Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(Cl)(=O)=O.[C:6]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21](=[O:30])[C:22]1[CH:27]=[CH:26][C:25]([CH2:28]O)=[CH:24][CH:23]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C.[NH2:38][CH2:39][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]1>ClCCl.O>[C:6]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21](=[O:30])[C:22]1[CH:23]=[CH:24][C:25]([CH2:28][NH:38][CH2:39][CH2:40][CH2:41][N:42]2[CH2:43][CH2:44][N:45]([CH3:48])[CH2:46][CH2:47]2)=[CH:26][CH:27]=1)=[O:12])([CH3:8])([CH3:7])[CH3:9]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(CO)cc1
Reactant: CN1CCN(CCCN)CC1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CN1CCN(CCCNCc2ccc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2)CC1
Reaction time: 0.67 h
Yield: 33 %

Procedure:
Under ice cooling, methanesulfonyl chloride (0.25 mL, 3.2 mmol) was added to a solution of N-(2-t-butoxycarbonylaminophenyl)-4-hydroxymethylbenzamide (Reference Compound No. 3-1, 1.0 g, 2.9 mmol) and triethylamine (0.61 mL, 4.4 mmol) in anhydrous dichloromethane (15 mL), and then the mixture was stirred for 40 minutes. 1-(3-Aminopropyl)-4-methylpiperazine (2.3 mL, 4.4 mmol) was added to the reaction mixture, and then stirred at room temperature for 2.5 hours additionally. Water (200 mL) was added thereto, the whole was extracted with ethyl acetate (200 mL) twice, and then the organic layer was washed with brine (200 mL). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH-modified silica gel, chloroform-methanol) to give 470 mg of the title reference compound as a colorless amorphous product. (Yield 33%)
Reaction SMILES: C(N(CC)CC)C.Cl.[NH:9]1[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])[CH2:10]1.Cl[C:23]1[N:28]=[C:27]([NH2:29])[C:26]([N+:30]([O-:32])=[O:31])=[CH:25][CH:24]=1.[Cl-].[NH4+]>C(OCC)(=O)C.C(#N)C>[NH2:29][C:27]1[N:28]=[C:23]([N:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([N:17]3[CH2:18][CH2:19][CH2:20][CH2:21]3)=[O:16])[CH2:10]2)[CH:24]=[CH:25][C:26]=1[N+:30]([O-:32])=[O:31]
Reactant: O=C([C@@H]1CCCNC1)N1CCCC1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Nc1nc(N2CCC[C@@H](C(=O)N3CCCC3)C2)ccc1[N+](=O)[O-]
Temperature: 17.5 °C
Reaction time: 0.5 h
Yield: 65.5 %

Procedure:
Triethylamine (4.65 kg, 46 mol) was added over a period of 1 h to a mixture of (R)-piperidin-3-yl(pyrrolidin-1-yl)methanone hydrochloride (4.8 kg, 22 mol) and acetonitrile (48 L), maintaining a temperature of 15-20° C. The mixture was held at that temperature for 30 min, then was warmed to 38-42° C. 6-Chloro-3-nitropyridin-2-amine (3.8 kg, 22 mol) was added portion-wise, and the mixture was held at 38-42° C. for 3 h. The mixture was then cooled to 15-20° C. and an aqueous solution of ammonium chloride (prepared from 6.24 kg ammonium chloride and 48 L water) and ethyl acetate (48 L) were added sequentially, and the layers were stirred and then separated. The aqueous layer was further extracted with ethyl acetate (2×24 L). The combined organic layers were washed with an aqueous solution of sodium chloride (prepared from 4.8 kg sodium chloride and 24 L water) and then were dried with sodium sulfate (1.92 kg). The organic layer was removed and solvent was evaporated under reduced pressure at 40° C. Ethyl acetate (14.4 L) was added to the crude product, and the mixture was heated to 35-40° C. and was held at that temperature for 15 min. The mixture was cooled to 20-25° C. and held at that temperature for 6 h, then cooled to 10-15° C. and held at that temperature for 1 h. The suspension was centrifuged and the mother liquor was removed. The resulting cake was washed with chilled ethyl acetate (4.8 L) and then was dried at 40-50° C. to afford (R)-(1-(6-amino-5-nitropyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (4.6 kg, 66%). HPLC retention time: 5.30 min (Column: Halo C18, 4.6×150 mm, 2.7 μm; Mobile Phase A: 0.1% orthophosphoric acid and 2% acetonitrile in water, Mobile Phase B: acetonitrile; Gradient: 20% B to 90% B over 7 min, then held for 3 min; Flow: 0.8 mL/min; Temperature: 25° C.; UV detection at 210 and 226 nM). Melting point: 118.5-123.5° C. Water content by Karl Fischer titration: 0.36% by weight.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:18])[C@H:9]([O:11]C2CCCCO2)[CH3:10])=[N:6][CH:7]=1.CS(O)(=O)=O>C(O)(C)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:18])[C@H:9]([OH:11])[CH3:10])=[N:6][CH:7]=1
Reactant: C[C@@H](OC1CCCCO1)C(=O)c1ccc(Br)cn1
Agent: CS(=O)(=O)O
Solvent: CC(C)O
Product: C[C@@H](O)C(=O)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 54.8 %

Procedure:
Compound 1a (4.0 g, 12.7 mmol) was dissolved in isopropanol (50 mL), and methylsulfonic acid (1.8 g, 18.5 mmol) was added. The reaction was agitated at room temperature for 5 hrs. The reaction was monitored by TLC (petroleum ether/ethyl acetate=5/1). After the reaction completed, the solvent and excess methylsulfonic acid was removed by evaporation. The mixture was then diluted with water. The pH value was adjusted to 7-8 with saturated NaHCO3 solution. The mixture was extracted by ethyl acetate (30 mL×2). The organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then dried by rotary dryer. Column chromatography (petroleum ether/ethyl acetate=7/1) afforded 1.6 g of white solid (compound 1b), yield 55%.
Reaction SMILES: [CH:1]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[OH-].[Na+].CCCCCCCC.[I-].C[P+](C)(C)C.[Cl:31][CH2:32][Cl:33]>C(Cl)(Cl)Cl>[Cl:31][C:32]1([Cl:33])[CH:14]2[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2
Reactant: C1=CCCCCCCCCCCCC1
Reactant: ClCCl
Agent: C[P+](C)(C)C
Agent: [I-]
Agent: [Na+]
Solvent: CCCCCCCC
Solvent: ClC(Cl)Cl
Product: ClC1(Cl)C2CCCCCCCCCCCCC21

Procedure:
Cyclotetradecene (4.0 g), chloroform (18 ml), 50% aqueous sodium hydroxide solution (22 ml), dichloromethane (5 ml), n-octane (1 ml) and tetramethylphosphonium iodide (0.01 g) were stirred together at 35° C. for 3 hours. At the end of this period the conversion of starting material to the desired product was found by GLC to be 100%.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])[N:10]=2)[CH2:3]1.[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(N(CC)CC)C>C(Cl)Cl>[CH3:19][S:20]([O:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11]([N:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)=[O:12])[N:10]=2)[CH2:3]1)(=[O:22])=[O:21]
Reactant: O=C(c1csc(N2CC(O)C2)n1)N1CCCCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CN(c2nc(C(=O)N3CCCCC3)cs2)C1
Reaction time: 1 h
Yield: 86.3 %

Procedure:
To a solution of 3-hydroxy-1-(4-piperidinocarbonyl-1,3-thiazol-2-yl)azetidine (310 mg, 1.16 mmol) (obtained as described in Reference Example 27(2)) in methylene chloride (10 ml) were added methanesulfonyl chloride (0.27 ml, 3.48 mmol) and triethylamine (0.49 ml, 3.48 mmol) in an ice bath, and then the mixture was stirred for 1 hour. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate as the eluant to afford 3-methanesulfonyloxy-1-(4-piperidinocarbonyl-1,3-thiazol-2-yl)azetidine (346 mg, yield 86%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Cl[C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][N:22]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[CH:13]=[C:14]([CH:20]=[CH:21][N:22]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1
Reactant: OB(O)c1ccc(F)cc1
Product: CCOC(=O)c1ccnc(-c2ccc(F)cc2)c1

Procedure:
4-Fluorophenylboronic acid (166 mg) and ethyl 2-chloroisonicotinate (200 mg) were reacted in the same manner as in Preparation Example 1 to obtain the title compound.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:9]([O:11][SiH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH3:10].P(OCC(CC)CCCC)(OCC(CC)CCCC)(O)=O>[Pt].C1(C)C=CC=CC=1>[CH2:1]([Si:12]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[O:11][CH2:9][CH3:10])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCO[SiH](OCC)OCC
Reactant: C=Cc1ccccc1
Agent: [Pt]
Agent: CCCCC(CC)COP(=O)(O)OCC(CC)CCCC
Solvent: Cc1ccccc1
Product: CCO[Si](CCc1ccccc1)(OCC)OCC
Yield: 16 %

Procedure:
Reaction between styrene and triethoxysilane with platinum catalyst in the presence of bis(2-ethylhexyl) hydrogenphosphate (C4H9CH(C2H5)CH2O)2P(═O)OH). 0.334 g Styrene and 0.540 g triethoxysilane were introduced into a glass tube, and 3 mg of bis(2-ethylhexyl) hydrogenphosphate were added using a microsyringe. 0.8 mg Of a toluene solution of a 0-valent platinum complex of divinylsiloxane (0.4 wt % platinum content) was added. The tube was sealed with Teflon tape and a septum and placed in a 100° C. oil bath where it was heated for 1 hour. After cooling, the tube contents were analyzed by gas chromatography revealing a styrene conversion of about 29% and a phenethyl triethoxysilane yield of 16%. The ratio between the phenethyl triethoxysilane and the (α-methylbenzyl)triethoxysilane was 5.8:1.
Reaction SMILES: [CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([O:20][CH3:21])=[CH:15][CH:16]=[C:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1.C(CN)O.O>COCC(O)CC>[CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([O:20][CH3:21])=[CH:15][CH2:16][C@@H:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1
Reactant: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Agent: CCC(O)COC
Solvent: O
Solvent: NCCO
Product: COC1=CC[C@H]2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Temperature: 20 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
Thebaine (4.0 g dry basis, 12.9 mmol) is placed in mixture of 1-methoxy-2-butanol (13.0 g) and ethanolamine (1.3 g, 21.3 mmol, 1.65 equiv) is heated at 110 to 114° C. p-Toluenesulfonylhydrazide (4.8 g, 25.8 mmol, 2.0 equiv) is dissolved at 15 to 25° C. in a mixture of ethanolamine (9.6 g, 157.2 mol, 12.2 equiv) and 1-methoxy-2-butanol (0.8 g) and the solution added in portions to the Thebaine mixture over 1 h 10 min. The reaction mixture is held at 110 to 114° C. for 1 h then cooled to 15 to 25° C. and water (24 g) added while maintaining the batch temperature at ≦30° C. The resulting slurry (pH 11.0) is stirred, further cooled to 0 to 5° C. and then filtered. The product is washed with water (3×8 g) and dried at 40° C. to a constant weight to give 8,14-dihydrothebaine (3.87 g, 96.0% yield; 98.3 area % purity by HPLC).
Reaction SMILES: CC([O-])(C)C.[K+].[Br:7][C:8]1[CH:9]=[C:10]([CH2:14][OH:15])[CH:11]=[CH:12][CH:13]=1.Cl[C:17]1[N:22]=[C:21]([NH2:23])[C:20]([F:24])=[CH:19][N:18]=1>O>[Br:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[CH2:14][O:15][C:17]1[N:22]=[C:21]([NH2:23])[C:20]([F:24])=[CH:19][N:18]=1
Reactant: OCc1cccc(Br)c1
Reactant: Nc1nc(Cl)ncc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: Nc1nc(OCc2cccc(Br)c2)ncc1F
Temperature: 90 °C
Reaction time: 4 h
Yield: 49.3 %

Procedure:
To a magnetically stirred mixture of KOtBu (1.0 M in tBuOH, 1.36 ml, 1.36 mmol) was added (3-bromophenyl)methanol (0.25 g, 1.36 mmol). To the resulting solution was added 2-chloro-5-fluoropyrimidine-4-ylamine (0.10 g, 0.68 mmol) and the mixture was capped and stirred at 90° C. for 4 h. The reaction mixture was cooled to room temperature, diluted with water, and the resulting precipitate was collected by filtration. The solid was washed with water, washed with cyclohexane, and dried in the vacuum oven. A CH2Cl2 solution of the compound was loaded onto Biotage SCX column and eluted with CH2Cl2 followed by 2.0 M NH3 in MeOH. The solvent was evaporated under reduced pressure to give the title compound (0.100 g, 49%) as an off-white solid: mp 143-145° C.; 1H NMR (400 MHz, DMSO-d6) δ 7.90 (d, J=2.5 Hz, 1H), 7.61 (s, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.36 (d, J=7.7 Hz, 1H), 7.22 (t, J=7.7 Hz, 1H), 5.28 (s, 2H), 5.20 (br s, 2H); GCMS (EI) m/z 297, 299 (M)+.
Reaction SMILES: Cl[C:2]1[N:3]2[CH:19]=[N:18][N:17]=[C:4]2[C:5]2[N:6]=[CH:7][N:8]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[C:9]=2[N:10]=1.[OH-:20].[Li+].O>C1COCC1>[O:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[N:8]1[CH:7]=[N:6][C:5]2[C:4]3=[N:17][N:18]=[CH:19][N:3]3[C:2](=[O:20])[NH:10][C:9]1=2
Reactant: Clc1nc2c(ncn2C2CCCCO2)c2nncn12
Reactant: [OH-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=c1[nH]c2c(ncn2C2CCCCO2)c2nncn12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To the solution of 5-chloro-7-(tetrahydro-2H-pyran-2-yl)-7H-[1,2,4]triazolo[3,4-i]purine (0.17 g, 0.50 mmol) in THF (10 mL) was added lithium hydroxide (420 mg, 18 mmol) and water (10 mL). After stirring at room temperature for 10 minutes, the reaction mixture was concentrated under reduced pressure to give the product, which is used for next step without further purification. LCMS calculated for C11H13N6O2 (M+H): 261.1; found: 261.0.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([NH:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=2[C:16]([O-:18])=O)[C:7]=1[Cl:8].[Na+].CN(C=O)C.C(Cl)(=O)C(Cl)=O.[CH2:32]([NH:39][OH:40])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl>C(Cl)Cl.C1COCC1.CCN(CC)CC.O>[Cl:8][C:7]1[C:2]([CH3:1])=[CH:3][CH:4]=[C:5]([Cl:19])[C:6]=1[NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=1[C:16]([N:39]([OH:40])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:18]
Reactant: ONCc1ccccc1
Reactant: Cc1ccc(Cl)c(Nc2ccccc2C(=O)[O-])c1Cl
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(Cl)c(Nc2ccccc2C(=O)N(O)Cc2ccccc2)c1Cl
Temperature: 0 °C
Reaction time: 20 h

Procedure:
Meclomen (5.92 g; 0.02 mol) is suspended in CH2Cl2 (150 ml) containing DMF (1.46 g, 0.02 mol) and cooled to 0° C. Oxalyl chloride is added to the solution over 30 minutes and the resulting yellow solution is stirred at 24° C. for 20 hours and then added to a cold solution of N-benzylhydroxylamine (2.46 g; 0.02 mol) in THF (60 ml)--H2O (15 ml)--Et3N (20 ml) mixture. The solution is allowed to come to 24° C. and treated with 2N HCl (160 ml). The product is extracted with CH2Cl2. The extracts are dried over sodium sulfate and evaporated to dryness. The residue is flash chromatographed through SiO2 gel eluting with CH2Cl2. The fractions containing the product are evaporated and the solid residue is recrystallized from isopropylether/n-hexane yielding white crystals. Yield 1.45 g (18.6%); mp 133°-135° C.
Reaction SMILES: [C:1]([Si:5]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[O:6][CH2:7][C:8]([C:11]1[CH:12]=[C:13]([NH2:32])[N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][O:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[CH:17]=2)[N:15]=1)([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl[C:48]([O:50][CH2:51][C:52]([Cl:55])([Cl:54])[Cl:53])=[O:49]>CCOC(C)=O.O>[Cl:53][C:52]([Cl:55])([Cl:54])[CH2:51][O:50][C:48](=[O:49])[NH:32][C:13]1[N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][O:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[CH:17]=2)[N:15]=[C:11]([C:8]([CH3:10])([CH3:9])[CH2:7][O:6][Si:5]([C:1]([CH3:2])([CH3:3])[CH3:4])([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:12]=1
Reactant: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1cc(N)n(-c2cccc(OCCOC3CCCCO3)c2)n1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(OCCOC3CCCCO3)c2)n1
Yield: 126.7 %

Procedure:
A solution of Intermediate 153e (0.41 g, 0.67 mmol) in EtOAc (3.6 mL) was treated with aqueous 1N NaOH (1.2 mL, 1.2 mmol) then 2,2,2-trichloroethyl chloroformate (0.10 mL, 0.74 mmol) and the mixture was stirred at RT for 4 h. The mixture was diluted with EtOAc and water and the phases were separated. The aqueous layer was extracted with EtOAc (×2) and the combined organic phase was washed with brine, dried (Na2SO4), and concentrated in vacuo to give a pale red oil (0.67 g). The oil was purified by FCC, using 0-25% EtOAc in cyclohexane to give the title compound as a pale golden gum (0.38 g, 72%). LCMS (Method 3): Rt 5.86 min, m/z 788.3, 790.3 [MH+].
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][C:16]([CH3:21])([CH3:20])[CH2:15]2)[C:3]=1[CH3:22].[O:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:30]=[C:31]3[NH:37][CH2:36][C:35]4([CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)[C:32]3=[N:33][CH:34]=2)[CH2:25][CH2:24]1.CC(C)([O-])C.[Na+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].C1(C)C=CC=CC=1>[CH3:20][C:16]1([CH3:21])[O:17][CH2:18][CH2:19][N:14]([C:4]2[C:3]([CH3:22])=[C:2]([N:37]3[C:31]4[C:32](=[N:33][CH:34]=[C:29]([N:26]5[CH2:27][CH2:28][O:23][CH2:24][CH2:25]5)[CH:30]=4)[C:35]4([CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)[CH2:36]3)[C:11]3[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=3[F:12])[N:5]=2)[CH2:15]1
Reactant: c1nc2c(cc1N1CCOCC1)NCC21CCOCC1
Reactant: Cc1c(N2CCOC(C)(C)C2)nc2cc(F)cc(F)c2c1Cl
Agent: Cl[Pd+]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(N2CCOC(C)(C)C2)nc2cc(F)cc(F)c2c1N1CC2(CCOCC2)c2ncc(N3CCOCC3)cc21

Procedure:
Prepared according to procedure Y by using 4-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)-2,2-dimethylmorpholine (47.5 mg, 0.14 mmol), 6′-morpholino-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine] (40 mg, 0.14 mmol), sodium tert-butoxide and XPhos precatalyst (10.7 mg, 0.01 mmol) in toluene (4 mL) for 2 h at reflux. Purification by reverse phase HPLC (10 to 60% acetonitrile in water) gave 1′-(2-(2,2-dimethyl-4-morpholinyl)-5,7-difluoro-3-methyl-4-quinolinyl)-6′-(4-morpholinyl)-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine]. 1H NMR (400 MHz, chloroform-d) δ ppm 7.57 (1H, d, J=2.5 Hz), 7.35-7.40 (1H, m), 6.75 (1H, ddd, J=11.8, 8.9, 2.5 Hz), 5.67 (1H, d, J=2.3 Hz), 4.09-4.18 (2H, m), 3.94-4.00 (2H, m), 3.82-3.94 (2H, m), 3.72-3.80 (4H, m), 3.51-3.63 (2H, m), 3.27-3.38 (2H, m), 3.11-3.25 (2H, m), 2.95-3.02 (4H, m), 2.23-2.38 (5H, m), 1.55-1.78 (2H, m), 1.40 (3H, s), 1.37 (3H, s). Mass Spectrum (ESI) m/e=566.2 (M+1).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.ClC[C:45]1[N:49](C)[N:48]=[C:47]([CH3:51])[N:46]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[N:49]([CH3:45])[N:48]=[C:47]([CH3:51])[N:46]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: Cc1nc(CCl)n(C)n1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: Cc1nc(Cn2nnc3c(N4CCC(F)(F)C4)nc(C(C)(C)C)nc32)n(C)n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo [4,5-d]pyrimidine and 5-(chloromethyl)-1,3-dimethyl-1H-1,2,4-triazole and isolated as light-yellow gum. MS(m/e): 392.3 (MH+).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1([CH3:24])[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([F:23])[CH:19]=2)[O:14]1.FC(F)(F)C(O)=O.S([O-])([O-])=O.[Na+].[Na+].C(=O)([O-])O.[Na+]>ClC(Cl)Cl>[CH3:12][C:13]1([CH3:24])[C:22](=[O:9])[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([F:23])[CH:19]=2)[O:14]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1(C)C=Cc2cc(F)ccc2O1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CC1(C)Oc2ccc(F)cc2CC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
40.6 g (0.2 mol) of m-chloroperbenzoic acid are added, while stirring at from 15° to 20°, to a solution of 17.8 g (0.1 mol) of 2,2-dimethyl-6-fluoro-2H-chromene in 300 ml of trichloromethane. 17.1 g (0.15 mol) of trifluoroacetic acid are added rapidly to the resulting suspension at room temperature. The reaction mixture is then stirred at room temperature for 2 hours and then an aqueous solution of sodium sulfite/sodium hydrogen carbonate (1:1) is added thereto. The organic phase is separated off, washed in succession with water and saturated sodium chloride solution, dried over sodium sulfate and concentrated by evaporation in vacuo. The resulting residue is subjected to bulb tube distillation under a high vacuum at 160°. The distillate is dissolved in diethyl ether and the solution is washed in succession with sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over sodium sulfate and again concentrated by evaporation in vacuo. The resulting oily residue is chromatographed on 500 g of silica gel (0.040- 0.063 mm) with toluene as eluant, yielding 7.76 g (40% of the theoretical yield) of 2,2-dimethyl-6-fluoro-3-oxo-chroman in the form of a light-yellow oil.
Reaction SMILES: [CH:1]1([C:7]2[C:8]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9][CH:10]=[C:11]([CH:15]=2)[C:12]([OH:14])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:22]1[CH:27]=[C:26]([NH2:28])[CH:25]=[N:24][CH:23]=1>>[CH:1]1([C:7]2[C:8]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9][CH:10]=[C:11]([CH:15]=2)[C:12]([NH:28][C:26]2[CH:27]=[N:22][CH:23]=[N:24][CH:25]=2)=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Reactant: Nc1cncnc1
Product: O=C(Nc1cncnc1)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1

Procedure:
This compound was prepared following the same procedure as described in Example 11 using 5-cyclohexyl-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (Example 4b) (100 mg, 0.33 mmol) and 5-pyrimidinamine (CAN 591-55-9, 31.4 mg, 0.33 mmol) as starting materials; off white solid (64 mg, 51.0%). MS (ESI): 381.4 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](F)[C:3]=1[C:4]#[N:5].[NH:11]1[CH:15]=[N:14][CH:13]=[N:12]1>CS(C)=O.O.C(Cl)Cl.CO>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[C:3]=1[C:4]#[N:5]
Reactant: c1nc[nH]n1
Reactant: N#Cc1c(F)cccc1F
Solvent: CS(C)=O
Solvent: O
Solvent: CO
Product: N#Cc1c(F)cccc1-n1cncn1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
A mixture of 2,6-difluoro-benzonitrile (10.34 g, 74.4 mmol), 1H-[1,2,4]triazole (5.34 g, 77.4 mmol), and CsCO3 (25.19 g, 77.4 mmol) in DMSO (30 mL) was stirred at ˜50° C. for 24 h. The yellowish easily stirred slurry was then diluted with water (200 mL), stirred at rt for 15 min, and filtered. The filter cake was washed with water (1×100 mL) and the filter cake was then partitioned with water (100 mL) and DCM (200 mL). The aqueous layer was extracted with DCM (1×300 mL), and the organic layers were combined, washed with 4 M NaCl (1×100 mL), dried (Na2SO4), and concentrated under vacuum at 90° C. to provide the crude title compound as an off-white solid (8.96 g). A portion of this crude material (3.33 g) was dissolved in DCM/MeOH, silica gel (8.5 g) was added, and the mixture was concentrated to a free-flowing powder. The silica-adsorbed crude title compound was applied to a silica flash column (40 mm×6″) and eluted with EtOAc to afford the title compound as a white solid [1.60 g, 31% (calculated from chromatographic purification of a portion of the crude material)].