Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][NH:9][C:10](=[O:11])[C:5]2=[N:4][CH:3]=1.[H-].[Na+].I[CH2:15][CH3:16]>CN(C)C=O.O>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][N:9]([CH2:15][CH3:16])[C:10](=[O:11])[C:5]2=[N:4][CH:3]=1
Reactant: CCI
Reactant: O=c1[nH]ccn2c(Br)cnc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1ccn2c(Br)cnc2c1=O
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 20.1 %

Procedure:
3-Bromo-7H-imidazo[1,2-a]pyrazin-8-one (prepared as described in Example 5, 1.6 g, 7 mmol) was suspended in N,N-dimethylformamide (15 ml) then treated with sodium hydride (420 mg of a 60% dispersion in mineral oil, 10.5 mmol). The resulting mixture was heated at 60° C. for 20 min then treated with iodoethane (840 μl, 10.6 mmol). After stirring for 40 min the reaction was cooled, diluted cautiously with water (150 ml) and then extracted with dichloromethane (2×100 ml). The organics were combined, washed with water, dried over anhydrous magnesium sulphate, filtered and concentrated under high vacuum. The residue was triturated with diethyl ether and the resulting solid collected by filtration and recrystallized from ethyl acetate/methanol to furnish 3-bromo-7-ethyl-7H-imidazo[1,2-a]pyrazin-8-one as a white solid (0.34 g): δH (400 MHz, DMSO) 1.23 (3H, t, J 7), 3.94 (2H, q, J 7), 7.31 (1H, d, J 6), 7.41 (1H, d, J 6), 7.62 (1H, s); m/z (ES+) 244 and 242 [M+H]+.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.O1CCCC1.[CH2:18]([NH2:21])[C:19]#[CH:20]>>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:21][CH2:18][C:19]#[CH:20])=[O:4]
Reactant: C#CCN
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: C1CCOC1
Product: C#CCNC(=O)c1ccccc1N
Reaction time: 2 h
Yield: 100 %

Procedure:
Isatoic Anhydride (4.00 g, 24.5 mmol) was dissolved in tetrahydrofuran (100 mL, 1.230 mol) at 0° C. Prop-2-ynylamine (2.52 mL, 36.8 mmol) was added and the reaction was stirred for 2 hours and then concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-50% EtOAc/hex as the eluting solvent to obtain 2-amino-N-prop-2-ynyl-benzamide as a white solid (4.27 g, 100%). m.p.=75° C.; LCMS (m/e) 120 (M—NHCH2CCH); 1H-NMR (CDCl3, 400 MHz) δ 7.35 (d, 1H, J=7.9 Hz), 7.24 (dd, 1H, J=7.3 and 8.2 Hz), 6.73-6.64 (m, 2H), 6.19 (bs, 1H), 5.56 (bs, 2H), 4.26-4.20 (m, 2H), 2.29 (t, 1H, J=1.5 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[CH:4]=[C:5]([CH3:14])[C:6](=[O:13])[NH:7]2.Cl[CH2:16][C:17]([CH3:19])=[CH2:18]>>[CH3:18][C:17](=[CH2:16])[CH2:19][O:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[CH:4]=[C:5]([CH3:14])[C:6](=[O:13])[NH:7]2
Reactant: Cc1cc2c(O)ccc(C)c2[nH]c1=O
Reactant: C=C(C)CCl
Product: C=C(C)COc1ccc(C)c2[nH]c(=O)c(C)cc12
Yield: 90.1 %

Procedure:
Reaction, post-treatment, and recrystallization (chloroform-n-hexane) were performed in a manner similar to that described in Reference Example 31 using 5-hydroxy-3,8-dimethylcarbostyril (3 g, 15.87 mmol) and 3-chloro-2-methyl-1-propene (1.58 g, 17.46 mmol). As a result, 3.48 g of the title compound was obtained as pale brown crystals (90.2%).
Reaction SMILES: C1C2C(CO[C:16]([N:18]3[CH2:23][C:22]4([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[O:21][CH2:20][CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:16][N:18]1[CH2:23][C:22]2([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[O:21][CH2:20][CH2:19]1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)N1CCOC2(CCNCC2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCOC2(CCNCC2)C1
Temperature: 25 °C
Yield: 154.3 %

Procedure:
To a mixture of compound 404 (586.4 mg, 1.545 mmol) in tetrahydrofuran (20 mL) was added lithium aluminum hydride (240.5 mg, 6.34 mmol). After 1.5 hours at reflux the reaction was cooled to room temperature and quenched with water (240.5 μL), followed by 1N NaOH (240.5 μL), and then water (2×240.5 μL). The remaining solids were filtered off, and the filtrate was concentrated to give compound 405 (406 mg), as a sticky white solid. LCMS-ESI (POS), M/Z, M+1: Found 171.1, Calculated 171.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[NH:13][C:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:15][N:16]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O>C(O)C.[H][H].[Pd]>[NH2:9][C:8]1[CH:7]=[CH:6][C:5]([C:12]2[NH:13][C:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:15][N:16]=2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: CCOC(=O)Cc1nnc(-c2ccc([N+](=O)[O-])c(OC)c2)[nH]1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)Cc1nnc(-c2ccc(N)c(OC)c2)[nH]1

Procedure:
50 mg of Pd/C were added to the solution of 200 mg of ethyl [5-(3-methoxy-4-nitrophenyl)-4H-[1,2,4]triazol-3-yl]acetate in 100 ml of ethanol and hydrogen was introduced into the mixture at room temperature until the theoretical amount had been taken up. The catalyst was then removed by filtration and the filtrate was concentrated.
Reaction SMILES: CO[C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([O:15][CH3:16])([O:13][CH3:14])[CH2:11][Br:12])[CH:5]=1.[C:18]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])[CH3:19].[Li]>>[C:22]([O:21][C:18](=[O:20])[CH2:19][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([O:13][CH3:14])([O:15][CH3:16])[CH2:11][Br:12])[CH:5]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: COC(=O)c1cccc(C(CBr)(OC)OC)c1
Reactant: CC(=O)OC(C)(C)C
Agent: [Li]
Product: COC(CBr)(OC)c1cccc(C(=O)CC(=O)OC(C)(C)C)c1

Procedure:
3-(2-Bromo-1,1-dimethoxy-ethyl)-benzoic acid methyl ester (3.9 g) was treated with lithium tert.-butyl acetate according to the general procedure K (method b) to give 3-oxo-3-[3-(2-bromo-1,1-dimethoxy-ethyl)-phenyl]-propionic acid tert-butyl ester (2.8 g) as a yellow oil.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[C:17]1([CH2:16][CH2:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[OH:8])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C(=Cc1ccccc1OCc1ccccc1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Oc1ccccc1CCc1ccccc1
Yield: 89 %

Procedure:
The whole of this 2-benzyloxystilbene was dissolved in 300 ml of ethanol, and the resulting solution was stirred at 60° C. for 3.5 hours in an atmosphere of hydrogen at atmospheric pressure and in the presence of 1.00 g of 5% w/w palladium-on-charcoal. The catalyst was removed by filtration, and the filtrate was concentrated by distillation under reduced pressure. The resulting residue was then purified by column chromatography through silica gel, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 6.41 g (yield 89%) of the title compound as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH:9]=O)=[CH:4][CH:3]=1.[C:18]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C([BH3-])#N.[Na+].O>CO>[C:21]([O:20][C:18]([N:25]1[CH2:30][CH2:29][N:28]([CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:27][CH2:26]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: O=CC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(CC(c2ccc(Cl)cc2)c2ccc(Cl)cc2)CC1
Reaction time: 18 h
Yield: 11.1 %

Procedure:
To a solution of bis-(4-chloro-phenyl)-acetaldehyde (3.74 mmol) in methanol under a nitrogen atmosphere, N-BOC-piperazine (1.05 g, 5.61 mmol) was added ???, the reaction mixture was stirred for 1 hour before addition of sodium cyanoborohydride (0.28 g, 4.49 mmol). The reaction mixture was stirred for 18 hours, water added (3 ml) and the solvent removed under reduced pressure. The residue was partitioned between dichloromethane and water, the organic layer was separated, dried (MgSO4), filtered and concentrated. Purified over flash silica chromatography eluting with ethyl acetate/petroleum ether (3:7) to yield the title compound (0.18 g, 11% yield for steps 30A and 30B combined). LC/MS: (PS-A2) Rt 2.66 [M−BOC+H]+ 335.02.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)=[CH:5][N:6]=1.[NH2:15][C:16]1[CH:17]=[C:18]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=1>CC(O)C>[C:11]([C:10]1[CH:13]=[CH:14][C:7]([C:4]2[O:3][C:2]([NH:15][C:16]3[CH:17]=[C:18]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=3)=[N:6][CH:5]=2)=[CH:8][CH:9]=1)#[N:12]
Reactant: N#Cc1ccc(-c2cnc(Cl)o2)cc1
Reactant: CS(=O)(=O)Nc1cccc(N)c1
Solvent: CC(C)O
Product: CS(=O)(=O)Nc1cccc(Nc2ncc(-c3ccc(C#N)cc3)o2)c1
Temperature: 80 °C

Procedure:
A mixture of 4-(2-chlorooxazol-5-yl)benzonitrile 2 (0.20 g, 0.98 mmol) and commercially available N-(3-aminophenyl)methanesulfonamide 6 (0.182 g, 0.98 mmol) in 2-propanol (20 mL) was heated to 80° C. for 18 h with stirring. Upon cooling, a white solid precipitated out which was filtered off, washed with 2-propanol, and dried. This was then triturated with ether and filtered to yield the title product, a white solid, as the hydrochloride salt of 7 (0.14 g, 40%). Free amine containing filtrate was evaporated and silica column purified (Biotage) (Acetone/hexane as an eluent) to provide 7 (0.151 g, 44% yield) as pale yellow solid. MS (ES) m/z 355 (M+H+).
Reaction SMILES: [Cl:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](Cl)=[O:9])(=[O:4])=[O:3].N1C=CC=CC=1.[CH3:20][OH:21]>ClCCl>[Cl:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([O:21][CH3:20])=[O:9])(=[O:4])=[O:3]
Reactant: CO
Reactant: O=C(Cl)c1cccc(S(=O)(=O)Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cccc(S(=O)(=O)Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.6 %

Procedure:
A solution (20 mL) of 3-(chlorosulfonyl)benzoyl chloride (2.4 g) in dichloromethane was cooled to 0° C., and pyridine (791 mg) and methanol (320 mg) were added. The reaction mixture was stirred at room temperature for 2 hr, and the solvent was evaporated under reduced pressure. The residue was filtrated, washed with a mixed solvent of ethyl acetate and isopropyl ether, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→4:1) to give the title compound as a colorless oil (yield 2.17 g, 92%).
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][C:12](O)=[O:13])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].O.Cl>C1(C)C=CC=CC=1>[CH2:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([CH2:11][CH2:12][OH:13])[CH2:9][CH2:10]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[C@H]1CC[C@H](CC(=O)O)CC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CCCC[C@H]1CC[C@H](CCO)CC1
Temperature: 90 °C
Reaction time: 3 h
Yield: 89.5 %

Procedure:
37 g (0.19 mol) of trans-4-butylcyclohexyl acetic acid was dispersed in 190 cm) of anhydrous toluene, 160 cm3 (0.57 mol) of 70% of NaAlH2 (OC2H4OCH3)2 in toluene was added dropwise while stirring at a rate where the toluene refluxed quietly, after which it was stirred for 3 hours on a 90° C. hot water bath. The reactant was cooled to room temperature, 40 cm3 of water and 500 cm3 of 15% HCl were added dropwise while stirring, the oily layer was taken off, and the water layer was extracted with toluene, combined with the oily layer and washed with 10% HCl and water. The toluene was removed, and the remaining oily substance was distilled under reduced pressure (b. p. 103° C./3 mmHg) to obtain 31 g (0.17 mol) of 2-(trans-4'-butylcyclohexyl)ethanol.
Reaction SMILES: [CH2:1]([N:5]([CH3:22])[C:6]([CH:8]1[CH2:13][CH2:12][C:11]2[C:14]3[C:19](Cl)=[N:18][CH:17]=[N:16][C:15]=3[S:21][C:10]=2[CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].[NH2:23][C:24]1[C:33]([O:34][CH3:35])=[CH:32][C:27]2[NH:28][C:29](=[O:31])[S:30][C:26]=2[CH:25]=1>>[CH2:1]([N:5]([CH3:22])[C:6]([CH:8]1[CH2:13][CH2:12][C:11]2[C:14]3[C:19]([NH:23][C:24]4[C:33]([O:34][CH3:35])=[CH:32][C:27]5[NH:28][C:29](=[O:31])[S:30][C:26]=5[CH:25]=4)=[N:18][CH:17]=[N:16][C:15]=3[S:21][C:10]=2[CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(C)C(=O)C1CCc2c(sc3ncnc(Cl)c23)C1
Reactant: COc1cc2[nH]c(=O)sc2cc1N
Product: CCCCN(C)C(=O)C1CCc2c(sc3ncnc(Nc4cc5sc(=O)[nH]c5cc4OC)c23)C1

Procedure:
100 mg (296 μmol) (RS)—N-butyl-4-chloro-N-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxamide (prepared according to intermediate example 89a) were transformed in analogy to example 1 using 6-amino-5-methoxy-1,3-benzothiazol-2(3H)-one to give after working up and purification 8.8 mg (6%) of the title compound.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:22])C=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N+:10]([O-:22])=[CH:9][CH:8]=[CH:7]2)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc2ncccc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)c1ccc2c(ccc[n+]2[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 40 mL of a chloroform solution containing 2.0 g of 6-isopropylquinoline, 2.9 g of m-chloroperbenzoic acid was added, and the mixture was stirred at room temperature overnight. Thereto was added an aqueous saturated sodium hydrogen carbonate solution, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, and the resultant solution was washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 2.1 g of a brown oily substance, 6-isopropylquinoline N-oxide.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][C:6]2=[C:8]([NH2:12])[CH:9]=[CH:10][CH:11]=[C:5]2[O:4][CH2:3]1.N[C:14](N)=[O:15]>CCOCC.CCCCCC>[CH3:1][CH:2]1[N:7]2[C:14](=[O:15])[NH:12][C:8]3=[CH:9][CH:10]=[CH:11][C:5](=[C:6]23)[O:4][CH2:3]1
Reactant: NC(N)=O
Reactant: CC1COc2cccc(N)c2N1
Solvent: CCCCCC
Solvent: CCOCC
Product: CC1COc2cccc3[nH]c(=O)n1c23
Yield: 52.6 %

Procedure:
3.3 g (0.02 mol) of 3-methyl-3,4-dihydro-1H-1,4-benzoxazin-5-amine are heated at 160°-165° C. in an oil bath for 1.5 hours in the presence of 1.7 g (0.028 mol) of urea. A solid is obtained which is taken up in a water/ether (50/50) mixture. The phases are separated, the organic phase is recovered, is washed, is dried and the solvent evaporated to dryness. The residue obtained is purified by chromatography on a column of silica gel, the eluent being ethyl ether. 2 g of product are obtained.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>C(O)CCC>[O:8]([C:7]1[C:2]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[N:3][CH:4]=[CH:5][CH:6]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C1CNCCN1
Reactant: Clc1ncccc1Oc1ccccc1
Solvent: CCCCO
Product: c1ccc(Oc2cccnc2N2CCNCC2)cc1

Procedure:
To a solution of 10.5 g of 2-chloro-3-phenoxypyridine in 25 ml of n-butanol is added 20 g of piperazine and the solution is refluxed for 24 hours. The resulting mixture is concentrated at reduced pressure. The residue is shaken with 500 ml of ether and excess dilute aqueous sodium hydroxide. The organic phase is separated, dried and filtered. The filtrate is concentrated and the product distilled to give 3-phenoxy-2-piperazinylpyridine; bp, 115°-117° C./0.15 mm, crystallized and has a mp 56°-59° C.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10](Cl)(=[O:14])[CH:11]([CH3:13])[CH3:12].[F:16][C:17]1[C:25]([O:26][C:27]2[C:36]3[C:31](=[CH:32][C:33]([O:39][CH2:40][CH:41]4[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]4)=[C:34]([O:37][CH3:38])[CH:35]=3)[N:30]=[CH:29][N:28]=2)=[CH:24][CH:23]=[C:22]2[C:18]=1[CH:19]=[C:20]([CH3:47])[NH:21]2>C(Cl)Cl>[F:16][C:17]1[C:25]([O:26][C:27]2[C:36]3[C:31](=[CH:32][C:33]([O:39][CH2:40][CH:41]4[CH2:46][CH2:45][N:44]([C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])[CH2:43][CH2:42]4)=[C:34]([O:37][CH3:38])[CH:35]=3)[N:30]=[CH:29][N:28]=2)=[CH:24][CH:23]=[C:22]2[C:18]=1[CH:19]=[C:20]([CH3:47])[NH:21]2
Reactant: CC(C)C(=O)Cl
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCC1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCC1CCN(C(=O)C(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.3 %

Procedure:
Diisopropylethylamine (72 μl, 0.41 mmol) and isobutyryl chloride (44 mg, 0.41 mmol), in methylene chloride (0.5 ml) were added to a suspension of 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline (150 mg, 0.34 mmol), (prepared as described for the starting material in Example 11), in methylene chloride (4 ml). After a few minutes all the material had gone into solution. The mixture was stirred for 3 hours at ambient temperature, washed with saturated sodium hydrogen carbonate solution, dried (MgSO4) and concentrated under reduced pressure. Column chromatography of the residue, eluting with 2% methanol/methylene chloride gave 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-7-[(1-isobutyrylpiperidin-4-yl)methoxy]-6-methoxyquinazoline (90 mg, 52%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[OH:21].C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[O:21][C:15]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=1[F:13]
Reactant: NS(=O)(=O)c1ccc(F)c(Br)c1
Reactant: Oc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: NS(=O)(=O)c1ccc(Oc2ccc(F)cc2F)c(Br)c1
Temperature: 120 °C
Yield: 58.4 %

Procedure:
A solution of 3-bromo-4-fluorobenzenesulfonamide (400 mg, 1.6 mmol) and 2,4-difluorophenol (228 mg, 1.76 mmol) in DMSO (16 ml) was treated with cesium carbonate (1 g, 3.2 mmol). The resulting mixture was heated to 120° C. for 20 min by microwave irriadation (normal). The mixture was treated with water (100 ml) and extracted with EtOAc (3×50 ml). The combined organic extracts were washed with saturated bicarbonate solution (aq), dried over sodium sulfate, filtered and concentrated in vacuo to afford a tan solid. The solid was purified by silica gel chromatography (12 g ISCO, 30% EtOAc in hexanes 30 ml/min) to give the title compound (340 mg, 58%) as a tan solid LCMS (M−H)−=362.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[O:9][CH3:10].C(=O)([O-])[O-].[K+].[K+].[CH2:17](I)[CH2:18][CH3:19]>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][CH2:18][CH3:19])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: CCCI
Reactant: COc1cc(O)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOc1ccc(Br)c(OC)c1
Temperature: 25 °C
Yield: 88 %

Procedure:
Prepare a solution of 4-bromo-3-methoxyphenol (6.5 g, 32 mmole), and potassium carbonate (15 g) in acetone (250 mL) under argon. Add n-propyl iodide (9.0 g, 5.2 mL, 53 mmole) and heat to reflux overnight. Cool to room temperature and filter. Rotovap to condense and evaporate the solvents. Check by thin layer chromatagraphy (25% ethyl aceate/75% hexane). Wash three times with 100 mL 3% potassium hydroxide. Dry the organic layer with magnesium sulfate. Filter and rotovap. Purify by chromatography and place under high vacuum to obtain the title compound (6.9 g, 88%). Rf=0.60 (EtOAc/hexane; 25:75).
Reaction SMILES: [C:1]1([N:7]2[C:25](=[O:26])[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[CH:15][C:16]([N:19]5[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]5)=[N:17][C:18]=4[C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:27]=C1CNCCN1>>[O:27]=[C:23]1[NH:22][CH2:21][CH2:20][N:19]([C:16]2[CH:15]=[CH:14][C:13]3[NH:12][CH:11]=[C:10]4[C:25](=[O:26])[N:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[N:8]=[C:9]4[C:18]=3[N:17]=2)[CH2:24]1
Reactant: O=C1CNCCN1
Reactant: O=c1c2c[nH]c3ccc(N4CCNCC4)nc3c-2nn1-c1ccccc1
Product: O=C1CN(c2ccc3[nH]cc4c(=O)n(-c5ccccc5)nc-4c3n2)CCN1

Procedure:
The title compound was prepared following the procedure described for 6a using 2-oxopiperazine instead of piperazine. 1H-NMR (DMSO-d6) δ (ppm): 3.08 (2H, m), 3.90 (2H, dd, J=5.67, 4.94), 4.19 (2H, s), 7.15 (1H, dd, J=7.42, 1.09 Hz), 7.20 (1H, d, J=9.34 Hz), 7.40 (2H, dd, J=8.51, 7.42 Hz), 7.85 (1H, d, J=9.06 Hz), 8.16 (1H, br), 8.22 (1H, dd, J=7.70, 1.09 Hz), 8.57 (1H, s). m/z 361.4 (MH+).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][O:14][CH2:15][CH2:16][F:17])(=O)=O)=CC=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C@H:25]2[C@H:30]([OH:31])[C@@H:29]([OH:32])[C@H:28]([OH:33])[C@@H:27]([CH2:34][OH:35])[O:26]2)=[CH:21][C:20]=1[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)C>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C@H:25]2[C@H:30]([OH:31])[C@@H:29]([OH:32])[C@H:28]([OH:33])[C@@H:27]([CH2:34][OH:35])[O:26]2)=[CH:21][C:20]=1[CH2:36][C:37]1[CH:38]=[CH:39][C:40]([O:43][CH2:12][CH2:13][O:14][CH2:15][CH2:16][F:17])=[CH:41][CH:42]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOCCF)cc1
Reactant: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(O)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(OCCOCCF)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 6.4 %

Procedure:
2-(2-fluoroethoxy)ethyl 4-methylbenzenesulfonate (52 mg, 0.19 mmol) dissolved in anhydrous DMF (3 mL) was added to a flask containing (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (intermediate D1) (57 mg, 0.15 mmol) in DMF (3 mL) at room temperature. Cesium carbonate (0.12 g, 0.36 mmol) was added to the flask, and the resulting mixture was stirred at room temperature for 48 hr. The reaction mixture was diluted with diethyl ether (50 mL) and the organic layer was washed with aqueous solutions of ammonium chloride (50 mL), sodium bicarbonate (50 mL), and NaCl (50 mL), followed by drying over sodium sulfate. The organic layer was concentrated in vacuo, followed by preparative TLC using 15% methanol in dichloromethane as the mobile phase to yield the title compound (4.5 mg, 5.0%). 1H NMR (CDCl3, 300 MHz): δ 7.30 (d, 1H, J=11.6 Hz), 7.17-7.12 (br m, 2H), 7.04 (d, 2H, J=11.6 Hz), 6.78 (d, 2H, J=11.6 Hz), 4.52 (dt, 2H, J1=5.6 Hz, J2=63.6 Hz), 4.33 (br s, 1H), 4.13 (br s, 1H), 4.04-3.96 (m, 4H), 3.81-3.67 (m, 5H), 3.63-3.49 (m, 2H), 3.38-3.21 (m, 3H), 2.78 (br s, 1H), 1.77 (br s, 2H); LC/MS: theoretical mass=470.15; observed M+1=471.6, M+Na=493.4).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][CH:11]=2)[CH:6]=[N:5]1)(=O)C.Cl.O.O.N>C(O)C>[NH:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][CH:11]=2)[CH:6]=[N:5]1
Reactant: CCOC(=O)c1ccc2c(cnn2C(C)=O)c1
Agent: Cl
Agent: N
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccc2[nH]ncc2c1
Yield: 48 %

Procedure:
The resulting ethyl 1-acetyl-1H-indazole-5-carboxylate was stirred in a mixture of concentrated hydrochloric acid (15 ml), water (15 ml) and ethanol (30 ml) for 15 hours at a room temperature. The resulting mixture was rendered faintly alkaline with a 25% ammonia water. The faintly alkalified mixture was subjected to extraction with chloroform. The extract was crystallized from n-hexane, and then the resulting crystal was separated by filtration and dried to give the title compound (6.45 g, 48%) as a light-brown powder.
Reaction SMILES: [C:1]([C:4]1[C:5]([Cl:17])=[C:6]2[C:11](=[C:12]([CH3:14])[CH:13]=1)S[CH2:9][CH2:8][C:7]2([CH3:16])[CH3:15])(=[O:3])[CH3:2].OO.[S:20]([O-:23])(O)=[O:21].[Na+]>C(O)(=O)C>[C:1]([C:4]1[C:5]([Cl:17])=[C:6]2[C:11](=[C:12]([CH3:14])[CH:13]=1)[S:20](=[O:23])(=[O:21])[CH2:9][CH2:8][C:7]2([CH3:16])[CH3:15])(=[O:3])[CH3:2]
Reactant: O=S([O-])O
Reactant: CC(=O)c1cc(C)c2c(c1Cl)C(C)(C)CCS2
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)c1cc(C)c2c(c1Cl)C(C)(C)CCS2(=O)=O
Temperature: 80 °C
Yield: 85 %

Procedure:
5 ml of acetic acid was added to 3.0 g (11 mmol) of 6-acetyl-5-chloro-4,4,8-trimethylthiochroman, 3.7 g (33 mmol) of a 30% hydrogen peroxide aqueous solution was further added, and the mixture was heated at 80° C. for 2 hours. 20 ml of a 2% sodium hydrogensulfite was added to the reaction mixture, and a precipitated solid was recovered by filtration to give 2.8 g (yield 85%) of 6-acetyl-5-chloro-4,4,8-trimethylthiochroman-1,1-dioxide.