Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[I-].[CH3:7][P+:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH:27][C:28]1[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][C:29]=1[C:30](OC)=[O:31]>CCCCCC.C1COCC1>[OH:27][C:28]1[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][C:29]=1[C:30](=[O:31])[CH:7]=[P:8]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1cccc(C)c1O
Agent: [I-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cccc(C(=O)C=P(c2ccccc2)(c2ccccc2)c2ccccc2)c1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
206.8 ml (330.9 mmol) of a 1.6 molar n-butyllithium solution in n-hexane are slowly added to 97.3 g (240.7 mmol) of methyltriphenylphosphonium iodide in 800 ml of absolute THF under argon. The mixture is stirred at room temperature for 3 h. Subsequently, 20.0 g (120.3 mmol) of methyl 2-hydroxy-3-methylbenzoate in 200 ml of absolute THF are added dropwise to the reaction mixture. The mixture is stirred at 60° C. for 3 h. After cooling to room temperature, the precipitated lithium iodide is filtered off. The filtrate is concentrated in vacuo, and the residue is recrystallized from methanol. 27 g (56% of theory) of the title compound are obtained.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:17](=O)[CH3:18])=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH3:15])=[CH:9][CH:8]=1.[NH:20]([C:22]([NH:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=1)=[S:23])[NH2:21].CN(C)C=O>Cl.O>[OH:1][C:2]1[C:3]([C:17](=[N:21][NH:20][C:22]([NH:24][C:25]2[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=2)=[S:23])[CH3:18])=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH3:15])=[CH:9][CH:8]=1
Reactant: NNC(=S)Nc1ccc(C(=O)O)cc1
Reactant: CCCc1ccc(-c2c(O)c(C(C)=O)nn2C)cc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1ccc(-c2c(O)c(C(C)=NNC(=S)Nc3ccc(C(=O)O)cc3)nn2C)cc1
Yield: 79.3 %

Procedure:
1-[4-Hydroxy-1-methyl-5-(4-n-propylphenyl)-1H-pyrazol-3-yl]ethanone (0.157 mmol, 40.5 mg) and 4-hydrazinocarbonothioylaminobenzoic acid (0.157 mmol, 33.1 mg) were stirred with dimethylformamide (2.3 mL) and three drops of concentrated hydrochloric acid at room temperature for 23.5 hours. After addition of water, the precipitated yellow solid was recovered by filtration, washed with water and dried by means of a vacuum pump. The resulting solid was stirred with chloroform/n-hexane for a while, then recovered by filtration and dried by means of a vacuum pump to give the desired product as a pale yellow solid (56.2 mg, yield 79%).
Reaction SMILES: [CH:1]1([NH2:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[C:9]1(=O)[O:14][C:12](=[O:13])[CH2:11][CH2:10]1.C(O)(=O)C>CCOCC>[CH:1]1([N:8]2[C:12](=[O:13])[CH2:11][CH2:10][C:9]2=[O:14])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: O=C1CCC(=O)O1
Reactant: NC1C=CCCCC1
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=C1CCC(=O)N1C1C=CCCCC1
Yield: 61 %

Procedure:
A mixture of 2-cycloheptenylamine (1.01 g), succinic anhydride (1.0 g) and acetic acid (10 ml) was heated under reflux for 24 hours. After cooling, ether (20 ml) was added to the reaction mixture which was then washed with a saturated aqueous sodium hydrogencarbonate solution, water and a saturated aqueous sodium chloride solution in this order. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The oily product thus obtained was purified by column chromatography on silica gel to obtain 1.07 g of N-(2-cycloheptenyl)succinimide [Compound (214)].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C@@H:5]1[CH2:9][S:8][C:7]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=3[N+:20]([O-])=O)=[N:6]1.[C:24]1(=O)[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C@@H:5]1[CH2:9][S:8][C:7]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=3[NH:20][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[N:6]1
Reactant: O=C1CCCC1
Reactant: COC(=O)C[C@@H]1CSC(c2cc3cc(Cl)cc([N+](=O)[O-])c3[nH]2)=N1
Product: COC(=O)C[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1

Procedure:
[(R)-2-(5-chloro-7-nitro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-acetic acid methyl ester prepared in Preparation 67 and cyclopentanone were reacted according to the same procedures as Steps A and B of Example 1 to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[C:24]([F:46])=[CH:25][C:26]([Cl:45])=[C:27]([CH:44]=1)[O:28][C:29]1[N:34]=[C:33]2[S:35][C:36]([NH:38][C:39]([CH:41]3[CH2:43][CH2:42]3)=[O:40])=[N:37][C:32]2=[CH:31][CH:30]=1.C(=O)([O-])O.[Na+]>O1CCCC1.CN(C)C=O>[Cl:1][C:2]1[C:10]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:22][C:23]1[CH:44]=[C:27]([O:28][C:29]2[N:34]=[C:33]3[S:35][C:36]([NH:38][C:39]([CH:41]4[CH2:42][CH2:43]4)=[O:40])=[N:37][C:32]3=[CH:31][CH:30]=2)[C:26]([Cl:45])=[CH:25][C:24]=1[F:46])=[O:6]
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1Cl
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)c(Cl)cc1F
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)sc4n3)c(Cl)cc2F)c1Cl
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 51.4 %

Procedure:
2-Chloro-3-(1-cyano-1-methylethyl)benzoic acid (71.6 mg, 0.320 mmol) produced in Example C61(v) was dissolved in tetrahydrofuran (2 mL)/N,N-dimethylformamide (40 μL), oxalyl chloride (36 μL, 0.420 mmol) was added, and the mixture was stirred at room temperature for 45 min. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (2 mL). N-[5-(5-Amino-2-chloro-4-fluorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (79.8 mg, 0.211 mmol) was added, and the mixture was stirred at room temperature for 15 hr. To the reaction mixture was added aqueous sodium hydrogen carbonate solution (5 mL), and the mixture was extracted with ethyl acetate (5 mL×4). The organic layer was washed successively with water (5 mL) and saturated brine (5 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20→10/90), and crystallized from diisopropyl ether/ethyl acetate to give the title compound (63.4 mg, 51%) as white crystals.
Reaction SMILES: [CH3:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][CH:22]([CH2:25][CH:26]=O)[CH2:23][N:24]=1)=[CH:16]2)[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:5])=[O:4].[NH2:28][CH2:29][CH2:30][OH:31].[BH4-].[Na+]>CO.C(OCC)(=O)C>[OH:31][CH2:30][CH2:29][NH:28][CH2:26][CH2:25][CH:22]1[S:21][C:20]([C:17]2[NH:18][C:19]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[N:2]([CH3:1])[S:3]([C:6]2[S:7][CH:8]=[CH:9][CH:10]=2)(=[O:5])=[O:4])=[N:24][CH2:23]1
Reactant: CN(c1cccc2cc(C3=NCC(CC=O)S3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: NCCO
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(c1cccc2cc(C3=NCC(CCNCCO)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Yield: 67 %

Procedure:
To a solution of N-methyl-N-{2-[5-(2-oxoethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}thiophene-2-sulfonamide (300 mg) in methanol (5 mL) was added 2-aminoethanol (70 μL), and the mixture was stirred with heating under reflux for 4 hr. The reaction mixture was allowed to cool to room temperature, sodium borohydride (55 mg) was added, and the mixture was stirred for 30 min. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to give the title compound (220 mg, yield 67%) as a colorless amorphous solid from a fraction eluted with ethyl acetate-methanol (10:1, volume ratio). MS:465(MH+).
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:17])[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1.[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>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(#N)C>[Cl:17][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1
Reactant: OB(O)c1ccc(F)cc1
Reactant: NC(=O)C1CCN(c2c(Cl)cncc2Cl)CC1
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: CC#N
Product: NC(=O)C1CCN(c2c(Cl)cncc2-c2ccc(F)cc2)CC1
Yield: 64.7 %

Procedure:
General procedure D was followed using 1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide (24 mg, 0.088 mmol), 4-fluorobenzene boronic acid (15 mg, 0.11 mmol) and tetrakis(triphenylphosphine)palladium(0) (5 mg, 5 mol %), acetonitrile (1 mL) and 0.5 M sodium carbonate (0.25 mL, 0.12 mmol) for 30 min. The crude product was purified by preparative tlc on silica gel (CH2Cl2, MeOH, 10:1) to give impure title compound (19 mg) which was further purified by preparative hplc (CH3CN, H2O, gradient 1:9 to 9:1) to furnish the title compound as a white solid, LC-MS (ESI, 3.5 min) Rt 1.71 min, m/z 334 (100%, [M+H]+); m/z (ESI) C17H18ClFN3O requires 334.1117 found [M+H]+ 334.1116.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]=1)=[O:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[N+:29]([CH3:32])([O-:31])=[O:30]>O1CCCC1.C(OCC)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[CH2:32][N+:29]([O-:31])=[O:30])=[O:4]
Reactant: COC(=O)C1=CCCCC1
Reactant: C[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)C1CCCCC1C[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A solution of cyclohex-1-enecarboxylic acid methyl ester 1 (5.15 g; 36.7 mmol), tetrabutyl ammonium fluoride (55.10 mL; 1 M in THF; 55.1 mmol) and nitromethane (3.97 mL; 73.5 mmol) in tetrahydrofuran (60 mL) was heated to reflux for 4 hours. After cooling to room temperature, the reaction mixture was diluted with diethyl ether (500 mL), washed with 2N HCl (2×100 mL) and then with brine (2×100 mL). The phases were separated. The organic phase was dried over MgSO4 and concentrated in vacuo. The crude mixture was purified over silica gel chromatography (EtOAc/heptane 1:4) to give 2 (5.46 g; cis and trans isomers; 73%) as a pale yellow liquid.
Reaction SMILES: [F:1][C:2]1([F:35])[CH2:4][CH:3]1[CH2:5][O:6][C:7]1[CH:34]=[CH:33][C:10]2[N:11]=[C:12]([C:14]3[N:19]=[CH:18][C:17]([O:20][CH2:21][C@@H:22]([NH:24][C:25](=[O:31])OC(C)(C)C)[CH3:23])=[CH:16][C:15]=3[F:32])[O:13][C:9]=2[CH:8]=1.Cl.[C:37](OCC)(=O)C>C(OCC)(=O)C>[F:35][C:2]1([F:1])[CH2:4][CH:3]1[CH2:5][O:6][C:7]1[CH:34]=[CH:33][C:10]2[N:11]=[C:12]([C:14]3[N:19]=[CH:18][C:17]([O:20][CH2:21][C@@H:22]([NH:24][C:25](=[O:31])[CH3:37])[CH3:23])=[CH:16][C:15]=3[F:32])[O:13][C:9]=2[CH:8]=1
Reactant: CCOC(C)=O
Reactant: C[C@@H](COc1cnc(-c2nc3ccc(OCC4CC4(F)F)cc3o2)c(F)c1)NC(=O)OC(C)(C)C
Agent: Cl
Product: CC(=O)N[C@@H](C)COc1cnc(-c2nc3ccc(OCC4CC4(F)F)cc3o2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl {(1S)-2-[(6-{6-[(2,2-difluorocyclopropyl)methoxy]-1,3-benzoxazol-2-yl}-5-fluoropyridin-3-yl)oxy]-1-methylethyl}carbamate (690 mg), 4 M hydrogen chloride/ethyl acetate (10 mL), and ethyl acetate (10 mL) was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. The residue was mixed with pyridine (10 mL) and acetic anhydride (5 mL). The mixture was stirred at room temperature overnight. 1 M hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) and recrystallization (ethyl acetate) to give the title compound (496 mg) as white crystals.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:22]=[CH:21][C:9]([CH:10]=[C:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:20])=[CH:8][C:7]=1[O:23][CH3:24].[NH:25]1[CH:29]=[CH:28][N:27]=[CH:26]1>>[N:25]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:22]=[CH:21][C:9]([CH:10]=[C:11]3[CH2:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]3=[O:20])=[CH:8][C:7]=2[O:23][CH3:24])[CH:29]=[CH:28][N:27]=[CH:26]1
Reactant: COc1cc(C=C2Cc3ccccc3C2=O)ccc1OCCCCl
Reactant: c1c[nH]cn1
Product: COc1cc(C=C2Cc3ccccc3C2=O)ccc1OCCCn1ccnc1

Procedure:
2-[4-(3-IMIDAZOL-1YL PROPOXY)-3-METHOXYBENZYLIDENE)INDAN-1-ONE (8) (RG-DPJ-195) was prepared by fusing compound 7 with imidazole following the method described for 2
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH:9]3O[CH:8]3[C:7]=2[CH:15]=1)#[N:2].[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]1[C:25]([O:27][CH2:28]C)=[O:26].[H-].[Na+].Cl>CN(C)C=O.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH:9]=[C:8]([N:16]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=[C:17]3[C:25]([O:27][CH3:28])=[O:26])[C:7]=2[CH:15]=1)#[N:2]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2ccccc2n1C1=CC(C)(C)Oc2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.9 %

Procedure:
To a solution of 6-cyano-3,4-epoxy-3,4-dihydro-2,2-dimethyl-2H-benzopyran (2.0 g, 9.95 mmol) (prepared according to Evans et al., J. Med. Chem., 1983, 26, 1582 and J. Med. Chem., 1986, 29, 2194), and indole-2-carboxylic acid, ethyl ester (2.25 g, 11.9 mmol) in dimethylforamide (10.0 mL) at 0° C. under argon was added sodium hydride (476 mg of 60% oil dispersion, 11.92 mmol) in portions. After the addition was finished, the reaction mixture was allowed to warm up to room temperature and then heated at 90° C. for 16 hours. It was cooled to 0° C. in ice bath and diluted with ethyl acetate. To the resulting solution was added 1N hydrochloric acid until pH~5. The organic layer was separated and the aqueous layer was reextracted with ethyl acetate. The combined organic extracts were washed with water, brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue in dichloromethanemethanol (90:10) at 0° C. was treated with freshly prepared diazomethane. The reaction mixture was warmed up to room temperature and stirred for 1 hour. Few drops of acetic acid were added to decompose excess diazomethane (until reaction mixture turned colorless) and the solvent was evaporated to yield a brown oil It was purified by flash chromatography (dichloromethane) to yield the less polar 1-(6-cyano-2,2-dimethyl-2H-benzopyran-4-yl)-1H-indole-2-carboxylic acid, methyl ester (1.6 g). Further elution furnished the more polar title compound (380 mg) as a colorless solid, m.p. 197°-200° C. (isopropyl ether): IR (KBr) 2227, 1710, 1489, 1207 cm-1 : 1H NMR (DMSO-d6) δ 7.7 (m, 2 H), 7.47, 7.41 (s, 1 H), 7.15 (m, 3 H), 7.0, 6.85 (d, J=10 Hz, 1 H), 6.6 (m, 1 H), 5.75 (d, J=5.8 Hz, 1 H), 4.5, 4.2 (m, 2 H), 3.9, 3.5 (s, 3 H), 1.48, 1.45 (s, 3 H), 1.37, 1.27 (s, 3 H) (doubling of signals due to rotamers present in solution); 13C NMR (DMSO-d6) 162.1, 156.2, 136.3, 133.3, 131.9, 129.8, 126.9, 124.7, 123.4, 123.2, 120.6, 118.5, 112.5, 111.0, 103.3, 81.25, 68.84, 54.8, 51.9, 26.5, 18.25 ppm. The peaks due to the minor rotamer appear at 132.5, 125.2, 123.0, 122.3, 121.0, 117.8, 113.2, 71.4, 56.2, 51.6, 26.8, 22.8, 18.7 ppm.
Reaction SMILES: [CH3:1][C@H:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:10](OCC)=[O:11]>>[CH3:1][C@H:2]([NH:9][CH:10]=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: CCOC=O
Product: C[C@H](NC=O)c1ccccc1
Temperature: 55 °C

Procedure:
(S)-(−)-α-Methylbenzylamine (1 molar eq.) was treated with ethyl formate (80 molar eq.; Aldrich). A precipitate formed immediately. The suspension was heated to reflux (55° C.) for 3 hours. The precipitate went into solution upon heating. The solution was cooled to ambient temperature and concentrated via rotary evaporation. The resultant solid was used without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8]C(C)(C)C)=[O:7])=[CH:4][C:3]=1[CH2:15][N:16](C(OC(C)(C)C)=O)[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]>C(Cl)Cl>[F:35][C:34]([F:37])([F:36])[C:32]([OH:38])=[O:33].[NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH2:15][NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)c(CN(CCc2ccccc2)C(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(C(=O)O)cc1CNCCc1ccccc1
Reaction time: 12 h

Procedure:
To a solution of tert-butyl 4-amino-3-[[N-(tert-butoxycarbonyl)-N-phenethylamino]methyl]benzoate (2.3 g, 5.4 mmole) in CH2Cl2 (100 mL) at RT was added TFA (25 mL). After 12 hr, the reaction solution was concentrated to an oil and the residue dried under high vacuum overnight. The resulting residue was washed with hexanes and diethyl ether to afford the title compound (2.7 g, 5.4 mmole) as an off-white solid: MS (ES) m/e 271 (M+H-2TFA)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[C:16]([SiH2:20][O:21][C:22]([CH3:32])([CH3:31])[C:23]1[CH:28]=[C:27](Cl)[N:26]=[C:25]([Cl:30])[CH:24]=1)([CH3:19])([CH3:18])[CH3:17]>>[C:16]([SiH2:20][O:21][C:22]([CH3:32])([CH3:31])[C:23]1[CH:24]=[C:25]([Cl:30])[N:26]=[C:27]([NH:15][C:5]2[CH:6]=[CH:7][C:8]([N:9]3[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:28]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(Cl)nc(Cl)c1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2cc(C(C)(C)O[SiH2]C(C)(C)C)cc(Cl)n2)ccc1-n1cnc(C)c1

Procedure:
Prepared in analogy to example 62 from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine and 4-(tert-butyl-dimethyl-silanyloxymethyl)-2,6-dichloro-pyridine. The title compound was obtained as a yellowish solid (Yield=31%). 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.64 (s, 1H), 7.36 (d, 1H), 7.17 (d, 1H), 6.95-6.85 (m, 2H), 6.75 (s, 1H), 6.73 (s, 1H), 6.68 (s broad, 1H), 4.65 (s, 2H), 3.86 (s, 3H), 2.30 (s, 3H), 0.94 (s, 9H), 0.11 (s, 6H).
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:17])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.CN1CCOCC1.[CH2:25]([O:27][C:28](=[O:32])[C:29](Cl)=[O:30])[CH3:26]>C(Cl)Cl>[CH2:25]([O:27][C:28](=[O:32])[C:29]([NH:17][C:3]1[C:2]([F:1])=[CH:7][N:6]=[C:5]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)[N:4]=1)=[O:30])[CH3:26]
Reactant: CCOC(=O)C(=O)Cl
Reactant: Nc1nc(OCc2ccc(F)cc2)ncc1F
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCOC(=O)C(=O)Nc1nc(OCc2ccc(F)cc2)ncc1F
Reaction time: 16 h
Yield: 49.4 %

Procedure:
To a mixture of 5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-ylamine (0.235 g, 0.99 mmol), N-methyl morpholine on polystyrene (0.538 g, 1.24 mmol), and CH2Cl2 (5 mL) was added chloro-oxo-acetic acid ethyl ester (0.135 g, 0.99 mmol) and the resulting mixture was agitated on an orbital shaker for 16 h. The reaction contents were filtered onto an acidic SPE cartridge and eluted with CH2Cl2. The CH2Cl2 filtrate was evaporated to give 0.165 g (50%) of N-[5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-yl]oxalamic acid ethyl ester as a clear oil: 1H NMR (300 MHz, CDCl3) δ 9.21 (bs, 1H), 8.38 (d, J=2.3 Hz, 1H), 7.48 (m, 2H), 7.03 (t, J=8.5 Hz, 2H), 5.40 (s, 2H), 4.48 (q, J=7.1 Hz, 2H), 1.45 (t, J=7.1 Hz, 3H); HPLC-MS (ESI) m/z 338 (M+H)+.
Reaction SMILES: C(O)(=O)C.[CH3:5][CH:6]1[CH:11]=[C:10]([C:12]([O:14]CC(Cl)(Cl)Cl)=[O:13])[N:9]2[C:20](=[O:39])[CH:21]([NH:22][C:23](=[O:38])[CH:24]([C:33]3[S:34][CH:35]=[CH:36][CH:37]=3)[NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:8]2[S:7]1>CN(C)C=O.[Zn]>[CH3:5][CH:6]1[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[N:9]2[C:20](=[O:39])[CH:21]([NH:22][C:23](=[O:38])[CH:24]([C:33]3[S:34][CH:35]=[CH:36][CH:37]=3)[NH:25][C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[C@H:8]2[S:7]1
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)C(NC(=O)OC(C)(C)C)c3cccs3)[C@H]2S1
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)C(NC(=O)OC(C)(C)C)c3cccs3)[C@H]2S1
Reaction time: 1 h
Yield: 59.4 %

Procedure:
Acetic acid (1.6 ml) and zinc powder (1.2 g) were added under and ice-cooling to a solution of 2,2,2-trichloroethyl 2-methyl-7-[N-tert.-butoxycarbonyl-2-(2-thienyl)glycyl]amino-3-cephem-4-carboxylate (1.52 g) in anhydrous dimethylformamide (10 ml), and the mixture was stirred for 1 hour at the same temperature. After the reaction, zinc powder was filtered off, and the filtrate was poured into an ice-cooled mixture of 2 to 3% hydrochloric acid and ethyl acetate and then extracted. The extract was washed with water, extracted with a sodium bicarbonate aqueous solution, after which the aqueous layer was acidified by adding 5% sulfuric acid and ethyl acetate and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was pulverized by adding isopropyl ether, collected by filtration and dried to give amorphous 2-methyl-7-[N-tert.-butoxycarbonyl-2-(2-thienyl)glycyl]amino-3-cephem-4-carboxylic acid (0.7 g).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]=[O:11])[C:5]#[N:6].[CH2:12]([OH:17])[C:13]([F:16])([F:15])[F:14]>C1COCC1.CCOC(C)=O>[CH:10]([C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[O:17][CH2:12][C:13]([F:16])([F:15])[F:14])=[O:11]
Reactant: OCC(F)(F)F
Reactant: N#Cc1ccc(C=O)c(F)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1ccc(C=O)c(OCC(F)(F)F)c1
Reaction time: 2 h

Procedure:
A solution of 3-fluoro-4-formyl-benzonitrile (CAS 105942-10-7, 1 g) in THF (25 ml) was cooled to 0° C. under argon. Trifluoroethanol (3.36 g) and potassium tert.-butylate (0.83 g) were added subsequently. The mixture was stirred for 2 h. The mixture was diluted with EtOAc and washed with water. The organic phase was dried, filtered and concentrated. The product was purified by flash chromatography (SiO2, cyclohexane/EtOAc 1:1) to give 4-formyl-3-(2,2,2-trifluoro-ethoxy)-benzonitrile. Yellow solid.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[CH:7][C:8]([F:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].[CH:15]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:15]1([NH:21][S:2]([C:5]2[CH:6]=[CH:7][C:8]([F:14])=[C:9]([CH:13]=2)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1F
Reactant: NC1CCCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1cc(S(=O)(=O)NC2CCCCC2)ccc1F
Yield: 95 %

Procedure:
5-Chlorosulfonyl-2-fluoro-benzoic acid (A, 0.508 g, 0.0021 mol), Cyclohexylamine (G, 0.211 g, 0.00212 mol) and DIEA (1.1 mL, 0.00636 mol) in CH2Cl2 were stirred at room temperature overnight. The solvent was evaporated and the crude product was purified by silica gel chromatography (MeOH containing 10% AcOH)/CH2Cl2) to give 5-cyclohexylsulfamoyl-2-fluoro-benzoic acid (H, 0.6 g, 95%). After drying overnight under vacuum, H (0.22 g, 0.737 mmol) in SOC12 (5 mL) was heated at 80° C. for 2 hours after which the SOCl2 was evaporated and the residue was dried overnight. The residue was then dissolved in tetrahydrofuran (5 mL), 3,4-difluoro-phenylamine (D, 95 mg, 0.737 mmol) was added followed by DIEA (0.8 mL). The mixture was heated to 70° C. overnight. The solvent was evaporated, followed by ethyl acetate extraction. After purification by silica gel chromatography (ethyl acetate/hexane), 0.192 g (63%) of 5-cyclohexylsulfamoyl-N-(3,4-difluoro-phenyl)-2-fluoro-benzamide (DVR-45) was obtained.