Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([C:11]2[C:12]3[CH:20]=[CH:19][NH:18][C:13]=3[C:14](Cl)=[N:15][CH:16]=2)=[O:10])[CH2:3][CH2:2]1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25].CS(O)(=O)=O>O1CCOCC1.CO>[O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([C:11]2[C:12]3[CH:20]=[CH:19][NH:18][C:13]=3[C:14]([NH:25][C:24]3[CH:26]=[CH:27][CH:28]=[C:22]([Cl:21])[CH:23]=3)=[N:15][CH:16]=2)=[O:10])[CH2:3][CH2:2]1
Reactant: O=C(NCC1CCOCC1)c1cnc(Cl)c2[nH]ccc12
Reactant: Nc1cccc(Cl)c1
Agent: CS(=O)(=O)O
Solvent: C1COCCO1
Solvent: CO
Product: O=C(NCC1CCOCC1)c1cnc(Nc2cccc(Cl)c2)c2[nH]ccc12
Temperature: 180 °C

Procedure:
A mixture of 7-chloro-1H-pyrrolo[2,3-c]pyridine-4-carboxylic acid (tetrahydro-pyran-4-ylmethyl)-amide (20 mg), 3-chloroaniline (15 ul), and methanesulfonic acid (9 ul) in 1,4-dioxane (0.5 ml) was heated under microwave conditions at 180° C. for 30 minutes. The solid mass obtained was dissolved in methanol, transferred to a round bottom flask and evaporated. The residue was partitioned between ethyl acetate and 5% sodium hydrogen carbonate solution whereby the title compound remained as a solid at the interface. The solid was filtered off, and washed with 5% sodium hydrogen carbonate solution, water and diethyl ether, then sucked dry and dried at 60° C. under vacuum to afford the title compound (17 mg).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[C:14]([O:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1O
Product: CC(=O)Oc1cc([N+](=O)[O-])ccc1C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 2-hydroxy-4-nitrobenzoic acid (16.84 g) in acetic anhydride (60 mL) was heated under reflux overnight. After cooling, the reaction solution was concentrated in vacuo, water and tetrahydrofuran were added to the residue, and the mixture was stirred at room temperature for 4 hours. The aqueous solution was extracted with ethyl acetate, the organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue was suspended in diisopropyl ether, the resultant precipitates were collected by filtration and washed with diisopropyl ether to give the titled compound (13.75 g) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](Cl)=[O:6].[C:12]([NH2:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:14])[CH3:13].C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([NH:21][C:12]([CH3:14])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:13])=[O:6]
Reactant: O=C(Cl)c1ccc(F)c(Cl)c1
Reactant: CC(C)(N)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(NC(=O)c1ccc(F)c(Cl)c1)c1ccccc1
Yield: 97.1 %

Procedure:
In a similar manner to Step 1 of Example 16, 3-chloro-4-fluorobenzoyl chloride (3.00 g, 15.5 mmol) was dissolved in dichloromethane (60 mL), and the solution was treated with cumylamine (2.45 mL, 17.1 mmol), triethylamine (3.24 mL, 23.3 mmol) and DMAP (189 mg, 1.05 mmol), followed by purification by slurry using diisopropylether to obtain 3-chloro-4-fluoro-N-(1-methyl-1-phenylethyl)benzamide (4.39 g, yield 97%).
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.COCN[C:15]([C@H:17]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1)=[O:16].[Cl-].[Na+]>O1CCCC1.O>[S:6]1[CH:10]=[CH:9][N:8]=[C:7]1[C:15]([C@H:17]1[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]1)=[O:16]
Reactant: COCNC(=O)[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: c1cscn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H](C(=O)c2nccs2)C1
Temperature: 0 °C
Yield: 88.6 %

Procedure:
136.6 g (0.32 mol) of n-butyllithium (15% in n-hexane) were added dropwise at −68° C. to a solution of 25 g (0.291 mol) of thiazole in 1 l of tetrahydrofuran. The mixture was warmed to 0° C. and subsequently cooled to −40° C. This mixture was then added dropwise to a solution of 79.2 g (0.291 mol) of tert-butyl (S)-3-(methoxymethylcarbamoyl)piperidine-1-carboxylate in 1.4 l of tetrahydrofuran at −50° C. The reaction mixture was then slowly warmed to 0° C., and 2 l of ice-water were added. After addition of 2 l of water and 2 l of saturated sodium chloride solution, the crude mixture was extracted with a total of 4 l of ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The crude product (87 g) was chromatographed over a silica-gel column, giving 76.4 g of tert-butyl (S)-3-(thiazole-2-carbonyl)piperidine-1-carboxylate as brown resin; rotation value in methanol [α]20D=+27.4°; 1H NMR (500 MHz, DMSO) δ 8.22 (d, J=3.0, 1H), 8.17 (d, J=3.0, 1H), 4.22-3.86 (m, 1H), 3.84-3.69 (m, 2H), 3.60-3.52 (m, 1H), 3.20-3.05 (m, 1H), 2.08-1.92 (m, 2H), 1.89-1.60 (m, 2H), 1.35 (s, 9H).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrC[C:45]1[CH:50]=[CH:49][CH:48]=C[C:46]=1[C:51]([F:54])([F:53])[F:52]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[CH:48]=[CH:49][CH:50]=[CH:45][C:46]=3[C:51]([F:54])([F:53])[F:52])[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: FC(F)(F)c1ccccc1CBr
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3ccccc3C(F)(F)F)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(bromomethyl)-2-(trifluoromethyl)benzene and isolated as colorless gum (8.5 mg, 47%). MS (m/e): 441.4 (MH+).
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:16]([CH:26]([NH:28][C:29]3[N:37]=[CH:36][N:35]=[C:34]4[C:30]=3[N:31]=[CH:32][NH:33]4)[CH3:27])=[CH:17][C:18]([Cl:25])=[C:19]3[C:24]=2[N:23]=[CH:22][CH:21]=[CH:20]3)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.F[Si-2](F)(F)(F)(F)F.[H+].[H+].O.[OH-].[Na+]>C(#N)C>[Cl:25][C:18]1[CH:17]=[C:16]([CH:26]([NH:28][C:29]2[N:37]=[CH:36][N:35]=[C:34]3[C:30]=2[N:31]=[CH:32][NH:33]3)[CH3:27])[C:15]([N:12]2[CH2:11][CH2:10][CH:9]([OH:8])[CH2:14][CH2:13]2)=[C:24]2[C:19]=1[CH:20]=[CH:21][CH:22]=[N:23]2
Reactant: CC(Nc1ncnc2[nH]cnc12)c1cc(Cl)c2cccnc2c1N1CCC(O[Si](C)(C)C(C)(C)C)CC1
Agent: [H+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CC(Nc1ncnc2[nH]cnc12)c1cc(Cl)c2cccnc2c1N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of N-{1-[8-(4-{[tert-butyl(dimethyl)silyl]oxy}piperidin-1-yl)-5-chloroquinolin-7-yl]ethyl}-9H-purin-6-amine (0.200 g, 0.372 mmol) in acetonitrile (1 mL) was added 2.0 M fluorosilicic acid in water (0.929 mL, 1.86 mmol). The reaction was stirred at room temperature for 30 minutes, then neutralized with aq. sodium hydroxide and extracted with dichloromethane. The extracts were combined and evaporated to dryness. The residue was purified on a RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at a flow rate of 30 mL/min) to give the desired product as the free base. LCMS calculated for C21H23ClN7O (M+H)+: m/z=424.2; Found: 424.1. 1H NMR (DMSO-d6, 400 MHz) δ 12.89 (1H, s), 8.95 (1H, m), 8.44 (1H, m), 8.27 (1H, m), 8.11 (1H, s), 8.01 (1H, s), 7.99 (1H, s), 7.58 (1H, dd, J=8.4 and 4.0 Hz), 6.35 (1H, br s), 4.67 (1H, m), 4.01 (1H, m), 3.76 (1H, m), 3.61 (1H, m), 2.78 (1H, m), 1.90 (2H, m), 1.79˜1.61 (3H, m), 1.52 (3H, d, J=7.2 Hz) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15](=[O:16])[N:14]3[CH:17]=[CH:18][S:19][C:13]3=[N:12][C:11]=2[CH3:20])=[CH:6][CH:5]=1)[CH3:2].[CH:21]1(CBr)C[CH2:22]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH:2]1([CH2:1][O:3][C:4]2[CH:5]=[CH:6][C:7]([C:10]3[C:15](=[O:16])[N:14]4[CH:17]=[CH:18][S:19][C:13]4=[N:12][C:11]=3[CH3:20])=[CH:8][CH:9]=2)[CH2:22][CH2:21]1
Reactant: BrCC1CC1
Reactant: CCOc1ccc(-c2c(C)nc3sccn3c2=O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc2sccn2c(=O)c1-c1ccc(OCC2CC2)cc1
Temperature: 80 °C

Procedure:
To a solution of Step 1 intermediate from Intermediate 10 (500 mg, 1.932 mmol) in DMF (5 ml) was added cyclopropylmethyl bromide (0.313 g, 2.321 mmol) at room temperature followed by Cs2CO3 (1.88 g, 5.770 mmol) and the reaction temperature was heated to 80° C. for 15.0 h overnight. The reaction mixture was diluted with ethyl acetate, washed with water and brine and purified by column chromatography using 1% methanol in chloroform to afford the desired compound; 1H NMR (300 MHz, CDCl3) δ 0.35-0.37 (m, 2H), 0.59-0.61 (m, 2H), 1.01-1.03 (m, 1H), 2.19 (s, 3H), 3.80-3.85 (m, 2H), 7.09-7.11 (m, 2H), 7.26-7.29 (m, 2H), 7.52 (d, J=4.8 Hz, 1H), 7.97 (d, J=4.5 Hz, 1H); MS (m/z) 313.25 (M+H)+.
Reaction SMILES: [BrH:1].[CH2:2]([O:7][CH2:8][CH2:9][C:10]([CH3:14])(O)[CH:11]=[CH2:12])[CH2:3][CH:4]([CH3:6])[CH3:5]>>[Br:1][CH2:12][CH:11]=[C:10]([CH3:14])[CH2:9][CH2:8][O:7][CH2:2][CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: Br
Reactant: C=CC(C)(O)CCOCCC(C)C
Product: CC(=CCBr)CCOCCC(C)C

Procedure:
To 40 mls of a 48% solution of hydrobromic acid are added dropwise with stirring at 5° during a period of 15 minutes 18.6 g (0.1 moles) of 5-isopentyloxy-3-methyl-1-penten-3-ol. After 30 minutes at 0°-5° the mixture is extracted with ether and the ethereal extract is washed with 10% sodium carbonate solution and then with saturated sodium chloride solution, dried with anhydrous sodium sulphate and evaporated.
Reaction SMILES: [N+:1]([C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:7]([NH2:13])=[C:6]([NH2:14])[CH:5]=1)([O-:3])=[O:2].O.[F:16][C:17]([F:29])([F:28])[C:18](=O)[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[N:13]=[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:18]([C:17]([F:16])([F:28])[F:29])=[N:14]2)([O-:3])=[O:2]
Reactant: O=C(C(=O)C(F)(F)F)c1ccccc1
Reactant: Nc1cc([N+](=O)[O-])c([N+](=O)[O-])cc1N
Solvent: O
Product: O=[N+]([O-])c1cc2nc(-c3ccccc3)c(C(F)(F)F)nc2cc1[N+](=O)[O-]

Procedure:
The title compound was prepared from 4,5-dinitro-1,2-phenylenediamine (890 mg, 4.5 mmol) and 3,3,3-trifluoro-1-phenyl-1,2-propanedione hydrate (1 g, 4.9 mmol) similarly as described in example 144.
Reaction SMILES: [C:1]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[CH2:14]([O:21][C:22]1[CH:23]=[C:24]([OH:28])[CH:25]=[CH:26][CH:27]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>C1COCC1>[CH2:14]([O:21][C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=1)[O:28][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Oc1cccc(OCc2ccccc2)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1cccc(OCc2ccccc2)c1

Procedure:
43.459 ml tert-butyl-chloro-dimethyl-silane were added at rt to a solution of 17 g imidazole and 25 g 3-benzyloxy-phenol in 400 ml THF. After 3 hours water was added to the reaction mixture and the mixture was then extracted with methylene chloride. The organic phase was extracted three times with water, dried over sodium sulfate and concentrated in vacuo. The residue was solved in methylene chloride and filtered over Alox (neutral) and concentrated.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]([F:15])([F:14])[F:13])[C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)C=O.[CH:16]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])OCC>CCCCCC>[Br:1][C:2]1[CH:3]=[C:4]([C:12]([F:13])([F:14])[F:15])[C:5]([O:10][CH3:11])=[C:6]([CH:16]([O:20][CH2:21][CH3:22])[O:23][CH2:24][CH3:25])[CH:9]=1
Reactant: CCOC(OCC)OCC
Reactant: COc1c(C=O)cc(Br)cc1C(F)(F)F
Solvent: CCCCCC
Product: CCOC(OCC)c1cc(Br)cc(C(F)(F)F)c1OC

Procedure:
5-bromo-2-methoxy-3-trifluoromethylbenzaldehyde (66.19 g) was dissolved in n-hexane (130 mL) and triethyl orthoformate (51 mL), and Amberlyst-15 (6.62 g) was added to the solution, and then the mixture was refluxed for 3 hours. The reaction solution was filtered, and then the solvent was distilled off under reduced pressure to obtain the title compound (82.81 g) as a brown oily substance.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])=[C:5]([C:18]([O:20]CC)=[O:19])[CH:4]=1)[CH3:2].[OH-].[Na+]>C(O)C.O>[CH2:1]([C:3]1[S:7][C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])=[C:5]([C:18]([OH:20])=[O:19])[CH:4]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(CC)sc1Nc1ccccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCc1cc(C(=O)O)c(Nc2ccccc2[N+](=O)[O-])s1

Procedure:
Ethyl 5-ethyl-2-(2-nitroanilino)-thiophene-3-carboxylate (6.0 g) dissolved in ethanol (100 ml) and water (50 ml) and heated to 60° C. with stirring. Sodium hydroxide (5 N, 50 ml) was then added and the temperature maintained for 16 hours. The reaction mixture was cooled and diluted with water (500 ml), and solid title product filtered off, m.p. 189°-191° C. (EtOAc).
Reaction SMILES: [CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[O:2]1.[N+](C1C=CC([O:18][C:19]([O:21][CH:22]2[CH:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:26][C:25]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[N:24][CH2:23]2)=O)=CC=1)([O-])=O>CN(C)C1C=CN=CC=1.C(#N)C>[CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH:6][C:19]([O:21][CH:22]3[CH:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:26][C:25]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[N:24][CH2:23]3)=[O:18])=[CH:4][C:3]=2[O:2]1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CN=C(c2ccccc2)OC1c1ccccc1
Reactant: Nc1ccc2c(c1)OCO2
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: O=C(Nc1ccc2c(c1)OCO2)OC1CN=C(c2ccccc2)OC1c1ccccc1
Yield: 48.1 %

Procedure:
3,4-Methylenedioxyaniline (1.1 g) is added at a temperature in the region of 20° C. to a solution, maintained under an argon atmosphere, of (5RS, 6SR)-5-(4-nitrophenoxycarbonyloxy)-2,6-diphenyl-5,6-dihydro-4H-1,3-oxazine (1.67 g) and 4-(dimethylamino)pyridine (0.2 g) in anhydrous acetonitrile (50 cc). The solution obtained is heated to reflux for 5 hours and then concentrated to dryness under reduced pressure (2.7 kPa). The oil obtained is purified by chromatography on silica (0.063-0.2 mm; 50 g) contained in a column 2 cm in diameter [eluent: cyclohexane/ethyl acetate/triethylamine (65:30:5 by volume)], collecting 15-cc fractions. Fractions 3 to 6 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization in diisopropyl ether, (5RS, 6SR)-5-(3,4-methylenedioxyphenylcarbamoyloxy)-2,6-diphenyl-5,6-dihydro-4H-1,3-oxazine (0.8 g), m.p. 138° C., is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][N:6]1[C@H:10]([CH3:11])[CH2:9][C@H:8]([CH2:12][CH2:13][C:14](=O)[CH3:15])[C:7]1=[O:17])[CH3:2].[NH2:19][C:20]1[C:25]([CH:26]=O)=[CH:24][CH:23]=[CH:22][N:21]=1.N1CCC[C@H]1C(O)=O>C(O)C>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][N:6]1[C@H:10]([CH3:11])[CH2:9][C@H:8]([CH2:12][CH2:13][C:14]2[CH:15]=[CH:26][C:25]3[C:20](=[N:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)[C:7]1=[O:17])[CH3:2]
Reactant: CCOC(=O)CN1C(=O)[C@@H](CCC(C)=O)C[C@H]1C
Reactant: Nc1ncccc1C=O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CCOC(=O)CN1C(=O)[C@@H](CCc2ccc3cccnc3n2)C[C@H]1C

Procedure:
A mixture of 11-9 (220 mg, 0.8619 mmol), 1-4, 2-amino-3-formylpyridine (137 mg, 1.12 mmol) and proline (99 mg, 0.8619 mmol) in absolute ethanol (5 mL) was heated at reflux for 12 h. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 70:25:5 chloroform/ethyl acetate/MeOH) to give 11-10 as a yellow oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][S:6][C:7]1[CH:8]=[C:9]([O:15][CH3:16])[C:10]([O:13][CH3:14])=[N:11][CH:12]=1.Br[CH:21](C1C=CC=CC=1)C>>[CH3:14][O:13][C:10]1[C:9]([O:15][CH3:16])=[CH:8][C:7]([S:6][CH:5]([C:4]2[CH:17]=[CH:18][CH:19]=[CH:2][CH:3]=2)[CH3:21])=[CH:12][N:11]=1
Reactant: COc1cc(SCc2cccc(Cl)c2)cnc1OC
Reactant: CC(Br)c1ccccc1
Product: COc1cc(SC(C)c2ccccc2)cnc1OC

Procedure:
Prepared as described for 5-(3-chlorobenzylthio)-2,3-dimethoxypyridine (Intermediate 8) but using (1-bromoethyl)benzene instead of 1-(bromomethyl)-3-chlorobenzene.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][CH2:8][C:9]2=O)=[CH:4][C:3]=1[O:15][CH2:16][CH3:17].N1C=CC=N[C:19]1=O.C[Mg]Br.C(OCC)C>C1COCC1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5](=[CH:4][C:3]=1[O:15][CH2:16][CH3:17])[C:6]([CH3:14])([CH3:13])[CH2:7][CH:8]=[C:9]2[CH3:19]
Reactant: CCOc1cc2c(cc1Br)C(=O)CCC2(C)C
Reactant: O=c1nccc[nH]1
Agent: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOc1cc2c(cc1Br)C(C)=CCC2(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 7-bromo-6-ethoxy-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one (Compound A-4, 1.05 g, 3.53 mmol) in THF (12 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1])-pyrimidinone (2 mL) at 0° C. was added a solution of methylmagnesium bromide (3M in diethylether (3.53 mL, 10.59 mmol). The reaction was allowed to warm up to room temperature and was stirred at 50° C. overnight. The reaction was quenched with ice water and extracted with diethylether. The organic layer was washed successively with water, brine, dried over Na2SO4, and concentrated in vacuo. The crude material was then dissolved in benzene (20 mL). After catalytic amount of p-toluenesulfonic acid was added, the reaction was stirred at reflux for 2 h. The solvent was removed in vacuo. The residue was purified by column chromatography (silica gel, 1% ethyl acetate in hexane) to afford the title compound as a pale yellow oil.
Reaction SMILES: [C:1]([Mg]Br)([CH3:3])=[CH2:2].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-])=O.[NH4+].[Cl-]>C1COCC1>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:9]=1[NH:14][C:1]([CH3:3])=[CH:2]2
Reactant: C=C(C)[Mg]Br
Reactant: COc1ccccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cccc2cc(C)[nH]c12
Reaction time: 1 h

Procedure:
800 ml of a 0.5M solution of isopropenylmagnesium bromide in THF is cooled to −40° C. under a nitrogen atmosphere, a solution of 20.4 g of 2-methoxynitrobenzene in 125 ml of THF is then added dropwise and the mixture is left stirring for 1 hour while allowing the temperature to return to 0° C. The reaction mixture is poured into a saturated NH4Cl solution and extracted with ether, the organic phase is washed with a saturated NaCl solution and dried over MgSO4, and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, elution being carried out with cyclohexane and then with a cyclohexane/EtOAc mixture (90/10; v/v). 2.45 g of the expected compound are obtained in the form of an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:14])([CH3:13])[CH:7]([CH3:12])[N:8]2[CH3:11])=[CH:4][CH:3]=1.[F:15][C:16]([F:26])([F:25])[C:17](=O)[CH2:18][C:19](OCC)=[O:20]>>[O:20]=[C:19]1[CH:18]=[C:17]([C:16]([F:26])([F:25])[F:15])[C:3]2[C:2](=[CH:10][C:9]3[N:8]([CH3:11])[CH:7]([CH3:12])[C:6]([CH3:13])([CH3:14])[C:5]=3[CH:4]=2)[NH:1]1
Reactant: CC1N(C)c2cc(N)ccc2C1(C)C
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Product: CC1N(C)c2cc3[nH]c(=O)cc(C(F)(F)F)c3cc2C1(C)C
Reaction time: 1 h

Procedure:
6-Amino-1,2,3,3-tetramethylindoline (6.9 g, 0.036 mole) was treated with 6.8 g of ethyl trifluoroacetoacetate. There was an immediate reaction with heat evolution and formation of a solid. The mixture was heated in an oil bath under a reflux condenser for 16 hrs at 135°-140° C., then for 1 hr at 145°-150° C. The cooled cake was broken up, triturated with 10 ml of diethyl ether, filtered and washed twice with cold ether; 7.7 g (69%). When recrystallized from 275 ml of 95% ethanol, the compound was obtained as felted, yellow needles; m.p. 248°-249° C., shrinking at 244° C.
Reaction SMILES: [F:1][C:2]([F:10])([CH3:9])[C:3]([CH3:8])([CH3:7])[C:4](O)=[O:5].C(Cl)(=O)C([Cl:14])=O>ClCCl>[F:1][C:2]([F:10])([CH3:9])[C:3]([CH3:8])([CH3:7])[C:4]([Cl:14])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(F)(F)C(C)(C)C(=O)O
Solvent: ClCCl
Product: CC(F)(F)C(C)(C)C(=O)Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To 1.55 g (9.86 mmol) 3,3-difluoro-2,2-dimethylbutanoic acid in 5 ml of dry dichloromethane was added 3.45 ml (39.5 mmol) of oxalyl chloride. The mixture was stirred at room temperature for 20 hours then solvent and excess reagent removed by distillation followed by addition of carbon tetrachloride and distillation of the solvent. The cooled 3,3-difluoro-2,2-dimethylbutanoyl chloride thus formed was dissolved in 8 ml of dry pyridine and added to a mixture of 2.15 g (4.93 mmol) of [1S-[1α(4R*,6R*),2α, 6β,8β,8aβ]]-4-[[(1,1-dimethylethyl)dimethylsilyl]oxy-[2-(1,2,6,7,8,8a-hexahydro-8-hydroxy-2,6-dimethyl-1-naphthalenyl)ethyl]tetrahydro-2H-pyran-2-one, 0.35 g of 4-pyrrolidinopyridine and 10 ml of dry pyridine. The mixture was heated at 50° overnight then cooled and quenched by the addition of ice chips. The mixture was taken up in diethyl ether and washed successively with water, dilute sulfuric acid and saturated sodium bicarbonate. The mixture was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with hexane/dichloromethane/ethyl acetate (25:25:50) to give 0.314 g of 3,3-difluoro-2,2-dimethylbutanoic acid, [1S-[1α,3α,7β,8β (2R*,4R*)8aβ]]-8-[2[tetrahydro-4-[[(1,1-dimethylethyl]dimethylsilyl]oxy]-6-oxo-2H-pyran-2-yl]ethyl]-1,2,3,7,8,8a-hexahydro-3,7-dimethyl-1-naphthalenyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]=[O:10])=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:14]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:14])[CH:9]=[O:10])=[CH:4][CH:3]=1
Reactant: CI
Reactant: O=CNc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of N-(4-bromophenyl)-formamide 50 (250 mg, 1.25 mmol) in DMF (3 mL) is added dropwise to a suspension of sodium hydride (65 mg, 1.63 mmol, 60% dispersion in mineral oil) in DMF (3 mL) at 0° C. After stirring 1 h, iodomethane (113 μl, 1.63 mmol) is added, the reaction mixture warmed to RT and stirred 16 h. The reaction is then quenched with water (10 mL) and extracted into EtOAc (3×10 mL). The combined organic phases are dried over Na2SO4 and reduced in vacuo to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=O)[S:8][C:4]=2[CH:3]=1.[NH4+].[OH-].O=P(Cl)(Cl)[Cl:16]>>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([Cl:16])[S:8][C:4]=2[CH:3]=1
Reactant: O=c1[nH]c2ccc(Br)cc2s1
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Product: Clc1nc2ccc(Br)cc2s1
Yield: 83 %

Procedure:
A solution of 6-bromobenzothiazolin-2-one (500 mg, 2.2 mmol) in POCl3 (5 mL) was refluxed during 18 h, then poured onto ice. The solution was neutralized to pH 9 by addition of NH4OH, and the resulting solid collected by filtration. Washing with water and drying in vacuo gave 6-bromo-2-chlorobenzothiazole (450 mg, 83%).