Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([N:10]2[CH2:15][C:14]3([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[O:13][CH2:12][CH2:11]2)=[O:9])[N:7]=1.[OH:21][CH2:22][CH2:23][C:24]1[CH:33]=[CH:32][C:27]([O:28][CH2:29][CH:30]=O)=[CH:26][CH:25]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1C(=O)CCC1.C(O)(=O)C.CO>[OH:21][CH2:22][CH2:23][C:24]1[CH:33]=[CH:32][C:27]([O:28][CH2:29][CH2:30][N:18]2[CH2:19][CH2:20][C:14]3([O:13][CH2:12][CH2:11][N:10]([C:8]([C:6]4[N:7]=[C:3]([CH3:2])[S:4][CH:5]=4)=[O:9])[CH2:15]3)[CH2:16][CH2:17]2)=[CH:26][CH:25]=1
Reactant: Cc1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Reactant: O=CCOc1ccc(CCO)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Product: Cc1nc(C(=O)N2CCOC3(CCN(CCOc4ccc(CCO)cc4)CC3)C2)cs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(2-Methylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone hydrochloride (example 1, step f) (0.63 g) was added to a solution of 2-(4-(2-hydroxyethyl)phenoxy)acetaldehyde (example 3, step b) (0.541 g) in a mixture of NMP (10 mL) and acetic acid (0.11 mL). The resulting mixture was stirred at room temperature for 30 min then cooled in an ice bath. Sodium triacetoxyborohydride (0.64 g) was then added and the reaction was allowed to warm to room temperature and stirred for 16 h. The reaction was diluted with methanol (30 mL) and applied to a SCX cartridge pre-wetted with methanol. The cartridge was washed with methanol (100 mL) and eluted with 3M ammonia in methanol solution (100 mL). The eluent was evaporated in vacuo and the residue purified by silica gel chromatography, eluting with 95:5 ethyl acetate:triethylamine to give the subtitled compound as a brown oil. Yield 0.74 g.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH:10]([C:12](O)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:15](=[O:26])[C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1.[CH2:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[CH3:28].CCN=C=NCCCN(C)C.O.[Cl-].[Na+].O>N1C=CC=CC=1>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([N:29]([CH2:27][CH3:28])[C:12]([C@@H:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]([C:15](=[O:26])[C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:20][CH:21]=3)[C@@H:2]([CH3:1])[CH2:11]2)=[O:13])=[CH:31][CH:32]=1
Reactant: CC1CC(C(=O)O)c2ccccc2N1C(=O)c1ccc(C(F)(F)F)cc1
Reactant: CCNc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: CCN(C(=O)[C@H]1C[C@H](C)N(C(=O)c2ccc(C(F)(F)F)cc2)c2ccccc21)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 39 %

Procedure:
A round bottom flask with magnetic stirrer was charged with 2-methyl-1-(4-trifluoromethyl-benzoyl)-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid (886 mg, 2.44 mmol) in anhydrous pyridine (25.0 mL). To the reaction was added N-ethyl-p-chloroaniline (0.410 mL, 2.95 mmol), followed by EDCI (833 mg, 4.34 mmol). The reaction was stirred at room temperature under an argon atmosphere for 18-20 hours. The reaction was poured into a 1:1 mixture of water/brine (50 mL) and extracted with ethyl acetate (3×35 mL). The combined extractions were washed with brine (1×50 mL), dried over magnesium sulfate, and filtered. The filtrate was concentrated in vacuo to afford a brown residue. The residue was purified via silica gel chromatography (hexanes/ethyl acetate) to yield (±)-trans-2-methyl-1-(4-trifluoromethyl-benzoyl)-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid (4-chloro-phenyl)-ethyl-amide (39%). 1H-NMR (CDCl3) δ: 1.02 (d, 3H), 1.12 (t, 3H), 1.64-1.74 (m, 1H), 2.49-2.58 (m, 1H), 3.59-3.72 (m, 1H), 3.77-3.90 (m, 2H), 5.03-5.14 (m, 1H), 6.35-6.41 (m, 1H), 6.74-6.84 (m, 2H), 6.89-6.95 (m, 1H), 7.17-7.25 (m, 2H), 7.44-7.52 (m, 2H), 7.63-7.69 (m, 2H). MS m/z: 501 (M+1).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:5]=2[O:4][CH2:3]1.CI.[C:16](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:1]=[C:2]1[N:7]([CH3:16])[C:6]2[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:5]=2[O:4][CH2:3]1
Reactant: COc1ccc2c(c1)OCC(=O)N2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc2c(c1)OCC(=O)N2C
Yield: 92 %

Procedure:
Following the procedure of Example 1, 21.7 g of 3-oxo-7-methoxy-3,4-dihydro-2H-[1,4]benzoxazine and 19.88 g of methyl iodide were reacted in 600 ml of acetone in the presence of 19.32 g of solid potassium carbonate. The reaction was carried out, and the product isolated and purified by the procedure of Example 1 to yield 3-oxo-4-methyl-7-methoxy-3,4-dihydro-2H-[1,4]benzoxazine; yield=92%; molecular ion by mass spectrum=193.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH3:14])[CH2:8][N:7]([CH:15]3[CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:19]=1.[NH2:20][C:21]1[CH:36]=[CH:35][C:24]([C:25]([NH:27][CH:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[O:26])=[CH:23][C:22]=1[O:37][CH3:38].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[CH:15]1([N:7]2[CH2:8][CH:9]([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:20][C:21]4[CH:36]=[CH:35][C:24]([C:25]([NH:27][CH:28]5[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]5)=[O:26])=[CH:23][C:22]=4[O:37][CH3:38])=[N:19][C:6]2=3)[CH2:18][CH2:17][CH2:16]1
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Reactant: CC1CN(C2CCC2)c2nc(Cl)ncc2N(C)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCC1)CC(C)C(=O)N2C
Yield: 58.6 %

Procedure:
A solution of 0.050 g (0.00018 mole) of (rac)-2-chloro-9-cyclobutyl-5,7-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-52), 0.047 g (0.00018 mole) of 4-amino-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide, 0.053 g (0.00028 mole) of p-toluenesulfonic acid monohydrate and 4.0 mL of 2-propanol was heated at 180 degrees for 2 hours in a microwave reactor. The reaction mixture was concentrated and the residue diluted with dichloromethane and washed twice with saturated sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane. The combined organic phases were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with dichloromethane-methanol (100:0-75:25 n) to give 0.0535 g of (rac)-4-(9-cyclobutyl-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-52) as white powder. HRMS (ES+) m/z Calcd for C27H37N7O3+H [(M+H)+]: 508.3031. Found: 508.3031.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][N:8]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:29])[C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=1[OH:28])[CH2:7][CH2:6]2.Cl[CH2:31][CH2:32][O:33][CH2:34][CH2:35][OH:36].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][N:8]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:29])[C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=1[O:28][CH2:31][CH2:32][O:33][CH2:34][CH2:35][OH:36])[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1OC)CN(CCCCNC(=O)c1cc(C)ccc1O)CC2
Reactant: OCCOCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)CN(CCCCNC(=O)c1cc(C)ccc1OCCOCCO)CC2
Temperature: 25 °C
Yield: 52.7 %

Procedure:
The mixture of 4a (0.65 g, 1.6 mmol), 2-(2-chloroethoxy)ethanol (0.64 g, 5.1 mmol), potassium carbonate (0.71 g, 5.1 mmol) in of N,N-Dimethylformamide (DMF) (25 mL) was refluxed over night under an atmosphere of nitrogrn. The reaction mixture was cooled to room temperature and quenched with 100 mL water. The aqueous solution was extracted with ethyl acetate (3 X2 50 mL). The combined organic layer was washed with brine (3×30 mL) and dried over Na2SO4. After concentrating under reduced pressure, the residue was purified by silica gel column chromatography with methanol/dichloromethane (10/90, v/v) as the mobile phase to afford compound 5a (0.41 g; 51% yield) as a viscous yellow oil. 1H NMR (300 MHz, CDCl3): 1.68-1.79 (m, 4H), 2.31 (s, 3H), 2.50-2.60 (m, 2H), 2.72-2.76 (m, 2H), 2.82-2.85 (m, 2H), 3.46-3.60 (m, 8H), 3.80-3.90 (m, 8H), 4.18-4.24 (m, 2H), 6.49 (s, 1H), 6.58 (s, 1H), 6.79-6.83 (d, 1H), 7.16-7.24 (m, 1H), 7.98-7.80 (m, 1H), 8.18-8.26 (s, 1H).
Reaction SMILES: C(O)(=O)CC(O)=[O:4].C1(C(O)C)C=CC=CC=1.[CH:17]1([N:23]=[C:24]=[N:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C(#N)C>[CH:26]1([NH:25][C:24]([NH:23][CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)=[O:4])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C(O)CC(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(O)c1ccccc1
Solvent: CC#N
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
Malonic acid (12 g, 0.11 mol) was dissolved in acetonitrile (450 mL) in an Erlenmeyer flask (1 L) together with 1-phenyl-ethanol (26 g, 0.22 mol). Dicyclohexylcarbodiimide (45 g) was added in portions and with cooling over 10 min so the temperature did not exceed 30° C. A precipitate of dicyclohexyl urea formed almost immediately. Stirring at RT continued over the week-end to complete the reaction. Dicyclohexyl urea was removed by filtration and the filter cake was washed with addition acetonitrile (10 mL). The combined solution was evaporated in vacuum to give the crude product as colourless oil. Yield: 29 g, 93%.
Reaction SMILES: [NH2:1][C:2]1[C:3](Br)=[N:4][CH:5]=[CH:6][CH:7]=1.C(O[C:12]([S-:14])=[S:13])C.[K+].CN(C)C=O.Cl>O>[N:1]1[C:2]2[C:3](=[N:4][CH:5]=[CH:6][CH:7]=2)[S:13][C:12]=1[SH:14]
Reactant: Nc1cccnc1Br
Reactant: CCOC(=S)[S-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Sc1nc2cccnc2s1
Temperature: 130 °C
Reaction time: 0.17 h
Yield: 96.5 %

Procedure:
In a round-bottomed flask, 3-amino-2-bromopyridine (1.14 g, 6.59 mmol), potassium ethylxanthate (2.32 g, 14.5 mmol) and dry dimethylformamide (4 mL) were mixed. The reaction mixture was heated to 130° C. overnight. After cooling to room temperature, the reaction mixture was diluted with water (150 mL). 5 N Hydrochloric acid (4 mL) was added and the mixture was stirred for 10 minutes. The precipitate formed was collected by filtration and dried in a vacuum oven at 80° C. overnight to give thiazolo[5,4-b]pyridine-2-thiol (1.07 g, 6.36 mmol, 97% yield) as tan solid. 1H NMR (300 MHz, DMSO-d) δ ppm 7.43 (dd, J=8.18, 4.82 Hz, 1 H) 7.63 (dd, J=8.18, 1.32 Hz, 1 H) 8.34-8.47 (m, 1 H). ESI (M+1) 168.9.
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[NH:6][C:5]1=[O:15])=[N+]=[N-]>CO.C(O)C.[Pd]>[NH2:1][CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[NH:6][C:5]1=[O:15]
Reactant: [N-]=[N+]=NC1CCc2ccccc2NC1=O
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: NC1CCc2ccccc2NC1=O
Reaction time: 5 h

Procedure:
To a suspension of 10.0 g (49.4 mmol) of 3-azido-2,3,4,5-tetrahydro-1H-[1]-benzazapin-2-one (Example 3 above) in 100 mL of methanol/ethanol (1:1) was added 1 g of 10% palladium on charcoal and the flask was purged with nitrogen and charged with 55 psig hydrogen. The mixture was shaken for 5 h, filtered through celite and concentrated. The residue was recrystallized from MeOH to give 6.77 g (78%) in two crops. 1H NMR (300 MHz, CDCl3) d 8.38 (1H, bs), 7.3-7.1 (3H, m), 6.98 (1H, d, J=8 Hz), 3.42 (1H, dd, J=11, 7 Hz), 2.90 (1H, m), 2.70-2.40 (2H, m), 1.89 (1H, m), 1.78 (bs, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.S(Cl)(Cl)=O.[NH2:18][C@@H:19]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:29][C:30]([F:33])([F:32])[F:31])[CH:27]=2)[O:22][C:21]([CH3:35])([CH3:34])[C@H:20]1[OH:36].C(N(CC)CC)C.C(N)(=O)C1C=CC=CC=1>C1C=CC=CC=1.ClCCl>[OH:36][C@H:20]1[C@H:19]([NH:18][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=2[N+:11]([O-:13])=[O:12])[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:29][C:30]([F:33])([F:31])[F:32])[CH:27]=2)[O:22][C:21]1([CH3:35])[CH3:34]
Reactant: CC1(C)Oc2ccc(OC(F)(F)F)cc2[C@@H](N)[C@@H]1O
Reactant: O=C(O)c1ccc(Cl)cc1[N+](=O)[O-]
Agent: NC(=O)c1ccccc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)Oc2ccc(OC(F)(F)F)cc2[C@@H](NC(=O)c2ccc(Cl)cc2[N+](=O)[O-])[C@@H]1O
Yield: 43.4 %

Procedure:
4-Chloro-2-nitrobenzoic acid (2.02 g, 10 mmol) was converted to the corresponding acid chloride by refluxing in benzene (30 mL) with thionyl chloride (2.38 g, 20 mmol) for 2 hours. The crude mixture was concentrated in vacuo and diluted with dichloromethane (10 mL). This solution was added to a cooled solution of (3S,4R)-4-amino-2,2-dimethyl-6-(trifluoromethoxy)-chroman-3-ol (2.75 g, 10 mmol), triethylamine (1.39 mL, 10 mmol) and dichloromethane (25 mL). The crude benzamide was worked-up in a method similar to that in Example 1 and chromatographed (1:1 hexanes/ethyl acetate) to afford 2.0 g (43%) of white solid: m.p. 64°-66° C.; 1H NMR (DMSO-d6): δ 9.24 (d, 1H), 8.19 (s, 1H), 7.96 (d, 1H), 7.83 (d, 1H), 7.29 (s, 1H), 7.18 (d, 1H), 6.86 (d, 1H), 5.88 (d, 1H), 4.94 (br t, 1H), 3.64 (dd, 1H), 1.42 (s, 3H), 1.19 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].OP(O)(O)=O>CN(C=O)C.C(Cl)Cl.CO>[Si:20]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(O)c1ccc(O)cc1
Agent: O=P(O)(O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C(=O)O)cc1
Reaction time: 12 h
Yield: 53000 %

Procedure:
To prepare 22, a solution of 4-hydroxybenzoic acid (21, 1.52 g, 10 mmol) in DMF (7 ml) was treated with DIPEA (5.2 ml, 30 mmol) and tert-butyldimethylsilyl chloride (3.7 g, 24.5 mmol). After 12 hours, the mixture was brought to a pH of 4 by addition of 1 M H3PO4. The mixture was extracted twice with hexanes (15 ml). The organic phase was washed twice with water (15 ml), dried over Na2SO4, and concentrated in vacuum. The residue (3.7 g) was dissolved in THF (10 ml), and treated with water (7 ml) and glacial acetic acid (21 ml). After stirring for 90 minutes, the mixture was added to ice water and extracted twice with a 1:1 mixture (v/v) of diethyl ether and hexanes (30 ml). The organic phase was washed with water (30 ml), dried over Na2SO4, and concentrated in vacuum. Flash column chromatography on silica using a gradient of 5-20% methanol in DCM containing 0.2% acetic acid afforded 4-tert-butyldimethylsilyloxybenzoic acid (22, 1.42 g, 5.3 mol, 53%) as a white solid. 1H NMR (400 MHz, chloroform-d1): δ (ppm) 0.24 (s, 6H), 0.99 (s, 9H), 6.89 (d, J=8.8 Hz, 2H), 8.02 (d, J=8.8 Hz, 2H); 13C NMR (100 MHz, chloroform-d1): δ (ppm)-4.22, 18.40, 25.73, 120.08, 122.39, 132.46, 132.46, 161.01, 172.23. See FIGS. 33A-B.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C:10]([F:37])([C:27]([F:36])([F:35])[C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])[CH2:11][CH2:12][CH2:13][CH2:14]OC1(C)C=CC(S([O-])(=O)=O)=CC1>CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:14][CH2:13][CH2:12][CH2:11][C:10]([F:9])([F:37])[C:27]([F:35])([F:36])[C:28]([F:33])([F:34])[C:29]([F:30])([F:31])[F:32])=[CH:4][CH:3]=1
Reactant: CC1(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C=CC(S(=O)(=O)[O-])=CC1
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CCCCOc1ccc(Br)cc1
Reaction time: 24 h

Procedure:
To a solution of commercially available 4-bromophenol (46) (1 equi.) and 4-(5,5,6,6,7,7,8,8,8-nonafluoro-octyloxy)-osylate (10) (1 equi.) in DMF (3 mL/mmole), cesium carbonate (1.25 equi.) was added at room temperature. The reaction mixture was stirred at that temperature for 24 h, quenched with water, extracted with ethyl acetate:hexane(1:1), washed with brine, dried over MgSO4, and concentrated in vacuo. Purification by chromatography on silica gel (5% EtOAc/hexanes) eafforded 1-bromo-4-(5,5,6,6,7,7,8,8,8-nonafluoro-octyloxy)-benzene (47) a colorless oil (65%).
Reaction SMILES: [OH-:1].[CH3:2][N+:3]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[N:5][C:4]=1[NH:13][CH2:14][C:15]1[CH:24]=[CH:23][C:20]([O:21][CH3:22])=[C:17]([O:18][CH3:19])[CH:16]=1.C[S:26]([OH:29])(=[O:28])=[O:27]>O1CCCC1>[S:26]([O-:29])([O-:1])(=[O:28])=[O:27].[CH3:2][N+:3]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[N:5][C:4]=1[NH:13][CH2:14][C:15]1[CH:24]=[CH:23][C:20]([O:21][CH3:22])=[C:17]([O:18][CH3:19])[CH:16]=1.[CH3:2][N+:3]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[N:5][C:4]=1[NH:13][CH2:14][C:15]1[CH:24]=[CH:23][C:20]([O:21][CH3:22])=[C:17]([O:18][CH3:19])[CH:16]=1
Reactant: [OH-]
Reactant: CS(=O)(=O)O
Agent: COC(=O)c1cnc(NCc2ccc(OC)c(OC)c2)[n+](C)c1
Solvent: C1CCOC1
Product: O=S(=O)([O-])[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 400 mg of 1-methyl-2-veratrylamino-5-methoxycarbonylpyrimidinium hydroxide dissolved in 15 ml of anhydrous tetrahydrofuran, are added 85 μl (1.1 eq; 1.31 mmol) of methanesulfonic acid. The mixture is stirred under argon at room temperature for one hour. The precipitate is filtered, rinsed with tetrahydrofuran and ether and then dried (weight: 490 mg - yield: 96%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.CC(C)([O-])C.[K+].F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1>CS(C)=O.O>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:10]=[C:2]2[CH3:1])=[CH:19][CH:20]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cc1cc2ccccc2[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc2ccccc2n1-c1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 26.1 %

Procedure:
A solution of 2-methylindol (1 g, 7.6 mmol) and potassium t-butoxide (897 mg, 8 mmol) in DMSO (10 mL) was stirred at room temperature under argon for 30 min. 4-Fluoronitrobenzene (0.81 mL, 7.62 mmol) was added and the reaction mixture was heated to 100° C. in an oil bath for 5 h. The reaction mixture was diluted with water, extracted with EtOAc, the organic extract with washed with water and dried (MgSO4). The oil obtained on concentration was flash chromatographed on silica gel and elution was -carried out with a gradient of 5-8% EtOAc in hexane to give 1-(4-nitrophenyl)-2-methylindol (500 mg).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[CH2:6][N:7]([CH:12]([CH3:14])[CH3:13])[S:8](=[O:11])(=[O:10])[NH:9][C:4]=2[CH:3]=1.[H-].[Na+].Br[CH2:20][CH2:21][Cl:22].O>CN(C=O)C>[Cl:22][CH2:21][CH2:20][N:9]1[C:4]2[CH:3]=[C:2]([F:1])[CH:16]=[CH:15][C:5]=2[CH2:6][N:7]([CH:12]([CH3:14])[CH3:13])[S:8]1(=[O:11])=[O:10]
Reactant: ClCCBr
Reactant: CC(C)N1Cc2ccc(F)cc2NS1(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)N1Cc2ccc(F)cc2N(CCCl)S1(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3,4-dihydro-7-fluoro-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide(1.48 g, 6.07 mmol) in dry DMF (15 ml) was added via a cannula to a flask containing sodium hydride (175 mg, 7.28 mmol) and DMF (2 ml) in Argon atmosphere, and stirred for 2 hours at room temperature when 1-bromo-2-chloroethane (7.28 mmol, 605 μl) was added dropwise. The mixture was stirred overnight at room temperature and water (75 ml) added. The product was extracted with EtOAc (3×50 ml) and the combined organic extracts were washed with water (1×100 ml) and then brine (1×100 ml), dried over sodium sulphate and solvent evaporated at reduced pressure. The residue was purified by flash chromatography on silica gel (EtOAc:Hexanes 1:4) affording pure 1-(2-chloroethyl)-3,4-dihydro-7-fluoro-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1.[C:21](Cl)(=[O:26])[CH2:22][CH:23]([CH3:25])[CH3:24]>>[Cl:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([NH:1][C:21](=[O:26])[CH2:22][CH:23]([CH3:25])[CH3:24])=[C:3]([C:12](=[O:20])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[NH:4]2)=[CH:9][CH:8]=1
Reactant: Nc1c(C(=O)c2cccc(Cl)c2)[nH]c2cc(Cl)ccc12
Reactant: CC(C)CC(=O)Cl
Product: CC(C)CC(=O)Nc1c(C(=O)c2cccc(Cl)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-amino-6-chloro-2-(3-chlorobenzoyl)indole (Example 30) and isovaleryl chloride. m.p.: 185-186° C. 1H-NMR (CDCl3) δ: 9.94 (1H, br s), 8.28 (1H, d, J=8.8 Hz), 8.19 (1H, br s), 7.78 (1H, t, J=1.8 Hz), 7.68 (1H, dt, J=1.5, 1.5, 7.3 Hz), 7.61 (1H, ddd, J=1.5, 1.8, 8.1 Hz), 7.51 (1H, t, J=7.7 Hz), 7.31 (1H, d, J=1.5 Hz), 7.11 (1H, dd, J=1.8, 8.8 Hz), 2.37-2.20 (3H, m), 1.06 (6H, d, J=6.2 Hz)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:12]=[C:13]([OH:15])[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[Cl:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[CH3:1][O:2][C:3](=[O:26])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:20][CH:21]=2)[CH:12]=[C:13]([O:15][C:31]2[CH:32]=[CH:33][C:28]([Cl:27])=[CH:29][CH:30]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)C(CC(C)C)c1cc(O)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: OB(O)c1ccc(Cl)cc1
Product: COC(=O)C(CC(C)C)c1cc(Oc2ccc(Cl)cc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Yield: 35 %

Procedure:
The title compound was prepared in 35% yield from 2-(5-hydroxy-4′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester (prepared in Example 15, step (f)) and 4-chlorobenzene boronic acid under the conditions described in Example 15, step (g).
Reaction SMILES: [NH:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@@H:2]([C:4]([NH:6][CH2:7][C:8]([OH:10])=O)=[O:5])[CH3:3].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[NH:33]([CH3:54])[C@H:34]([C:42]([NH:44][C@H:45]([C:50]([O:52][CH3:53])=[O:51])[CH2:46][CH:47]([CH3:49])[CH3:48])=[O:43])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(N(C)[C@H](C(N[C@H](C(OC)=O)CC(C)C)=O)CC1C=CC=CC=1)(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O.C(Cl)Cl>C1COCC1.CN(C=O)C>[NH:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@@H:2]([C:4]([NH:6][CH2:7][C:8]([N:33]([CH3:54])[C@H:34]([C:42]([NH:44][C@H:45]([C:50]([O:52][CH3:53])=[O:51])[CH2:46][CH:47]([CH3:49])[CH3:48])=[O:43])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:10])=[O:5])[CH3:3]
Reactant: CN[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)OC
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Agent: CC(C)COC(=O)Cl
Agent: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccccc1)N(C)C(=O)OC(C)(C)C
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccccc1)N(C)C(=O)CNC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Reaction time: 0.08 h

Procedure:
To a solution of 24.6 g of Boc-(D)-Ala-Gly-OH and 11.2 ml of N-methylmorpholine in 400 ml of THF are added 13.2 ml of chloroformic acid isobutyl ester at -25°. After 5 minutes, at 25°, 11.2 ml of N-methyl-morpholine and 42.1 g of H-MePhe-Leu-OMe (trifluoroacetate) in DMF [which has previously been prepared by the treatment of Boc-MePhe-Leu-OMe with TFA-methylene chloride (1:1)] are added. After 2 hours, at -15°, the title compound is isolated as described under (a) above, as a solid foam.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)([OH:11])[C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1.[C@@:21]12(O)[N:28](C)[C@@H:25]([CH2:26][CH2:27]1)[CH2:24][CH:23]=[CH:22]2>>[F:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)([OH:11])[C:7]([O:9][C@@:10]23[N:28]([CH3:21])[C@@H:25]([CH2:26][CH2:27]2)[CH2:24][CH:23]=[CH:22]3)=[O:8])=[CH:4][CH:3]=1
Reactant: CN1[C@@H]2CC=C[C@@]1(O)CC2
Reactant: COC(=O)C(O)(c1ccc(F)cc1)c1ccc(F)cc1
Product: CN1[C@@H]2CC=C[C@@]1(OC(=O)C(O)(c1ccc(F)cc1)c1ccc(F)cc1)CC2

Procedure:
4.5 is prepared analogously to the method according to II.1. Yield: 8.71 g (69% of theory) starting from 8.35 g (0.03 mol) of 3c and 4.18 g (0.03 mol) of tropenol; TLC: Rf value: 0.34 (eluant as in step II.1); melting point: 167° C.-169° C.