Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[NH2:12].[F:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.O>N1C=CC=CC=1>[CH3:11][C:6]1[C:5]([NH:12][S:21]([C:18]2[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=2)(=[O:23])=[O:22])=[C:4]([CH:9]=[C:8]([Br:10])[CH:7]=1)[C:3]([OH:2])=[O:13]
Reactant: COC(=O)c1cc(Br)cc(C)c1N
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1cc(Br)cc(C(=O)O)c1NS(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.7 %

Procedure:
To a solution of 25.0 g (0.102 mol) of 2-amino-3-methyl-5-bromobenzoic acid methyl ester (U.S. Pat. No. 5,776,961) in 300 mL of pyridine was added 21.93 g (0.113 mol) of 4-fluorobenzenesulfonyl chloride. The reaction mixture was stirred for 18 h at 80°, cooled to room temperature and poured into water. The resulting mixture was extracted with ethyl acetate and the combined organics were then washed with 5% HCl solution and water. The organic layer was then dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:3) to provide 14.53 g (39%) of the desired product as a tan solid. Electrospray Mass Spec: 388.0 (M−H)−
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]([CH:10]2[CH2:12][CH2:11]2)[CH2:8][CH3:9])=[C:4]([CH3:15])[CH:3]=1.[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18]>C(N(CC)CC)C.[Cu]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>[CH:10]1([N:7]([CH2:8][CH3:9])[CH2:6][C:5]2[CH:13]=[CH:14][C:2]([C:21]#[C:20][Si:17]([CH3:19])([CH3:18])[CH3:16])=[CH:3][C:4]=2[CH3:15])[CH2:12][CH2:11]1
Reactant: C#C[Si](C)(C)C
Reactant: CCN(Cc1ccc(Br)cc1C)C1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCN(Cc1ccc(C#C[Si](C)(C)C)cc1C)C1CC1
Temperature: 70 °C
Yield: 98.6 %

Procedure:
Using General Procedure D; (4-bromo-2-methyl-benzyl)-cyclopropyl-ethyl-amine (Intermediate 159, 620.0 mg, 2.31 mmols) in triethylamine (8 mL) was treated with copper(I)iodide (44.0 mg, 0.23 mmol) and then sparged with argon for 15 minutes. Trimethylsilylacetylene (1.04 g, 10.6 mmols) was then added followed by dichlorobis-(triphenylphosphine)palladium(II) (162.0 mg, 0.23 mmol). The resulting reaction mixture was heated to 70° C. for 5 days. The title compound (650.0 mg, 98%) was isolated by chromatography (1-4% EtOAc-hexanes).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=[O:15])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH2:18]([O:20][C:21](=[O:28])[CH2:22][CH2:23][CH2:24][CH2:25]CBr)[CH3:19]>CN(C=O)C>[CH2:18]([O:20][C:21](=[O:28])[CH2:22][CH2:23][CH2:24][CH2:25][C:9]1([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:15])[CH3:19]
Reactant: CCOC(=O)CCCCCBr
Reactant: COc1cccc(C2CCCCC2=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCC1(c2cccc(OC)c2)CCCCC1=O
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
2-(3-Methoxy-phenyl)-cyclohexanone (0.80 g, 4.05 mmol) was added slowly to a suspension of NaH (60%) (0.185 g, 5.1 mmol) in anhydrous DMF (5 mL) at 0° C. under Ar over 15 min. After an additional 15 min. at 20° C. 6-bromohexanoic acid ethyl ester (1.0 g, 4.5 mmol) was added followed by stirring at 60° C. for 6 hr. The reaction mixture was cooled, quenched with saturated NH4Cl solution, partitioned between EtOAc (150 mL) and H2O (100 mL), the organic layer washed with H2O (2×100 mL), dried (Na2SO4), filtered, and concentrated to dryness to give the title compound after silica gel chromatography eluting with hexane:EtOAc, 50:1 to 10:1.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[CH3:26][N:27]([CH3:31])[C:28]([NH2:30])=[O:29]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:30][C:28](=[O:29])[N:27]([CH3:31])[CH3:26])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: CN(C)C(N)=O
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC(=O)N(C)C)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 1,1-dimethylurea. MS obsd. (ESI+) [(M+H)+] 425, 1H NMR (400 MHz, CD3OD) δ ppm 7.83 (d, J=7.6 Hz, 1 H), 7.68 (t, J=3.6 Hz, 2 H), 7.42 (q, J=7.2 Hz, 2 H), 7.23-7.20 (m, 2 H), 7.15 (s, 1 H), 5.00 (s, 2 H), 4.45 (brs, 2 H), 3.42 (s, 2 H), 3.02 (s, 6 H), 2.30 (s, 3 H).
Reaction SMILES: Cl.[NH:2]1[CH:6]=[C:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[N:4]=[CH:3]1.[C:12]1([C:18](Cl)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.O>CN(C=O)C>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:5]1[N:4]=[CH:3][N:2]([C:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:6]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)Cc1c[nH]cn1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.5 %

Procedure:
A solution of 2.78 g (19.80 mmol) of the compound from example 1c, 5.52 g (19.80 mmol) of triphenylmethyl chloride and 2.00 g (19.80 mmol) of triethylamine in 5 ml of DMF was stirred at RT overnight, then poured into 200 ml of water and stirred at RT for one hour. The precipitate which separated out was filtered off with suction. The filtrate was extracted three times with EA. The combined organic phases were dried over Na2SO4, filtered and concentrated. The yellow oil resulting from this and the precipitate were combined and chromatographed on silica gel. 4.2 g of the desired compound resulted.
Reaction SMILES: [C:1](ON=O)(C)([CH3:3])[CH3:2].C(Br)C=C.[CH3:12][O:13][C:14]1[CH:20]=[CH:19][C:17](N)=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22].NC1C=CC=CC=1>CC#N>[CH2:3]([C:17]1[CH:19]=[CH:20][C:14]([O:13][CH3:12])=[C:15]([N+:21]([O-:23])=[O:22])[CH:16]=1)[CH:1]=[CH2:2]
Reactant: COc1ccc(N)cc1[N+](=O)[O-]
Reactant: CC(C)(C)ON=O
Solvent: Nc1ccccc1
Solvent: CC#N
Solvent: C=CCBr
Product: C=CCc1ccc(OC)c([N+](=O)[O-])c1
Temperature: 37.5 °C
Reaction time: 1 h
Yield: 39.7 %

Procedure:
To a solution of t-butylnitrite (535 μl, 4.5 mmol) and allyl bromide (3.9 ml, 45.0 mmol) in CH3CN (3 ml), 4-methoxy-3-nitroaniline (504 mg, 3.0 mmol) was added during 20 minutes, while maintaining the temperature of the reaction mixture at 35-40° C. At the end of the addition of the aniline, extra t-butylnitrite (180 μl, 1.5 mmol) was added to the reaction mixture which then was stirred at 40° C. for one hour. The volatile material in the reaction mixture was removed at reduced pressure. The crude product was dissolved in ethyl acetate-heptane (1:2, 20 ml) and filtered through a pad of silica. The solvent was removed at reduced pressure. Column chromatography (heptane-ethyl acetate 97:3) gave 230 mg (40%) allyl-4-methoxy-3-nitrobenzene as a yellow oil. 1H NMR (CDCl3, 400 MHz) δ 7.45, (d, 1H, J=2.7 Hz), 7.27, (d, 1H, J=8.6 Hz), 7.10, (dd, 1H, J=8.6, 2.7 Hz), 6.02-5.90, (m, 1H), 5.12-5.02, (m, 2H), 3.86, (s, 3H), 3.62, (m, 2H, J=6.4 Hz); 13C NMR (CDCl3, 100 MHz) δ 158.8, 150.0, 135.9, 133.2, 127.2, 120.2, 117.1, 109.6, 56.2, 36.8; Anal HRMS Calcd. for C10H11NO3 (M): 193.0739. Found: 193.0743
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:17][OH:18])[CH:5]=[C:6]([F:16])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1.Cl[C:20]1[CH:21]=[C:22]2[N:29]([CH3:30])[C@@H:28]([CH3:31])[CH2:27][N:23]2[C:24](=[O:26])[N:25]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:16])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1)[CH2:17][O:18][C:20]1[CH:21]=[C:22]2[N:29]([CH3:30])[C@@H:28]([CH3:31])[CH2:27][N:23]2[C:24](=[O:26])[N:25]=1
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C
Reactant: OCc1cc(F)c(Oc2cccc(F)c2)c(F)c1
Product: C[C@H]1Cn2c(cc(OCc3cc(F)c(Oc4cccc(F)c4)c(F)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3,5-difluoro-4-(3-fluorophenoxy)phenyl)methanol and (S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:9][C:8]=2[Cl:19])[N:5]=[C:4]([C:20]#[N:21])[C:3]=1[C:22]#[C:23][Si](C)(C)C.[F-]>ClCCl.O1CCCC1>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([O:14][C:15]([F:16])([F:18])[F:17])=[CH:9][C:8]=2[Cl:19])[N:5]=[C:4]([C:20]#[N:21])[C:3]=1[C:22]#[CH:23]
Reactant: C[Si](C)(C)C#Cc1c(C#N)nn(-c2c(Cl)cc(OC(F)(F)F)cc2Cl)c1N
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C#Cc1c(C#N)nn(-c2c(Cl)cc(OC(F)(F)F)cc2Cl)c1N

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethoxyphenyl)-4-trimethylsilylethynylpyrazole (0.4657 g) in dichloromethane (5 ml) cooled in an ice-water bath was slowly added tetra-n-butylamntmonium fluoride (1.07 ml of a 1M solution in tetrahydrofuran). After five minutes the ice-water bath was removed. Stirring was continued for ten minutes then the reaction mixture was washed with water. The aqueous layer was washed with dichloromethane. The combined organic layers were washed with brine, dried (Na2SO4) and evaporated to provide the title compound as an oily solid which upon drying in an oven crystallised to a white solid, m.p. 175.7-176.1° C.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[CH3:13][C:14]([C:17]1[CH:18]=[C:19]([CH:24]=[C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:26]=1[OH:27])[C:20]([NH:22][NH2:23])=[O:21])([CH3:16])[CH3:15].C(N(CC)CC)C>O1CCCC1>[CH3:16][C:14]([C:17]1[CH:18]=[C:19]([C:20]2[O:21][C:1](=[O:2])[NH:23][N:22]=2)[CH:24]=[C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:26]=1[OH:27])([CH3:13])[CH3:15]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)c1cc(C(=O)NN)cc(C(C)(C)C)c1O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(-c2n[nH]c(=O)o2)cc(C(C)(C)C)c1O
Yield: 51.7 %

Procedure:
1,1'-Carbonyl diimidazole (0.8 g, 0.005 mole) is added in one portion to a stirred 0° C. solution of 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzoic acid hydrazide (1.0 g, 0.004 mole) and triethylamine (0.6 ml, 0.004 mole) in tetrahydrofuran (12 ml). After 18 hours the mixture is concentrated in vacuo and the residue dissolved in ether. The solution is washed with aqueous 2M HC, saturated aqueous NaHCO3, saturated aqueous NaCl, and dried over MgSO4. Filtered and concentrated in vacuo to obtain a residue which is purified by flash chromatography using 10% ethyl acetate/hexane eluent. Recrystallize from ethyl acetate/hexane to obtain 0.6 g (1.1 g theor., 55%) 5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-oxadiazol-2(3H)-one, mp 246° C.
Reaction SMILES: ClCC([NH:5][C:6]([CH3:16])([CH3:15])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=O.Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1>[Cl:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][C:6]([CH3:16])([NH2:5])[CH3:15])=[CH:13][CH:12]=1
Reactant: CC(C)(Cc1ccc(Cl)cc1)NC(=O)CCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(N)Cc1ccc(Cl)cc1
Temperature: 105 °C
Reaction time: 16 h
Yield: 38.1 %

Procedure:
To a mixture of 2-chloro-N-(1-(4-chlorophenyl)-2-methylpropan-2-yl)acetamide (259 mg, 1.00 mmol) in dioxane (5.0 mL) was added conc. hydrochloric acid (20 mL). After stirring at 105° C. for 16 hours, the reaction mixture was poured onto ice and basified by the addition of saturated aq. sodium bicarbonate to pH>8. The mixture was extracted with ethyl acetate and the combined organic fractions were washed with water, dried over sodium sulfate and concentrated under vacuum. The crude product was then purified by reverse phase flash chromatography (0 to 25% acetonitrile in aq. 0.01% formic acid) to give 1-(4-chlorophenyl)-2-methylpropan-2-amine (70 mg, 38% yield) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][CH:9]([CH3:11])[CH3:10])=[N:6][CH:7]=1.[OH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH:21]([NH:23][C:24](=[O:26])[CH3:25])[CH3:22])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.[Cu](Br)Br>[CH:9]([O:8][C:5]1[N:4]=[CH:3][C:2]([O:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][CH:21]([NH:23][C:24](=[O:26])[CH3:25])[CH3:22])=[CH:17][CH:18]=2)=[CH:7][N:6]=1)([CH3:11])[CH3:10]
Reactant: CC(=O)NC(C)CCc1ccc(O)cc1
Reactant: CC(C)Oc1ncc(Br)cn1
Agent: Br[Cu]Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CC(=O)NC(C)CCc1ccc(Oc2cnc(OC(C)C)nc2)cc1
Reaction time: 3 h

Procedure:
5-Bromo-2-isopropoxypyrimidine (100 mg, 0.46 mmol), N-[3-(4-hydroxyphenyl)-1-methylpropyl]acetamide (95 mg, 0.46 mmol), cesium carbonate (180 mg, 0.552 mmol), copper bromide (66 mg, 0.46 mmol) were stirred in 5 ml of NMP at 160° C. under argon for 5 h. Following addition of equimolar amounts of the components stirring was continued at 160° C. for a further 3 h. The batch was filtered, the filtrate was concentrated and admixed with ethyl acetate and water, and the organic phase was separated off, concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 3 mg (1%), M+H+: 344.23.
Reaction SMILES: Cl[C:2]1[C:3]([F:23])=[CH:4][C:5]2[C:6]([CH:22]=1)=[N:7][C:8]1[N:9]([CH:19]3[CH2:21][CH2:20]3)[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>N1C=CC=CC=1>[CH:19]1([N:9]2[C:8]3[N:7]=[C:6]4[CH:22]=[C:2]([N:28]5[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]5)[C:3]([F:23])=[CH:4][C:5]4=[CH:14][C:13]=3[C:12](=[O:15])[C:11]([C:16]([OH:18])=[O:17])=[CH:10]2)[CH2:21][CH2:20]1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1cn(C2CC2)c2nc3cc(Cl)c(F)cc3cc2c1=O
Solvent: c1ccncc1
Product: CN1CCN(c2cc3nc4c(cc3cc2F)c(=O)c(C(=O)O)cn4C2CC2)CC1
Yield: 52.9 %

Procedure:
1-Cyclopropyl-7-fluoro-8-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is prepared under the conditions of Example 5 but starting from 1 g of 8-chloro-1-cyclopropyl-7-fluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid and 3 g of 1-methylpiperazine in 10 cm3 of pyridine. After recrystallizing from 10 cm3 of dimethylformamide, 0.63 g of 1-cyclopropyl-7-fluoro-8-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is obtained in the form of a yellow solid melting at 250° C.
Reaction SMILES: C(OC([N:7]1[CH2:12][CH:11]=[C:10]([C:13]2[N:14]=[C:15]([S:18][C:19]3[C@H:25]([CH3:26])[C@H:24]4[N:21]([C:22](=[O:30])[C@@H:23]4[C@H:27]([OH:29])[CH3:28])[C:20]=3[C:31]([O:33]CC=C)=[O:32])[S:16][CH:17]=2)[CH2:9][C@@H:8]1[CH2:37][OH:38])=O)C=C.C(O)(=O)C.C([SnH](CCCC)CCCC)CCC.P([O-])([O-])([O-])=O>ClCCl>[OH:29][C@@H:27]([C@H:23]1[C:22](=[O:30])[N:21]2[C@@H:24]1[C@@H:25]([CH3:26])[C:19]([S:18][C:15]1[S:16][CH:17]=[C:13]([C:10]3[CH2:9][C@H:8]([CH2:37][OH:38])[NH:7][CH2:12][CH:11]=3)[N:14]=1)=[C:20]2[C:31]([OH:33])=[O:32])[CH3:28]
Reactant: C=CCOC(=O)C1=C(Sc2nc(C3=CCN(C(=O)OCC=C)[C@@H](CO)C3)cs2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: CCCC[SnH](CCCC)CCCC
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(Sc3nc(C4=CCN[C@@H](CO)C4)cs3)[C@H](C)[C@H]12
Temperature: 0 °C
Yield: 58.3 %

Procedure:
To a solution of allyl (4R,5S,6S)-3-({4-[(2R)-1-[(allyloxy)carbonyl]-2-(hydroxymethyl)-1,2,3,6-tetrahydro-4-pyridinyl]-1,3-thiazol-2-yl}sulfanyl)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (110 mg, 0.20 mmol) in dichloromethane (15 ml) were added acetic acid (28 μl) and tributyltin hydride (0.54 ml, 2.6 mmol) and then was added at room temperature bis(triphenylphosphine)palladium chloride(II) (14 mg, 0.020 mmol). Ten minutes later the reaction mixture was poured into a mixture of ice (10 g) and phosphate buffer (pH7.0, 10 ml). After separation of the mixture with a separating funnel, the organic layer was extracted twice with water and the aqueous layer was washed twice with dichloromethane (3 ml). The organic solvent in the aqueous layer was evaporated under reduced pressure, and the residue was purified by polymer chromatography (CHP-20P). The fractions eluted with 1–3% aqueous THF solution were combined and lyophilized to give (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-3-({4-[(2R)-2-(hydroxymethyl)-1,2,3,6-tetrahydro-4-pyridinyl]-1,3-thiazol-2-yl}sulfanyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (51 mg, yield 54%) as a white amorphous.
Reaction SMILES: CN(C)C=O.[C:6]([O:10][C:11](=[O:46])[N:12]([CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][N:32]2[C:41]3[C:36](=[C:37](Br)[CH:38]=[C:39]([O:42][CH3:43])[CH:40]=3)[CH:35]=[CH:34][C:33]2=[O:45])[CH2:26][CH2:25]1)[CH2:13][C:14]1[CH:23]=[CH:22][C:17]2[O:18][CH2:19][CH2:20][O:21][C:16]=2[CH:15]=1)([CH3:9])([CH3:8])[CH3:7].[C:47]([O:51][CH2:52][CH3:53])(=[O:50])[CH:48]=[CH2:49]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.C(N(CC)CC)C>[C:6]([O:10][C:11]([N:12]([CH2:13][C:14]1[CH:23]=[CH:22][C:17]2[O:18][CH2:19][CH2:20][O:21][C:16]=2[CH:15]=1)[CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][N:32]2[C:41]3[C:36](=[C:37](/[CH:49]=[CH:48]/[C:47]([O:51][CH2:52][CH3:53])=[O:50])[CH:38]=[C:39]([O:42][CH3:43])[CH:40]=3)[CH:35]=[CH:34][C:33]2=[O:45])[CH2:26][CH2:25]1)=[O:46])([CH3:9])([CH3:8])[CH3:7]
Reactant: C=CC(=O)OCC
Reactant: COc1cc(Br)c2ccc(=O)n(CCN3CCC(N(Cc4ccc5c(c4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cc(OC)cc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Temperature: 90 °C

Procedure:
To 4.0 mL of an N,N-dimethylformamide solution containing 0.15 g of tert-butyl(1-(2-(5-bromo-7-methoxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)carbamate, 39 μl of ethyl acrylate, 50 μL of triethylamine and 6.1 mg of bis(tri-tert-butylphosphine)palladium(0) were added and heated under nitrogen atmosphere at 90° C. for 1.5 hours. The reaction mixture was cooled to the room temperature, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=20:1] to give 0.15 g of ethyl (2E)-3-(1-(2-(4-((tert-butoxycarbonyl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-2-oxo-1,2-dihydroquinolin-5-yl)acrylate as a light brown foam.
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:7])[CH2:4][CH2:5][CH3:6].[CH3:8][CH:9]1[CH2:14][CH2:13][CH2:12][C:11]([CH3:16])([CH3:15])[C:10]1=[O:17]>>[OH:17][C:10]1([C:1]#[C:2][CH:3]([OH:7])[CH2:4][CH2:5][CH3:6])[C:11]([CH3:16])([CH3:15])[CH2:12][CH2:13][CH2:14][CH:9]1[CH3:8]
Reactant: CC1CCCC(C)(C)C1=O
Reactant: C#CC(O)CCC
Product: CCCC(O)C#CC1(O)C(C)CCCC1(C)C

Procedure:
the addition of hex-1-yn-3-ol to 2,6,6-trimethylcyclohexanone to give 1-(1-hydroxy-2,6,6-trimethylcyclohexyl)-hex-1-yn-3-ol;
Reaction SMILES: C[O:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[C:11]([C:12]3[CH:17]=[C:16]([CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:15]=[CH:14][C:13]=3[NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:10][N:9]([CH3:30])[C:8]=12.Cl>CO>[CH3:30][N:9]1[C:8]2[C:3](=[O:2])[NH:4][CH:5]=[CH:6][C:7]=2[C:11]([C:12]2[CH:17]=[C:16]([CH2:18][S:19]([CH3:22])(=[O:20])=[O:21])[CH:15]=[CH:14][C:13]=2[NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:10]1
Reactant: COc1nccc2c(-c3cc(CS(C)(=O)=O)ccc3Nc3ccccn3)cn(C)c12
Agent: Cl
Solvent: CO
Product: Cn1cc(-c2cc(CS(C)(=O)=O)ccc2Nc2ccccn2)c2cc[nH]c(=O)c21
Temperature: 75 °C
Reaction time: 3.5 h
Yield: 99.9 %

Procedure:
A mixture of Example 79a (0.062 g, 0.147 mmol) in methanol (1 mL) was treated with hydrogen chloride solution (4 M in 1,4-dioxane) (1 mL, 4 mmol) and heated at 75° C. for 2.5 hours. Additional hydrogen chloride solution (4 M in 1,4-dioxane) (1 mL, 4 mmol) was added and heating was continued for another 3.5 hours. The reaction mixture was concentrated to dryness to provide 0.06 g (92%) of the title compound as the HCl salt.
Reaction SMILES: COC([N:5]1[CH2:9][CH:8]([C:10]2[C:18]3[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH:7]2[N:20]([C:23](=[O:39])[CH:24]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:21][CH2:22][CH:6]12)=O.C([O-])([O-])=O.[K+].[K+].Br[CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49]>C(#N)C.O>[CH2:51]([O:50][C:48](=[O:49])[CH2:47][N:5]1[CH2:9][CH:8]([C:10]2[C:18]3[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH:7]2[N:20]([C:23](=[O:39])[CH:24]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:21][CH2:22][CH:6]12)[CH3:52]
Reactant: CCOC(=O)CBr
Reactant: COC(=O)N1CC(c2c[nH]c3cc(F)ccc23)C2C1CCN2C(=O)C(NC(=O)OC(C)(C)C)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)CN1CC(c2c[nH]c3cc(F)ccc23)C2C1CCN2C(=O)C(NC(=O)OC(C)(C)C)C1CCCCC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 82.9 %

Procedure:
A solution containing amine 50 (200 mg, 0.41 mmol) in ACN (5 mL) was cooled to 0° C. K2CO3 (63 mg, 0.46 mmol) was added followed by ethyl bromoacetate (75 mg, 0.45 mmol) and the reaction mixture was warmed to ambient temperature. After 16 h, the reaction mixture was diluted with water and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash silica gel chromatography (1:1 hexanes/EtOAc) to afford 194 mg (82%) of 58 as an off-white-colored foam. 1H NMR (300 MHz, CDCl3), mixture of amide rotamers: δ8.50 (s, 0.8H), 8.29 (s, 0.2H), 7.55 (dd, J=5.4, 8.7 Hz, 1H), 7.11 (s, 1H), 6.99 (d, J=9.0 Hz, 0.2H), 6.82 (d, J=9.6 Hz, 0.8H), 5.30-5.24 (m, 1H), 4.85-4.82 (m, 1H), 4.34 (t, J=6.0 Hz, 1H), 4.23-4.07 (m, 2H), 3.93 (t, J=8.7 Hz, 1H), 3.68-3.64 (m, 2H), 3.59-3.54 (m, 2H), 3.44-3.40 (m, 2H), 2.82 (app t, J=9.0 Hz, 1H), 2.05-2.01 (m, 1H), 1.83-1.65 (m, 6H), 1.38 (s, 9H), 1.28 (t, J=6.9 Hz, 3H), 1.24-1.05 (m, 2H) ppm. Mass spectrum, m/z [571.4] (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([O:5][N:6]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][C:26]2[N:27]=[C:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:29][C:30]=2[CH3:31])=[CH:19][CH:18]=1)[C:7]([NH:9][C:10]1[CH:15]=CC=C[CH:11]=1)=[O:8])=[O:4].C1(N(O)C(N)=O)C=CC=CC=1>>[CH3:15][CH:10]([NH:9][C:7]([N:6]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][C:26]2[N:27]=[C:28]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[O:29][C:30]=2[CH3:31])=[CH:19][CH:18]=1)[O:5][C:3]([O:2][CH3:1])=[O:4])=[O:8])[CH3:11]
Reactant: COC(=O)ON(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)Nc1ccccc1
Agent: NC(=O)N(O)c1ccccc1
Product: COC(=O)ON(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)NC(C)C

Procedure:
By the same method, N-(methoxycarbonyloxy)-N-(phenylaminocarbonyl) -4-[2-(5-methyl-2-phenyl-4-oxazolyl) ethoxy]benzylamine is prepared from the corresponding phenyl-hydroxyurea of Preparation J.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[C:10]([F:16])[CH:9]=2)=[C:4]([Cl:17])[C:3]=1[N+:18]([O-])=O>CC(O)=O.C1COCC1.O.[Zn]>[NH2:18][C:3]1[C:4]([Cl:17])=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[C:10]([F:16])[CH:9]=2)[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: N#Cc1ccc(-c2ccc(N)c([N+](=O)[O-])c2Cl)cc1F
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(-c2ccc(N)c(N)c2Cl)cc1F
Temperature: 25 °C
Yield: 103.1 %

Procedure:
To a cooled solution (0° C.) of zinc dust (9.34 g, 143 mmol) in AcOH (33 mL), THF (33 mL) and water (9.5 mL) was added 4′-amino-2′-chloro-3-fluoro-3′-nitrobiphenyl-4-carbonitrile (Preparation 93, 2.6 g, 8.93 mmol) and the reaction was allowed to warm to room temperature for 1 hour before filtering through arbocel. The filtrate was diluted with water (200 mL) and EtOAc (200 mL) and the organic layer was collected, dried over MgSO4 and concentrated in vacuo to afford the title compound (2.41 g, quant).