:5]=[N:6][C:7]=1[CH3:8]
Reactant: Fc1ccccc1CBr
Reactant: Cc1cc(C(=O)c2c[nH]c3ccccc3c2=O)cnc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2cn(Cc3ccccc3F)c3ccccc3c2=O)cnc1C
Yield: 92.3 %

Procedure:
Compound 4g was prepared following the procedure described in Step 3 of Example 1. 63 mg (0.23 mmol) of 3-(5,6-dimethyl-pyridine-3-carbonyl)-1H-quinolin-4-one 3c, 11 mg (0.27 mmol) of 60% sodium hydride and 51 mg (0.27 mmol) of 2-fluorobenzyl bromide were combined in 1 mL N,N-dimethylformamide at rt for 1 h. The product was purified using reverse phase HPLC, mobile phase with a gradient 10-70% acetonitrile in 50 min. The HPLC fractions containing pure product were combined and the combined solutions was lyophilized with 1 mL of 1 M HCl to give 82 mg of a pale yellow solid 4g as its HCl salt: LC-MSD, m/z for C24H19FN2O2 [M+H]+=387.5, HPLC retention time: 1.2 min; 1H NMR (400 MHz, CDCl3): δ 2.55 (s, 3H), 2.9 (s, 3H), 5.55 (s, 2H), 7.05-7.2 (m, 3H), 7.3-7.4 (m, 1H), 7.45-7.55 (m, 2H), 7.65-7.75 (m, 1H), 8.35-8.45 (m, 2H), 8.6 (s, 1H), 8.85 (s, 1H).
Reaction SMILES: [F:1][CH:2]([F:31])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[C:24]([C:26]([O:28]CC)=[O:27])[CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1.O.[OH-].[Li+]>O1CCCC1.O>[F:31][CH:2]([F:1])[C:3]1[CH:7]=[C:6]([CH:8]([F:9])[F:10])[N:5]([CH2:11][C:12]([N:14]2[CH2:15][CH2:16][N:17]([C:20]3[N:25]=[C:24]([C:26]([OH:28])=[O:27])[CH:23]=[CH:22][CH:21]=3)[CH2:18][CH2:19]2)=[O:13])[N:4]=1
Reactant: CCOC(=O)c1cccc(N2CCN(C(=O)Cn3nc(C(F)F)cc3C(F)F)CC2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cccc(N2CCN(C(=O)Cn3nc(C(F)F)cc3C(F)F)CC2)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of ethyl 6-(4-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperazin-1-yl)pyridine-2-carboxylate (1.3 g) in tetrahydrofuran (20 ml) and water (5 ml) is added, at room temperature, lithium hydroxide monohydrate (185 mg). The mixture is stirred at room temperature for 5 hours, and then ice-cold 1N HCl solution is added. The aqueous phase is extracted with ethyl acetate and then the combined organic phases are dried over sodium sulphate. The solids are filtered off and the solvent is distilled off. This gives 6-(4-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-1-yl)pyridine-2-carboxylic acid (700 mg).
Reaction SMILES: [F:1][C:2]1[C:3]([N+:28]([O-:30])=[O:29])=[C:4]([N:8]=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:5]=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O>O>[F:1][C:2]1[C:3]([N+:28]([O-:30])=[O:29])=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1c(F)cccc1N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Nc1cccc(F)c1[N+](=O)[O-]
Yield: 99.7 %

Procedure:
A 2-5 mL microwave vial equipped with a magnetic follower was charged with 3-fluoro-2-nitro-N-(triphenylphosphoranylidene)benzenamine (585 mg, 1.4 mmol), water (3 mL) and TFA (0.1 mL). The reaction mixture was irradiated at 160° C. for 15 min and then partitioned between water and EtOAc. The organic layer was separated and washed with an saturated aqueous solution of sodium bicarbonate and brine, dried over Na2SO4, filtered and concentrated. The residue was subjected to flash chromatography (Si—PCC, 0-100% Et2O in pentane) to give 3-Fluoro-2-nitrophenylamine as an orange solid (218 mg, 100%). 1H NMR (CDCl3, 400 MHz): δ 7.22 (ddd, J=8.2, 8.2, 5.5 Hz, 1 H); 6.57 (ddd, J=8.5, 1.4, 1.4 Hz, 1 H); 6.48 (ddd, J=11.3, 8.2, 1.4 Hz, 1 H.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[C:9]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[N:10][N:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)=[O:7])C.C(#N)C.Cl>CO>[C:6]([C:8]1[C:9]([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)=[N:10][N:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)([OH:7])=[O:5]
Reactant: CCOC(=O)c1cn(C(C)(C)C)nc1-c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC#N
Product: CC(C)(C)n1cc(C(=O)O)c(-c2ccc(F)cc2)n1
Temperature: 50 °C
Reaction time: 3 h
Yield: 101.7 %

Procedure:
Add a solution of NaOH (15%, 6 mL) to a solution of 4-ethoxycarbonyl-3-(4-fluorophenyl)-1-tert-butyl-1H-pyrazole (0.350 g, 1.2 mmol) in MeOH (3 mL) and then add acetonitrile (1 mL). Stir the mixture at 50° C. for 3 h, cool to RT and add HCl (10%) until the pH=3. Extract the mixture with EtOAc (3×100 mL). Combine the organic layers and wash with brine (100 mL), dry (MgSO4) and concentrate to provide 4-carboxy-3-(4-fluorophenyl)-1-tert-butyl-1H-pyrazole as a yellow solid (0.320 g), MS (ESi+): 229.1 (M+H)+. Next treat a solution of 4-carboxy-3-(4-fluorophenyl)-1-tert-butyl-1H-pyrazole (0.315 g, 1.2 mmol) in DMF (15 mL) previously degassed with N-bromosuccinimide (0.235 g, 1.32 mmol) at RT for about 18 h. Dilute the mixture with EtOAc (80 mL) and wash with cooled water (5×10 mL), dry (MgSO4), and concentrate to provide the desired compound as yellow solid (0.262 g, 73% yield).
Reaction SMILES: [NH:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH3:7].[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[C:10]=1[N:17]=[C:18]=[O:19]>C1C=CC=CC=1>[C:9]1([CH3:8])[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[C:10]=1[NH:17][C:18]([N:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH3:7])=[O:19]
Reactant: Cc1cc(C)c(N=C=O)c(C)c1
Reactant: CN1CCCC1=N
Solvent: c1ccccc1
Product: Cc1cc(C)c(NC(=O)N=C2CCCN2C)c(C)c1
Temperature: 25 °C

Procedure:
The hydrochloride salt of 2-imino-1-methylpyrrolidine (6.73 g.; 0.05 mole) is converted to free base (4.0 g.; 0.05 mole) by adding 10 ml. of 50% NaOH to an aqueous slurry (minimal amount of water) of the salt and benzene extraction. After drying over K2CO3, the benzene solution is stirred at room temperature and 8.06 g. (0.05 mole) of 2,4,6-trimethylphenylisocyanate [made according to the method of K. Inukai and Y. Maki, Kogyo Kagaku Zasshi, 70 (4), 491-4 (1967)] dissolved in anhydrous benzene is added. The reaction mixture is stirred at room temperature for 11/2 hours and then the solvent is evaporated in vacuo leaving an oily residue, which crystallizes on cooling. Recrystallization from acetone yields the pure product, 1-mesityl-3-(1-methyl-2-pyrrolidylidene)urea, m.p. = 121°-123° C.
Reaction SMILES: C(OC(=O)C([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([CH:24]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C@H:17]2[CH2:22][CH2:21][C@H:20]([CH3:23])[CH2:19][CH2:18]2)=[O:15])=[N:10][CH:9]=1)C)C.C1(N[C@H]2CC[C@H](C)CC2)CCCCCC1.NC1SC=NC=1.C([O:55][C:56](=[O:60])[CH:57](S)[CH3:58])C>>[CH:24]1([N:16]([C@H:17]2[CH2:18][CH2:19][C@H:20]([CH3:23])[CH2:21][CH2:22]2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][CH2:58][CH2:57][C:56]([OH:60])=[O:55])=[CH:9][N:10]=2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: CCOC(=O)C(C)Sc1cnc(NC(=O)N(C2CCCCCC2)[C@H]2CC[C@H](C)CC2)s1
Reactant: CCOC(=O)C(C)S
Agent: C[C@H]1CC[C@H](NC2CCCCCC2)CC1
Agent: Nc1cncs1
Product: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCCC(=O)O)s2)C2CCCCCC2)CC1

Procedure:
{2-[3-Cycloheptyl-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionic acid ethyl ester prepared as described in general procedure (A) using cycloheptyl-(trans-4-methyl-cyclohexyl)-amine and 5-aminothiazole-2-mercaptopropionic acid ethyl ester. Hydrolysis using general procedure (F) gave the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=O)#[N:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[NH2:55][CH2:56][C:57]1[CH:62]=[CH:61][C:60]([S:63]([NH2:66])(=[O:65])=[O:64])=[CH:59][CH:58]=1>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([NH:55][CH2:56][C:57]1[CH:58]=[CH:59][C:60]([S:63](=[O:65])(=[O:64])[NH2:66])=[CH:61][CH:62]=1)=[O:11])#[N:2]
Reactant: NCc1ccc(S(N)(=O)=O)cc1
Reactant: N#Cc1cccc(Oc2ncccc2C(=O)O)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cccc(Oc2ncccc2C(=O)NCc2ccc(S(N)(=O)=O)cc2)c1
Temperature: 25 °C
Yield: 40.8 %

Procedure:
To a solution of 2-(3-Cyano-phenoxy)-nicotinic acid (0.140 g 0.600 mmole), BOP (0.260 grams, 0.600 mmole) and DIEA (0.310 μl, 1.8 mmole) in dimethylformamide (5 ml) was added 4-Aminomethyl-benzenesulfonamide (0.135 grams, 0.600 mmole) and stirred at room temperature over night. The reaction was quenched with water and extracted with ethyl acetate. The combined organics were washed with alternating portions of 5% citric acid and sat'd bicarb, dried over Na2SO4, filtered and concentrated to a product which was recrystalized from ethyl acetate to give a white solid (0.100 g). M.P. 179-180° C.; Anal. calcd. for C20H16N4O4S; C, 58.81; H, 3.95; N, 13.72. Found: C, 57.47; H, 4.15; N. 13.45.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16].CON(C)[C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:29][C:30]([CH3:33])=[N:31][N:32]=2)=[CH:24][CH:23]=1>>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][C:12]([C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]3[CH:23]=[CH:24][C:25]([C:28]4[O:29][C:30]([CH3:33])=[N:31][N:32]=4)=[CH:26][CH:27]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COC(C(=O)N(C)OC)c1ccc(-c2nnc(C)o2)cc1
Reactant: COc1cc(-c2ccco2)cc(OC)c1Br
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(-c4nnc(C)o4)cc3)o2)cc(OC)c1Br
Yield: 40 %

Procedure:
2-(4-Bromo-3,5-dimethoxyphenyl)furan was coupled with N,2-dimethoxy-N-methyl-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamide according to the method used for the synthesis of Example 12. Purification by chromatography (50-80% EtOAc-hexanes) provided 1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)ethanone as a yellow foam (0.356 g, 40% yield). MS: m/z 513.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([N:12]([CH3:16])[C:13](Cl)=[O:14])(=[O:11])=[O:10].C(N(CC)CC)C.[CH3:24][NH:25][C:26]1[N:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([CH3:34])[N:27]=1>O1CCCC1>[CH3:33][O:32][C:30]1[CH:29]=[C:28]([CH3:34])[N:27]=[C:26]([N:25]([CH3:24])[C:13]([N:12]([CH3:16])[S:9]([C:3]2[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=2[Cl:1])(=[O:11])=[O:10])=[O:14])[N:31]=1
Reactant: CN(C(=O)Cl)S(=O)(=O)c1cc(Cl)ccc1Cl
Reactant: CNc1nc(C)cc(OC)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(C)nc(N(C)C(=O)N(C)S(=O)(=O)c2cc(Cl)ccc2Cl)n1

Procedure:
To 3.0 g of N-[(2,5-dichlorophenyl)sulfonyl]-N-methylcarbamyl chloride in 50 ml of tetrahydrofuran containing 1.0 g of triethylamine is added 1.5 g of 2-methylamino-4-methoxy-6-methylpyrimidine. After stirring at reflux for several hours, the precipitated salts are filtered off and the filtrate is concentrated to yield N-[N-(4-methoxy-6-methylpyrimidin-2-yl)-N-methylaminocarbonyl]2,5-dichloro-N-methylbenzenesulfonamide.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[C:13](Cl)[CH:12]=[CH:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Li+].[CH3:21][N:22](C)C=O>[C-]#N.[Zn+2].[C-]#N.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]>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[C:13]([C:21]#[N:22])[CH:12]=[CH:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(n1)CCN(Cc1ccccc1)C2
Reactant: CN(C)C=O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [C-]#N
Product: N#Cc1ccc2c(n1)CCN(Cc1ccccc1)C2
Temperature: 100 °C

Procedure:
6-Benzyl-2-chloro-5,6,7,8-tetrahydro-[1,6]naphthyridine (129 mg, 0.5 mmol) (See Reference WO9830560 Example 33b) was added to zinc cyanide (58.7 mg, 0.5 mmol), lithium chloride (27 mg, 0.65 mmol) and tetrakis(triphenylphosphine)palladium (0) (35 mg, 0.03 mmol) in N,N-dimethylformamide (3 ml). The mixture was purged with argon and was heated at 100° C. for 17 hours. The reaction mixture was cooled to room temperature and a further quantity of tetrakis(triphenylphosphine)palladium (0) (35 mg, 0.03 mmol) was added and the mixture was heated at 125° C. for 3 hours. The reaction mixture was cooled to room temperature and a further quantity of tetrakis(triphenylphosphine)palladium (0) (35 mg, 0.03 mmol) was added and the mixture was heated at 125° C. for 3 hours. The reaction mixture was cooled to room temperature and was partitioned between ethyl acetate (40 ml) and water (40 ml). The phases were separated and the organic phase was washed with water (3×30 ml) dried over magnesium sulphate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using ethyl acetate in pentane as eluant (33:67) to give the title compound as a brown gum (97 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[CH3:12][O:13][C:14]1[CH:15]=[C:16](/[CH:22]=[CH:23]/[C:24](O)=O)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CC#N>[CH3:12][O:13][C:14]1[CH:15]=[C:16](/[CH:22]=[CH:23]/[C:24]2[NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8](=[O:9])(=[O:10])[N:11]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: COc1ccc(/C=C/C(=O)O)cc1OC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(/C=C/C2=NS(=O)(=O)c3ccccc3N2)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 14 %

Procedure:
2-Aminobenzenesulfonamide (0.25 g, 1.4 mmol) was added to a suspension of (E)-3-(3,4-dimethoxyphenyl)acrylic acid (0.25 g, 1.2 mmol), HBTU (0.55 g, 1.4 mmol) and NEt3 (0.67 mL, 4.8 mmol) in MeCN (5 mL) and the reaction was stirred at rt for 16 h. Extra NEt3 (0.67 mL, 4.8 mmol) in MeCN (5 mL) was added and the reaction was stirred at rt for 64 h. The solution was acidified and the precipitate was collected by filtration. Hot EtOH (15 mL) was added to the crude product and the undissolved solid was collected by hot filtration, providing (E)-3-[2-(3,4-dimethoxyphenyl)ethenyl]-4H-1,2,4-benzothiadiazine-1,1-dioxide (58 mg, 14%) as a colourless crystalline solid; mp 276-279° C.; δH (500 MHz, DMSO-d6) 3.81 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 6.75 (d, J=15.6 Hz, 1H, CH═CHCO), 7.05 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.29 (d, J5′,6=8.0 Hz, 1H, H6′), 7.31 (s, 1H, H2′), 7.38 (d, J5,6=8.0 Hz, 1H, H5), 7.45 (t, J5,6=J6,7=8.0 Hz, 1H, H6), 7.68 (t, J6,7=J7,8=8.0 Hz, 1H, H7), 7.80 (d, J7,8=8.0 Hz, 1H, H8), 7.82 (d, J=15.6 Hz, 1H, CH═CHCO), 12.13 (s, 1H, NH); δC (125 MHz, DMSO-d6) 55.4, 55.6, 110.3, 111.8, 116.6, 117.6, 122.0, 122.7, 123.3, 126.3, 126.9, 133.0, 135.2, 142.2, 149.0, 151.1, 153.5; HRMS (ESI) calculated for C17H16N2O4S [M+H]+ 345.0904, found 345.0900; νmax 756, 1134, 1263, 1513, 1568, 1600, 3024, 3117, 3163, 3200 cm−1.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([F:13])[CH:7]=1)[CH2:3][CH2:4][OH:5].[CH3:14][C:15]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])[CH3:16].CCN(C(C)C)C(C)C.C(Cl)Cl>CN(C1C=CN=CC=1)C.O>[Si:18]([O:5][CH2:4][CH2:3][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([F:13])[CH:7]=1)[NH2:1])([C:15]([CH3:17])([CH3:16])[CH3:14])([CH3:20])[CH3:19]
Reactant: NC(CCO)c1ccc(F)c(F)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OCCC(N)c1ccc(F)c(F)c1
Yield: 69.8 %

Procedure:
A solution of 304 (0.400 g, 2.14 mmol), TBDMS-Cl (0.386 g, 2.56 mmol), DIPEA (0.744 mL, 4.27 mmol), DMAP (0.0261 g, 0.214 mmol) and DCM (10 mL) was stirred at RT for 1 h and then poured into water and extracted with DCM. The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with DCM/MeOH (500:7) to afford 0.45 g (69.9%) of 3-(tert-butyldimethylsilyloxy)-1-(3,4-difluorophenyl)propan-1-amine (306).
Reaction SMILES: CS[C:3]([S:13][CH3:14])=[C:4]([C:10](=O)[CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[C:17]=1[NH:24][NH2:25].O>C(O)C>[CH2:8]([O:7][C:5]([C:4]1[C:3]([S:13][CH3:14])=[N:25][N:24]([C:17]2[C:18]([Cl:23])=[CH:19][C:20]([Cl:22])=[CH:21][C:16]=2[Cl:15])[C:10]=1[CH3:11])=[O:6])[CH3:9]
Reactant: CCOC(=O)C(C(C)=O)=C(SC)SC
Reactant: NNc1c(Cl)cc(Cl)cc1Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(SC)nn(-c2c(Cl)cc(Cl)cc2Cl)c1C
Yield: 56.4 %

Procedure:
A mixture of 1.22 g (5.23 mmol) of ethyl 3,3-bismethylthio-2-acetylacrylate and 1.11 g (5.23 mmol) of 2,4,6-trichlorophenylhydrazine in 12 mL of ethanol was heated at reflux for 2 hours. The cooled reaction mixture was then poured into cold water and the product was extracted into ether. The ethereal extracts were dried and evaporated and the residues were chromatographed on silica gel using 6:1 hexane/ethyl acetate as eluent to give 1.12 g (56%) of the desired product as a crystalline solid, m.p. 95-98° C. 1H-NMR (CDCl3) δ1.38 (3H, t, J=7), 2.30 (3H, s), 2.49 (3H, s.), 4.31 (2H, q, J=7), 7.47 m(2H, s).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:14])([CH3:13])[C:8](OCC)=[O:9].[H-].C([Al+]CC(C)C)C(C)C>C(OCC)C>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:14])([CH3:13])[CH2:8][OH:9]
Reactant: CCOC(=O)C(C)(C)CCCCCBr
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOCC
Product: CC(C)(CO)CCCCCBr
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 7-bromo-2,2-dimethylheptanoate (example 102, step a) (1.5 g) in dry diethyl ether (50 mL) at 0° C. under N2 was added diisobutylaluminium hydride (1M in toluene, 12.5 mL) dropwise. The reaction mixture was stirred at 0° C. for 1 h then quenched by addition of saturated potassium sodium tartrate (150 mL). The mixture was stirred for 1 h then extracted with ethyl acetate (×3). The combined organics were washed with brine and dried over sodium sulphate, filtered and evaporated in vacuo. Purification was by silica gel chromatography eluting with 0-25% ethyl acetate in cyclohexane to give the subtitled compound as a colourless liquid. Yield 1.16 g.