Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH3:32])=[CH:27][CH:26]=1>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH3:32])=[CH:27][CH:26]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: CC(=O)c1ccc(O)cc1
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(Oc2ncnc3c2cnn3C2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
4-[4-(4-Acetyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester was prepared according to General Procedure B by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19) with 4′-hydroxyacetophenone (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA) in dimethylformamide. 1H NMR (400 MHz, DMSO-d6) δ 1.43 (s, 9H), 1.94-2.06 (m, 4H), 2.67 (s, 3H), 2.94-3.04 (m, 2H), 4.02-4.10 (m, 2H), 5.00-5.04 (m, 1H), 7.48-7.50 (m, 2H), 8.08-8.10 (m, 1H), 8.32 (s, 1H), 8.55 (s, 1H). Mass spectrum MH+=438.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13](Cl)=[O:14])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:20](=O)([O-])[O-].[K+].[K+].[NH2:26][C:27]1[C:40]([Cl:41])=[CH:39][C:38]([Cl:42])=[CH:37][C:28]=1[C:29]([N:31]=[S:32]([CH2:35][CH3:36])[CH2:33][CH3:34])=[O:30]>C(#N)C>[CH:27]([O:14][CH:13]([CH3:12])[CH3:20])([CH3:40])[CH3:28].[Cl:42][C:38]1[CH:39]=[C:40]([Cl:41])[C:27]([NH:26][C:13]([C:12]2[N:8]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[N:9]=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[O:14])=[C:28]([C:29](=[O:30])[N:31]=[S:32]([CH2:35][CH3:36])[CH2:33][CH3:34])[CH:37]=1
Reactant: CCS(CC)=NC(=O)c1cc(Cl)cc(Cl)c1N
Reactant: O=C([O-])[O-]
Reactant: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Agent: [K+]
Solvent: CC#N
Product: CC(C)OC(C)C
Product: CCS(CC)=NC(=O)c1cc(Cl)cc(Cl)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 173.6 %

Procedure:
A solution of 2-(3-chloro-2-pyridyl)-5-(trifluoromethyl)pyrazole-3-carbonyl chloride (210.7 g, 0.68 mol, 1.10 equiv.) in acetonitrile (500 mL) was added at 22° C. to a suspension of potassium carbonate (103.34 g, 0.74 mol, 1.20 equiv) and 2-amino-3,5-dichloro-N-(diethyl-λ4-sulfanylidene)-benzamide (181.79 g, 0.62 mol, 1.00 equiv) in acetonitrile (2 L). After 2.5 h at this temperature, the reaction mixture was poured into ice-water with stirring. The resulting precipitate was collected by filtration and washed with water and petrol ether. Trituration from diisopropyl ether yielded the crystalline title compound (305 g, 87%).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[C:15]2[NH:14][CH:13]3[CH2:16][CH2:17][N:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:19][CH:12]3[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:5])[CH3:2].[H-].[Na+].[C:27](Cl)(=[O:29])[CH3:28]>CN(C=O)C.O>[O:29]=[C:27]1[N:14]2[CH:13]3[CH2:16][CH2:17][N:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:19][CH:12]3[C:11]3[C:15]2=[C:7]([CH:8]=[CH:9][CH:10]=3)[N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:28]1
Reactant: CC(=O)Cl
Reactant: CCOC(=O)Nc1cccc2c1NC1CCN(C(=O)OCC)CC21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1CCC2C(C1)c1cccc3c1N2C(=O)CN3C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.6 %

Procedure:
To a solution of ethyl 6-[(ethoxycarbonyl)amino]-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate (2.2 g, 6.6 mmol) in DMF (20 mL) at 0° C. was added NaH (660 mg, 16.5 mmol) DMAP (878 mg, 7.2 mmol), acetyl chloride (0.6 mL, 7.2 mmol) and stirred at rt for 16 hours. The solution was diluted with water (30 mL), and extracted with EtOAc (2×30 mL). The combined extracts were dried over magnesium sulfate, concentrated, and purified by flash chromatography to afford diethyl 1-oxo-6b,9,10,10a-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-3,8-(2H,7H)-dicarboxylate (1.1 g, 57%) as a clear oil. MS [M+H]+374. 1H NMR (CDCl3, 300 MHz): δ 6.75 (t, 1H, J=7.7 Hz), 6.59 (m, 1H), 6.45 (m, 1H), 4.05 (m, 1H), 3.60-4.00 (m, 7H), 3.40 (m, 1H), 3.00 (m, 3H), 1.92 (m, 2H), 0.91 (m, 1H), 0.85 (m, 6H) ppm.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[O:11]([C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])(C)(C)C.[K+]>CS(C)=O>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:21][C:20]1[CH:22]=[CH:23][CH:24]=[C:18]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:19]=1)([O-:10])=[O:9]
Reactant: Nc1cccc(Oc2ccccc2)c1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccccc1Nc1cccc(Oc2ccccc2)c1

Procedure:
The product (2.08 g) is obtained according to the method of stage 1 of Example 4, by using 1.23 mL of 2-fluoronitrobenzene and 3.3 g of 3-phenoxyaniline in the presence of 2.13 g of potassium tert-butanolate in 10 mL of DMSO.
Reaction SMILES: [H][H].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH:12][C:13](=[O:35])[C@H:14]([CH2:24][CH2:25][CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:15](CC2C=CC=CC=2)[CH3:16])=[CH:6][CH:5]=1.Cl>C(O)C.[Pd]>[OH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH:12][C:13](=[O:35])[C@H:14]([CH2:24][CH2:25][CH2:26][NH:27][C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[NH:15][CH3:16])=[CH:6][CH:5]=1
Reactant: CN(Cc1ccccc1)[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)NCCc1ccc(O)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CN[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)NCCc1ccc(O)cc1

Procedure:
Hydrogen gas was bubbled through a solution of Nα-benzyl-Nδ-Boc-Nα-methylornithine 2-(4-hydroxyphenyl)ethylamide (A) (540 mg) in ethanol (20 ml) in the presence of 1 eq. of conc. hydrochloric acid (1.30 ml) and 5% palladium-on-charcoal (50 mg). After disappearance of starting material, as determined by thin-layer chromatography, the reaction mixture is filtered through a 0.45 μm nylon pad and concentrated in vacuo.
Reaction SMILES: COC1[N:8]=CC2N(C3SC(C(OC)=O)=C(OCC4C=CC=CC=4C(F)(F)F)C=3)C=NC=2C=1.[CH3:33][O:34][C:35]1[N:40]=[CH:39][C:38]2[N:41]=[CH:42][N:43]([C:44]3[S:48][C:47]([C:49]([O:51]C)=O)=[C:46]([O:53][CH2:54][C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=4[C:61]([F:64])([F:63])[F:62])[CH:45]=3)[C:37]=2[CH:36]=1.N>CO>[CH3:33][O:34][C:35]1[N:40]=[CH:39][C:38]2[N:41]=[CH:42][N:43]([C:44]3[S:48][C:47]([C:49]([NH2:8])=[O:51])=[C:46]([O:53][CH2:54][C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=4[C:61]([F:62])([F:63])[F:64])[CH:45]=3)[C:37]=2[CH:36]=1
Reactant: COC(=O)c1sc(-n2cnc3cc(OC)ncc32)cc1OCc1ccccc1C(F)(F)F
Reactant: COC(=O)c1sc(-n2cnc3cnc(OC)cc32)cc1OCc1ccccc1C(F)(F)F
Agent: N
Solvent: CO
Product: COc1cc2c(cn1)ncn2-c1cc(OCc2ccccc2C(F)(F)F)c(C(N)=O)s1
Temperature: 130 °C
Reaction time: 5 h

Procedure:
A suspension of 140 mg of an isomeric mixture of methyl 5-(6-methoxy-3H-imidazo[4,5-c]pyridin-3-yl)-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxylate and methyl 5-(6-methoxy-1H-imidazo[4,5-c]pyridin-1-yl)-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxylate (compounds B6a and B6b) in 20 ml of a saturated solution of ammonia in methanol was stirred in a microwave vial at 130° C. for 5 h in the microwave cavity. The reaction mixture was concentrated to dryness, the residue dissolved in 4 ml acetonitrile and 3 ml acidic buffer (KH2PO4, pH=2) and the isomers were separated and purified by preparative HPLC (acidic buffer/acetonitrile, 7/3 (v/v)). The acetonitrile was removed under vacuum and the aqueous solution was treated with NH4OH until pH 8-9 was reached. The aqueous solution was extracted with dichloromethane three times and the combined organic layers were dried and concentrated to dryness under vacuum to yield the title compound.
Reaction SMILES: [C:1]([NH:7][C:8](=[O:30])[NH:9][C:10]1[N:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:29])OC(C)=C)[CH:18]=2)=[CH:12][CH:11]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.CN1CCCC1>O1CCOCC1>[C:1]([NH:7][C:8](=[O:30])[NH:9][C:10]1[N:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:29])[CH:18]=2)=[CH:12][CH:11]=1)(=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5]
Reactant: C1CCNC1
Reactant: C=C(C)OC(=O)Nc1cc(Oc2ccc(NC(=O)NC(=O)C(C)(C)C)nc2)ccn1
Agent: CN1CCCC1
Solvent: C1COCCO1
Product: CC(C)(C)C(=O)NC(=O)Nc1ccc(Oc2ccnc(NC(=O)N3CCCC3)c2)cn1
Temperature: 25 °C
Yield: 70.2 %

Procedure:
A mixture of Example C2 (0.163 g, 0.394 mmol), pyrrolidine (0.028 g, 0.394 mmol) and N-methylpyrrolidine (0.017 g, 0.197 mmol) in dioxane (3 mL) was heated at 80° C. for 45 min, cooled to RT, and concentrated to dryness. The residue was suspended in MeCN and the mixture was sonicated for a few minutes. The light beige solid was collected by filtration, washed with MeCN and dried overnight at 80° C. to provide N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)pyrrolidine-1-carboxamide (0.118 g, 67%). 1H NMR (400 MHz, DMSO-d6): δ 11.22 (s, 1H), 10.44 (s, 1H), 8.72 (s, 1H), 8.23 (d, J=2.9 Hz, 1H), 8.13-8.04 (m, 2H), 7.71 (dd, J=9.0, 2.9 Hz, 1H), 7.47 (d, J=2.4 Hz, 1H), 6.60 (dd, J=5.7, 2.4 Hz, 1H), 3.39-3.30 (m, 4H), 1.84-1.71 (m, 4H), 1.21 (s, 9H); MS (ESI) m/z: 427.2 (M+H+).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([S:33]([F:38])([F:37])([F:36])([F:35])[F:34])[CH:32]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([N:16]2[C:23]3[N:19]([N:20]=[C:21]([C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)[CH:22]=3)[CH:18]=[CH:17]2)[CH:10]=1)=[O:7])=O.[N:39]1(C(OC(C)(C)C)=O)[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCl>[CH3:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:4]=[C:3]([CH2:1][N:39]3[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]3)[CH:32]=[C:31]([S:33]([F:38])([F:36])([F:34])([F:37])[F:35])[CH:30]=2)=[CH:10][C:11]=1[N:16]1[C:23]2[N:19]([N:20]=[C:21]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[CH:22]=2)[CH:18]=[CH:17]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1ccc(NC(=O)c2cc(C=O)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cccnc3)cc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2cc(CN3CCNCC3)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cccnc3)cc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
90 mg (0.16 mmol) of the compound of Example 55A and 34 mg (0.18 mmol) of tert-butyl piperazine-1-carboxylate were dissolved in 3.2 ml of dichloromethane, 52 mg (0.25 mmol) of sodium triacetoxyborohydride were added and the mixture was stirred at RT for 3 h. 3 ml of water were then added, and the mixture was extracted with 6 ml of ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was then stirred in 2 ml of dichloromethane and 1 ml of trifluoroacetic acid at RT for 2 h. The reaction was then concentrated on a rotary evaporator and the residue was separated into its components by preparative HPLC (Method 24). The product-containing fractions were combined and concentrated under reduced pressure and the residue dried under high vacuum. This gave 11 mg (11% of theory) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH:11](C(O)=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:15])[NH:3]1.C([O-])(=[O:19])C.[K+].C([O-])(=O)C.[Pb+4].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.O[Li].O>C(O)(=O)C.C1C=CC=CC=1.O>[OH:19][CH:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:15])[NH:3][C:2]1([CH3:16])[CH3:1]
Reactant: CC1(C)NC(=O)c2ccccc2C1C(=O)O
Reactant: CC(=O)[O-]
Agent: [K+]
Agent: [Li]O
Agent: [Pb+4]
Solvent: O
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CC1(C)NC(=O)c2ccccc2C1O
Temperature: 25 °C

Procedure:
To a solution of 3,3-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline-4-carboxylic acid (5.0 g, 22.8 mmol) in acetic acid (450 mL) and benzene (160 mL) is added successively, potassium acetate (15.7 g, 160 mmol), cupric acetate (210 mg, 1.14 mmol), and lead (IV) acetate (18.2 g, 41.1 mmol). The green solution is heated to reflux for 4 h, at which time additional lead (IV) acetate (2.0 g 4.5 mmol) is added. After a total of 5 h at reflux the reaction is cooled to room temperature and quenched by the addition of ethylene glycol (ca. 5 mL). The reaction is concentrated in vacuo to near dryness. The resulting dark green oil is dissolved in ethyl acetate and stirred vigorously while cautiously treating with saturated aqueous sodium bicarbonate followed by solid NaHCO3 until the aqueous layer reached a pH greater than 8. The layers are separated and the aqueous layer is extracted 3 times with ethyl acetate. The organic layer is dried with Na2SO4 filtered and concentrated. The resulting brown oil is then dissolved in THF (200 mL). Water (40 ml) and LiOH.H2O (5.0 g, 118.6 mmol) are added. The reaction mixture is heated to 45° C. and stirred for 18 h, at which time it is cooled to room temperature. The reaction is concentrated in vacuo to ca. ¾ of its original volume, diluted with methylene chloride and saturated aqueous NaHCO3. The layers are separated and the aqueous layer is extracted 3 times with ethyl acetate. The organic layers are combined, dried with Na2SO4, filtered and concentrated in vacuo to afford a brown oil, which is pre-adsorbed on silica gel for further purification. Purification by silica gel flash chromatography (dichloromethane-methanol, 99:1 to 23:2) furnished 4-hydroxy-3,3-dimethyl-3,4-dihydro-2H-isoquinolin-1-one as an off-white foam; MS (ESI) m/z 192.1 (M+H).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[C:4]([C:7]1([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13](Cl)[CH:12]=2)[CH2:10][CH2:9][CH2:8]1)(=O)[CH3:5].Cl>C(O)=O.O>[ClH:17].[CH2:1]([NH:3][CH:4]([C:7]1([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[CH2:8][CH2:9][CH2:10]1)[CH3:5])[CH3:2]
Reactant: CCN
Reactant: CC(=O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Agent: Cl
Solvent: O=CO
Solvent: O
Product: CCNC(C)C1(c2ccc(Cl)cc2)CCC1
Temperature: 140 °C

Procedure:
A mixture of 70% aqueous ethylamine (50 ml) and water (100 ml) was gradually mixed with a mixture of 98% formic acid (50 ml) and water (100 ml) to give a neutral solution which was evaporated at 100° C./100 mm Hg until 180 ml of water had been collected. The residue was heated to 140° C. and 1-acetyl-1-(4-chlorophenyl)cyclobutane (10.4 g) prepared in a similar manner to that described in Example 1 for 1-acetyl-1-(3,4-dichlorophenyl)cyclobutane and 98% formic acid (10 ml) were added. The mixture was heated on an oil bath at a temperature of 180°-200° C. for sixteen hours. The mixture was distilled until an internal temperature of 170° C. was obtained and this temperature was maintained for two hours. Any volatile material was removed by distillation at 160° C./20 mm and the residue heated under reflux with concentrated hydrochloric acid (15 ml) and industrial methylated spirit (IMS) (15 ml) for three hours. The IMS was evaporated on a rotary evaporator and the residue washed with ether. The aqueous phase was brought to pH 12 with sodium hydroxide and extracted with ether. The ether extract was dried and on evaporation yielded a residue which was treated with aqueous hydrochloric acid to give N-ethyl-1-[1-(4-chlorophenyl)cyclobutyl]ethylamine hydrochloride (m.p. 203°-205° C.) (Formula I (R1 =Me; R2 =H; R3 =Et; R4 =H; R5 =4--Cl; R6 =H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[S:29]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]([CH2:39][CH2:40]O)[CH2:31][CH2:30]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.O>[S:29]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]([CH2:39][CH2:40][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:31][CH2:30]1
Reactant: O=Cc1ccc(O)cc1
Reactant: OCCN1CCSc2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc(OCCN2CCSc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 43.4 %

Procedure:
To a mixture of 4-hydroxy benzaldehyde (1.8 g, 14.8 mmol) and triphenyl phosphine (4.85 g, 18.5 mmol) in tetrahydrofuran (15 ml) was added 2-(2,3-dihydro-1,4-benzothiazin-4-yl)ethanol (2.39 g, 12.3 mmol) and diisopropyl azodicarboxylate (3.74 g, 18.5 mmol) in THF (20 ml) at 25° C. The reaction mixture was stirred for 12 h at 25° C. Water (100 ml) was added and the mixture was extracted with ethyl acetate (2×100 ml). The organic extracts were dried (Na2SO4) and solvent was evaporated under reduced pressure. The crude product was chromatographed over silica gel using a mixture of methanol and chloroform (5:95) as an eluent to afford the title compound (1.6 g, 44%) as an oil.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][C:8]=1[C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=O)=O.[OH:31][CH2:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:31][CH2:32][C:33]1[CH:38]=[C:37]([C:7]2[C:16]3[C:11](=[C:12]([C:17]([F:18])([F:20])[F:19])[CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][C:8]=2[C:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:28])[CH:36]=[CH:35][CH:34]=1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1OS(=O)(=O)C(F)(F)F
Reactant: OCc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(CO)c1
Reaction time: 3 h
Yield: 96 %

Procedure:
A solution of (3-benzoyl-8-(trifluoromethyl)quinolin-4-yl trifluoromethanesulfonate). (3.0 g, 6.0 mmol), 3-hydroxymethylphenylboronic acid (1.5 g, 10 mmol), K3PO4 (3.0 g) and Pd(PPh3)4 (0.30 g) in dioxane (30 ml) was heated to reflux. After 3 hr, the reaction was cooled and poured into water. The aqueous layer was extracted with EtOAc, dried, concentrated to give an oil which was purified by column chromatography (eluent 30% EtOAc/Hexane) to give the title compound as a foam (2.6 g, 96%); MS (ESI) m/z 407([M+H]+); 1H NMR (DMSO) δ 9.149 (s, 1H), 8.33 (d, 1H, J=7.1 Hz), 7.96 (d, 1H), 7.8 Hz), 7.80 (t, 1H, J=7.4 Hz), 7.62 (d, 2H, H=7.1 Hz), 7.55 (t, 1H, J=7.5 Hz), 7.40-7.28 (m, 5H), 7.18-7.14 (m, 1H), 5.23 (t, 1H, J=5.6 Hz), 4.41 (d, 1H, J=5.6 Hz).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[S:33][C:34]([CH3:37])=[CH:35][N:36]=4)[C:28](=[O:38])[N:27]([CH3:39])[CH:26]=3)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.ClCCl>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:19][OH:20])=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[S:33][C:34]([CH3:37])=[CH:35][N:36]=4)[C:28](=[O:38])[N:27]([CH3:39])[CH:26]=3)[CH:22]=[CH:23][N:24]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cnc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3C=O)cn(C)c2=O)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1cnc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)cn(C)c2=O)s1
Reaction time: 1 h
Yield: 30.5 %

Procedure:
To a solution of 120c (98 mg, 0.18 mmol) in methanol/dichloromethane (3/3 mL) was added NaBH4 (21 mg, 0.55 mmol) at room temperature. After the reaction was stirred for 1 h, LCMS indicated the reaction was complete. The mixture was quenched with water (5 mL) and concentrated under reduced pressure. The residue was extracted with dichloromethane (3×15 mL). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 120 (30 mg, 31%) as a white solid. MS-ESI: [M+H]+ 546.7. 1H NMR (500 MHz, DMSO-d6) δ 9.92 (s, 1H), 8.58 (d, J=5.5 Hz, 1H), 8.56 (d, J=2.5 Hz, 1H), 8.54 (d, J=2.0 Hz, 1H), 7.91 (d, J=2.0 Hz, 1H), 7.78 (d, J=13.0 Hz, 1H), 7.56 (d, J=2.0 Hz, 1H), 7.51 (d, J=5.0 Hz, 1H), 6.96 (d, J=1.0 Hz, 1H), 4.91 (bs, 1H), 4.42-4.41 (m, 2H), 3.60 (s, 3H), 2.28 (d, J=1.0 Hz, 3H), 1.40 (s, 9H).
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][C@@H:11]([CH3:24])[CH2:12][CH2:13][CH2:14][C:15](=[O:23])[CH2:16]P(=O)(OC)OC)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[Cl:25][C@H:26]1[C@H:30]([CH2:31][CH2:32][CH2:33][C:34]2[S:38][C:37]([C:39]([O:41][CH3:42])=[O:40])=[CH:36][CH:35]=2)[C@@H:29]([CH:43]=O)[C@H:28]([O:45][CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][O:47]2)[CH2:27]1>C1COCC1>[Si:3]([O:10][C@@H:11]([CH3:24])[CH2:12][CH2:13][CH2:14][C:15](=[O:23])/[CH:16]=[CH:43]/[C@H:29]1[C@H:28]([O:45][CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][O:47]2)[CH2:27][C@@H:26]([Cl:25])[C@@H:30]1[CH2:31][CH2:32][CH2:33][C:34]1[S:38][C:37]([C:39]([O:41][CH3:42])=[O:40])=[CH:36][CH:35]=1)([C:6]([CH3:7])([CH3:8])[CH3:9])([CH3:4])[CH3:5]
Reactant: COC(=O)c1ccc(CCC[C@@H]2[C@@H](C=O)[C@H](OC3CCCCO3)C[C@H]2Cl)s1
Reactant: COP(=O)(CC(=O)CCC[C@H](C)O[Si](C)(C)C(C)(C)C)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CCC[C@@H]2[C@@H](/C=C/C(=O)CCC[C@H](C)O[Si](C)(C)C(C)(C)C)[C@H](OC3CCCCO3)C[C@H]2Cl)s1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 94.1 %

Procedure:
To a suspension of 160.3 mg of sodium hydride (60% oil dispersion, 4.00 mmol) in 8 ml of THF at 0° C. was added a solution of dimethyl (S)-6-(tert-butyldimethylsilyl-oxy)-2-oxoheptylphosphonate 13 (1.41 g, 4.00 mmol) in 4 mL THF. The mixture was stirred at 0° C. for 30 min before a solution of aldehyde 7 (1.10 g, 2.65 mmol) in 4 ml of THF was added dropwise. The syringe containing the aldehyde was rinsed with 2 mL of THF to complete the addition and the mixture was stirred at 25° C. for 2.5 h. The reaction was worked up with addition of saturated aqueous ammonium chloride (50 mL) and the aqueous layer was extracted with ethyl acetate (2×75 mL). The ethyl acetate layers were combined and washed with brine, dried over 30 g of anhydrous sodium sulfate, filtered and concentrated in vacuo. FCC (flash column chromatography) purification (silica gel, 6:1 hex/EtOAc) provided 1.60 g (95%) of enone 14.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]1([S:14]([C:17]2[C:18]([S:28][CH3:29])=[N:19][N:20]3[C:25](Cl)=[CH:24][C:23]([Cl:27])=[N:22][C:21]=23)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:8]1([S:14]([C:17]2[C:18]([S:28][CH3:29])=[N:19][N:20]3[C:25]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:24][C:23]([Cl:27])=[N:22][C:21]=23)(=[O:16])=[O:15])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CN1CCNCC1
Reactant: CSc1nn2c(Cl)cc(Cl)nc2c1S(=O)(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CSc1nn2c(N3CCN(C)CC3)cc(Cl)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
0.1 g (1 mmol) of 1-methyl-piperazine in 3 ml of CH2Cl2 was added to a solution of 0.37 g (1 mmol) of 3-benzenesulphonyl-5,7-dichloro-2-methylsulphanyl-pyrazolo[1,5-a]-pyrimidine in 20 ml of CH2Cl2 and stirred at RT for 1 hr. The mixture was poured on to ice-water, adjusted to pH8 with NaHCO3 solution and extracted three times with 30 ml of CH2Cl2. The combined organic phases were dried (MgSO4), filtered and evaporated. Subsequent chromatography (silica gel, CH2Cl2/MeOH 4:1) yielded 0.38 g (86%) of 3-benzenesulphonyl-5-chloro-7-(4-methyl-piperazin-1-yl)-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine as colorless crystals, m.p.>230°.