Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[CH:8][N+:9]([O-])=[CH:10][CH:11]=2)[O:6][CH2:5]1.P(Cl)(Cl)([Cl:16])=O>C(Cl)Cl>[CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[C:8]([Cl:16])[N:9]=[CH:10][CH:11]=2)[O:6][CH2:5]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CON=C1COc2c[n+]([O-])ccc21
Solvent: ClCCl
Product: CON=C1COc2c1ccnc2Cl
Temperature: 50 °C

Procedure:
To a solution of 3-(methoxyimino)-2,3-dihydrofuro[2,3-c]pyridine 6-oxide (5.35 mmol) in 30 mL DCM were added 2.9 mL phosphoryl chloride at 0° C. The mixture was heated to 50° C. for 7 h, concentrated in vacuo, redissolved in DCM and quenched with solid NaHCO3 and then water. The aqueous layer was extracted with DCM (2×). The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification by CC (KP-SIL™ from Biotage) using Hept/EtOAc (8/2) gives the desired product as beige solid;
Reaction SMILES: [ClH:1].C(OCC)(=O)C.[Cl:8][C:9]1[N:10]=[C:11]([C:16]([NH:18][C@H:19]2[CH2:24][CH2:23][N:22]([C:25]3[S:26][C:27]([C:31]([NH:33][CH:34]4[CH2:39][CH2:38][N:37](C(OC(C)(C)C)=O)[CH2:36][CH2:35]4)=[O:32])=[C:28]([CH3:30])[N:29]=3)[CH2:21][C@H:20]2[O:47][CH3:48])=[O:17])[NH:12][C:13]=1[CH2:14][CH3:15]>CO>[ClH:8].[ClH:1].[Cl:8][C:9]1[N:10]=[C:11]([C:16]([NH:18][C@H:19]2[CH2:24][CH2:23][N:22]([C:25]3[S:26][C:27]([C:31]([NH:33][CH:34]4[CH2:35][CH2:36][NH:37][CH2:38][CH2:39]4)=[O:32])=[C:28]([CH3:30])[N:29]=3)[CH2:21][C@H:20]2[O:47][CH3:48])=[O:17])[NH:12][C:13]=1[CH2:14][CH3:15]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C)c(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)s3)C[C@H]2OC)nc1Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C)c(C(=O)NC4CCNCC4)s3)C[C@H]2OC)nc1Cl
Reaction time: 0.5 h
Yield: 144.1 %

Procedure:
A 4 N hydrochloric acid/ethyl acetate solution (2 ml, 8 mmol) was added to a solution of tert-butyl cis(±)-4-({[2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-methyl-1,3-thiazol-5-yl]carbonyl}amino)piperidine-1-carboxylate obtained in Example (266a) (30 mg, 0.05 mmol) in methanol (0.4 mL), followed by stirring for 30 minutes. The solvent was evaporated under reduced pressure. The residue was solidified by adding ethyl acetate, diethyl ether and hexane, to obtain 21 mg of the title compound as a cream-colored solid (72%).
Reaction SMILES: C(O[C:4]1[CH2:9][CH:8]([CH3:10])[CH2:7][CH2:6][N:5]=1)C.[CH3:11][C:12]1([CH3:20])[CH2:19][C:17](=[O:18])[CH2:16][C:14](=[O:15])[CH2:13]1>C(OCC)C>[CH3:11][C:12]1([CH3:20])[CH2:13][C:14](=[O:15])[C:16](=[C:4]2[CH2:9][CH:8]([CH3:10])[CH2:7][CH2:6][NH:5]2)[C:17](=[O:18])[CH2:19]1
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: CCOC1=NCCC(C)C1
Solvent: CCOCC
Product: CC1CCNC(=C2C(=O)CC(C)(C)CC2=O)C1
Yield: 17 %

Procedure:
A mixture of 2-ethoxy-4-methyl-3,4,5,6-tetrahydropyridine (9.27 grams, 0.066 mole) and dimedone (9.20 grams, 0.066 mole) is heated at 112°-113° C. for a 3-hour period. The cooled residue is dissolved in ethyl ether and extracted with three portions of 3N HCl. A solution of 6N sodium hydroxide is added to the strongly acidic solution causing the product to separate as a white solid, with precipitation complete at a final pH of 1. The crude product weighs 4.32 grams on drying and melts at 172°-175° C. Recrystallization from a large volume of cyclohexane gives 2.64 grams of pure material, m.p. 174° C.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH2:23][OH:24])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]=[O:24])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(CO)cc1OCC2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C=O)cc1OCC2
Yield: 118.9 %

Procedure:
A solution of [2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-methanol (0.294 g, 0.91 mmol) and Dess-Martin periodinane (3.32 mL, 1.0 mmol, 3M solution in DCM) in DCM (15 mL) was stirred at RT for 1.5 h then washed with 1M sodium hydroxide. The aqueous phase was extracted with DCM and the combined organic extracts dried (Na2SO4) and concentrated in vacuo to give 2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-8-carb aldehyde (0.35 g, quant.). LCMS: RT=3.07 min, [M+H]+=324.
Reaction SMILES: [CH3:1][S-:2].[Na+].CO.[CH:6]([CH:8](Cl)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[CH2:7].C(OCC)C>O1CCCC1>[CH:6]([CH:8]([S:2][CH3:1])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[CH2:7]
Reactant: C=CC(Cl)c1ccccc1
Reactant: C[S-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Solvent: C1CCOC1
Product: C=CC(SC)c1ccccc1
Yield: 91 %

Procedure:
Sodium methanethiolate (24.67 g, 0.35 mol) was combined with methanol (250 ml) in a 1 liter round bottomed flask outfitted with an addition funnel and a nitrogen inlet. Vinylbenzyl chloride (41.0 ml, 60:40 mixture of p- and o-isomers, 0.29 mol) in tetrahydrofuran (100 ml) was added via addition funnel over 30 minutes. The reaction mixture grew slightly warm and a milky suspension resulted. This was allowed to stir at room temperature for 20 hours at which point only a small amount of vinylbenzyl chloride was still evident by thin layer chromatography (2:1 hexanes/CH2Cl2 eluent). Another portion of sodium methanethiolate was added (5.25 g, 7.49×10−2 mol) and after ten minutes, the reaction had proceeded to completion by thin layer chromatography. Diethyl ether (400 ml) was added and the resulting mixture was extracted twice with 600 ml of water and once with 600 ml of brine. The resulting organic extracts were dried over magnesium sulfate, a small amount (about 1 mg) of 3-t-butyl-4-hydroxy-5-methyl phenyl sulfide was added, and the solvents were stripped by rotary evaporation to afford a yellowish oil. Purification by vacuum distillation through a long Vigreux column yielded 43.35 g (91%) of the pure product as a clear liquid.
Reaction SMILES: CC(C)([O-])C.[K+].[I-].C[N+:9](C)(C)N.[Br:13][C:14]1[CH:15]=[C:16]([CH:28]=[C:29]([Cl:31])[CH:30]=1)[O:17][C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:27]>CN(C=O)C.[Cu]Cl>[Br:13][C:14]1[CH:15]=[C:16]([CH:28]=[C:29]([Cl:31])[CH:30]=1)[O:17][C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[C:22]([CH:21]=[CH:20][C:19]=1[Cl:27])[NH2:9]
Reactant: O=[N+]([O-])c1cccc(Cl)c1Oc1cc(Cl)cc(Br)c1
Reactant: C[N+](C)(C)N
Agent: Cl[Cu]
Agent: CC(C)(C)[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: Nc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2)c1[N+](=O)[O-]
Temperature: -40 °C

Procedure:
To copper (I) chloride (5.45 mg, 0.055 mmol) and potassium tert-butoxide (247 mg, 2.204 mmol) suspended in DMF (3 mL) at 0° C. was added 1,1,1-trimethylhydrazinium iodide (139 mg, 0.689 mmol). This mixture was allowed to stir for several minutes at which point the mixture was cooled to −40° C. and 2-(3-bromo-5-chlorophenoxy)-1-chloro-3-nitrobenzene (200 mg, 0.551 mmol) as a solution in DMF (1 mL) was added dropwise. The reaction was maintained at −40° C. for 15 minutes and was then quenched at −40° C. with saturated aqueous ammonium chloride (10 mL). Water (10 mL) was added and the mixture was allowed to warm to room temperature. The mixture was extracted with ethyl acetate (2×50 mL). The combined organic fractions were washed with water (3×50 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The resulting residue was purified by automated column chromatography on silica gel (40 g) eluting with 0-25% EtOAc/hexanes to give the title product. LRMS (M+1)=378.7.
Reaction SMILES: [CH:1]1([NH:5][S:6]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21](Br)[CH:20]=2)[CH2:13][C:12]3([CH3:28])[CH3:27])(=[O:8])=[O:7])[CH2:4][CH2:3][CH2:2]1.[NH2:29][C:30]1([C:33]([OH:35])=[O:34])[CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH:1]1([NH:5][S:6]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]([C:19]2[CH:20]=[C:21]([NH:29][C:30]4([C:33]([OH:35])=[O:34])[CH2:32][CH2:31]4)[CH:22]=[C:23]([F:25])[CH:24]=2)[CH2:13][C:12]3([CH3:28])[CH3:27])(=[O:8])=[O:7])[CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)CC(c2cc(F)cc(Br)c2)Nc2ccc(S(=O)(=O)NC3CCC3)cc21
Reactant: NC1(C(=O)O)CC1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC1(C)CC(c2cc(F)cc(NC3(C(=O)O)CC3)c2)Nc2ccc(S(=O)(=O)NC3CCC3)cc21
Temperature: 25 °C
Yield: 46.9 %

Procedure:
A mixture solution of 2-(3-bromo-5-fluoro-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-sulfonic acid cyclobutylamide (150 mg, 0.32 mmol), copper(I) iodide (20 mg, 0.1 mmol), 1-amino-cyclopropanecarboxylic acid (135 mg, 1.3 mmol) and potassium carbonate (140 mg, 1.0 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (70 mL×2), washed with water (30 mL×3) and saturated aqueous ammonium chloride solution (30 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 1-[3-(6-cyclobutylsulfamoyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-5-fluoro-phenylamino]-cyclopropanecarboxylic acid (73.2 mg, 47.0%) as a white solid: MS (ESI) M+1=488.1.
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9]2[N:10]=[CH:11][C:12]([C:15](OC)=[O:16])=[N:13][CH:14]=2)[CH2:6]1.[NH3:24]>CO>[Br:1][C:2]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9]2[N:10]=[CH:11][C:12]([C:15]([NH2:24])=[O:16])=[N:13][CH:14]=2)[CH2:6]1
Reactant: N
Reactant: COC(=O)c1cnc(N2CC(Oc3cc(F)ccc3Br)C2)cn1
Solvent: CO
Product: NC(=O)c1cnc(N2CC(Oc3cc(F)ccc3Br)C2)cn1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
To methyl 5-[3-(2-bromo-5-fluorophenoxy)azetidin-1-yl]pyrazine-2-carboxylate (0.080 g, 2.1 mmol) in MeOH was bubbled ammonia and the mixture was heated at 50° C. After 2 d, the methanol was evaporated followed by the addition of ether. The solid was filtered to provide the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]([Cl:12])[C:3]=1[C:4]([OH:6])=[O:5].C(N(CC)CC)C.[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=O>CCCCCCC.C(OCC)(=O)C>[Cl:12][C:7]1[C:3]2[C:4](=[O:6])[O:5][C:23]([C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[F:20])=[N:1][C:2]=2[C:10]([Cl:11])=[CH:9][CH:8]=1
Reactant: Nc1c(Cl)ccc(Cl)c1C(=O)O
Reactant: O=C(Cl)c1ccccc1F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCCCCCC
Product: O=c1oc(-c2ccccc2F)nc2c(Cl)ccc(Cl)c12
Temperature: 25 °C

Procedure:
2-Amino-3,6-dichlorobenzoic acid (0.5 g) and triethyl amine (20 ml) were mixed. 2-Fluorobenzoyl chloride (0.77 g) was added dropwise under cooling and stirring. The mixture was subsequently heated to RT and stirred until disappearance of starting material was seen on TLC (silicagel) using heptane/ethyl acetate (4/1) as eluent. After cooling on ice the precipitate was filtered off and the filtrate evaporated to dryness. The residue was partitioned between methylene chloride and potassium carbonate (2N), the organic layers separated, dried over magnesium sulfate and evaporated to dryness. The raw product was purified by column chromatography on silicagel using heptane/ethyl acetate as eluent. Yield 0.31 g. m.p. 140° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.N1C=CC=CC=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>O>[C:22]([O:1][CH2:2][C:3]1([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:4][CH2:5][C:6](=[O:9])[CH2:7][CH2:8]1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1CCC(CO)(c2ccccc2)CC1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OCC1(c2ccccc2)CCC(=O)CC1
Reaction time: 20 h
Yield: 35.8 %

Procedure:
6.6 g. of 4-hydroxymethyl-4-phenylcyclohexanone is dissolved in 40 ml. of pyridine and 20 ml. acetic anhydride. After about 20 hours of standing at room temperature, the mixture is poured into ice and water. The gum that precipitates is extracted with ether. The organic layer is washed successively with water, 2.5 N hydrochloric acid, water, sodium bicarbonate solution, and brine, and then evaporated to dryness. The solid residue is recrystallized from Skellysolve B to give 6.74 g. (35.8% yield) of 4-acetoxymethyl-4-phenylcyclohexanone, having a melting point of 74° to 79°C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](Br)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[CH3:24][N:25]1[C:29]([Sn](CCCC)(CCCC)CCCC)=[CH:28][C:27]([C:43]([F:46])([F:45])[F:44])=[N:26]1>>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:29]2[N:25]([CH3:24])[N:26]=[C:27]([C:43]([F:46])([F:45])[F:44])[CH:28]=2)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4]
Reactant: COC(=O)c1nc(Br)c2cc(Oc3ccccc3)ccc2c1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C(F)(F)F)nn1C
Product: COC(=O)c1nc(-c2cc(C(F)(F)F)nn2C)c2cc(Oc3ccccc3)ccc2c1O

Procedure:
4-Hydroxy-1-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester was prepared from 1-bromo-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester using 1-methyl-5-tributylstannanyl-3-trifluoromethyl-1H-pyrazole under conditions analogous to Example 132(a). MS ESI(−) m/e: 442.0128 (M−1.)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[F:23][C:24]([F:41])([F:40])[C:25]1[CH:29]=[C:28]([NH:30][C:31](=O)[O:32]C2C=CC=CC=2)[O:27][N:26]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([NH:19][C:31]([NH:30][C:28]2[O:27][N:26]=[C:25]([C:24]([F:41])([F:23])[F:40])[CH:29]=2)=[O:32])[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: O=C(Nc1cc(C(F)(F)F)no1)Oc1ccccc1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(F)(F)F)no4)c3)c2cc1OC
Yield: 6 %

Procedure:
According to the procedure described in Example 113C, 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (104 mg, 0.35 mmol) and phenyl 3-(trifluoromethyl)isoxazol-5-ylcarbamate described in Example 229A (124 mg, 0.45 mmol) were reacted to give 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-(trifluoromethyl)isoxazol-5-yl)urea (9.23 mg, 6%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.90 (bs, 1H), 9.30 (bs, 1H), 8.59 (bs, 1H), 7.8-7.20 (m, 5H), 7.06 (bs, 1H), 6.50 (s, 1H), 4.09 (s, 6H); LC-MS (ESI) m/z 476 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:10][N:11](C)[CH2:12]CO.C([Sn](=O)CCCC)CCC>>[CH3:1][N:2]([CH2:3][C:4]([O:6][CH2:7][CH2:8][N:11]([CH3:12])[CH3:10])=[O:5])[CH3:9]
Reactant: CCOC(=O)CN(C)C
Reactant: CN(C)CCO
Agent: CCCC[Sn](=O)CCCC
Product: CN(C)CCOC(=O)CN(C)C
Temperature: 130 °C

Procedure:
A mixture of 65.5 g (0.5 mol) of ethyl N,N-dimethylglycinate, 44.6 g (0.5 mol) of N,N-dimethylethanolamine and 0.82 g of dibutyltin oxide was heated at about 130° C. The ethanol by-product was collected in a Dean-Stark trap. When the rate of ethanol evolution and amount of ethanol collected showed that the reaction was essentially complete, the reaction was heated at about 180° C. until ethanol evolution ceased. The liquid product was purified by distillation at reduced pressure to provide 2-(N,N-dimethylamino)ethyl N,N-dimethylaminoacetate.
Reaction SMILES: CC(C)([O-])C.[K+].Cl[C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)=[C:10]([NH2:23])[N:9]=1.[CH3:24][O:25][CH2:26][CH2:27][OH:28]>>[CH3:24][O:25][CH2:26][CH2:27][O:28][C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)=[C:10]([NH2:23])[N:9]=1
Reactant: Nc1nc(Cl)nc2c1ncn2C1CCCCO1
Reactant: COCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: COCCOc1nc(N)c2ncn(C3CCCCO3)c2n1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
Potassium tert.-butoxide (46.5 g, 475 mmol) was added to 2-methoxyethanol (200 mL) in 20 min at room temperature, then 2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (30 g) was added and the resulted mixture was heated at 80-90° C. for about 3 h. Evaporation of most of the solvent, to the residue was added 100 ml of water, stirred for 1 h at 0° C., filtered and dried. This gave product (30 g, 87%) that was almost identical to that from Intermediate 119, method A.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[Na+].[Na+].[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[C:13]#[N:14]>C(O)C>[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[C:13](=[N:2][OH:3])[NH2:14]
Reactant: NO
Reactant: N#Cc1ccccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: NC(=NO)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 32 g (0.46 moles) hydroxylamine hydrochloride and 49 g (0.46 moles) sodium carbonate in ethanol (about 200 ml) was stirred at room temperature for several minutes; then, 52.4 g (0.381 moles) chlorobenzonitrile was added slowly. The reaction mixture was heated to reflux and allowed to reflux about 6 hours. The reaction mixture was cooled at room temperature and suction-filtered. The solids were washed with acetone. The acetone washings were combined with the filtrate; the combined filtrate-washings were stripped. Acetone (about 200 ml) was added to the residue; the resulting mixture was allowed to sit overnight at room temperature. The mixture was filtered. The filtrate was stripped to give the crude product which was washed with hexane and ethyl ether, suction-filtered, and then air-dried to give the above-identified product as an off-white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@@H:8]([NH:17][C:18]([C@@H:20]2[CH2:25][CH2:24][CH2:23][N:22]([C:26](=[O:42])[CH2:27][CH2:28][CH:29]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]3)[CH2:21]2)=[O:19])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:5]=[N:6][CH:7]=1.[C:43]([C:45]1[CH:46]=[C:47]([OH:51])[CH:48]=[CH:49][CH:50]=1)#[CH:44]>CN(C=O)C.C(N)CCC.CS(C)=O.[Cu](I)I.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:13]([O:12][C:10](=[O:11])[CH2:9][C@H:8]([NH:17][C:18]([C@@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26](=[O:42])[CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:39])[CH3:40])=[O:36])[CH2:31][CH2:30]2)[CH2:21]1)=[O:19])[C:4]1[CH:5]=[N:6][CH:7]=[C:2]([C:44]#[C:43][C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([OH:51])[CH:46]=2)[CH:3]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(Br)c1
Reactant: C#Cc1cccc(O)c1
Agent: I[Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCN
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(C#Cc2cccc(O)c2)c1
Yield: 91.2 %

Procedure:
To a degassed solution of tert-butyl 4-[3-((3R)-3-{[(1S)-1-(5-bromopyridin-3-yl)-3-tert-butoxy-3-oxopropyl]carbamoyl}piperidin-1-yl)-3-oxopropyl]piperidine-1-carboxylate (example 27c, 300 mg, 0.46 mmol), copper iodide (13 mg, 70 μmol) and tetrakis(triphenylphosphine) palladium(0) (53 mg, 50 μmol) in DMF (1.5 mL) and n-butyl amine (0.68 mL) was added a solution of 3-ethynylphenol (103 mg, 0.88 mmol) in DMF (1.0 mL) over 35 minutes at 100° C. After 5 additional minutes at 100° C. the mixture was diluted with DMSO and purified by preparative HPLC to yield 289 mg of tert-butyl 4-{3-[(3R)-3-{[(1S)-3-tert-butoxy-1-{5-[(3-hydroxyphenyl)ethynyl]pyridin-3-yl}-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.
Reaction SMILES: [I:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[CH2:7]([O:9][CH:10]([O:13][CH2:14][CH3:15])[CH2:11]Br)[CH3:8].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.O>[CH2:7]([O:9][CH:10]([O:13][CH2:14][CH3:15])[CH2:11][N:5]1[CH:6]=[C:2]([I:1])[N:3]=[CH:4]1)[CH3:8]
Reactant: Ic1c[nH]cn1
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(Cn1cnc(I)c1)OCC
Temperature: 110 °C
Yield: 71 %

Procedure:
To a stirred solution of 4-iodoimidazole (10 g, 51.6 mmol) and bromoacetaldehyde diethyl acetal (9.31 mL) in DMSO (30 mL) was added K2CO3 (10.69 g, 77 mmol). The reaction mixture was heated at 110° C. for 16 h. After cooling to RT, the reaction mixture was diluted with water and extracted with AcOEt. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 80 g cartridge; AcOEt/Hex:0/100 to 50/50 over 20 CV). The desired fractions were collected and concentrated to afford title compound 260 (11.29 g, 36.4 mmol, 71% yield) as yellow oil. MS (m/z): 310.97 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]([CH:11]1[CH2:13][CH2:12]1)[NH2:10].CCN(C(C)C)C(C)C.CN([CH:26]=[O:27])C>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[C:26](=[O:27])[NH:10][CH:9]2[CH:11]1[CH2:13][CH2:12]1
Reactant: CN(C)C=O
Reactant: NC(c1cc(Cl)ccc1Br)C1CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1NC(C2CC2)c2cc(Cl)ccc21
Temperature: 130 °C
Yield: 68.7 %

Procedure:
A mixture of (2-bromo-5-chlorophenyl)(cyclopropyl)methanamine (2 g, 7.7 mmol), Pd(dppf)Cl2 (0.2 g), DIPEA (3 g, 23.1 mmol) in 20 mL of DMF was heated in an autoclave at 130° C. under 2 MPa of CO (g) for 16 hours. After the reaction, the mixture was diluted with AcOEt (150 mL) and washed with brine (30 mL×3). The organic layer was dried over anhy. Na2SO4, filtered, and concentrated in vacuo to give a crude product which was purified by chromatography to give title compound (1.1 g, yield 68.7%) as a yellow solid. MS: 207.9 (M+H+, 1C1).
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[Br:11]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:11][C:4]1[O:3][C:2]([CH3:1])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccoc1C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)oc1C
Temperature: 25 °C
Yield: 72.2 %

Procedure:
To a solution of methyl 2-methyl-3-furoate (7.0 g) in N,N-dimethylformamide (50 mL) was added N-bromosuccinimide (10.7 g) over 45 min under ice-cooling, and the mixture was stirred under ice-cooling for 30 min and at room temperature overnight. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was collected, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 5% ethyl acetate/hexane) to give the title compound (7.9 g, 72%) as an oil.