Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]23[CH:17]4[CH2:18][CH:14]([CH2:15][CH2:16]4)[CH:13]2[CH2:12][N:11](C)[CH2:10]3)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1(C)C=CC=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]23[CH:17]4[CH2:18][CH:14]([CH2:15][CH2:16]4)[CH:13]2[CH2:12][N:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:10]3)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)Cl
Reactant: CN1CC2C3CCC(C3)C2(c2ccc(Cl)c(Cl)c2)C1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)N1CC2C3CCC(C3)C2(c2ccc(Cl)c(Cl)c2)C1

Procedure:
To a solution of 5.0 g of 3a-(3,4-dichlorophenyl)octahydro-2-methyl-4,7-methano-1H-isoindole in 200 ml of toluene was added, dropwise over a 30 minute period, at room temperature, 30 ml of a solution of freshly distilled ethyl chloroformate in toluene. The reaction mixture was heated under reflux for 16 hours, then was concentrated in vacuo to give a colorless, viscous liquid. This liquid was dissolved in dichloromethane and chromatographed by preparative liquid chromatography on a silica gel column, eluting with 10% ethyl acetate/hexane and gave 1.9 g of 3a-(3,4-dichlorophenyl)octahydro-4,7-methano-2H-isoindole-2-carboxylic acid, ethyl ester as a slightly yellow, viscous liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[C:4]([O:20][CH3:21])[CH:3]=1.[F:22][C:23]([F:38])([F:37])[C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[N:32]=1)[C:27](O)=[O:28]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH2:15][C:16]([F:18])([F:17])[F:19])[C:27](=[O:28])[C:26]2[CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[N:32]=[C:24]([C:23]([F:38])([F:22])[F:37])[CH:25]=2)=[C:4]([O:20][CH3:21])[CH:3]=1
Reactant: COc1cc(F)ccc1-c1ccncc1NCC(F)(F)F
Reactant: O=C(O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Product: COc1cc(F)ccc1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from [4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-yl]-(2,2,2-trifluoro-ethyl)-amine (example 133, intermediate a) and 2,6-bis(trifluoromethyl)isonicotinic acid (Key Organics Ltd.) after a reaction time of 96 hours. The compound was purified by silica gel chromatography on a 20 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50). Light brown solid (44%). MS (ESI): m/z=542.09 [M+H]+.
Reaction SMILES: [F:1][C:2]1[S:6][C:5]([NH2:7])=[N:4][CH:3]=1.[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl>[F:1][C:2]1[S:6][C:5]([NH:7][CH2:14][C:13]2[CH:16]=[CH:17][C:10]([O:9][CH3:8])=[CH:11][CH:12]=2)=[N:4][CH:3]=1
Reactant: Nc1ncc(F)s1
Reactant: COc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(CNc2ncc(F)s2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.1 %

Procedure:
To a solution of 5-fluorothiazol-2-amine (15.0 g, 127 mmol) and 4-methoxybenzaldehyde (17.3 g, 127 mmol, Spectrochem) in dichloromethane (1.0 L) was added TiCl(O-iPr)3 (66.1 g, 254 mmol, Aldrich). The mixture was stirred at room temperature for 3 h. The reaction mixture was cooled to 0° C. and NaBH(OAc)3 (108 g, 508 mmol) was added in portions and stirred at room temperature for 16 h. The reaction mixture (in portions of 200 mL) was quenched with saturated NaHCO3 solution (100 mL) and extracted with dichloromethane (2×500 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude material which was further purified by column chromatography (silica gel 100 to 200 mesh and 50 to 100% dichloromethane in hexanes) to obtain 5-fluoro-N-(4-methoxybenzyl)thiazol-2-amine (20.0 g, 45%) as brown solid. 1H NMR (400 MHz, DMSO) δ 7.84 (t, J=5.7 Hz, 1H), 7.37-7.13 (m, 2H), 6.89 (dd, J=6.4, 2.2 Hz, 2H), 6.77 (d, J=2.4 Hz, 1H), 4.28 (d, J=5.6 Hz, 2H), 3.73 (s, 3H). m/z (ESI) 239.0 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([NH2:16])=[N:12][NH:13][C:14]=2[NH2:15])=[CH:6][CH:5]=1.CN(C)[CH:21]=[CH:22][C:23](=O)[CH3:24].C(O)(=O)C>C(O)C>[CH3:24][C:23]1[CH:22]=[CH:21][N:13]2[N:12]=[C:11]([NH2:16])[C:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:17])[F:18])=[CH:5][CH:6]=3)=[C:14]2[N:15]=1
Reactant: CC(=O)C=CN(C)C
Reactant: Nc1n[nH]c(N)c1-c1ccc(OC(F)(F)F)cc1
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ccn2nc(N)c(-c3ccc(OC(F)(F)F)cc3)c2n1
Temperature: -10 °C

Procedure:
The product from Example 1B (200 mg, 0.775 mmol) was charged to a microwave vial with a stir bar. A solution of 4-(dimethylamino)but-3-en-2-one (175 mg, 1.55 mmol) in ethanol (2 mL) was added, and the mixture was stirred at room temperature as acetic acid (25 ΞL, 0.437 mmol) was added. The solution was irradiated in the microwave at 150° C. for 35 minutes, then cooled to room temperature and finally to −10° C. The precipitate was removed by filtration, and the filtrate was concentrated under vacuum. The residue was purified by flash chromatography (silica gel eluted with hexanes-EtOAc, 70:30-40:60) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.47 (s, 3H), 5.71 (s, 2H), 6.69 (d, J=7.1 Hz, 1H), 7.39 (d, J=8.1 Hz, 2H), 7.87-7.98 (m, 2H), 8.62 (d, J=7.1 Hz, 1H).
Reaction SMILES: [Na].[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.O=[C:12]1[CH2:17][CH2:16][CH:15]([C:18]([O:20]C)=[O:19])[CH2:14][CH2:13]1>CO>[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:12]1[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=[O:19])[CH2:14][CH:13]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: COC(=O)C1CCC(=O)CC1
Agent: [Na]
Solvent: CO
Product: O=C(O)C1CC=C(c2cc3ccccc3[nH]2)CC1
Yield: 28.8 %

Procedure:
To 50 mL of methanol is added sodium (3.32 g, 144.3 mmol). After the metal has dissolved indole (2.89 g, 24.6 mmol) and methyl 4-oxocyclohexanecarboxylate (5.0 g, 32.0 mmol) are added. The mixture is heated to reflux for 3 hours. The methanol is removed under reduced pressure and the residue partitioned between water and methylene chloride. The organic layer is discarded. The aqueous layer is acidified to pH 5 and extracted with three portions of methylene chloride. The combined organics are dried over sodium sulfate and evaporated to give 4-indolyl-3-cyclohexenecarboxylic acid (1.71 g). The material is hydrogenated in methanol (75 mL) under 50 psi of hydrogen int he presence of 5% palladium on carbon (0.5 g). After filtration and removal of solvent, the product is obtained as a mixture of diastereomers.
Reaction SMILES: C(#N)C.N1C=CC=CC=1.F.[C:11]([C:13]1[CH2:27][C@@H:26]([O:28][Si](C(C)(C)C)(C)C)[C@H:25](/[CH:36]=[CH:37]/[C@@H:38]([O:46][Si](C(C)(C)C)(C)C)[CH2:39][C@H:40]([CH3:45])[CH2:41][CH2:42][CH2:43][CH3:44])[C:14]=1[S:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])#[N:12]>N1C=CC=CC=1>[C:11]([C:13]1[CH2:27][C@@H:26]([OH:28])[C@H:25](/[CH:36]=[CH:37]/[C@@H:38]([OH:46])[CH2:39][C@H:40]([CH3:45])[CH2:41][CH2:42][CH2:43][CH3:44])[C:14]=1[S:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])#[N:12]
Reactant: CCCC[C@@H](C)C[C@@H](/C=C/[C@@H]1C(SCCCCCC(=O)OC)=C(C#N)C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: F
Solvent: c1ccncc1
Solvent: CC#N
Product: CCCC[C@@H](C)C[C@H](O)/C=C/[C@@H]1C(SCCCCCC(=O)OC)=C(C#N)C[C@H]1O
Reaction time: 15 h
Yield: 86.8 %

Procedure:
To a solution of ice-cooled acetonitrile (2 mL) and pyridine (0.2 mL) was added hydrogen fluoride-pyridine (0.2 mL). To this solution was added methyl (11R,12S,13E,15S,17R)-9-cyano-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate (170 mg, 0.261 mmol) in pyridine (0.2 mL). The ice bath was removed and the solution was agitated for 15 hours while returning it to room temperature. The reaction solution was poured into a mixture of ethyl acetate and saturated aqueous sodium hydrogencarbonate. The desired product was extracted from this mixed solution with ethyl acetate. The extract was washed with brine, then dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, then was purified by silica gel column chromatography (40 to 50% ethyl acetate/hexane) to obtain methyl (11R,12S,13E,15S,17R)-9-cyano-11,15-dihydroxy-17,20-dimethyl-7-thiaprosta-8,13-dienoate 96 mg, 87%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:4]=1[CH2:5][N:6]([C:30]1[CH:35]=[CH:34][N:33]=[CH:32][N:31]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:22][CH2:21][CH2:20][C@@H:19]2[C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)=[CH:12][C:11]=1[F:29])(=[O:9])=[O:8]>CCCCCC.C(O)(C)C>[CH3:1][O:2][C:3]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:4]=1[CH2:5][N:6]([C:30]1[CH:35]=[CH:34][N:33]=[CH:32][N:31]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@@H:18]2[CH2:22][CH2:21][CH2:20][C@H:19]2[C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)=[CH:12][C:11]=1[F:29])(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Solvent: CC(C)O
Solvent: CCCCCC
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@@H]3CCC[C@H]3c3ccnn3C)cc2F)c(OC)c1

Procedure:
The N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide prepared in Example 14c was optically resolved with CHIRALPAK AD (Daicel Corp.; hexane/isopropanol=4:1), to yield the title compound as a colorless oil.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[NH:5][CH:6]=[C:7]([CH3:12])[C:8]=1[C:9](=[O:11])[CH3:10].I[CH3:14].O>CS(C)=O>[CH3:14][N:5]1[CH:6]=[C:7]([CH3:12])[C:8]([C:9](=[O:11])[CH3:10])=[C:4]1[CH3:3]
Reactant: CC(=O)c1c(C)c[nH]c1C
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)c1c(C)cn(C)c1C
Reaction time: 0.08 h
Yield: 96 %

Procedure:
KOH (818 mg, 14.6 mmol) was partially dissolved in DMSO (115 mL) and stirred for 5 min. 1-(2,4-dimethyl-1H-pyrrol-3-yl)-ethanone (1 g, 7.3 mmol) was added in small portions and the mixture was stirred for 45 min. Iodomethane (0.54 mL, 8.75 mmol) was added dropwise at such a rate as to maintain the internal temperature ≦30° C. The mixture was stirred for a further 45 min then poured into H2O (50 mL) and extracted with Et2O (3×60 mL). The combined organic extracts were washed (brine), dried (MgSO4), filtered, and evaporated in vacuo to afford 1-(1,2,4-trimethyl-1H-pyrrol-3-yl)-ethanone (1.06 g) as a pink solid. This was suspended in 1,1-bis-dimethylamino-3,3-dimethyl-butan-2-one (3.6 mL, 17.5 mmol) in a N2-flushed flask and heated at 70° C. for 36 h. The mixture was evaporated in vacuo and the residue triturated in EtOAc. The titled compound (973 mg) was obtained as a reddish solid. 1H-NMR (DMSO-d6) δ: 1.30 (s, 3H, CH3), 1.51 (s, 3H, CH3), 2.20 (br. s, 6H, CH3), 2.66 (s, 3H, CH3), 4.57 (d, 1H, J=12.5 Hz, CH), 5.53 (s, 1H, pyrrolyl-H), 6.72 (d, 1H, J=12.7 Hz, CH).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][N:3]=1.C(O[CH:15]=[C:16]([C:22]#[N:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])C.CCCCCC>C1(C)C=CC=CC=1>[C:22]([C:16](=[CH:15][NH:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][N:3]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])#[N:23]
Reactant: Nc1nccc2c1CCCC2
Reactant: CCOC=C(C#N)C(=O)OCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCOC(=O)C(C#N)=CNc1nccc2c1CCCC2
Temperature: 105 °C
Yield: 75.6 %

Procedure:
A solution of 1-amino-5,6,7,8-tetrahydroisoquinoline [2.96 g., 0.02 mole; E. Ochiai and Y. Kawazoe, Pharm. Bull. (Tokyo), 5, 606 (1957)] and ethyl ethoxymethylenecyanoacetate (3.38 g., 0.02 mole) in toluene (8 ml.) was heated by means of an oil bath maintained at 105° C. for 15 minutes. The cooled solution was poured into Skellysolve B (175 ml.) with good stirring. The mixture was triturated and cooled with an ice bath. The mixture was filtered and the collected gummy solid recrystallized from cyclohexane to give the title compound (4.1 g., 75%), m.p. 116°-120° C. The product was recrystallized from cyclohexane to give analytical material, m.p. 121°-123° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]=[C:13]([O:17][CH3:18])[C:14]=1[O:15][CH3:16])[CH:6]=[C:7]([C:10]#[N:11])[C:8]#[N:9].[OH:19][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][CH:24]=[N:25]2>>[NH2:9][C:8]1[O:19][C:20]2[C:21]3[CH:22]=[CH:23][CH:24]=[N:25][C:26]=3[CH:27]=[CH:28][C:29]=2[CH:6]([C:5]2[CH:12]=[C:13]([O:17][CH3:18])[C:14]([O:15][CH3:16])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:7]=1[C:10]#[N:11]
Reactant: COc1cc(C=C(C#N)C#N)cc(OC)c1OC
Reactant: Oc1cccc2ncccc12
Product: COc1cc(C2C(C#N)=C(N)Oc3c2ccc2ncccc32)cc(OC)c1OC

Procedure:
The title compound was prepared from 3,4,5-trimethoxybenzylidenemalononitrile (244 mg, 1 mmol) and 5-hydroxyquinoline by a procedure similar to that described for Example 145. 1H NMR (CDCl3): 8.96 (m, 1H), 8.52 (d, J=8.7, 1H), 7.82 (d, J=9.0, 1H), 7.52 (m, 1H), 7.33 (d, J=8.7, 1H), 6.43 (s, 2H), 4.83 (m, 3H), 3.83 (s, 3H), 3.80 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH3:9])=[C:7]([C:10]2[N:14]=[CH:13][NH:12][N:11]=2)[O:6][N:5]=1)[CH3:2].C(N(CC)CC)C.[C:22](Cl)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[CH2:1]([O:3][C:4]1[C:8]([CH3:9])=[C:7]([C:10]2[N:14]=[CH:13][N:12]([C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:11]=2)[O:6][N:5]=1)[CH3:2]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOc1noc(-c2nc[nH]n2)c1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1noc(-c2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 100.5 %

Procedure:
3-(3-Ethoxy-4-methylisoxazol-5-yl)-1H-1,2,4-triazole (1.1 g, 5.7 mmol), triethylamine (2.5 mL, 18 mmol) and DMF (20 mL) was added trityl chloride (1.6 g, 5.7 mmol) in DMF (5 mL). The mixture was stirred at room temperature for 5 h and poured onto an ice/water mixture (200 mL). The aqueous phase was extracted with diethyl ether (3×200 mL) and the organic extracts were washed with an aqueous solution of Na2CO3 (10%) (200 mL) and brine (200 mL). The solution was dried (Na2SO4) and concentrated in vacuo to give crude title compound (2.5 g). A small sample was crystallized (EtOAc) to give a single isomer as colourless crystals: mp 181-183° C. The crude product was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([O:25][C:26](=[O:28])[CH3:27])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2].C1C(=O)N([Cl:36])C(=O)C1>CC#N>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:25][C:26](=[O:28])[CH3:27])=[C:8]2[C:16]([Cl:36])=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2cccc(F)c2)c1OC(C)=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CCOC(=O)c1nc(C#N)c2c(c(Cl)cn2Cc2cccc(F)c2)c1OC(C)=O

Procedure:
Prepared in analogy to that of Example 124(a) from 4-acetoxy-7-cyano-1-(3-fluoro-benzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester and NCS in MeCN. The title compound, ESI MS (m/z): 416 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:30])[CH3:29])=[O:9])=[C:4](I)[CH:3]=1.[CH2:34]([OH:37])[C:35]#[CH:36]>>[F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:30])[CH3:29])=[O:9])=[C:4]([C:36]#[C:35][CH2:34][OH:37])[CH:3]=1
Reactant: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1I)c(OCc1ccccc1)c2=O
Reactant: C#CCO
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1C#CCO)c(OCc1ccccc1)c2=O
Yield: 84.4 %

Procedure:
Reaction of intermediate 174, N-(4-fluoro-2-iodobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.563 g, 1.00 mmol) with propargyl alcohol (0.18 ml, 3.2 mmol) using the conditions described for intermediate 178 gave 0.415 g (85% yield) of the title material as a white solid. 1HNMR 400 MHz (CDCl3) δ ppm: 1.64 (6H, s, 2×CH3), 4.04 (4H, m, 2×CH2), 4.39 (2H, d, J=6.6 Hz, CH2), 4.68 (2H, d, J=6.0 Hz, CH2), 5.29 (2H, s, OCH2), 6.99 (1H, m, aromatic), 7.13 (1H,dd, J=2.5 Hz and J=9.1 Hz, aromatic), 7.22 (1H,dd, J=5.6 Hz and J=8.6 Hz, aromatic), 7.33–7.37 (3H, m, aromatics), 7.44–7.47 (2H, m, aromatics), 7.68 (1H, broad t, NH). HRMS (ESI+) calculated for C27H27FN3O5 [M+H+]: 492.1935. found: 492.1939.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([OH:23])=O)[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.Cl.[NH2:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44]([NH:47][C:48]2[N:53]=[C:52]([NH2:54])[CH:51]=[CH:50][N:49]=2)=[CH:43][CH:42]=1.CCN(C(C)C)C(C)C>ClCCCl>[NH2:54][C:52]1[CH:51]=[CH:50][N:49]=[C:48]([NH:47][C:44]2[CH:45]=[CH:46][C:41]([CH2:40][NH:39][C:21]([C:18]3[CH:17]=[C:16]([CH2:15][N:13]([S:10]([C:6]4[C:5]([CH3:24])=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=4[CH3:9])(=[O:12])=[O:11])[CH3:14])[O:20][CH:19]=3)=[O:23])=[CH:42][CH:43]=2)[N:53]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Reactant: NCc1ccc(Nc2nccc(N)n2)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)NCc3ccc(Nc4nccc(N)n4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AE using 5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (60 mg, 0.16 mmol), CDI (48 mg, 0.29 mmol), N2-[4-(aminomethyl)phenyl]pyrimidine-2,4-diamine dihydrochloride (46 mg, 0.15 mmol) and DIPEA (0.17 mL, 0.97 mmol) in DCE (2 mL).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.CO.CC(O)=O.[Br:19]Br>>[Br:19][C:4]1[CH:3]=[C:2]([CH3:1])[CH:11]=[C:10]2[C:5]=1[C:6](=[O:12])[NH:7][CH:8]=[N:9]2
Reactant: BrBr
Reactant: Cc1ccc2c(=O)[nH]cnc2c1
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(Br)c2c(=O)[nH]cnc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.9 %

Procedure:
To a solution of 7-methylquinazolin-4(3H)-one (900 mg, 5.63 mmol) in MeOH (180 mg, 5.63 mmol) and AcOH (5.07 g, 84.45 mmol) was added bromine (300 μL, 5.63 mmol) and the reaction mixture was stirred at rt for 4 h. Then the reaction mixture was quenched with an aq. solution of sodium thiosulphate. The precipitate obtained was filtered and dried to afford 900 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 12.24 (br s, 1H), 8.18 (s, 1H), 8.08 (s, 1H), 7.66 (s, 1H), 2.48 (s, 3H).
Reaction SMILES: ClC1[CH:3]=[C:4](C=CC=1)[C:5]([OH:7])=O.C(O[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)C=C>C(Cl)Cl>[C:27]([C:24]1[CH:23]=[CH:22][C:21]([C:18]2[CH:17]=[CH:16][C:15]([CH2:3][CH:4]3[O:7][CH2:5]3)=[CH:20][CH:19]=2)=[CH:26][CH:25]=1)#[N:28]
Reactant: C=CCOc1ccc(-c2ccc(C#N)cc2)cc1
Reactant: O=C(O)c1cccc(Cl)c1
Solvent: ClCCl
Product: N#Cc1ccc(-c2ccc(CC3CO3)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.4 %

Procedure:
20 g of m-chlorobenzoic acid was added to a reaction mixture obtained by dissolving 19 g of 4-allyloxy-4′-cyanobiphenyl in 150 mL of methylene chloride as divided into several times, and the mixture was stirred at room temperature for 24 hours. Insoluble matters thus deposited were removed by filtration, and water was added thereto. After separating the mixture, the organic layer was washed with a saturated aqueous solution of sodium hydrosulfite and then dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain a residue, which was purified by silica gel column chromatography and then subjected to recrystallization from ethanol to obtain 13 g of 4-cyano-4′-glycidylbiphenyl.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[CH3:19][O:20][C:21](=[O:28])[C@H:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[NH2:23]>>[CH3:19][O:20][C:21](=[O:28])[C@@H:22]([NH:23][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[C:24]([CH3:27])([CH3:26])[CH3:25]
Reactant: COC(=O)[C@@H](N)C(C)(C)C
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Agent: Cl
Product: COC(=O)[C@@H](NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1)C(C)(C)C

Procedure:
The title compound was synthesized in analogy to Example 6, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g) and 3-methyl-L-valine methyl ester hydrochloride (1:1) (CAN 63038-27-7) as starting materials, and isolated (98 mg, 91%) as light yellow oil; LC-MS (UV peak area, ESI) 100%, 362.2081 (M+H).
Reaction SMILES: [CH3:1][S:2]([C:5](C(OC)=O)([CH2:16][CH2:17][CH2:18][CH:19]([O:29]CC1C=CC=CC=1)[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]C)=[O:13])(=[O:4])=[O:3].[Cl-].[Na+].CN(C)C=O>O>[CH3:1][S:2]([CH:5]([CH2:16][CH2:17][CH2:18][CH:19]([OH:29])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])(=[O:4])=[O:3]
Reactant: COC(=O)CCCCCCC(CCCC(COc1ccc(F)cc1)OCc1ccccc1)(C(=O)OC)S(C)(=O)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)C(CCCCCCC(=O)O)CCCC(O)COc1ccc(F)cc1
Temperature: 160 °C

Procedure:
A mixture of methyl 8-methylsulfonyl-8-methoxycarbonyl-12-benzyloxy-13-(4-fluorophenoxy)tridecanoate (2.60 g., 4.5 mmoles), sodium chloride (0.5 g., 8.5 mmoles), dimethylformamide (8 ml.) and water (0.2 ml.) is heated with an oil bath at 160° C. overnight (ca. 15 hours). The reaction mixture is allowed to cool to room temperature, quenched with cold water, and then extracted with chloroform three times. The combined extracts are washed with brine and dried over anhydrous magnesium sulfate. The solvent is removed by evaporation in vacuo leaving the desired product as a viscous oil residue (2.30 g., 4.4 mmoles, 98%). ir (neat) 3.40, 5.72, 6.20, 6.62, 6.87, 7.71, 8.00, 8.28, 8.90, 12.04, 13.17, 14.37μ; pmr (CCl4) δ 1.0-2.9 (22H, m, containing a methyl singlet at 2.60 δ), 3.54 (3H, s); 3.5-4.1 (3H, m), 4.47 (1H, d, J=12Hz), 4.70 (1H, d, J= 12Hz), 6.6-7.1 (4H, m), 7.20 (5H, s).
Reaction SMILES: O.NN.[CH3:4][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[C:11]2[N+:16]([O-])=O.C.NN>C(O)C>[NH2:16][C:11]1[C:12]2[C:7](=[C:6]([O:5][CH3:4])[CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: COc1cccc2c([N+](=O)[O-])cccc12
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1cccc2c(N)cccc12
Temperature: 50 °C

Procedure:
Hydrazine hydrate (150 ml) is added slowly to a stirred mixture of 5-methoxy-1-nitro-naphthalene (320 g), and palladized charcoal (0.1 g) in 95% ethanol (2 liters) previously warmed to 50° C. When the hydrazine addition is complete, additional palladized charcoal (0.1 g) is added and the mixture heated to reflux for about one hour. The reaction mixture is filtered through Celite and the filtrate evaporated in vacuo resulting in a white solid which is recrystallized from H2O and ethanol.