Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([C:13]#[N:14])[C:8](=[O:12])[NH:9][C:10]=1[CH3:11])=O.[NH2:15][C:16]([NH2:18])=[S:17]>CN(C)C=O>[NH2:18][C:16]1[S:17][CH:2]=[C:3]([C:5]2[CH:6]=[C:7]([C:13]#[N:14])[C:8](=[O:12])[NH:9][C:10]=2[CH3:11])[N:15]=1
Reactant: NC(N)=S
Reactant: Cc1[nH]c(=O)c(C#N)cc1C(=O)CBr
Solvent: CN(C)C=O
Product: Cc1[nH]c(=O)c(C#N)cc1-c1csc(N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.6 %

Procedure:
A mixture containing 25.4 g of 5-bromoacetyl-1,2-dihydro-6-methyl-2-oxo-3-pyridinecarbonitrile, 7.9 g of thiourea and 100 ml of dimethylformamide was heated on a steam bath for 3 hours and then evaporated to dryness. The residual material was diluted with 100 ml of water followed by the addition of 10 ml of concentrated aqueous ammonium hydroxide. The resulting mixture was reacidified with acetic acid and the solid that separated was collected, washed with water and dried. The solid (15.8 g) was suspended in 400 ml of water and the mixture treated with 25 ml of concentrated ammonium hydroxide. The resulting mixture was stirred for 30 minutes and a small quantity of insoluble material was filtered off. The filtrate was concentrated on a rotary evaporator to a volume of about 200 ml and allowed to cool to room temperature. The crystalline precipitate was collected, washed with distilled water and dried in a vacuum oven at 90° C. to produce 7.3 g of 5-(2-amino-4-thiazolyl)-1,2-dihydro-6-methyl-2-oxo-3-pyridinecarbonitrile, m.p. 294°-296° C. with decomposition.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][O:12][CH3:13])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C([Li])CCC.C([O:22][B:23]([O:28]C(C)C)[O:24]C(C)C)(C)C.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH2:11][O:12][CH3:13])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:22][B:23]([OH:28])[OH:24]
Reactant: COCc1cc(OC)cc(OC)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCc1cc(OC)c(OB(O)O)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3,5-dimethoxy(methoxymethyl)benzene (23.7 g) in tetrahydrofuran (500 mL) was added n-butyllithium (1.56M hexane solution; 100 mL) at −78° C., and the reaction mixture was stirred for 30 minutes while cooling with ice. After cooling the internal temperature of the obtained reaction mixture to −78° C., to a reaction mixture was added triisopropoxyborane (39 mL), and the internal temperature was raised to room temperature while stirring. After completion of the reaction, saturated aqueous ammonium chloride was added to the reaction mixture while cooling with ice, and then ethyl acetate was added to the reaction mixture, the organic extract was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and the title compound (7.5 g) was obtained as a yellow oil from the ethyl acetate fraction.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].F[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1.C(=O)([O-])O.[Na+].CS(C)=O>O>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH:5][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: COC(CN)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(CNc1ccc([N+](=O)[O-])cc1)OC
Reaction time: 12 h
Yield: 95.6 %

Procedure:
To 5.05 g (0.048 mole) of aminoacetaldehyde dimethylacetal were added 5.64 g (0.040 mole) of p-fluoronitrobenzene, 4.03 g (0.048 mole) of sodium hydrogencarbonate and 5 ml of dimethyl sulfoxide and reaction was carried out at 80° C. for 12 hours. After the reaction, the reaction mixture was poured into 100 ml of water to precipitate a yellow solid. The solid was dissolved in 150 ml of benzene, and the solution was washed with a liquid mixture comprising 50 ml of water and 1 ml of hydrochloric acid and with 50 ml of water two times. The residual benzene layer was dried with anhydrous sodium carbonate. After the drying, the benzene layer was concentrated and the obtained yellow solid was washed with hexane and dried under reduced pressure to obtain 8.65 g (the yield was 95.6%) of a crystal of 4-nitrophenylaminoacetaldehyde dimethyl acetal.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH3:6][O:7][C:8]1[CH:9]=[C:10](/[CH:20]=[CH:21]/[C:22]([NH:24][CH2:25][C:26]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)=O)=O)[CH:11]=[CH:12][C:13]=1[N:14]1[CH:18]=[C:17]([CH3:19])[N:16]=[CH:15]1>C(O)(=O)C>[CH3:35][O:34][C:31]1[CH:32]=[CH:33][C:28]([C:26]2[N:5]=[C:22](/[CH:21]=[CH:20]/[C:10]3[CH:11]=[CH:12][C:13]([N:14]4[CH:18]=[C:17]([CH3:19])[N:16]=[CH:15]4)=[C:8]([O:7][CH3:6])[CH:9]=3)[NH:24][CH:25]=2)=[CH:29][CH:30]=1
Reactant: COc1ccc(C(=O)CNC(=O)/C=C/c2ccc(-n3cnc(C)c3)c(OC)c2)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: COc1ccc(-c2c[nH]c(/C=C/c3ccc(-n4cnc(C)c4)c(OC)c3)n2)cc1
Temperature: 120 °C
Reaction time: 12 h
Yield: 15.7 %

Procedure:
Ammonium acetate (379 mg) was added to a solution of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-[2-(4-methoxyphenyl)-2-oxoethyl]acrylamide (100 mg) in acetic acid (3 mL), and the reaction solution was stirred at 120° C. for 12 hours. The reaction solution was concentrated. Ethyl acetate and saturated sodium bicarbonate water were added to the resulting residue, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: ethyl acetate:2-propanol=20:1) to obtain 15 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: Cl[C:2]1[N:24]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[C:13]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[N:14][CH:15]=[CH:16][CH:17]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[N:25]1([CH2:30][CH2:31][O:32][C:33]2[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:23][N:18]([C:13]1[C:12]([CH2:11][NH:10][C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:39][C:36]4[CH:37]=[CH:38][C:33]([O:32][CH2:31][CH2:30][N:25]5[CH2:29][CH2:28][CH2:27][CH2:26]5)=[CH:34][CH:35]=4)[N:24]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:17][CH:16]=[CH:15][N:14]=1)[S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Reactant: CN(c1ncccc1CNc1cccn2nc(Cl)nc12)S(C)(=O)=O
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN(c1ncccc1CNc1cccn2nc(Nc3ccc(OCCN4CCCC4)cc3)nc12)S(C)(=O)=O

Procedure:
N-Methyl-N-[3-({2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino}-methyl)-pyridin-2-yl]-methanesulfonamide was prepared from N-{3-[(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-pyridin-2-yl}-N-methyl-methanesulfonamide and 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (51.0 mg, 0.247 mmol) (prepared as described in J. Med. Chem., 2006, 49, 4451-4454) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.021 g, 19%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.42-8.39 (m, 1H), 7.85 (d, J=7.6 z, 1H), 7.80 (d, J=6.6 Hz, 1H), 7.48 (d, J=8.9 Hz, 2H), 7.30-7.25 (m, 1H), 6.92 (d, J=9.0 Hz, 2H), 6.64 (t, J=7.4 Hz, 1H), 6.52 (s, 1H), 6.29 (d, J=7.8 Hz, 1H), 5.27 (t, J=6.2, 1H), 4.77 (d, J=6.4 Hz, 2H), 4.10 (t, J=6.0 Hz, 2H), 3.32 (s, 3H), 3.09 (s, 3H), 2.90 (t, J=6.0 Hz, 2H), 2.68-2.58 (m, 4H), 1.86-1.76 (m, 4H). MS=537 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[CH3:12].[ClH:15].[Cl:16][CH2:17][C:18]([CH3:25])([OH:24])[CH2:19][NH:20][CH:21]([CH3:23])[CH3:22].C(N(CC)CC)C>[OH-].[Na+]>[ClH:16].[ClH:15].[OH:24][C:18]([CH3:25])([CH2:19][NH:20][CH:21]([CH3:23])[CH3:22])[CH2:17][NH:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[CH3:12]
Reactant: COc1cc(N)c2nccc(C)c2c1
Reactant: CC(C)NCC(C)(O)CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Product: COc1cc(NCC(C)(O)CNC(C)C)c2nccc(C)c2c1
Reaction time: 24 h

Procedure:
A stirred mixture of 10.7 g (0.057 mole) of 8-amino-6-methoxy-4-methylquinoline and 11.7 g (0.057 mole) of 3-chloro-2-methyl-1-(2-propylamino)propan-2-ol, hydrochloride was heated in an oil bath (150°) for 1 hr while 5.8 g (0.057 mole) of triethylamine was added, dropwise. The reaction mixture was stirred at 150° for 24 hrs, cooled, basified with 30 ml of 5% aqueous sodium hydroxide, then extracted with dichloromethane (3×100 ml). The organic extracts were combined, washed with water (2×200 ml), dried over anhydrous magnesium sulfate, then concentrated in vacuo to 50 ml. The solution was chromatographed on a column (60 cm× 7.5 cm) of silica gel (2.5 kg; activity III) using dichloromethane (10 l) followed by methanol-concentrated ammonium hydroxide (25:1) (7 l) as the eluent. The fractions (1 l each) 13-18 were combined then concentrated in vacuo to an oil. The oil was dissolved in ether (100 ml), and the solution was washed with water (2×200 ml), dried over anhydrous magnesium sulfate, then saturated with anhydrous hydrogen chloride. The solid that separated was collected on a filter, dried, then recrystallized from 300 ml of absolute ethanol; yield 4.6 g; mp 232°-234°, dec.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7](=[O:9])[CH3:8])[O:4][N:3]=1.[Br-:10].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.O1CCCC1>O>[Br:1][C:2]1[CH:6]=[C:5]([C:7](=[O:9])[CH2:8][Br:10])[O:4][N:3]=1
Reactant: [Br-]
Reactant: CC(=O)c1cc(Br)no1
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(CBr)c1cc(Br)no1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.7 %

Procedure:
A mixture of 3-bromo-5-acetylisoxazole (which was obtained in Example 117) (16.7 g, 87.9 mmol), phenyltrimethylammonium tribromide (33.4 g, 88.8 mmol) and tetrahydrofuran (150 mL) was stirred at ambient temperature for 18 hours, poured into water and extracted with ether. The organic extracts were washed with brine and dried over MgSO4. Evaporation and purification by distillation gave a light yellow oil (8.9 g, 40% yield); 1H NMR (300 MHz, CDCl3) δ 4.40. (s, 3H), 7.10 (s, 1H).
Reaction SMILES: [NH:1]1[C:11]2[C:12]3[C:3]([CH2:4][NH:5][CH2:6][C:7]=3[CH:8]=[CH:9][CH:10]=2)=[CH:2]1.C(N(CC)CC)C.[Cl:20][CH2:21][CH2:22][C:23](Cl)=[O:24].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Cl:20][CH2:21][CH2:22][C:23]([N:5]1[CH2:4][C:3]2=[CH:2][NH:1][C:11]3[C:12]2=[C:7]([CH:8]=[CH:9][CH:10]=3)[CH2:6]1)=[O:24]
Reactant: c1cc2c3c(c[nH]c3c1)CNC2
Reactant: O=C(Cl)CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(CCCl)N1Cc2cccc3[nH]cc(c23)C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 1,3,4,5-tetrahydropyrrolo[4,3,2-de]isoquinoline (3.24 g), described in Example 5, in chloroform (350 ml), triethylamine (6.0 ml) is added, followed by dropwise addition of 3-chloropropionyl chloride (4.2 ml). The mixture is stirred at room temperature for 2.5 hr. Aqueous sodium bicarbonate is added and the stirring is continued for 15 minutes. The layers are separated and the organic phase washed with water, dried and concentrated to give 4-(3-chloropropionyl)-1,3,4,5-tetrahydropyrrolo[4,3,2-de]isoquinoline, mp 158°-161°C after recrystallizaton from chloroform.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:14](=[O:16])[CH3:15])[CH:8]=[C:9]([OH:13])[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].Br[CH2:18][CH2:19][CH2:20][O:21][CH3:22]>>[C:1]([C:5]1[CH:6]=[C:7]([C:14](=[O:16])[CH3:15])[CH:8]=[C:9]([O:13][CH2:18][CH2:19][CH2:20][O:21][CH3:22])[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(O)cc(C(C)=O)cc1C(C)(C)C
Reactant: COCCCBr
Product: COCCCOc1cc(C(C)=O)cc(C(C)(C)C)c1OC
Yield: 56.6 %

Procedure:
1-(3-tert-Butyl-5-hydroxy-4-methoxyphenyl)ethanone (O3.070; 2.00 g) and 1-bromo-3-methoxypropane (1.65 g) were converted, worked up and purified analogously to O2.110. 1.50 g of the title compound were obtained.
Reaction SMILES: N#N.[CH2:3]([O:5][C:6]([C:8]1[S:9][CH:10]=[C:11]([CH2:13][N:14]2[CH:18]=[C:17]([NH2:19])[CH:16]=[N:15]2)[N:12]=1)=[O:7])[CH3:4].CCN(C(C)C)C(C)C.[CH:29]1[CH:34]=[C:33]([CH2:35][O:36][C:37](Cl)=[O:38])[C:32]([Cl:40])=[CH:31][CH:30]=1>C(Cl)Cl>[CH2:3]([O:5][C:6]([C:8]1[S:9][CH:10]=[C:11]([CH2:13][N:14]2[CH:18]=[C:17]([NH:19][C:37]([O:36][CH2:35][C:33]3[CH:34]=[CH:29][CH:30]=[CH:31][C:32]=3[Cl:40])=[O:38])[CH:16]=[N:15]2)[N:12]=1)=[O:7])[CH3:4]
Reactant: O=C(Cl)OCc1ccccc1Cl
Reactant: CCOC(=O)c1nc(Cn2cc(N)cn2)cs1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1nc(Cn2cc(NC(=O)OCc3ccccc3Cl)cn2)cs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 4-(4-amino-pyrazol-1-ylmethyl)-thiazole-2-carboxylic acid ethyl ester (1.43 g, 5.65 mmol) in CH2Cl2 (56.0 mL) was treated with DIPEA (1.15 mL, 8.47 mmol) followed by 2-chlorobenzylchloroformate (1.04 mL, 6.78 mmol). The reaction mixture was stirred at rt for 1 h before being quenched with water (50 mL), extracted with CH2Cl2 (3×40 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (96:4 CH2Cl2-MeOH) gave the title compound as a pink foam. TLC: rf (96:4 CH2Cl2-MeOH)=0.28. LC-MS-conditions 02: tR=0.99 min; [M+H]+=421.14.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:8][C:7]=1[Cl:16].C(N(C(C)C)C(C)C)C>ClCCl>[Cl:16][C:7]1[CH:8]=[C:9]([S:12]([NH2:15])(=[O:13])=[O:14])[CH:10]=[CH:11][C:6]=1[N:5]=[C:1]=[O:2]
Reactant: O=C(Cl)Cl
Reactant: Nc1ccc(S(N)(=O)=O)cc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: NS(=O)(=O)c1ccc(N=C=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a round bottom flask containing a solution of phosgene (1.573 mL) in dichloromethane (5 mL) was added 4-amino-3-chlorobenzenesulfonamide (0.206 g) and N-ethyl-N-isopropylpropan-2-amine (0.521 mL). The resulting clear solution was stirred at room temperature overnight. The mixture was concentrated and further dried under vacuum to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:18]([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH:13]=[C:12]2[C:28]1[CH:33]=[N:32][CH:31]=[C:30](Cl)[N:29]=1.[NH:35]1[CH2:40][CH2:39][CH:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:37][CH2:36]1>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:18]([C:21]1[CH:22]=[CH:23][C:24]([CH3:25])=[CH:26][CH:27]=1)(=[O:19])=[O:20])[CH:13]=[C:12]2[C:28]1[N:29]=[C:30]([N:35]2[CH2:36][CH2:37][CH:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:46])([CH3:45])[CH3:47])[CH2:39][CH2:40]2)[CH:31]=[N:32][CH:33]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(Cl)n3)c3cc(-c4c(F)cccc4Cl)ccc32)cc1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CS(C)=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(N4CCC(NC(=O)OC(C)(C)C)CC4)n3)c3cc(-c4c(F)cccc4Cl)ccc32)cc1
Reaction time: 1 h
Yield: 70.5 %

Procedure:
A slurry of 5-(2-chloro-6-fluorophenyl)-3-(6-chloropyrazin-2-yl)-1-tosyl-1H-indole (Ref, 0.200 g, 0.390 mmol) and tert-butyl piperidin-4-ylcarbamate (Combi-blocks Inc., 0.313 g, 1.561 mmol) in 2 mL DMSO in a sealed tube was heated to 130° C. The solids dissolved and the reaction became a yellow solution. After 1 h, reaction was complete by LCMS. The reaction was cooled and partitioned between water and EtOAc. The organic layer was washed with water once, satd NaHCO3 once, satd NaCl once, and the organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was suspended in MeOH and filtered, rinsing 1×1 mL MeOH. The solid was collected and dried in vacuo to give tert-butyl 1-(6-(5-(2-chloro-6-fluorophenyl)-1-tosyl-1H-indol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamate (0.186 g, 0.275 mmol, 70.5% yield) as a light yellow solid. MS (ESI, pos. ion) m/z: 676 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([CH2:8][O:9][C:10]([CH:12]2[N:16]3[C:17](=[O:22])[C@H:18]([C@H:19]([OH:21])[CH3:20])[C@H:15]3[C@@H:14]([CH3:23])[C:13]2=O)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:51][N:52]1[CH2:56][C@H:55]([SH:57])[CH2:54][C:53]1=[S:58].P([O-])([O-])([O-])=O>C(#N)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([C:12]2[N:16]3[C:17](=[O:22])[C@H:18]([C@H:19]([OH:21])[CH3:20])[C@H:15]3[C@@H:14]([CH3:23])[C:13]=2[S:57][C@H:55]2[CH2:56][N:52]([CH3:51])[C:53](=[S:58])[CH2:54]2)=[O:11])=[CH:25][CH:26]=1)([O-:3])=[O:2]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: CN1C[C@H](S)CC1=S
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@@H]3CC(=S)N(C)C3)[C@H](C)[C@H]12
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
(1R, 5R, 6S)-6-[(1R)-1-Hydroxyethyl]-1-methyl-2- oxocarbapenam-3-carboxylic acid 4-nitrobenzyl ester (25.2 g) is dissolved in anhydrous acetonitrile (173 ml), and thereto are added dropwise diisopropylethylamine (13 ml) and diphenylphosphoryl chloride (15.5 ml) in this order under nitrogen gas below 0° C. After stirring the mixture at the same temperature for 30 minutes, a solution of (4R)-N-methyl-4- mercaptopyrrolidine-2-thione (13 g) and diisopropylethylamine (11.5 g) in anhydrous acetonitrile (173 ml) is added dropwise to the reaction mixture below -5° C. After stirring the mixture at 0° C. for 1.5 hour, the reaction mixture is poured into phosphate buffer (pH 7.0, one liter). The precipitated crystal is separated by filtration and dissolved in a mixture of chloroform (2 liters) and tetrahydrofuran (1 liter), and the solution is washed with water, dried and concentrated to dryness under reduced pressure. The residue is crystallized from diethyl ether to give (1R, 5S, 6S)-2-[(4R)-N-methyl- pyrrolidine-2-thion-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen -2-em-3-carboxylic acid 4-nitrobenzyl ester (23.5 g) as colorless needles.
Reaction SMILES: [F:1][C:2]1[C:3](I)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:9]([C:13]1[O:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)[CH2:10][C:11]#[CH:12]>C(N(CC)CC)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[C:3]([C:12]#[C:11][CH2:10][CH2:9][C:13]2[O:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#CCCc1nc2ccccc2o1
Reactant: Fc1cccnc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: Fc1cccnc1C#CCCc1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 15.2 %

Procedure:
In a dry reaction tube containing in suspension copper iodide (28 mg, 0.148 mol) and triethylamine (8.30 mL, 59.20 mmol), were added 3-fluoro-2-iodopyridine (660 mg, 2.96 mmol) and Pd(PPh3)2Cl2 (104 mg, 0.148 mmol) under N2. A yellow suspension was obtained. After a 5 minutes of stirring at room temperature, was added a solution 2-(But-3-ynyl)benzo[d]oxazole (compound 8(A), 510 mg, 3 mmol) in triethylamine (0.2 mL) under N2. Immediately the color of the reaction turns to black. The mixture was stirred at room temperature for 30 min and heated at 50° C. overnight under N2. Triethylamine was removed under reduce pressure and the crude product was purified by flash chromatography (Prepacked column 50 g, Cyclohexane/AcOEt: 60/40 as eluent) following by C18 chromatography (Prepacked column 15 g, H2O/CH3CN: from 80/20 to 40/600 as eluent) to afford 120 mg of 2-(4-(3-fluoropyridin-2-yl)but-3-ynyl)benzo[d]oxazole (Yield: 15%) as white powder (Mp=86-88° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:24])[NH:5][C:6]([C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([O:19][CH2:20][CH2:21]O)=[C:14]([CH3:23])[CH:13]=1)=[N:7]2.C(Br)(Br)(Br)[Br:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C>[Br:26][CH2:21][CH2:20][O:19][C:15]1[C:16]([CH3:18])=[CH:17][C:12]([C:6]2[NH:5][C:4](=[O:24])[C:3]3[C:8](=[CH:9][CH:10]=[CH:11][C:2]=3[Cl:1])[N:7]=2)=[CH:13][C:14]=1[CH3:23]
Reactant: Cc1cc(-c2nc3cccc(Cl)c3c(=O)[nH]2)cc(C)c1OCCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc3cccc(Cl)c3c(=O)[nH]2)cc(C)c1OCCBr
Temperature: 25 °C
Reaction time: 27 h
Yield: 88.8 %

Procedure:
To a solution of 5-chloro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one (0.40 g, 1.16 mmol) in anhydrous DMF (10 mL) was added carbon tetrabromide (0.42 g, 1.27 mmol) and triphenylphosphine (0.33 g, 1.27 mmol). The reaction mixture was stirred at room temperature for 27 hours. Solvent was evaporated to dryness in vacuo and the residue triturated with Et2O (15 mL)/EtOAc (15 mL) to give 2-(4-(2-bromoethoxy)-3,5-dimethylphenyl)-5-chloroquinazolin-4(3H)-one (0.42 g). It was used without further purification. The 1H NMR indicated a purity of about 45%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]([CH3:16])[CH2:11][C:12]([F:15])([F:14])[F:13])=[CH2:9])=[CH:4][CH:3]=1.[OH-:17].[Na+].OO.[Cl-].[Na+]>C1COCC1.O>[F:15][C:12]([F:14])([F:13])[CH2:11][CH:10]([CH3:16])[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)[CH2:9][OH:17]
Reactant: [OH-]
Reactant: C=C(c1ccc(C)cc1)C(C)CC(F)(F)F
Agent: OO
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C(CO)C(C)CC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Under argon, 9.4 g (41.2 mmol) of 1-methyl-4-(5,5,5-trifluoro-3-methylpent-1-en-2-yl)benzene were dissolved in 130 ml of THF, 57.6 ml of a 1 M borane/THF complex solution were added and the mixture was stirred at room temperature for 24 h. With vigorous stirring, initially 79 ml of water, then 24 ml of 6 M aqueous sodium hydroxide solution and finally 14.5 ml (475 mmol) of 30% strength aqueous hydrogen peroxide solution were added. Subsequently, the reaction solution was added to 200 ml of saturated sodium chloride solution, the organic phase was separated off and the aqueous phase was extracted three more times with diethyl ether. The combined organic phases were dried over magnesium sulfate and filtered, and the solvent was removed under reduced pressure. The crude product was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 4:1→2:1). This gave 5 g (20.3 mmol, 49% of theory) of the title compound as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH3:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C)C=O>[CH2:18]([O:1][C:2]1[CH:3]=[C:4]([CH3:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClCc1ccccc1
Reactant: Cc1ccc([N+](=O)[O-])c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1

Procedure:
61.2 g of 3-hydroxy-4-nitrotoluene, 66.3 g of potassium carbonate, and 54.7 ml of benzyl chloride are heated in 800 ml of dimethylformamide to 100° C. for 1.5 hours; after cooling, the mixture is poured into water, and the thus-precipitated material is recrystallized from ethanol, yielding 82.0 g of 3-benzyloxy-4-nitrotoluene, mp 49°-51° C.