Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([N+:22]([O-])=O)[C:8]([N:11]2[CH2:16][CH2:15][S:14][CH2:13][CH:12]2[C:17](OCC)=[O:18])=[N:9][CH:10]=1)=[O:4].P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1.[H][H]>ClCCl.[NH4+].[O-][V](=O)=O.[Pt]>[O:18]=[C:17]1[NH:22][C:7]2[CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:10]=[N:9][C:8]=2[N:11]2[CH2:16][CH2:15][S:14][CH2:13][CH:12]12
Reactant: [H][H]
Reactant: CCOC(=O)C1CSCCN1c1ncc(C(=O)OC)cc1[N+](=O)[O-]
Agent: O=[V](=O)[O-]
Agent: [Pt]
Agent: [NH4+]
Solvent: ClCCl
Product: COC(=O)c1cnc2c(c1)NC(=O)C1CSCCN21
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.8 %

Procedure:
Ethyl 4-(5-(methoxycarbonyl)-3-nitropyridin-2-yl)thiomorpholine-3-carboxylate (600 mg g, 1.69 mmol) was dissolved in dichloromethane (5 mL). To the yellow solution was added ammonium metavanadate (10.0 mg, 0.085 mmol), triphenyl phosphite (aprox 10 ul, 0.032 mmol), and Pt/C (50 mg, 5% w/w). The reaction mixture was pressurized with hydrogen gas (110 psi) and stirred at room temperature for 16 h. The reaction was then depressurized and diluted with dichloromethane (20 mL) which was refluxed for 30 min. The hot solution was filtered through a pad of celite and washed with hot dichloromethane (3×10 mL). The filtrate was concentrated to yield the title compound (452 mg, 96%) as a white solid. [M+H] calc'd for C, 12; H, 13; N, 3; O, 3; S, 280; found, 280.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[Cl:12][C:13]1[CH:14]=[C:15](Br)[CH:16]=[CH:17][C:18]=1[Cl:19]>>[Cl:1][C:2]1[N:3]=[C:4]([C:16]2[CH:15]=[CH:14][C:13]([Cl:12])=[C:18]([Cl:19])[CH:17]=2)[CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[N:7]=1
Reactant: Clc1ccc(Br)cc1Cl
Reactant: FC(F)(F)c1ccnc(Cl)n1
Product: FC(F)(F)c1cc(-c2ccc(Cl)c(Cl)c2)nc(Cl)n1

Procedure:
4A was prepared from 2-chloro-4-trifluoromethylpyrimidine and 3,4-dichlorobromobenzene by the method reported for 1A. (Method A) 1H NMR 1H,(8.29,8.28,d) 1H,(8.01,8.00,7.98,7.97,dd) 1H, (7.92,s) 1H,(7.66,7.63,d).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([O:12][C:13]2[NH:14][C:15]([NH2:24])=[C:16]3[C:20]([N:21]=2)=[N:19][C:18]([O:22][CH3:23])=[N:17]3)[CH2:11][CH2:10][CH2:9]1.Br[CH2:26][CH2:27][CH2:28][CH2:29][Cl:30]>>[Cl:30][CH2:29][CH2:28][CH2:27][CH2:26][N:19]1[C:18]([O:22][CH3:23])=[N:17][C:16]2[C:20]1=[N:21][C:13]([O:12][CH:8]1[CH2:9][CH2:10][CH2:11]1)=[N:14][C:15]=2[NH2:24]
Reactant: ClCCCCBr
Reactant: COc1nc2nc(OC3CCC3)[nH]c(N)c-2n1
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OC3CCC3)nc2n1CCCCCl

Procedure:
Prepared similarly to Intermediate 44 from 2-(cyclobutyloxy)-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 1-bromo-4-chlorobutane.
Reaction SMILES: [O:1]=[C:2]([N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1)[CH2:3][N:4]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:5](=[O:18])[CH2:6][N:7]1[C:11](=[O:12])C2=CC=CC=C2C1=O.O.NN.[CH3:38][C:39]1[CH:40]=[C:41]([N:45]=C=O)[CH:42]=[CH:43][CH:44]=1>>[CH3:38][C:39]1[CH:40]=[C:41]([NH:45][C:11](=[O:12])[NH:7][CH2:6][C:5]([N:4]([CH2:3][C:2](=[O:1])[N:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28][CH2:27][CH2:26]2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])[CH:42]=[CH:43][CH:44]=1
Reactant: O=C1c2ccccc2C(=O)N1CC(=O)N(CC(=O)N1CCCc2ccccc21)c1ccccc1
Reactant: Cc1cccc(N=C=O)c1
Agent: NN
Solvent: O
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)N2CCCc3ccccc32)c2ccccc2)c1
Yield: 28.8 %

Procedure:
The procedure is analogous to that described in Example 23, but 3.1 g of N-[2-oxo-2-(1,2,3,4-tetrahydro-1-quinolyl)ethyl]-N-phenyl-2-phthalimidoacetamide, 0.69 g of hydrazine hydrate and 0.91 g of 3-methylphenyl isocyanate are used as the starting material. The product obtained is purified by chromatography on 25 g of silica (0.065-0.200 mm) contained in a column 1.7 cm in diameter [eluent: methylene chloride/ethyl acetate (80-20 by volume)], collecting 25 cm3 fractions. Fractions 12 to 23 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization from ethyl acetate, 0.9 g of 2-[3-(3-methylphenyl)ureido]-N-[2-oxo-2-(1,2,3,4-tetrahydro-1-quinolyl)ethyl]-N-phenylacetamide melting at 167° C. is obtained.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[CH2:17][CH2:18][CH2:19][NH2:20])=[CH:4][CH:3]=1.[N+:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[O:34])([O-:25])=[O:24]>>[F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[CH2:17][CH2:18][CH2:19][NH:20][C:33]([NH:32][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N+:23]([O-:25])=[O:24])=[O:34])=[CH:4][CH:3]=1
Reactant: NCCCN1Cc2ccccc2CC1Cc1ccc(F)cc1
Reactant: O=C=Nc1ccccc1[N+](=O)[O-]
Product: O=C(NCCCN1Cc2ccccc2CC1Cc1ccc(F)cc1)Nc1ccccc1[N+](=O)[O-]

Procedure:
The reaction and treatment were carried out in the same manner as in Example 208 using 3-[3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]propanamine obtained in Example 214-b) as a starting material, and using 2-nitrophenyl isocyanate instead of phenyl isocyanate to obtain a title compound as a pale yellow amorphous substance.
Reaction SMILES: FC(F)(F)C(O)=O.C1(C2C3C([N:27]4[CH2:32][CH2:31][CH2:30][C@@H:29]([C:33](=[O:43])[CH2:34][P:35]([O:40]CC)([O:37]CC)=[O:36])[C@@H:28]4[C:44]([O:46][C:47](C)(C)C)=[O:45])=CC=CC=3C3C2=CC=CC=3)C=CC=CC=1.C(=O)([O-])O.[Na+].C[Si](Cl)(C)C>C(#N)C.O.CO.C(O)(C)C>[P:35]([CH2:34][C:33]([C@@H:29]1[CH2:30][CH2:31][CH2:32][NH:27][C@H:28]1[C:44]([O:46][CH3:47])=[O:45])=[O:43])([OH:37])([OH:40])=[O:36]
Reactant: CCOP(=O)(CC(=O)[C@@H]1CCCN(c2cccc3c2C(c2ccccc2)c2ccccc2-3)[C@H]1C(=O)OC(C)(C)C)OCC
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1NCCC[C@H]1C(=O)CP(=O)(O)O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Mix trifluoroacetic acid (30 mL) with acetonitrile (10 mL) and add, by dropwise addition, to an ice-cold solution of N-(9-phenylfluorenyl)-3(R)-[(diethoxyphosphinyl)acetyl]piperidine-2(R)-carboxylic acid, tert-butyl ester (3.5 g, 5.8 mmol) in acetonitrile (40 mL) and water (4 mL). Stir for 15 minutes, warm to room temperature and stir for an additional hour. Pour into saturated aqueous sodium hydrogen carbonate (500 mL) and extract into ethyl acetate (3×200 mL). Evaporate to a residue and take up the residue in acetonitrile (20 mL) and methylene chloride (20 mL). Place under a nitrogen atmosphere and add trimethylsilyl chloride (5 mL, 35 mmol). Stir overnight then add water. Stir for 15 minutes then blow to a residue with a stream of dry nitrogen. Take up the residue in water (100 mL) and wash with toluene (5×100 mL). Freeze dry to give a residue. Take up the residue in methanol (10 mL) and isopropanol (5 mL). Add propylene oxide (5 mL) and filter to give the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1.[CH:12](=O)[CH2:13][CH2:14][CH3:15].[BH4-].[Na+].C(OCC)(=O)C>CO>[CH2:12]([NH:1][CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)[CH2:13][CH2:14][CH3:15]
Reactant: N#Cc1ccc(CCN)cc1
Reactant: CCCC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCNCCc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
700 mg 4-(2-Amino-ethyl)-benzonitrile and 63 μl Butyraldehyde were dissolved in 20 ml methanol. 1.0 g molecular sieves 4 Angström were added the mixture was stirred at room temperature for two hours. Then 270 mg sodium borohydride were added and the mixture was stirred for an additional hour at room temperature. 100 ml ethyl acetate were added, and the reaction was quenched by addition of 1 ml water. The reaction mixture was filtered through a pad of celite and MgSO4. The filtrate was evaporated in vacuo to provide 750 mg crude 4-(2-Butylamino-ethyl)-benzonitrile. This material was used without further purification.
Reaction SMILES: C1(CCOC2C=CC(C(NC(CC3C=CC(CCC)=CC=3)C(NCCO)=O)=O)=CC=2)CC1.[CH:33]1([CH2:36][CH2:37][O:38][C:39]2[CH:67]=[CH:66][C:42]([C:43]([NH:45]/[C:46](/[C:59]([NH:61][CH2:62][CH2:63][CH2:64][OH:65])=[O:60])=[CH:47]\[C:48]3[CH:53]=[CH:52][C:51]([O:54][C:55]([F:58])([F:57])[F:56])=[CH:50][CH:49]=3)=[O:44])=[CH:41][CH:40]=2)[CH2:35][CH2:34]1>>[CH:33]1([CH2:36][CH2:37][O:38][C:39]2[CH:67]=[CH:66][C:42]([C:43]([NH:45][CH:46]([CH2:47][C:48]3[CH:49]=[CH:50][C:51]([O:54][C:55]([F:58])([F:57])[F:56])=[CH:52][CH:53]=3)[C:59]([NH:61][CH2:62][CH2:63][CH2:64][OH:65])=[O:60])=[O:44])=[CH:41][CH:40]=2)[CH2:34][CH2:35]1
Reactant: O=C(NCCCO)/C(=C/c1ccc(OC(F)(F)F)cc1)NC(=O)c1ccc(OCCC2CC2)cc1
Agent: CCCc1ccc(CC(NC(=O)c2ccc(OCCC3CC3)cc2)C(=O)NCCO)cc1
Product: O=C(NC(Cc1ccc(OC(F)(F)F)cc1)C(=O)NCCCO)c1ccc(OCCC2CC2)cc1
Yield: 85.4 %

Procedure:
A reaction similar to that described in Example (1 (1e) was conducted using 4-(2-cyclopropylethoxy)-N-{(Z)-1-{[(3-hydroxypropyl)amino]carbonyl}-2-[4-(trifluoromethoxy)phenyl]vinyl}benzamide (197 mg) to give 169 mg of the title compound (white powder).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[C:3]=1[NH:10][CH2:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)[CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36])=[C:4]([CH3:9])[C:3]=1[NH:10][CH2:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)[CH:13]=1
Reactant: COc1cc(CNc2c(F)ccc(O)c2C)cc(-c2cccc(F)c2)c1
Reactant: CC(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(CNc2c(F)ccc(OCC(=O)OC(C)C)c2C)cc(-c2cccc(F)c2)c1
Reaction time: 0.5 h
Yield: 79.8 %

Procedure:
To a solution of 4-fluoro-3-[[3-(3-fluorophenyl)-5-methoxy-phenyl]methylamino]-2-methyl-phenol (390 mg, 1.1 mmol, 1.0 eq) in DMF (6 mL) was added Cs2CO3 (538 mg, 1.65 mmol, 1.5 eq). The reaction was stirred 30 min, then isopropyl 2-bromoacetate (239 mg, 1.32 mmol, 1.2 eq) was added at room temperature. The reaction mixture was stirred at room temperature for a further 1 h, then water was added and the aqueous layer was extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The crude product was purified by column chromatography (petroleum ether:EtOAc, 1:0, 100:1, to 20:1) to give the title compound as a colorless oil (400 mg, 80%).
Reaction SMILES: [C:1](=[C:4]([C:10]#[N:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])([CH3:3])[CH3:2].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>C(O)C>[C:10]([C:4](=[C:1]([CH3:2])[CH:3]=[CH:14][N:15]([CH3:17])[CH3:16])[C:5]([O:7][CH2:8][CH3:9])=[O:6])#[N:11]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)C(C#N)=C(C)C
Solvent: CCO
Product: CCOC(=O)C(C#N)=C(C)C=CN(C)C
Yield: 71 %

Procedure:
A mixture of 127.7 g (0.839 mole) of ethyl isopropylidenecyanoacetate (4) and 100 g (0.839 mole) of N.N-dimethylformamide dimethyl acetal in 500 mL of ethanol was refluxed for 24 hours. The ethanol was removed under reduced pressure to give 124 g (100%) of a dark oil.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[N:12]=1>>[CH3:29][C:27]1[NH:26][N:25]=[C:24]([NH:23][C:13]2[N:12]=[C:11]([O:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[C:20]3[C:15]([CH:14]=2)=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[CH:28]=1
Reactant: OCCN1CCOCC1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1ccc2c(OCCN3CCOCC3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 10 was used, starting from 2-morpholin-4-yl-ethanol and (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (5-methyl-1H-pyrazol-3-yl)-[1-(2-morpholin-4-yl-ethoxy)-6-methoxy-isoquinolin-3-yl]-amine. LC-MS m/e 384(MH+).
Reaction SMILES: [C:1]1([CH:7](Cl)[N:8]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[S:9]2(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].C1([N:28]2[C:32]([SH:33])=[N:31][N:30]=[N:29]2)C=CC=CC=1>CN(C=O)C>[C:1]1([C:1]2([CH:7]([S:33][C:32]3[NH:31][N:30]=[N:29][N:28]=3)[N:8]3[C:18](=[O:19])[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[S:9]3(=[O:10])=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH2:6]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1c2ccccc2S(=O)(=O)N1C(Cl)c1ccccc1
Reactant: Sc1nnnn1-c1ccccc1
Agent: [Na]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2S(=O)(=O)N1C(Sc1nnn[nH]1)C1(c2ccccc2)C=CC=CC1
Temperature: 25 °C
Yield: 63 %

Procedure:
A solution of 2.2 g (0.0071 mol) of 2-(phenyl-chloromethyl)saccharin and 1.4 g (0.0071 mol) of the sodium salt of 1-phenyl-5-mercaptotetrazole in 30 ml of DMF was heated at 55° for three and one half hours, then stirred at ambient temperature for about sixteen hours and poured into ice water containing dilute sodium bicarbonate. The solid which separated was collected, washed with water, air dried and chromatographed on silica gel, eluting with 98:2 MDC: diethyl ether, to give 2 g (63%) of 2-(1-phenyl-1H-tetrazol-5-ylthiophenylmethyl) saccharin, mp 192°-193 ° C.
Reaction SMILES: C([C@H]1[O:9][C:8](=[O:10])[C@@:7]([C@@H:17]2[CH2:21][CH2:20][C:19]([F:23])([F:22])[CH2:18]2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:6]1)(C)(C)C>CO.[OH-].[Na+].O>[F:22][C:19]1([F:23])[CH2:20][CH2:21][C@@H:17]([C@@:7]([OH:6])([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:8]([OH:10])=[O:9])[CH2:18]1
Reactant: CC(C)(C)[C@H]1OC(=O)[C@](c2ccccc2)([C@@H]2CCC(F)(F)C2)O1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)[C@](O)(c1ccccc1)[C@@H]1CCC(F)(F)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.6 %

Procedure:
To a solution of 2.4 g of (2R,5R)-2-(t-butyl)-5-((1R)-3,3-difluorocyclopentyl)-5-phenyl-1,3-dioxolan-4-one in 30 ml of methanol, 10 ml of 1N aqueous sodium hydroxide solution was added, followed by 3 hours' stirring at room temperature. Distilling the methanol off under reduced pressure, the reaction liquid was diluted with water and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted from diethyl ether, and the organic layer was dried over anhydrous magnesium sulfate. Distilling the solvent off under reduced pressure, 1.66 g of the title compound was obtained.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:20]=[C:19]2[C:10]([O:11][C:12]3[CH:13]=[CH:14][C:15]([C:26]4[C:27]([F:32])=[N:28][CH:29]=[CH:30][CH:31]=4)=[CH:16][C:17]=3[C@:18]32[CH2:24][O:23][C:22]([NH2:25])=[N:21]3)=[C:9]([F:33])[CH:8]=1)(=O)=O.[CH3:36][C:37]([OH:41])([C:39]#[CH:40])[CH3:38].C(NC(C)C)(C)C>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.[Cu]I.CN(C=O)C>[NH2:25][C:22]1[O:23][CH2:24][C@:18]2([N:21]=1)[C:17]1[CH:16]=[C:15]([C:26]3[C:27]([F:32])=[N:28][CH:29]=[CH:30][CH:31]=3)[CH:14]=[CH:13][C:12]=1[O:11][C:10]1[C:19]2=[CH:20][C:7]([C:40]#[C:39][C:37]([CH3:38])([OH:41])[CH3:36])=[CH:8][C:9]=1[F:33]
Reactant: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3F)ccc1Oc1c(F)cc(OS(=O)(=O)C(F)(F)F)cc12
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CC(C)(O)C#Cc1cc(F)c2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cccnc3F)ccc1O2
Temperature: 85 °C

Procedure:
A 15 ml resealable tube was charged with (S)-2-amino-5′-fluoro-2′-(2-fluoropyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthene]-7′-yl trifluoromethanesulfonate (300 mg, 0.584 mmol), tetrakis(triphenylphosphine)palladium(0) (67.5 mg, 0.058 mmol), copper(i) iodide (11.13 mg, 0.058 mmol), DMF (2922 μL), 2-methylbut-3-yn-2-ol (114 μL, 1.169 mmol) and diisopropylamine (416 μL, 2.92 mmol). The mixture was capped with argon, sealed and heated at 85° C. for 1 hr. Concentration and purification of the crude residue by silica gel chromatography (10-60% CH2Cl2/MeOH/NH4OH 90:10:1 in CH2Cl2) afforded (S)-4-(2-amino-5′-fluoro-2′-(2-fluoropyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthene]-7′-yl)-2-methylbut-3-yn-2-ol. MS m/z=448.0 [M+H].
Reaction SMILES: Cl.C(OCC)(=O)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C@@H:18]2[CH2:22][CH2:21][CH2:20][N:19]2C(OC(C)(C)C)=O)=[O:17])=[C:11]([C:30]([O:32][CH3:33])=[O:31])[CH:10]=1>C(OCC)(=O)C>[ClH:8].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:17])[C@@H:18]2[CH2:22][CH2:21][CH2:20][NH:19]2)=[C:11]([CH:10]=1)[C:30]([O:32][CH3:33])=[O:31]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Cl)ccc1NC(=O)[C@@H]1CCCN1
Temperature: 25 °C
Reaction time: 5 h
Yield: 196.9 %

Procedure:
4N hydrogen chloride/ethyl acetate (10 mL) was added to an ethyl acetate (10 mL) solution comprising 1.40 g (3.66 mmol) of tert-butyl (2S)-2-{[4-chloro-2-(methoxycarbonyl)phenyl]carbamoyl}pyrrolidine-1-carboxylate at 0° C., and the mixture was stirred at room temperature for 5 hours. After the reaction mixture was condensed, IPE was added to the residue, and white solids were collected by filtration, washed with IPE, and dried under reduced pressure at room temperature, thereby giving 1.15 g of methyl 5-chloro-2-(L-prolylamino)benzoate hydrochloride (yield: 98%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[CH2:24]([N:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1)[CH3:25]>>[CH2:24]([N:26]1[CH2:31][CH2:30][CH:29]([NH:32][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:16][CH:17]=2)[CH2:28][CH2:27]1)[CH3:25]
Reactant: CCN1CCC(N)CC1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: CCN1CCC(NC(=O)c2ccc(OCc3c(-c4ccccc4)noc3C)nc2)CC1
Yield: 73 %

Procedure:
As described for example 34, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using 1-ethylpiperidin-4-amine instead of 1-methylpiperidin-4-amine, to the title compound (99 mg, 73%) which was obtained as an off white solid. MS: m/e=421.1 [M+H]+.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[Br-].[CH:10]([O:23][C:24]([C:26]1[N:31]2[C:32](=[O:44])[CH:33]([NH:34][C:35](=[O:43])[CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C@H:30]2[S:29][CH2:28][C:27]=1[CH2:45][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:25])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O.C(OCC)(=O)C>[C:37]1([CH2:36][C:35]([NH:34][CH:33]2[C:32](=[O:44])[N:31]3[C:26]([C:24]([O:23][CH:10]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[O:25])=[C:27]([CH:45]=[CH:1][C:2]4[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=4)[CH2:28][S:29][C@H:30]23)=[O:43])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Reactant: O=Cc1cccnc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=Cc3cccnc3)CS[C@H]12
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.5 %

Procedure:
Nicotinaldehyde (32.1 g) was added to a solution of [4-benzhydryloxycarbonyl-7-(2-phenylacetamido)-3-cephem-3-ylmethyl]triphenylphosphonium bromide (84.0 g) in a mixture of tetrahydrofuran (800 ml) and water (400 ml) and the solution was adjusted to pH 9.0 with 20% aqueous sodium carbonate. The solution was stirred at ambient temperature for 2 hours under keeping the pH 8.8 to 9.2 with 20% aqueous potassium carbonate. Ethyl acetate (800 ml) and water (800 ml) were added to the resulting solution. The separated organic layer was washed with saturated aqueous sodium chloride and dried over magnesium sulfate. The crude product obtained by concentration was purified by silica gel column chromatography using a mixture of acetone and dichloromethane (1:1 U/U) as eluent. The eluted fraction was evaporated to give benzhydryl 7-(2-phenylacetamido)-3-[2-(3-pyridyl)vinyl]-3-cephem-4-carboxylate (cis-trans mixture) (28.5 g).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)=[N:4][C:3]=1[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[CH2:27][OH:28])=[CH:21][CH:20]=1>[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)=[N:4][C:3]=1[CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22](/[CH:25]=[CH:26]/[CH:27]=[O:28])=[CH:23][CH:24]=1
Reactant: Cc1oc(-c2ccc3ccccc3c2)nc1COc1ccc(/C=C/CO)cc1
Agent: [Mn+4]
Agent: [O-2]
Product: Cc1oc(-c2ccc3ccccc3c2)nc1COc1ccc(/C=C/C=O)cc1

Procedure:
According to the method described for Reference Example 34, (E)-3-[4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]phenyl]-2-propen-1-ol was subjected to oxidation with activated manganese dioxide to give (E)-3-[4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]phenyl]-2-propen-1-al. Recrystallization from chloroform-ether gave colorless prisms, m.p.179°-180° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([F:24])([F:23])[F:22])=[C:6]([C:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH:9]=2)[CH:7]=1.[ClH:25]>C(Cl)Cl.CCOCC>[ClH:25].[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([F:24])([F:22])[F:23])=[C:6]([C:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(F)ccc2C(F)(F)F)CC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: Fc1ccc(C(F)(F)F)c(C2=CCNCC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88 %

Procedure:
A mixture of tert-butyl 4-(5-fluoro-2-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (9, 0.542 g, 1.58 mmol) and HCl (2 N solution in Et2O, 10 mL) in CH2Cl2 (20 mL) stirred at ambient temperature for 18 h. The reaction mixture was diluted with Et2O (30 mL), and the resulting precipitate was collected by filtration to provide 4-(5-fluoro-2-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine hydrochloride (10) as a white solid (0.393 g, 88%): 1H NMR (300 MHz, DMSO-d6) δ 9.26-9.00 (m, 2H), 7.84 (dd, J=8.7, 5.4 Hz, 1H), 7.46-7.36 (m, 1H), 7.24 (dd, J=9.3, 2.4 Hz, 1H), 5.67 (br s, 1H), 3.76-3.64 (m, 2H), 3.27 (t, J=5.1 Hz, 2H), 2.70-2.40 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:12]2[C:13](=[O:23])[N:14]([CH3:22])[N:15]=[C:16]([S:20][CH3:21])[C:17]=2[O:18][CH3:19])[C:4]2[C:9]([C:10]=1[Cl:11])=[CH:8][CH:7]=[CH:6][CH:5]=2.C1C=C(Cl)C=C(C(OO)=[O:32])C=1.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[N:3]([C:12]2[C:13](=[O:23])[N:14]([CH3:22])[N:15]=[C:16]([S:20]([CH3:21])=[O:32])[C:17]=2[O:18][CH3:19])[C:4]2[C:9]([C:10]=1[Cl:11])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: COc1c(SC)nn(C)c(=O)c1-n1c(Cl)c(Cl)c2ccccc21
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: COc1c(S(C)=O)nn(C)c(=O)c1-n1c(Cl)c(Cl)c2ccccc21
Reaction time: 0.17 h

Procedure:
To a stirred solution of 4-(2,3-dichloroindol-1-yl)-5-methoxy-2-methyl-6-methylsulfanyl-pyridazin-3-one (60 mg, 0.16 mmol) in DCM (2 mL) at −20° C. is added mCPBA (36 mg, 0.17 mmol). After stirring for 10 min at this temperature, a yellow precipitate had appeared. The reaction was poured into a mixture of DCM (20 mL), sodium bicarbonate saturated solution (10 mL) and sodium thiosulphate saturated solution (10 mL), then stirred for 10 min. The resulting mixture was then passed through a phase separator and the DCM layer was concentrated under reduced pressure to afford the desired product 4-(2,3-dichloroindol-1-yl)-5-methoxy-2-methyl-6-methylsulflnyl-pyridazin-3-one (59 mg, 0.12 mmol, 95%) as a yellow solid, which was used without further purification.