Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.[CH3:21][N:22]1[C:26]2[C:27]([CH3:42])=[CH:28][C:29]([C:31]([C:33]3[CH:34]=[C:35]([CH:38]=[C:39](F)[CH:40]=3)[C:36]#[N:37])=[O:32])=[CH:30][C:25]=2[O:24][C:23]1=[O:43]>CN(C=O)C>[CH3:21][N:22]1[C:26]2[C:27]([CH3:42])=[CH:28][C:29]([C:31]([C:33]3[CH:34]=[C:35]([CH:38]=[C:39]([N:17]4[CH2:18][CH2:19][CH:14]([N:10]5[CH2:9][CH2:8][C:7]6[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=6[NH:12][C:11]5=[O:13])[CH2:15][CH2:16]4)[CH:40]=3)[C:36]#[N:37])=[O:32])=[CH:30][C:25]=2[O:24][C:23]1=[O:43]
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cc1cc(C(=O)c2cc(F)cc(C#N)c2)cc2oc(=O)n(C)c12
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C#N)cc(C(=O)c4cc(C)c5c(c4)oc(=O)n5C)c3)CC1)C(=O)N2
Temperature: 300 °C

Procedure:
0.22 g (0.80 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one and 0.12 g (0.40 mmol) 3-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-5-fluoro-benzonitrile were combined and heated to 300° C. for approx. 10 min. Then the mixture was dissolved in DMF and purified by preparative HPLC-MS. The fractions containing the product were combined and the organic solvent was evaporated down. The residue was neutralised with 1N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried i. vac.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[N:3]=1.[NH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>>[Cl:9][C:4]1[N:5]=[C:6]([Cl:8])[N:7]=[C:2]([NH:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:3]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: NCCN1CCOCC1
Product: Clc1nc(Cl)nc(NCCN2CCOCC2)n1

Procedure:
Following the general procedure A, 2,4,6-trichloro-1,3,5-triazine was coupled with N-(2-aminoethyl)morpholine with reaction time of 2 h. Purification by column chromatography gave the title compound.
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]([O:15][C:16]1[C:23]([Br:24])=[CH:22][C:19]([CH:20]=[O:21])=[C:18]([CH3:25])[CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:26](O)[CH2:27][OH:28].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)(=O)C>[CH2:8]([O:15][C:16]1[C:23]([Br:24])=[CH:22][C:19]([CH:20]2[O:28][CH2:27][CH2:26][O:21]2)=[C:18]([CH3:25])[CH:17]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: OCCO
Reactant: Cc1cc(OCc2ccccc2)c(Br)cc1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(OCc2ccccc2)c(Br)cc1C1OCCO1
Yield: 71 %

Procedure:
To a suspension of 4-(benzyloxy)-5-bromo-2-methylbenzoic acid (16.6 g, 51.7 mmol) in chloroform (80 mL) were added oxalyl chloride (5 mL, 56.9 mmol) and N,N-dimethylformamide (6 drops), and the mixture was stirred for an hour at room temperature. And then the reaction solution was concentrated to obtain 4-(benzyloxy)-5-bromo-2-methylbenzoyl chloride. Then to a chloroform suspension (60 mL) of N,O-dimethylhydroxylamine hydrochloride (5.55 g, 56.9 mmol) and triethylamine (15 mL, 103 mmol) cooled in ice was added dropwise a chloroform solution (60 mL) of 4-(benzyloxy)-5-bromo-2-methylbenzoyl chloride, and the mixture was stirred for an hour at room temperature. To the reaction solution cooled in ice were added water and chloroform to separate an organic layer. The organic layer was washed with a saturated sodium bicarbonate aqueous solution and brine, and dried with anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was evaporated under reduced pressure to obtain 4-(benzyloxy)-5-bromo-N-methoxy-N-methylbenzamide. To a tetrahydrofuran solution (150 mL) of the 4-(benzyloxy)-5-bromo-N-methoxy-N-methylbenzamide was added at −10° C. lithium aluminum hydride (1.96 g, 51.7 mmol), and the mixture was stirred for an hour at the same temperature. To the reaction solution were added 1 M hydrochloric acid, and then ethyl acetate to separate an organic layer. The organic layer was washed with 1 M hydrochloric acid, a saturated sodium bicarbonate aqueous solution and brine, and dried with anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was evaporated under reduced pressure to obtain 4-(benzyloxy)-5-bromo-2-methylbenzaldehyde. To a toluene solution (120 mL) of the 4-(benzyloxy)-5-bromo-2-methylbenzaldehyde were added ethylene glycol (30 mL, 517 mmol) and p-toluenesulfonic acid monohydrate (0.50 g, 2.58 mmol), and heated to reflux for 1.5 hours with a Dean-Stark apparatus. To the reaction solution was added ethyl acetate to separate an organic layer. The organic layer was washed with water, a saturated sodium bicarbonate aqueous solution and brine, and dried with anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was evaporated under reduced pressure. Thus obtained residue was purified with silica gel column chromatography (hexane:ethyl acetate=5:1). In addition, the residue was further purified with NH type silica gel column chromatography (chloroform) to obtain the title compound (12.8 g, 71%, 3 steps) as a colorless powder.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].[H-].[Na+].Cl[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][N:10]=1.Cl>CCCCCC.CN(C=O)C>[OH:4][CH2:3][CH2:2][CH2:1][O:5][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][N:10]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: OCCCO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: OCCCOc1ccc(C(F)(F)F)cn1
Reaction time: 1 h
Yield: 43.5 %

Procedure:
A mixture of 12.6 g of 1,3-propanediol and 100 ml of N,N-dimethylformamide was stirred under a nitrogen stream, to which 3.30 g of an oily mixture containing 60% sodium hydride was added in small portions at room temperature over 30 minutes. After further stirring continued at room temperature for 1 hour, 20 ml of a DMF solution of 10.0 g of 2-chloro-5-trifluoromethylpyridine was added dropwise over 40 minutes. After further stirring continued under a nitrogen stream at room temperature overnight, 100 ml of about 2N diluted hydrochloric acid was added over 15 minutes to stop the reaction. The reaction mixture was extracted twice with toluene at a total volume of 500 ml. The combined toluene layer was successively washed with diluted hydrochloric acid and aqueous sodium bicarbonate solution, dried with magnesium sulfate, and concentrated to obtain an oily product. The oily product was dissolved in 300 ml of hexane by heating, followed by recrystallization, which afforded 5.3 g of 2-(3-hydroxypropyloxy)-5-trifluoromethylpyridine as almost pure crystals (44% yield), m.p. 46.6° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2([C:23]3[CH:31]=[C:30]([O:32][CH2:33][C:34]4[CH:43]=[CH:42][C:41]5[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=5)[N:35]=4)[CH:29]=[CH:28][C:24]=3[C:25](O)=[O:26])[CH2:21][CH:20]3[CH2:22][CH:17]2[CH2:18][CH2:19]3)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[NH2:44][CH2:45][C:46]1[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[C:10]1([C:16]2([C:23]3[CH:31]=[C:30]([O:32][CH2:33][C:34]4[CH:43]=[CH:42][C:41]5[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=5)[N:35]=4)[CH:29]=[CH:28][C:24]=3[C:25]([NH:44][CH2:45][C:46]3[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=3)=[O:26])[CH2:21][CH:19]3[CH2:18][CH:17]2[CH2:22][CH2:20]3)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)c1ccc(OCc2ccc3ccccc3n2)cc1C1(c2ccccc2)CC2CCC1C2
Reactant: NCc1cccnc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCc1cccnc1)c1ccc(OCc2ccc3ccccc3n2)cc1C1(c2ccccc2)CC2CCC1C2

Procedure:
DIPEA (3.0 equiv.) is added to a stirred solution of 2c (1.0 equiv.), 3-(aminomethyl)pyridine (1.0 equiv.) and HATU (1.5 equiv.) in DMF at ambient temperature. After completion of reaction, the reaction mixture is poured into water and extracted three times with EtOAc. The combined organic extracts are washed with water, brine, dried (Na2SO4) and concentrated in vacuo. The crude residue can be purified according to the method described in Step E.
Reaction SMILES: N1(O[C:11]([CH:13]=[CH:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)=[O:12])C2C=CC=CC=2N=N1.CCN(CC)CC.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH:38]=[C:39]([O:43][CH3:44])[C:40]=1[O:41][CH3:42])[NH2:37]>C(Cl)Cl>[CH3:44][O:43][C:39]1[CH:38]=[C:36]([NH:37][C:11]([CH:13]=[CH:14][C:15]2[CH:16]=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:23][CH:24]=2)=[O:12])[CH:35]=[C:34]([O:33][CH3:32])[C:40]=1[O:41][CH3:42]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: COC(=O)c1ccc(C=CC(=O)On2nnc3ccccc32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C=CC(=O)Nc2cc(OC)c(OC)c(OC)c2)cc1
Temperature: 60 °C
Reaction time: 20 h
Yield: 75 %

Procedure:
To a stirred suspension at room temperature of VIII (150 mg, 0.46 mmol) in anhydrous CH2Cl2 (10 ml) under nitrogen were added Et3N (194 μl, 1.39 mmol) and 3,4,5-trimethoxyaniline (94 mg, 0.51 mmol) or ArNH2(1.1–1.2 equiv.), respectively. The reaction mixture was heated to 60° C. After 20 h, the reaction mixture was concentrated, diluted with AcOEt, and successively washed with a saturated aqueous solution of NH4Cl, H2O and brine, dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (AcOEt/CH2Cl2:15/85→20/80) to give the title product IXa (130 mg, 0.35 mmol, 75% yield) as a yellow solid. 1H NMR (300 MHz, acetone-d6) δ(ppm): 9.42 (bs, 1H), AB system (δA=8.09, δB=7.78, J=8.1 Hz, 4H), 7.75 (d, J=15.6 Hz, 1H), 7.21 (s, 2H), 7.00 (d, J=15.8 Hz, 1H), 3.94 (s, 3H), 3.85 (s, 6H), 3.73 (s, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][CH2:12][CH2:11][CH2:10]2)[C:2]1=[O:14].C([O-])(=O)C.[Na+].[Br:20]Br.C(=O)([O-])O.[Na+]>C(O)(=O)C>[Br:20][CH:13]1[C:3]2([C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:14])[CH2:10][CH2:11][CH2:12]1
Reactant: BrBr
Reactant: O=C1Nc2ccccc2C12CCCC2
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1Nc2ccccc2C12CCCC2Br
Yield: 105 %

Procedure:
A solution of spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one (0.27 g, 1.4 mmol) and sodium acetate (0.12 g, 1.46 mmol) in acetic acid (10 cm3) was treated with bromine (0.24 g, 1.51 mmol) in acetic acid (2 cm3). After 30 min. the mixture was poured into sat. sodium hydrogen carbonate solution and extracted with EtOAc (×2), the combined organic layers were washed with water, sat. sodium hydrogen carbonate solution, water, dried (MgSO4), and evaporated to give the title compound (0.37 g, 1.47 mmol, 96%) as an off-white solid which was used without further purification: 1H NMR (CDCl3) δ 1.8-2.27 (m, 8H), 6.79 (d, J=8 Hz, 1H), 7.30-7.39 (m, 2H), 8.63 (br s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@@H:13]([OH:14])[CH2:12][CH2:11][C@H:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C@H:9]2[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:4][CH:3]=1.[F:25][C:26]([F:47])([F:46])[C:27]1[CH:28]=[C:29]([C@@H:37](OC(=N)C(Cl)(Cl)Cl)[CH3:38])[CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1.[H+].[B-](F)(F)(F)F>CCOCC>[F:25][C:26]([F:46])([F:47])[C:27]1[CH:28]=[C:29]([C@H:37]([O:14][C@H:13]2[CH2:12][CH2:11][C@H:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C@@H:9]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C@@H:8]2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH3:38])[CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:32]=1
Reactant: CCOC(=O)[C@H]1[C@H](c2ccc(F)cc2)[C@@H](O)CC[C@@H]1C(=O)OCC
Reactant: C[C@H](OC(=N)C(Cl)(Cl)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CCOCC
Product: CCOC(=O)[C@H]1[C@H](c2ccc(F)cc2)[C@@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC[C@@H]1C(=O)OCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
To a solution of 9.09 g (26.9 mmol) of the first eluting isomer diethyl(1S,2S,3R,4S)-3-(4-fluorophenyl)-4-hydroxycyclohexane-1,2-dicarboxylate (step D) and 21.5 g (53.5 mmol) of (1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl-2,2,2-trichloroethanimidoate (step E) in 250 mL of cyclohexane/1,2-chloroethane (3/1) under nitrogen atmosphere at −5° C. was added 0.51 mL (3.58 mmol) of 54% HBF4 in ether. The reaction mixture was stirred at −5° C. to at 0° C. for 2 hr then diluted with ether. The mixture was washed with sat. aq. NaHCO3. The organic layer was dried over drying agent, filtered and the solvent evaporated under vacuum. The residue was purified by flash column chromatography on silica gel eluting with EtOAc/hexanes (1/4) to give 9.2 g of the title compound as an oil. 1H-NMR (CDCl3): δ: δ: 7.70 (1 H, s), 7.20 (2 H, s), 7.00 (2 H, m), 6.85 (2 H, t, J=8.5 Hz), 4.43 (1 H, q, J=6.0 Hz), 4.20-4.10 (2 H, m), 3.80-3.73 (2 H, m), 3.36 (1 H, m), 2.90-2.76 (2 H, m), 2.40 (1 H, m), 2.28 (1 H, m), 1.63-1.55 (2 H, m), 1.33 (3 H, d, J=6.0 Hz), 1.25 (3 H, t, J=7.2 Hz), 0.82 (3 H, t, J=7.2 Hz). Unreacted starting alcohol could be recovered by flushing the column with EtOAc and reused in the above reaction.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][N:6]2[C:9]([C:12]3[CH:13]=[C:14]([C:18]4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:15]=[CH:16][CH:17]=3)=[CH:10][N:11]=[C:5]2[CH:4]=1.C(N(S(F)(F)[F:32])CC)C.C(=O)([O-])O.[Na+]>ClCCl>[F:32][CH2:2][C:3]1[CH:8]=[CH:7][N:6]2[C:9]([C:12]3[CH:13]=[C:14]([C:18]4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:15]=[CH:16][CH:17]=3)=[CH:10][N:11]=[C:5]2[CH:4]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: N#Cc1ccccc1-c1cccc(-c2cnc3cc(CO)ccn23)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1ccccc1-c1cccc(-c2cnc3cc(CF)ccn23)c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 85.5 %

Procedure:
To a cooled (−78° C.) suspension of 3′-(7-hydroxymethylimidazo[1,2-α]pyridin-3-yl)biphenyl-2-carbonitrile (96 mg, 0.30 mmol) in dichloromethane (20 ml) was added (diethylamino)sulfur trifluoride (50 mg, 0.31 mmol) dropwise over 5 min. The mixture was stirred at −78° C. for 20 min then allowed to warm to −40° C. for 5 min before quenching the reaction with a pre-cooled −40° C. solution of acetic acid (0.5 ml) in dichloromethane (5 ml). The mixture was warmed to ambient temperature, made basic with saturated sodium hydrogencarbonate solution (30 ml) and extracted with dichloromethane (2×75 ml). The combined organics were washed with brine (30 ml), dried over anhydrous sodium sulfate and evaporated to dryness. Purification by silica gel chromatography eluting with dichloromethane and 1% conc. ammonia on a gradient of methanol (1-2%) gave a solid which was triturated with diethyl ether to give the title compound (84 mg, 87%) as a white powder. 1H NMR (400 MHz, CDCl3) δH 5.45 (2H, d, J 47), 6.90 (1H, dd, J 7 and 2), 7.50 (1H, dt, J 8 and 1), 7.57-7.60 (2H, m), 7.61-7.72 (4H, m), 7.78-7.84 (3H, m), 8.61 (1H, dd, J 7 and 1); m/z (ES+) 328 (M++H).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][S:5][C:4](=[S:7])[N:3]1[NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12].[N+:18]([C:21]1[CH:22]=[C:23]([C:27]2[O:31][C:30]([CH:32]=O)=[CH:29][CH:28]=2)[CH:24]=[CH:25][CH:26]=1)([O-:20])=[O:19].C(O)(=O)C.C(O)(=O)C.C(N)CN.S([O-])(O)=O.[Na+]>CO>[N+:18]([C:21]1[CH:22]=[C:23]([C:27]2[O:31][C:30]([CH:32]=[C:6]3[S:5][C:4](=[S:7])[N:3]([NH:8][C:9]4[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=4[C:11]([OH:13])=[O:12])[C:2]3=[O:1])=[CH:29][CH:28]=2)[CH:24]=[CH:25][CH:26]=1)([O-:20])=[O:19]
Reactant: O=Cc1ccc(-c2cccc([N+](=O)[O-])c2)o1
Reactant: O=C(O)c1ccccc1NN1C(=O)CSC1=S
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: NCCN
Product: O=C(O)c1ccccc1NN1C(=O)C(=Cc2ccc(-c3cccc([N+](=O)[O-])c3)o2)SC1=S
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.5 %

Procedure:
A mixture of 2-(4-oxo-2-thioxo-thiazolidin-3-ylamino)-benzoic acid (0.092 g, 0.34 mmol), 5-(3-nitrophenyl)furan-2-carbaldehyde (0.071 g, 0.33 mmol) (purchased from Aldrich Chemical Company) and ethylenediamine diacetate (0.059 g, 0.033 mmol) in methanol (10 mL) was stirred at room temperature for 18 h. The reaction mixture was poured into stirred 0.6 N aq sodium hydrogensulfite (50 mL). The mixture was vigorously stirred for 30 min. The solid product was filtered off and washed on funnel successively with 0.6 N aq sodium hydrogensulfite (1 mL), water (2×2 mL), acetonitrile (1 mL), ether (2×2 mL) and acetonitrile (1 mL). The material was dried in a vacuum oven at 65° C. for 17 h to afford 2-{5-[1-[5-(3-Nitro-phenyl)-furan-2-yl]-methylidene]-4-oxo-2-thioxo-thiazolidin-3-ylamino}-benzoic acid (115 mg, 72%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ 6.62 (1H, m), 6.90 (1H, m), 7.37 (1H, m), 7.44 (1H, d, J=3.6 Hz), 7.64 (1H, d, J=3.6 Hz), 7.80 (1H, s), 7.88 (1H, m), 7.92 (1H, m), 8.28 (2H, m), 8.65 (1H, m), 10.2 (1H, bs). LC/MS: APCI 466.7, HPLC 96.5%
Reaction SMILES: F[B-](F)(F)F.[O:6]=[N+:7]=[O:8].[CH3:9][C:10]([C:19]1[S:20][CH:21]=[C:22]([CH3:24])[CH:23]=1)([CH3:18])[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12].O>C(COC)OC>[CH3:18][C:10]([C:19]1[S:20][C:21]([N+:7]([O-:8])=[O:6])=[C:22]([CH3:24])[CH:23]=1)([CH3:9])[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12]
Reactant: Cc1csc(C(C)(C)C(=O)N2CCCC2)c1
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: O
Solvent: COCCOC
Product: Cc1cc(C(C)(C)C(=O)N2CCCC2)sc1[N+](=O)[O-]

Procedure:
Nitronium tetrafluoroborate (0.168 g, 1.26 mmol) was added to a solution of 1-[2-methyl-2-(4-methyl-2-thienyl)propanoyl]pyrrolidine (0.145 g, 0.61 mmol) in dimethoxy ethane (5 ml) cooled to −50 C. The mixture was allowed to warm to −30 C over 1 hour. The mixture was poured into water and extracted with ethyl acetate. The organic layer was separated and washed sequentially with a saturated solution of sodium bicarbonate and then with a saturated brine solution. The ethyl acetate solution was dried over magnesium sulfate and then evaporated to afford 1-[2-methyl-2-(4-methyl-5-nitro-2-thienyl)propanoyl]pyrrolidine as a yellow solid which was used in the next step without purification.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[N:15][C:16]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[C:21]([O:33][CH3:34])[CH:20]=2)[NH:11][N:10]=1)(=O)=O.[OH:35][CH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[CH3:34][O:33][C:21]1[CH:20]=[C:19]([NH:18][C:16]2[N:15]=[CH:14][N:13]=[C:12]3[NH:11][N:10]=[C:9]([O:8][CH2:7][CH2:6][N:39]4[CH2:40][CH2:41][CH:36]([OH:35])[CH2:37][CH2:38]4)[C:17]=23)[CH:24]=[CH:23][C:22]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: COc1cc(Nc2ncnc3[nH]nc(OCCOS(C)(=O)=O)c23)ccc1OCc1ccccn1
Reactant: OC1CCNCC1
Product: COc1cc(Nc2ncnc3[nH]nc(OCCN4CCC(O)CC4)c23)ccc1OCc1ccccn1
Yield: 54 %

Procedure:
The procedure described in Example 55 was repeated using 2-[(4-{[3-methoxy-4-(pyridin-2-ylmethoxy)phenyl]amino}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)oxy]ethyl methanesulfonate and 4-hydroxypiperidine to give the title compound in 54% yield; NMR Spectrum: 1.36 (d, 2H), 1.69 (d, 2H), 2.18 (t, 2H), 2.78 (m, 4H), 3.81 (s, 3H), 4.41 (t, 2H), 4.53 (d, 1H), 5.16 (s, 2H), 7.03 (d, 1H), 7.23 (dd, 1H), 7.37 (m, 2H), 7.54 (d, 1H), 7.85 (td, 1H), 8.26 (s, 1H), 8.30 (s, 1H), 8.58 (d, 1H); Mass Spectrum: 492 (MH+).
Reaction SMILES: CC[C@H]1[C@H]2C[C@H]([C@H](OC3C4C(=CC=CC=4)C(O[C@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:22]C)C=C4)N(CC2)C1.[Cl:59][C:60]1[CH:65]=[CH:64][C:63]([C:66]2[C:75]3[C:70](=[CH:71][CH:72]=[CH:73][CH:74]=3)[CH:69]=[C:68](C)[C:67]=2C=C)=[CH:62][CH:61]=1.S([O-])([O-])=O.[Na+].[Na+].[C:85]([OH:89])(C)([CH3:87])[CH3:86]>ClCCl.O>[Cl:59][C:60]1[CH:65]=[CH:64][C:63]([C:66]2[C:75]3[C:70](=[CH:71][CH:72]=[CH:73][CH:74]=3)[CH:69]=[C:68]([CH3:67])[C:86]=2[C@H:85]([OH:89])[CH2:87][OH:22])=[CH:62][CH:61]=1
Reactant: CC[C@@H]1CN2CC[C@@H]1C[C@@H]2[C@H](Oc1nnc(O[C@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Reactant: C=Cc1c(C)cc2ccccc2c1-c1ccc(Cl)cc1
Reactant: CC(C)(C)O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1cc2ccccc2c(-c2ccc(Cl)cc2)c1[C@H](O)CO
Temperature: 0 °C
Reaction time: 6 h

Procedure:
A biphasic mixture of AD-mix-α (4.928 g) in tert-butanol (17.5 mL)/H2O (17.5 mL) was cooled to 0° C. and 1-(4-chlorophenyl)-3-methyl-2-vinyl-naphthalene (3F) (0.980 g, 3.52 mmol) was added. The reaction mixture was stirred for 6 h at 0° C., then stored at −20° C. overnight. The reaction was resumed for 10 h at 0° C., then stored at −20° C. overnight. The reaction was resumed for 8 h at 0° C. until complete. Sodium sulfite (5.3 g) was added at 0° C., then warmed to room temperature and stirred for 30 min to give a white mixture. The mixture was diluted with dichloromethane and H2O. The mixture was extracted with dichloromethane (3×) and the combined organic layer was dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give 3G as a white solid (0.9813 g). 1H-NMR: 300 MHz, (CDCl3) δ 7.72 (d, J=8.1 Hz, 1H), 7.65 (s, 1H), 7.50-7.303 (m, 3H), 7.26-7.07 (m, 4H), 4.92 (dd, J=9.9, 3.6 Hz, 1H), 3.94 (dd, J=10.2, 10.2 Hz, 1H), 3.57 (dd, J=11.1, 3.6 Hz, 1H), 2.69 (s, 3 H).
Reaction SMILES: [CH:1]1[CH2:5][CH2:4][CH2:3][CH:2]=1.[OH:6][CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[OH:6][CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH:8]1[CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCc2ccccc21
Reactant: C1=CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: OC1c2ccccc2CCC1C1CCCC1

Procedure:
40 g of cyclopentene are added dropwise at 120° C to 148 g of 1-hydroxytetraline and 10 g of p-toluene sulphonic acid. The catalyst is removed by washing with sodium hydrogen carbonate solution. The reaction mixture is fractionated. At 161° C (2 mm Hg) 58 g of 1-hydroxy-2-cyclopentyltetraline are obtained.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][C:21](=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.BrC[CH:28]1[CH2:32][CH2:31][CH2:30][O:29]1>>[ClH:19].[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[S:20][CH2:21][CH:28]1[CH2:32][CH2:31][CH2:30][O:29]1
Reactant: BrCC1CCCO1
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Product: Cl
Product: Clc1ccc2c(c1SCC1CCCO1)CCNCC2

Procedure:
Use a method similar to the Example 330, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine and 2-(bromomethyl)tetrahydrofuran to give, after deprotection by the General Procedure 1-4, the title compound as white crystals. MS (APCI+) m/z: 298 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])=[O:9])[CH:7]=1.[CH2:27]([N:31]=[C:32]=[O:33])[CH2:28][CH2:29][CH3:30]>O1CCOCC1>[CH2:27]([NH:31][C:32]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8](=[O:9])[C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])[CH:7]=1)=[O:33])[CH2:28][CH2:29][CH3:30]
Reactant: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: CCCCN=C=O
Solvent: C1COCCO1
Product: CCCCNC(=O)Nc1ccc(C)c(C(=O)c2ccc(Nc3ccc(F)cc3F)cc2Cl)c1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
Compound 494 (0.03 g, 0.08 mmol) was dissolved in 1,4-dioxan (0.5 mL) and n-butyl isocyanate (0.014 mL, 0.12 mmol) was added. The solution was stirred at 50° C. for 18 h. Work up as described in the preparation of compound 259. The crude product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 15:85→60:40 as the eluent. This afforded the title compound as a slightly coloured solid. 13C NMR (CD3OD) δ 198.5, 161.0 (dd), 158.3, 157.9 (dd), 151.1, 141.0, 138.9, 136.1, 135.0, 132.7, 132.1, 128.9, 127.4 (dd), 126.0 (dd), 122.5, 120.9, 116.6, 112.9, 112.6 (dd), 105.8 (dd), 40.6, 33.3, 21.0, 19.7, 14.1