Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:55]=[CH:54][C:18]([CH2:19][N:20]2[CH:24]=[C:23](/[CH:25]=[CH:26]/[C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:22]([O:32]CC3C=CC(OCC4N=C(C5C=CC=CC=5)OC=4C)=CC=3)=[N:21]2)=[CH:17][CH:16]=1>[C].[Pd].O1CCCC1>[OH:32][C:22]1[C:23]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:24][N:20]([CH2:19][C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]3[N:4]=[C:5]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[O:6][C:2]=3[CH3:1])=[CH:55][CH:54]=2)[N:21]=1
Reactant: CCOC(=O)/C=C/c1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl(E)-3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1H-pyrazol-4-yl]propenoate (24.15 g), 5% palladium-carbon (34.22 g), and tetrahydrofuran (400 ml) was stirred at room temperature under a hydrogen atmosphere overnight. After removal of the catalyst by filtration, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-hydroxy-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate was obtained from the fraction eluted with ethyl acetate-hexane (2:1, volume ratio) as colorless crystals (13.93 g, yield: 92%). This was recrystallized from tetrahydrofuran-hexane. Melting point: 137–138° C.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].CON([C:9](=[O:26])[C@H:10]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)C.O>C(OCC)C.O1CCCC1>[O:26]=[C:9]([CH2:1][CH3:2])[C@H:10]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH2:11][C:12]1[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=1
Reactant: CC[Mg]Br
Reactant: CON(C)C(=O)[C@@H](Cc1ccncc1)NC(=O)OC(C)(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CCC(=O)[C@@H](Cc1ccncc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 48 h

Procedure:
50 cm3 of a 3N solution of ethyl magnesium bromide dissolved in diethyl ether are added over 1 hour to a mixture, under an inert atmosphere, of 14 g of tert-butyl N-{2-[N-methoxy-N-(methyl)amino]-2-oxo-(1R)-1-(4-pyridylmethyl)ethyl}carbamate in 350 cm3 of tetrahydrofuran, cooled to a temperature in the region of 0° C. After stirring for 48 hours at 0° C., water is added to the reaction medium, the resulting mixture is extracted with dichloromethane and the extracts are washed with water. The organic phase is dried over sodium sulphate, filtered and then concentrated under reduced pressure (2 kPa) at a temperature in the region of 40° C. 10.5 g of tert-butyl N-[(1R)-2-oxo-1-(4-pyridylmethyl)butyl]carbamate are obtained in the form of a yellow oil [1H NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 0.94 (t, J=7 Hz: 3H); 1.32 (s: 9H); from 2.40 to 2.65 (mt: 2H); 2.70 (dd, J=14 and 10.5 Hz: 1H); 3.06 (dd, J=14 and 4.5 Hz: 1H); 4.22 (mt: 1H); 7.26 (broad d, J=5.5 Hz: 2H); 7.44 (broad d, J=8 Hz: 1H); 8.45 (broad d, J=5.5 Hz: 2H)].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH:19]=C)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.ClCCl.C[OH:27]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH:19]=[O:27])[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1
Reactant: C=Cc1cnc2c(c1)C(=O)N(C)c1ccc(Cl)nc1N2CC
Reactant: CO
Solvent: ClCCl
Product: CCN1c2ncc(C=O)cc2C(=O)N(C)c2ccc(Cl)nc21
Temperature: -78 °C
Yield: 81 %

Procedure:
The 2-chloro-5,11-dihydro-11-ethyl-5-methyl-8-vinyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (2.34 g, 7.43 mmol) was dissolved in 1:1 dichloromethane/methanol (40 mL) and cooled to -78° C. This solution was then saturated with ozone and a stream ozone was bubbled through for 10 minutes while stirring. The mixture was warmed to ambient temperature and quenched with excess dimethylsulfide. The mixture was then concentrated and the resulting residue was purified by flash chromatography (gradient of hexanes to 1:1 hexanes/ethyl acetate) to give the title compound (1.9 g, 81%), m.p. 199°-201° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2=[N:15][C:16]3[C:17](=[C:18]([C:22]([O:24]C)=[O:23])[CH:19]=[CH:20][CH:21]=3)[N:13]2[CH2:12][CH2:11][CH2:10]1.[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2=[N:15][C:16]3[C:17](=[C:18]([C:22]([OH:24])=[O:23])[CH:19]=[CH:20][CH:21]=3)[N:13]2[CH2:12][CH2:11][CH2:10]1
Reactant: COC(=O)c1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 90 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A mixture of methyl 1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxylate (Example 81; 10.0 g, 26.6 mmol), methanol (100 mL), 8.0 M aqueous sodium hydroxide (150 mL) was stirred at 90° C. for 2 hr. The mixture was acidified with 6.0 M hydrochloric acid, and the precipitate was collected by filtration, washed with water, washed with ethyl acetate to give the title compound as a colorless powder (8.47 g, 23.4 mmol, 88%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.Cl.[CH3:17][S:18]([NH:21][CH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)(=[O:20])=[O:19].C(N(CC)CC)C>C(O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][N:3]=[C:2]2[N:27]1[CH2:26][CH2:25][CH:24]([CH2:23][CH2:22][NH:21][S:18]([CH3:17])(=[O:20])=[O:19])[CH2:29][CH2:28]1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: CS(=O)(=O)NCCC1CCNCC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(N3CCC(CCNS(C)(=O)=O)CC3)c2cc1OC
Temperature: 25 °C
Yield: 88 %

Procedure:
4-Chloro-6,7-dimethoxy quinazoline (1.1 g.), 4- (2-methanesulphonamidoethyl)piperidine hydrochloride (1.5 g.) and triethylamine (1.5 ml.) in ethanol (30 ml.) were heated together under reflux for 1.5 hours. The solution was then cooled to room temperature, concentrated in vacuo, suspended in water (70 ml.) and basified to pH 10 with 10% aqueous sodium carbonate solution. The mixture was extracted with chloroform (2×70 ml.), the extracts combined, dried (MgSO4), and taken to dryness in vacuo. The resultant pale yellow oil was triturated with ether (70 ml.) to give a white solid which was collected by filtration. Crystallization of this solid from ethanol yielded 6,7-dimethoxy-4-[4-(2-methanesulphonamidoethyl)-piperidino]quinazoline (1.7 g.), m.p. 162°-164° C.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][C:16]=3[O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Cl[C:29]1[N:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][N:30]=1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]12([C:11]3[CH:12]=[C:13]([C:29]4[N:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][N:30]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: OB(O)c1ccc(OCc2ccccc2)c(C23CC4CC(CC(C4)C2)C3)c1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cnc(-c2ccc(OCc3ccccc3)c(C34CC5CC(CC(C5)C3)C4)c2)nc1
Temperature: 90 °C
Yield: 18.7 %

Procedure:
To a solution of 3-(1-adamantyl)-4-benzyloxyphenylboronic acid (1) (833 g, 2.3 mmol) and 2-chloro-5-nitropyrimidine (2) (320 mg, 2.00 mmol) in degassed toluene (15 mL) was added tetrakis(triphenylphosphine)palladium (347 mg, 0.300 mmol), NaHCO3 (336 mg, 4.00 mmol) and degassed H2O (3 mL). The mixture was heated at reflux (90° C. oil-bath) for 24 h, cooled to room temperature and extracted with EtOAc (180 mL). The extract was washed (H2O and brine) and dried. After solvent removal at reduced pressure, the residue was chromatographed (3% EtOAc/hexane) to give 165 mg (19%) of 2-[3-(1-adamantyl)-4-benzyloxyphenyl]-5-nitropyrimidine as a yellow solid, mp 206° C. (dec). IR 2902, 1405, 1179 cm−1; 1H NMR (CDCl3) δ 1.76 (bs, 6H, AdCH2), 2.09 (bs, 311, AdCH), 2.22 (m, 6H, AdCH2), 5.24 (s, 2H, C6H5CH2), 7.07 (d, J=8.7 Hz, 1H, 5′-ArH), 7.34-7.53 (m, 5H, C6H5), 8.40 (dd, J=8.7 Hz, 2.4 Hz, 1H, 6′-ArH), 8.51 (d, J=2.4 Hz, 1H, 2′-ArH), 9.46 ppm (s, 2H, 4-ArH, 6-ArH). HRMS calcd C27H27N3O3 [M+H]+ 442.2125. found 442.2137.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]2[C:11]([C:12](OCC)=[O:13])=[CH:10][CH:9]=[CH:8][N:7]2[CH:17]=1)([CH3:3])[CH3:2].[K+].[Br-]>>[OH:13][CH2:12][C:11]1[C:6]2[N:7]([CH:17]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:5]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)c1cccn2cc(C(C)C)nc12
Agent: [Br-]
Agent: [K+]
Product: CC(C)c1cn2cccc(CO)c2n1

Procedure:
From 2f (yield: 47%); mp 97-99° C.; IR (KBr) 3250-3000, 2960, 1498, 1307 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.30 (d, 6H, J=7 Hz), 3.06 (sept, 1H, J=7 Hz), 4.99 (s, 2H), 6.65 (t, 1H, J=7 Hz), 7.07 (d, 1H, J=7 Hz), 7.27 (s, 1H), 7.92 (d, 1H, J=7 Hz); 13C NMR (100 MHz, CDCl3) δ 22.5, 28.3, 62.6, 107.5, 111.8, 121.5, 124.4, 129.3, 143.7, 153.3; MS m/z 190 (M+, 43), 189 (100), 161 (25), 157 (23), 78 (15).
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[CH2:28][OH:29])[CH2:12][C@@H:11]([O:30][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(OCC)(=O)C>[OH:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[CH2:28][OH:29])[CH2:12][C@@H:11]([OH:30])[CH2:10]1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](CO)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](O[Si](C)(C)C(C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@]12CC[C@H]3C(=CC=C4C[C@@H](O)C[C@H](O)[C@@]43C)[C@@H]1CC[C@@H]2CO
Yield: 96.2 %

Procedure:
To 1α,3β-bis(tert-butyldimethylsilyloxy)-17β-(hydroxymethyl)androsta-5,7-diene (1.0 g), was added a 1M tetra-n-butylammonium fluoride tetrahydrofuran solution (11 ml), followed by reflux for 6 hours. After adding ethyl acetate, the reaction mixture was washed with saturated brine, a saturated aqueous sodium bicarbonate solution (twice) and then saturated brine. The organic layer was dried over anhydrous magnesium sulfate, evaporated under reduced pressure to remove the solvent and the thus obtained residue was purified by column chromatography (hexane:ethyl acetate=1:2) to give the titled compound (560 mg).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11]([F:16])[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[NH:6][C:5]2=[O:19])[CH2:3][CH2:2]1.CS(O[CH2:25][CH2:26][CH2:27][C@@H:28]1[O:32][C:31](=[O:33])[N:30]([C:34]2[CH:35]=[CH:36][C:37]3[S:42][CH2:41][C:40](=[O:43])[NH:39][C:38]=3[CH:44]=2)[CH2:29]1)(=O)=O>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11]([F:16])[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[N:6]([CH2:25][CH2:26][CH2:27][C@@H:28]3[O:32][C:31](=[O:33])[N:30]([C:34]4[CH:35]=[CH:36][C:37]5[S:42][CH2:41][C:40](=[O:43])[NH:39][C:38]=5[CH:44]=4)[CH2:29]3)[C:5]2=[O:19])[CH2:2][CH2:3]1
Reactant: COc1c(F)c(F)cc2c(=O)[nH]c(=O)n(C3CC3)c12
Reactant: CS(=O)(=O)OCCC[C@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1
Product: COc1c(F)c(F)cc2c(=O)n(CCC[C@H]3CN(c4ccc5c(c4)NC(=O)CS5)C(=O)O3)c(=O)n(C3CC3)c12
Yield: 65 %

Procedure:
Starting from 1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione (described in Org. Process Res. Dev. (2007), 11(3), 441-449) and 6-[(5S)-5-[3-[(methylsulfonyl)oxy]propyl]-2-oxo-3-oxazolidinyl]-2H-1,4-benzothiazin-3(4H)-one (prepared according to WO 2010/041194) and using Procedure E, the title compound was obtained as a colourless solid (140 mg; 65% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[CH2:7][NH:8][CH2:9][CH2:10][CH2:11][S:12][CH3:13])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:22]([S:25][CH2:26][CH:27]([CH3:31])[C:28](Cl)=[O:29])(=[O:24])[CH3:23]>O1CCOCC1>[C:1]([O:5][C:6](=[O:14])[CH2:7][N:8]([C:28](=[O:29])[CH:27]([CH3:31])[CH2:26][S:25][C:22](=[O:24])[CH3:23])[CH2:9][CH2:10][CH2:11][S:12][CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSCCCNCC(=O)OC(C)(C)C
Reactant: CC(=O)SCC(C)C(=O)Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CSCCCN(CC(=O)OC(C)(C)C)C(=O)C(C)CSC(C)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 29.8 %

Procedure:
To a solution of N-(3-methylthiopropyl)glycine t-butyl ester (36.4 g, 0.166 mol) and triethylamine (20.2 g, 0.199 mol) in 300 ml of dioxane was added dropwise 3-acetylthio -2-methylpropanoyl chloride (30.0 g, 0.166 mol). After stirring at room temperature for 16 hours the mixture was filtered and concentrated to yield 52.9 g. Purification by medium pressure liquid chromatography eluting with 20% ethyl acetate in hexane gave 18.0 g (30%) of N-(3-acetylthio-2-methylpropanoyl)-N-(3-methylthiopropyl)glycine t-butyl ester as a colorless oil. Rf =0.19 (20% ethyl acetate in hexane).
Reaction SMILES: [CH2:1]([CH:3]([C:11]1[CH:12]=[C:13]([OH:18])[CH:14]=[C:15]([CH:17]=1)[OH:16])[CH:4]([CH3:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH3:2].[C:19]([CH:22]1[CH2:27][CH2:26][CH:25]([CH3:28])[CH2:24][C:23]1=O)(=O)[CH3:20]>>[CH2:1]([CH:3]([C:11]1[CH:17]=[C:15]([OH:16])[C:14]2[CH:19]([CH3:20])[C:22]3[CH2:27][CH2:26][CH:25]([CH3:28])[CH2:24][C:23]=3[O:18][C:13]=2[CH:12]=1)[CH:4]([CH3:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: CCCCCC(C)C(CC)c1cc(O)cc(O)c1
Reactant: CC(=O)C1CCC(C)CC1=O
Product: CCCCCC(C)C(CC)c1cc(O)c2c(c1)OC1=C(CCC(C)C1)C2C

Procedure:
Condensation of 5-(1-ethyl-2-methylheptyl)resorcinol and 2-acetyl-5-methylcyclohexanone as described in Example 1 gives the title compound.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]1[N:19]([S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])[C:18]2[C:13](=[N:14][C:15](Cl)=[CH:16][CH:17]=2)[CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH:30]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].C([O-])([O-])=O.[Cs+].[Cs+]>C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.NC1C=CC=CC=1C1C=CC=CC=1[Pd]Cl.C1(C)C=CC=CC=1>[Si:1]([O:8][CH2:9][CH2:10][C:11]1[N:19]([S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])[C:18]2[C:13](=[N:14][C:15]([N:30]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])=[CH:16][CH:17]=2)[CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NNC(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)OCCc1cc2nc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Agent: Nc1ccccc1-c1ccccc1[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(cc(CCO[Si](C)(C)C(C)(C)C)n2S(=O)(=O)c2ccccc2)n1
Temperature: 108 °C

Procedure:
A flask was charged with 2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-5-chloro-1-(phenylsulfonyl)-1H-pyrrolo[3,2-b]pyridine (5.0 g, 11 mmol, from Step 1), di-tert-butyl hydrazine-1,2-dicarboxylate (2.8 g, 12 mmol, Aldrich), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (0.77 g, 0.98 mmol, Aldrich), Cs2CO3 (3.61 g, 11.1 mmol, Aldrich) and toluene (35 mL). The mixture was degassed by a stream of nitrogen through the solution. The mixture was then heated to 108° C. for 3 h then overnight at 100° C. The mixture was cooled to room temperature and diluted with DCM, then was filtered and the filtrate was concentrated. Flash chromatography, eluting with a gradient from 0-20% EtOAc in hexanes afforded product as a light yellow solid (4.9 g, 68%).
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].C([Li])CCC.CCCCCC.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]C>C1COCC1.C(O)C>[CH2:10]([O:9][C:3](=[O:8])[CH2:4][C:5](=[O:6])[CH2:7][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH3:24])[CH3:11]
Reactant: CCOC(=O)CC(C)=O
Reactant: CCCCCCCCCCCCCCCCBr
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCCCCCCCCCCCC(=O)CC(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of sodium hydride (1.2 g, 50 mmol) in THF, distilled ethyl acetoacetate (4.16 g, 32 mmol) was added dropwise. The resulting mixture was stirred for 30 min at room temperature and then cooled at −78° C. A solution of n-butyllithium in hexane (16.1 mL, 35.2 mmol) was added dropwise. After stirring for an additional 1 h at 0° C., 1-bromohexadecane (19.1 mmol) in THF was added and the mixture was stirred for 12 h. Ethanol (15 mL) was added slowly at room temperature. The resulting solution was filtered through a Celite pad, concentrated in vaccum and purified by chromatography on silica gel to give the 3-oxo-nonadecanoic acid ethyl ester as a solid. Anal. C21H40O3: Calcd: C, 74.07; H, 11.84; O, 14.09. Found: C, 73.98; H, 11.59; O, 14.25. MS (ESIMS): m/z: 340.3.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23](B(O)O)[CH:22]=1>>[CH3:20][C:18]1[NH:17][N:16]=[C:15]([NH:14][C:4]2[N:3]=[C:2]([C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:19]=1
Reactant: OB(O)c1cccnc1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1ccc2c(-c3cccnc3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 3-pyridine-boronic acid to give (5-methyl-1H-pyrazol-3-yl)-(1-pyridin-3-yl-6-methoxy-isoquinolin-3-yl)-amine. LC-MS m/e 332(MH+).
Reaction SMILES: [F:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]#[C:10][CH2:11][CH2:12][NH2:13])[CH:6]=[CH:5][CH:4]=1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21](Cl)(=[O:23])=[O:22]>>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([NH:13][CH2:12][CH2:11][C:10]#[C:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][F:1])[N:8]=1)(=[O:23])=[O:22]
Reactant: NCCC#Cc1cccc(CF)n1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Product: O=S(=O)(NCCC#Cc1cccc(CF)n1)c1ccccc1Cl
Yield: 18.6 %

Procedure:
The title compound was prepared in accordance with the general method of Example 184, from 4-(6-(fluoromethyl)pyridin-2-yl)but-3-yn-1-amine (39 mg, 0.22 mmol, Example 189(D)) and 2-chlorobenzenesulfonyl chloride (60 mg, 0.28 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 7:3) to yield 14.4 mg (41 μmol, 19%) of 2-chloro-N-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)benzenesulfonamide as an orange oil.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]2[N:12]=[CH:13][C:14]([C:15]([NH2:17])=[O:16])=[C:4]2[N:3]=1.CC(O[CH2:22][C:23]1[CH2:32][S:31][C@@H:26]2[C@H:27]([NH2:30])[C:28](=[O:29])[N:25]2[C:24]=1[C:33]([OH:35])=[O:34])=O.B(F)(F)F.O>C(#N)C>[NH2:30][C@@H:27]1[C:28](=[O:29])[N:25]2[C@@H:26]1[S:31][CH2:32][C:23]([CH2:22][S:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:9])[F:10])[N:5]3[N:12]=[CH:13][C:14]([C:15](=[O:16])[NH2:17])=[C:4]3[N:3]=1)=[C:24]2[C:33]([OH:35])=[O:34]
Reactant: NC(=O)c1cnn2c(C(F)(F)F)cc(S)nc12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: FB(F)F
Solvent: CC#N
Solvent: O
Product: NC(=O)c1cnn2c(C(F)(F)F)cc(SCC3=C(C(=O)O)N4C(=O)[C@@H](N)[C@H]4SC3)nc12
Reaction time: 5 h

Procedure:
A mixture of 1.60 g of 5-mercapto-7-(trifluoromethyl)-pyrazolo[1,5-a]pyrimidine-3-carboxamide and 1.66 g of (7R)-7-aminocephalosporanic acid in 120 ml of acetonitrile was treated while stirring with 20 ml of a 20 percent solution of boron trifluoride in acetonitrile and stirred at 20° for a further 5 hours. 100 ml of water were added and the mixture was concentrated in a vacuum to a volume of about 80 ml. The pH was adjusted to 2.8 with 25 percent aqueous ammonia. After stirring for 1 hour, the precipitate obtained was filtered, washed in succession with water, acetone and ether and dried. There was obtained (6R,7R)-7-amino-3-[[(3-carbamoyl-7-(trifluoromethyl)pyrazolo[1,5-a]-pyrimidin-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[CH2:8][N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N+:14]=3[O-:19])[C:6]=2[CH:20]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1>[C:21]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[CH2:8][N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N+:14]=3[O-:19])[C:6]=2[CH:20]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)CN(c2cccc[n+]2[O-])c2cc(N)ccc2O1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2c(c1)N(c1cccc[n+]1[O-])CC(C)(C)O2
Temperature: 25 °C
Reaction time: 63 h

Procedure:
To a solution of 0.474 g of 2-(6-amino-3,4-dihydro-2,2-dimethyl-2H-1,4-benzoxazin-4-yl)pyridine N-oxide in 5 ml of acetic anhydride was added 3 drops of pyridine and the mixture was stirred at room temperature for 63 hours. After concentration, the residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate solution, dried and concentrated. The residue was recrystallized from chloroform-ether to give 0.285 g of 2-(6-acetamido-3,4-dihydro-2,2-dimethyl-2H-1,4-benzoxazin-4-yl)pyridine N-oxide.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([NH:8][C:9]2[S:10][C:11]3[N:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Li+].[CH2:24](I)[CH2:25][CH3:26]>>[N+:1]([C:4]1[CH:21]=[CH:20][C:7]([N:8]=[C:9]2[N:14]([CH2:24][CH2:25][CH3:26])[C:13](=[O:15])[C:12]3[CH:16]=[CH:17][CH:18]=[N:19][C:11]=3[S:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=c1nc(Nc2ccc([N+](=O)[O-])cc2)sc2ncccc12
Reactant: CCCI
Agent: [H-]
Agent: [Li+]
Product: CCCn1c(=Nc2ccc([N+](=O)[O-])cc2)sc2ncccc2c1=O
Yield: 58.7 %

Procedure:
The reaction procedure of Example 11 was followed except that 901 mg (3.0 mmol) of 2-(4-nitroanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 30 mg of lithium hydride and 612 mg of propyl iodide were used. The resulting residue was then purified through silica gel column chromatography (eluant: chloroform) to obtain 603 mg of 2,3-dihydro-2-[(4-nitrophenyl)imino]-3-propyl-4H-pyrido[3,2-e]-1,3-thiazin-4-one (59%, recrystallized from a mixture of ether and ethanol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([F:13])[CH2:10][CH:9]1[C:14](O)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].B.C1COCC1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([F:13])[CH2:10][CH:9]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(F)CC1C(=O)O
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(F)CC1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a stirred solution of 1-tert-butoxycarbonyl-4-fluoropyrrolidine-2-carboxylic acid (1.1 g, 4.7 mmol) in THF (10.0 ml) was added BH3.THF(1.0 M solution in THF, 10.0 ml, 10.0 mmol) at 0° C. After stirred at room temperature for 1.0 h. After cooled, the mixture was concentrated in vacuo. Water was added thereto at 0° C., and extracted with EtOAc. The extract was washed with water, then dried over Na2SO4, and concentrated in vacuo to give 1-tert-butoxycarbonyl-4-fluoro-2-pyrrolidinylmethanol (1.0 g, quant) as a a colorless oil. 1H-NMR (CDCl3) δ 1.48 (s, 9H), 2.29–2.39 (m, 1H), 3.38–3.59 (m, 2H), 3.74–3.88 (m, 2H), 4.09–4.14 (m, 2H), 4.85 (m, 1H), 5.03 (br s, 1H), 5.16 (br s, 1H).