Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)OC1.[NH2:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][N:17]=[CH:18]2.C(O)(=O)C>CO>[CH:18]1[C:19]2[C:14](=[C:13]([NH:12][CH:4]3[CH2:5][CH2:6][C:7](=[O:10])[CH2:8][CH2:9]3)[CH:22]=[CH:21][CH:20]=2)[CH:15]=[CH:16][N:17]=1
Reactant: Nc1cccc2cnccc12
Reactant: O=C1CCC2(CC1)OCCO2
Solvent: CC(=O)O
Solvent: CO
Product: O=C1CCC(Nc2cccc3cnccc23)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.9 %

Procedure:
1,4-Cyclohexanedione monoethylene ketal (6.2 g), 5-amino-isoquinoline (4.3 g), and acetic acid (0.5 ml) were dissolved in methanol (50 ml), and a borane-pyridine complex (4.0 ml) was added dropwise to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr, was then cooled to room temperature, and was concentrated. The residue was dissolved in acetic acid-water (1:1, 50 ml), and the mixture was then stirred at 80° C. for 3 hr. The reaction mixture was concentrated to remove a major part of acetic acid. A saturated aqueous sodium hydrogencarbonate solution was then added to the residue, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel [chloroform/methanol] to give the title compound (5.8 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[CH3:10])[NH2:6].C([O:13][C:14](=O)[CH:15]([CH3:19])[C:16]([CH3:18])=O)C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:7]([C:14]([OH:13])=[C:15]([CH3:19])[C:16]([CH3:18])=[N:6]2)=[CH:8][C:9]=1[CH3:10]
Reactant: COc1cc(N)ccc1C
Reactant: CCOC(=O)C(C)C(C)=O
Product: COc1cc2nc(C)c(C)c(O)c2cc1C

Procedure:
Prepared according to procedure R using 3-methoxy-4-methylaniline (617.8 mg, 4.5 mmol), ethyl-2-methyl-acetoacetate (1.3 mL, 9.1 mmol), and PPA (1.87 g, 18.7 mmol) to give 7-methoxy-2,3,6-trimethylquinolin-4-ol.
Reaction SMILES: Cl.[CH3:2][N:3]([CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[C:4]([C:6]1[CH:14]=[CH:13][C:9]2=[N:10][O:11][N:12]=[C:8]2[CH:7]=1)=[O:5].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)(Cl)Cl>[CH3:2][N:3]([CH:15]1[CH2:20][CH2:19][N:18]([S:29]([CH3:28])(=[O:31])=[O:30])[CH2:17][CH2:16]1)[C:4]([C:6]1[CH:14]=[CH:13][C:9]2=[N:10][O:11][N:12]=[C:8]2[CH:7]=1)=[O:5]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C(=O)c1ccc2nonc2c1)C1CCNCC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(C(=O)c1ccc2nonc2c1)C1CCN(S(C)(=O)=O)CC1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
N-Methyl-N-piperidin-4-yl-[2,1,3]-benzoxadiazole-5-carboxamide hydrochloride (0.38 g, 1.3 mmol) was suspended in chloroform (70 ml) and triethylamine (2 ml) was added. A solution of methane sulfonyl chloride (0.14 g, 1.26 mmol) in chloroform (10 ml) was added and the mixture was stirred at 20° C. for 2 h. The mixture was washed with water (50 ml) and H2SO4 (→pH 2) and NaHCO3 solution (50 ml) and the aqueous re-extracted with dichloromethane (2×50 ml). The combined organics were dried (MgSO4), concentrated under vacuum, and the crude product was purified on a silica gel column eluting with dichloromethane/THF (85:15) to give a white crystalline product, after crystallization from MTBE/hexane (204 mg). Mp=177-179° C., 1H NMR (300 MHz, CDCl3) δ 7.93 (d, J=9.3 Hz, 1H); 7.85 (s, 1H); 7.42 (d, J=9.3 Hz, 1H); 4.75-4.46 and 4.10-3.90 and 3.10-2.40 (m, 5H); 2.92 (s, 3H), 2.83 (s, 3H) and 2.10-1.70 ppm (m, 4H).
Reaction SMILES: [C:1]12([CH2:11][CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH2:20][CH2:21][NH:22][CH2:23][C@@H:24]([C:33]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=5)=[C:39]5[C:34]=4[CH:35]=[CH:36][C:37](=[O:51])[NH:38]5)[O:25][Si](C(C)(C)C)(C)C)[CH:17]=[CH:18][CH:19]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:1]12([CH2:11][CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH2:20][CH2:21][NH:22][CH2:23][C@@H:24]([C:33]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=5)=[C:39]5[C:34]=4[CH:35]=[CH:36][C:37](=[O:51])[NH:38]5)[OH:25])[CH:17]=[CH:18][CH:19]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CNCCc1cccc(OCCC23CC4CC(CC(C4)C2)C3)c1)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: O=c1ccc2c([C@@H](O)CNCCc3cccc(OCCC45CC6CC(CC(C6)C4)C5)c3)ccc(OCc3ccccc3)c2[nH]1
Temperature: 45 °C
Reaction time: 3.5 h
Yield: 93 %

Procedure:
To a solution of Intermediate 32 (0.48 g, 0.68 mmol) in tetrahydrofuran (12 mL) was added tetrabutylammonium fluoride trihydrate (0.284 g, 1.09 mmol). The reaction mixture was stirred at 45° C. for 3.5 hours. The solvent was removed under reduced pressure and the crude was partitioned between ethyl acetate and water. The organic layer was washed several times with water and the solvent was removed under reduced pressure to give the title compound as a yellow solid (0.375 g, 88%). MS (M+): 593.
Reaction SMILES: C([O:3][C:4](=[O:22])/[C:5](/[CH3:21])=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:8]=1)C.O[Li].O>CO.O>[CH:16]1([O:15][C:9]2[CH:8]=[C:7](/[CH:6]=[C:5](\[CH3:21])/[C:4]([OH:22])=[O:3])[CH:12]=[CH:11][C:10]=2[O:13][CH3:14])[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: CCOC(=O)/C(C)=C/c1ccc(OC)c(OC2CCCC2)c1
Agent: [Li]O
Solvent: O
Solvent: CO
Product: COc1ccc(/C=C(\C)C(=O)O)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66 %

Procedure:
A suspension of (E)-3-(3-cyclopentoxy-4-methoxyphenyl)-2-methyl-acrylic acid ethyl ester (30 g, 98.6 mmol) and LiOH.H2O (lithium hydroxide hydrate) (5.0 g, 119.2 mmol, 1.2 equiv.) in methanol-water (4:1, 100 mL) was stirred at room temperature for 24 hours. Methanol was removed under reduced pressure and the resulting residue was dissolved in water (100 mL), washed with three 100 mL portions of ethyl acetate, neutralized with 1.0 N HCl (hydrochloric acid) (100 mL), and extracted with two 150 mL portions of ethyl acetate. The extract was washed with brine, dried over anhydrous Na2SO4 (sodium sulfate), and concentrated under reduced pressure to afford the desired product as a light yellow powder (18.2 9, 66% yield). 1H NMR (300 MHz, CDCl3) δ (ppm): 12.4 (br. s, 1H, COOH), 7.56 (s, 1H, olefinic), 7.04 (m, 3H, aromatic), 4.81 (m, 1H), 3.78 (s, 3H, OCH3), 2.06 (s, 3H, CH3), 1.91-1.57 (m, 8H, cyclopentyl).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=[O:28])[CH:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:12][CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.[C:29]([O:33]C)(=[O:32])[CH:30]=[CH2:31]>CO.C(COC)OC>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([CH:14]=[CH:13][CH2:12][C:11]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:10](=[O:28])[CH:9]=[CH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:31][CH2:30][C:29]([OH:33])=[O:32])=[CH:20][CH:19]=1
Reactant: C=CC(=O)OC
Reactant: O=C(C=Cc1ccc(Cl)cc1)C(CC=Cc1ccc(Cl)cc1)c1ccccc1
Solvent: COCCOC
Solvent: CO
Product: O=C(O)CCC(CC=Cc1ccc(Cl)cc1)(C(=O)C=Cc1ccc(Cl)cc1)c1ccccc1
Reaction time: 24 h

Procedure:
Triton B (1 ml., 40% in MeOH) is added to a stirred solution of 1,7-bis-(p-chlorophenyl)-4-phenyl-1,6-heptadien-3-one (16.10 g., 0.039 mole) in glyme (150 ml.), followed by addition of methyl acrylate (3.87 g., 0.045 mole) in glyme (25 ml.). After stirring for 24 hours, the solvent is removed in vacuo and water (600 ml.) and dilute hydrochloric acid (25 ml.) are added to the residue. The organic material is extracted into ether and these extracts are washed with water, saturated brine and dried (Na2SO4). After removal of the solvent, the residue is heated on a steam bath with a solution of 20% sodium hydroxide (20 ml.) in methanol (300 ml.) for 20 hours. The methanol is removed in vacuo and the residue is dissolved in water (1200 ml.). Extraction with ether removes unreacted ketone. Ether is expelled from the aqueous phase by warming. The solution is cooled in an ice bath, acidified with dilute hydrochloric acid (25 ml.) and the solid (yellowish) that precipitates is filtered and air-dried; yield 16.5 g., m.p. 75°-173°C. Several recrystallizations from n-butyl chloride gives material with m.p. 178.5°-180°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:10]([O:20][C@H:21]3[CH2:30][O:29][C@H:28]4[C@@H:23]([O:24][CH:25]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[O:26][CH2:27]4)[CH2:22]3)=[N:9][C:5]2=[N:6][C:7]=1I.[B:37]1([C:46]2[CH:51]=[CH:50][C:49](B3OC(C)(C)C(C)(C)O3)=[CH:48][CH:47]=2)[O:41][C:40]([CH3:43])([CH3:42])[C:39]([CH3:45])([CH3:44])[O:38]1>C1COCC1.CCOC(C)=O.C(=O)([O-])[O-].[Ag+2].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>[Cl:1][C:2]1[CH:3]=[C:4]2[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:10]([O:20][C@H:21]3[CH2:30][O:29][C@H:28]4[C@@H:23]([O:24][CH:25]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[O:26][CH2:27]4)[CH2:22]3)=[N:9][C:5]2=[N:6][C:7]=1[C:49]1[CH:50]=[CH:51][C:46]([B:37]2[O:41][C:40]([CH3:43])([CH3:42])[C:39]([CH3:45])([CH3:44])[O:38]2)=[CH:47][CH:48]=1
Reactant: CC1(C)OB(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)OC1(C)C
Reactant: C[Si](C)(C)CCOCn1c(O[C@H]2CO[C@@H]3COC(c4ccccc4)O[C@H]3C2)nc2nc(I)c(Cl)cc21
Agent: [Ag+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(-c3nc4nc(O[C@H]5CO[C@@H]6COC(c7ccccc7)O[C@H]6C5)n(COCC[Si](C)(C)C)c4cc3Cl)cc2)OC1(C)C
Temperature: -78 °C
Reaction time: 21 h

Procedure:
To a stirred solution of 6-chloro-5-iodo-2-(((4aR,7R,8aS)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine (4.29 g, 9.31 mmol) under nitrogen in anhydrous THF (30 mL) was added silver carbonate (3.08 g, 11.18 mmol), Pd(PPh3)4 (538 mg, 0.466 mmol), and 1,4-benzenediboronic acid bis(pinacol) ester (9.22 g, 27.9 mmol). The mixture was cooled to −78° C., a hard vacuum was pulled, and nitrogen was introduced (3×). The mixture was allowed to warm to room temperature, then heated to reflux. After 21 hours, the mixture was cooled to room temperature and diluted with EtOAc (80 mL). The mixture was filtered through celite with EtOAc rinse until filtrate was colorless. The filtrate was concentrated under reduced pressure. The resultant residue was chromatographed using a Biotage™ 150 g (100 g+50 g in series) silica gel cartridge eluted with 0-30% EtOAc in 1:1 Hexane/DCM over 15 column volumes. The product fractions were combined and concentrated under reduced pressure, then the resultant oil was dissolved in MeCN and water, frozen at −78° C., and lyophilized to dryness to provide the title compound as a yellow solid. LC-MS: calculated for C37H47BClN3O7Si 719.30, observed m/e: 720.43 (M+H)+ (Rt 3.25/4 min).
Reaction SMILES: [OH:1][C:2]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[C:6](=[O:12])[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[CH:3]=1.N1CCCCC1.[CH2:23]([CH:25]1[O:27][CH2:26]1)[Cl:24]>>[Cl:24][CH2:23][CH:25]([OH:27])[CH2:26][O:1][C:2]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[C:6](=[O:12])[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[CH:3]=1
Reactant: ClCC1CO1
Reactant: O=c1c2ccccc2cc(O)c2sccc12
Solvent: C1CCNCC1
Product: O=c1c2ccccc2cc(OCC(O)CCl)c2sccc12

Procedure:
A mixture of 15.0 g of 10-hydroxy-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-one, 150 ml of epichlorohydrin and 0.7 ml of piperidine is heated to the boil for 30 minutes. After concentration by evaporation at reduced pressure, the mixture is dried at 40°, whereupon a mixture of 10-(2,3-epoxypropoxy)-4H-benzo[4,5]-cyclohepta[1,2-b]thiophen-4-one and 10-(3-chloro-2-hydroxypropoxy)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-one is obtained, which is used further as such.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([NH:12][C:13]1[CH:21]=[CH:20][C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=1)=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[BrH:22].Br.CCN(C(C)C)C(C)C.[NH:33]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][C:35](O)=[O:36]>CN(C=O)C>[NH:33]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][C:35]([NH:1][C@H:2]([C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([N+:17]([O-:19])=[O:18])=[CH:20][CH:21]=1)=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9])=[O:36].[BrH:22]
Reactant: N=C(N)NCCC[C@H](N)C(=O)Nc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)N[C@@H](CCCNC(=N)N)C(=O)Nc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 75 %

Procedure:
1 g (2.19 mmol) of H-L-Arg-pNA.2HBr is dissolved in 10 ml of DMF, and 0.854 ml (6.57 mmol) of DIEA is then added. In another vessel, a solution of 384 mg (2.19 mmol) of Boc-Gly-OH in 5 ml of DMF is neutralized with 0.285 ml of DIEA. The two solutions obtained in this way are mixed and 970 mg of Bop are added to the resulting medium, the latter being kept at RT; also, the pH is kept at a value of between 7 and 8 by the addition of small portions of DIEA throughout the reaction. After one hour, the reaction has completely finished and the reaction medium is evaporated to dryness under vacuum; the evaporation residue is taken up with an AcOEt/MeOH mixture and extracted with a 0.5M aqueous solution of NaHCO3. The organic phase is dried over sodium sulfate, concentrated under vacuum and then precipitated in ether (MeOMe or EtOEt) to give 874 mg (yield: 75%) of the expected product.
Reaction SMILES: [N+:1]([C:4]1[C:5](=[O:14])[NH:6][C:7](=[O:13])[N:8]([CH2:10][O:11][CH3:12])[CH:9]=1)([O-:3])=[O:2].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[N+:1]([C:4]1[C:5](=[O:14])[N:6]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:7](=[O:13])[N:8]([CH2:10][O:11][CH3:12])[CH:9]=1)([O-:3])=[O:2]
Reactant: COCn1cc([N+](=O)[O-])c(=O)[nH]c1=O
Reactant: CCOC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)Cn1c(=O)c([N+](=O)[O-])cn(COC)c1=O
Temperature: 25 °C

Procedure:
The compound of example 41 (10.0 g, 50 mmole) is dissolved in tetrabutylammonium flouride (120 mL of a 1.0M solution in tetrahydrofuran, 0.124 mole). Ethyl bromoacetate (8.3 mL, 75 mmole) is added. The reaction is stirred at room temperature. The reaction mixture is concentrated, then partitioned between dichloromethane and water. The aqueous layer is extracted with dichloromethane. The combined organic extracts are washed with water, brine, and dried over anhydrous magnesium sulfate. The solvent is removed under vacuum to afford the title compound.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:16]1[CH:21]=[C:20]([Cl:22])[N:19]=[C:18]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:17]=1>CN1C(=O)CCC1>[Cl:22][C:20]1[N:19]=[C:18]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:17]=[C:16]([N:2]([CH3:1])[CH:3]2[CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)[CH:21]=1
Reactant: Clc1cc(Cl)nc(N2CCOCC2)n1
Reactant: CNC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CN(c1cc(Cl)nc(N2CCOCC2)n1)C1CCOCC1
Temperature: 95 °C
Reaction time: 1.5 h
Yield: 22.6 %

Procedure:
The crude N-methyltetrahydro-2H-pyran-4-amine (104 mg, 0.9 mmol) was dissolved in NMP (0.8 mL). To the solution, Cs2CO3 (366 mg, 1.13 mmol) and 4-(4,6-dichloropyrimidin-2-yl)morpholine (prepared as in Method 22) (80 mg, 0.34 mmol) were added at room temperature. The reaction mixture was heated to 95° C. After 90 minutes, the reaction mixture was cooled to room temperature, filtered and purified by reverse phase preparative HPLC yielding 24 mg (23%) of pure 6-chloro-N-methyl-2-morpholino-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine. LC/MS (m/z): 313.2 (MH+), Rt 2.61 minutes.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:31])OC3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[OH:32][C:33]1[CH:34]=[C:35]([S:39]([NH2:42])(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=1>>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:42][S:39]([C:35]3[CH:36]=[CH:37][CH:38]=[C:33]([OH:32])[CH:34]=3)(=[O:40])=[O:41])=[O:31])=[CH:16][CH:15]=2)[N:3]=1
Reactant: NS(=O)(=O)c1cccc(O)c1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3cccc(O)c3)cc2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 42 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 3-hydroxybenzenesulfonamide [Tetrahedron Lett., 1993, 34, 2043]: 1H-NMR (CDCl3) δ 7.49-7.20 (11H, m), 7.05-7.00 (1H, m), 6.56 (1H, br.s), 6.17 (1H, br.s), 3.59-3.52 (2H, m), 2.92 (2H, t, J=6.1 Hz), 2.36 (3H, s), 2.30 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]3[C:12](=[O:16])[NH:13][CH:14]=[N:15][C:6]3=[C:5]([C:17]([F:20])([F:19])[F:18])[C:4]=2[CH:3]=1.[Br:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][Mg]Br)=[CH:24][CH:23]=1>C1COCC1>[Br:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][C:5]2([C:17]([F:18])([F:20])[F:19])[C:4]3[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:9]=3[NH:8][C:7]3[C:12](=[O:16])[NH:13][CH:14]=[N:15][C:6]2=3)=[CH:24][CH:23]=1
Reactant: Br[Mg]Cc1ccc(Br)cc1
Reactant: O=c1[nH]cnc2c(C(F)(F)F)c3cc(Cl)ccc3nc12
Solvent: C1CCOC1
Product: O=c1[nH]cnc2c1Nc1ccc(Cl)cc1C2(Cc1ccc(Br)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 42.7 %

Procedure:
To a stirred suspension of 7 (200 mg, 0.667 mmol) in THF (4 mL) at −40° C. was added 4-bromobenzyl magnesium bromide (0.25 M in Et2O, 13.3 mL, 3.34 mmol). The reaction was warmed slowly to 0° C. over 2 h. After stirring an additional 2 h, the reaction was quenched with H2O (20 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine, dried (MgSO4) and concentrated. Chromatography (SiO2, 40 to 50% EtOAc-hexane) afforded the desired product as a viscous orange oil (134 mg, 43%). ESI-MS m/z 470.2 (M++H, C19H12BrClF3N3O).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]=[C:12]([CH3:14])[O:11][N:10]=2)=[CH:5][C:4]=1[N+:15]([O-:17])=[O:16].[C:18]1(=[O:28])[NH:22][C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.[K].O>CN(C=O)C>[CH3:14][C:12]1[O:11][N:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:22]3[C:18](=[O:28])[C:19]4[C:20](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:21]3=[O:23])=[C:4]([N+:15]([O-:17])=[O:16])[CH:5]=2)[N:13]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1nc(-c2ccc(CBr)c([N+](=O)[O-])c2)no1
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(CN3C(=O)c4ccccc4C3=O)c([N+](=O)[O-])c2)no1
Temperature: 25 °C
Yield: 89.6 %

Procedure:
A solution of compound 1c (5.64 g, 19 mmol) and potassium pthalimide (3.9 g, 20.9 mmol) in DMF (42 mL) was heated to 40° C. for 4 h. The reaction mixture was cooled to rt and poured into water (200 mL). The solid was filtered, washed with water (3×), and dried in vacuo to give compound 1d as a white solid (6.2 g, 90%). ESI-MS m/e 365.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:25]=[C:24]([O:26][C@H:27]3[C@H:31]4[O:32][CH2:33][C@@H:34]([OH:35])[C@H:30]4[O:29][CH2:28]3)[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=1.[N:44]1([S:48]([CH3:58])(=[O:57])=[N:49][C:50]2[CH:55]=[CH:54][C:53](Br)=[CH:52][CH:51]=2)[CH2:47][CH2:46][CH2:45]1>>[N:44]1([S:48](=[N:49][C:50]2[CH:55]=[CH:54][C:53]([C:11]3[CH:12]=[CH:13][C:8]([C:7]4[N:6]=[C:5]5[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:42])([CH3:41])[CH3:43])[C:24]([O:26][C@H:27]6[C@H:31]7[O:32][CH2:33][C@@H:34]([OH:35])[C@H:30]7[O:29][CH2:28]6)=[N:25][C:4]5=[CH:3][C:2]=4[Cl:1])=[CH:9][CH:10]=3)=[CH:52][CH:51]=2)([CH3:58])=[O:57])[CH2:45][CH2:46][CH2:47]1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)OC1(C)C
Reactant: CS(=O)(=Nc1ccc(Br)cc1)N1CCC1
Product: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2cc(Cl)c(-c3ccc(-c4ccc(N=S(C)(=O)N5CCC5)cc4)cc3)nc21

Procedure:
The title compound is prepared from (3R,3aR,6R,6aR)-6-(6-chloro-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridin-2-yloxy)hexahydrofuro[3,2-b]furan-3-ol and N-[azetidin-1-yl(methyl)oxo-λ6-sulfanylidene]-4-bromoaniline following a procedure analogous to that described for Intermediate 3 (Step 3). LC (method 1): tR=1.12 min; Mass spectrum (ESI+): m/z=712 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[CH2:10][C:11]([O:13][CH3:14])=[O:12].O.O.O.C([O-])(=O)C.[Na+].CO>O>[CH3:14][O:13][C:11](=[O:12])[CH2:10][NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([Br:1])[CH:3]=1
Reactant: Nc1cccc(Br)c1
Reactant: COC(=O)CCl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)CNc1cccc(Br)c1

Procedure:
A mixture of 3-bromoaniline (88.6 g), methyl chloroacetate (44 ml), sodium acetate trihydrate (114 g) and methanol (70 ml) was heated under reflux for 18 h. The mixture was poured into water (500 ml) and extracted with dichloromethane (3×250 ml). The combined, dried organic extracts were evaporated and the residue was treated with 10% concentrated sulphuric acid in methanol (250 ml). After 3 h the solution was poured carefully into 8% sodium bicarbonate (1200 ml). The resulting solid was filtered off, dissolved in dichloromethane (1000 ml), and this solution was dried and evaporated to give a solid (94 g). A portion of this solid (1 g) was purified by FCC eluting with System A (1:1) to give a semi-solid which was recrystallised from System A to give the title compound, m.p. 66°-68°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][OH:9].[H][H]>[Ru]>[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][OH:9]
Reactant: [H][H]
Reactant: OCCc1ccccn1
Agent: [Ru]
Product: OCCC1CCCCN1
Temperature: 10 °C

Procedure:
Low pressure hydrogenations were carried out by charging solvent, 2-pyridineethanol, and different quantities of various ruthenium supported catalysts into a pressure vessel capable of agitation, agitating the resulting mixture and pressurizing the vessel and its contents to 500 psi with hydrogen. Under constant hydrogen pressure and continued agitation, the reaction mixture was either heated to a constant reaction temperature or heated to an initial reaction temperature with incremental increases of 10° C. to a final reaction temperature. Reactions were allowed to continue until hydrogen uptake ceased. The pressure vessel and its contents were cooled, vented and the catalyst removed with vacuum filtration. Upon distillation of the filtrate, 2-piperidineethanol was obtained and analyzed on a gc column (6′ CW 20M 160° C.) to provide product yield and composition of the distillate. The results are provided in Table II.