Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[C:28]([CH3:29])=[CH:27][S:26][C:17]=2[N:18]=[C:19]([C:21]2[O:25][N:24]=[CH:23][CH:22]=2)[N:20]=1>>[O:25]1[C:21]([C:19]2[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:13][CH2:1][O:2][C:3]=4[CH:4]=3)[C:16]3[C:28]([CH3:29])=[CH:27][S:26][C:17]=3[N:18]=2)=[CH:22][CH:23]=[N:24]1
Reactant: Cc1csc2nc(-c3ccno3)nc(Cl)c12
Reactant: NCCc1ccc2c(c1)OCCO2
Product: Cc1csc2nc(-c3ccno3)nc(NCCc3ccc4c(c3)OCCO4)c12

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(isoxazol-5-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3,4-ethylenedioxyphenethylamino)-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[N:8]=[CH:9][C:10]3[CH:14]=[CH:13][S:12][C:11]=3[C:6]2=[C:5]([C:15]([OH:17])=[O:16])[CH:4]=[C:3]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>[OH-].[K+]>[C:9]([C:10]1[CH:14]=[CH:13][S:12][C:11]=1[C:6]1[NH:7][C:2](=[O:1])[C:3]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][C:5]=1[C:15]([OH:17])=[O:16])#[N:8]
Reactant: O=C(O)c1cc(-c2ccccc2)c(=O)n2ncc3ccsc3c12
Agent: [K+]
Agent: [OH-]
Product: N#Cc1ccsc1-c1[nH]c(=O)c(-c2ccccc2)cc1C(=O)O
Yield: 99.8 %

Procedure:
48.7 g of 7-oxo-8-phenyl-7H-pyrido[1,2-b]thieno[2,3-d]-pyridazine-10-carboxylic acid were added to a methanolic potassium hydroxide solution (prepared from 72 g of potassium hydroxide and 640 ml of methanol) and the mixture was heated to boiling under reflux for about 24 hours. The reaction mixture was evaporated to half in a vacuum, treated with 80 ml of water and adjusted to pH 1 by the addition of 1N hydrochloric acid. The separated crystals were filtered off under suction, washed with water and dried in a vacuum. There was obtained 48.6 g of 2-(3-cyano-2-thienyl)-1,6-dihydro-6-oxo-5-phenylnicotinic acid as yellow crystals with a m.p. of 255°-257° (methanol/N,N-dimethylformamide).
Reaction SMILES: [Na+].[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11](=O)(=[O:13])[O-:12])=[C:6]([O:15][CH3:16])[CH:5]=1)#[N:3].P(Cl)(Cl)(Cl)(Cl)[Cl:18]>O=P(Cl)(Cl)Cl>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([Cl:18])(=[O:13])=[O:12])=[C:6]([O:15][CH3:16])[CH:5]=1)#[N:3]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COc1cc(C#N)ccc1NS(=O)(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(C#N)ccc1NS(=O)(=O)Cl

Procedure:
To a soultion of N-(4-cyano-2-methoxyphenyl)-sulfamic acid sodium salt (1 mmol) at 0° C. in POCl3 (1 mL) is added phosphorous pentachloride (1.2 mmol). Upon reaction completion, the reaction mixture is concentrated and the crude material will be carried onto the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[C:34]([C:36]#[N:37])[CH:33]=[CH:32][C:31]=1[F:38])=[O:29])C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[C:34]([C:36]#[N:37])[CH:33]=[CH:32][C:31]=1[F:38])=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1N
Reactant: CCOC(=O)CC(=O)c1cc(C#N)ccc1F
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1cc(C#N)ccc1F
Yield: 71.6 %

Procedure:
Prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G37) (302 mg, 1.0 mmol) and 3-(5-cyano-2-fluoro-phenyl)-3-oxo-propionic acid ethyl ester (Example H18) (362 mg, 1.5 mmol) according to the general procedure K. Obtained as a yellow-brown solid (352 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][NH:18][CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:29]=[C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32](=[O:39])[N:31]1[CH2:40][CH2:41][C:42]1([CH:45]=O)[CH2:44][CH2:43]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][N:18]([CH2:45][C:42]1([CH2:41][CH2:40][N:31]2[C:30](=[O:29])[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]2=[O:39])[CH2:44][CH2:43]1)[CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1c(CNC2CCCc3cccnc32)nc2ccccc21
Reactant: O=CC1(CCN2C(=O)c3ccccc3C2=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(CN(CC2(CCN3C(=O)c4ccccc4C3=O)CC2)C2CCCc3cccnc32)nc2ccccc21
Yield: 29.5 %

Procedure:
Using General Procedure B: Reaction of (1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (0.269 g, 0.70 mmol) and 1-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-cyclopropanecarboxaldehyde (0.25, 1.03 mmol) with NaBH(OAc)3 (0.433 g, 2.04 mmol) in CH2Cl2 (7 mL) for 6 hours followed by purification of the crude material by column chromatography on silica gel (50:1:1 CH2Cl2—CH3OH—NH4OH) followed by radial chromatography on silica gel (1 mm plate, 100:1:1 CH2Cl2—CH3OH—NH4OH) provided 0.125 g (29%) of 2-{[{1-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-cyclopropylmethyl}-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzimidazole-1-carboxylic acid tert-butyl ester as a white foam.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[C:29]([CH3:35])[CH:28]=1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]([CH2:31][C:30]3[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][C:29]=3[CH3:35])[N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: COc1ccc(CCl)c(C)c1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: COc1ccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCN(C(=O)OC(C)(C)C)CC3)c(C)c1
Temperature: 110 °C

Procedure:
To a solution of 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.4 mmol) in toluene (3 mL) was added 4-methoxy-2-methyl-benzyl chloride (0.9 mmol) and cyanomethylene-tri-n-butylphosphorane (1 mmol). The mixture was heated at 110° C. for 16 h. After concentration and purification (SiO2, EtOAc/hexanes), 3-(4-chloro-phenyl)-1-(4-methoxy-2-methyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester was obtained (54 mg). The other regioisomer, 3-(4-chloro-phenyl)-2-(4-methoxy-2-methyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester, was also obtained (86 mg). 3-(4-Chloro-phenyl)-1-(4-methoxy-2-methyl-benzyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (20 mg) was treated with TFA (1 mL) in CH2Cl2 (10 mL) for 4 h. After concentration of the reaction mixture, the title compound was obtained (0.02 g). MS (ESI): exact mass calculated for C22H24ClN3O, 381.16. found, m/z 382.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.39-7.37 (m, 2H), 7.34-7.32 (m, 2H), 6.68-6.66 (br m, 1H), 6.54-6.52 (br m, 1H), 6.37 (d, J=8.3 Hz, 1H), 5.21 (s, 2H), 2.81-2.79 (m, 4H), 2.71-2.69 (m, 4H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([O:23][CH2:24][C:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[C:30]([O:36][C:37]([F:40])([F:39])[F:38])[CH:29]=1)=O)(=[O:22])[CH3:21].C[Si]([N:45]=[N+:46]=[N-:47])(C)C>C1COCC1>[C:20]([O:23][CH2:24][C:25]1[N:27]([C:28]2[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[C:30]([O:36][C:37]([F:40])([F:39])[F:38])[CH:29]=2)[N:47]=[N:46][N:45]=1)(=[O:22])[CH3:21]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(=O)OCC(=O)Nc1ccc(C#N)c(OC(F)(F)F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)OCc1nnnn1-c1ccc(C#N)c(OC(F)(F)F)c1
Reaction time: 0.5 h
Yield: 80.7 %

Procedure:
Triphenylphosphine (17.29 g, 65.7 mmol) and diisopropylazodicorboxylate (13.3 g, 65.7 mmol) were added to a solution of 2-({4-cyano-3-[(trifluoromethyl)oxy]phenyl}amino)-2-oxoethyl acetate (Intermediate 52, 8.0 g, 26.5 mmol) in THF (160 mL) at 0° C. and the mixture was stirred for 30 min. Trimethylsilyl azide (7.60 g, 66.0 mmol) was added dropwise at room temperature and the mixture was heated to reflux for 4 hr. THF was removed under reduced pressure and the residue was diluted with EtOAc and washed with ice-cooled water. The extracted organic layer was washed with brine solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude product. This was purified by column chromatography (100-200 mesh silica gel), eluting with 20% EtOAc/pet ether to give the title compound (7.0 g).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:46])=[C:5]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]2C(=O)C3=CC=CC=C3C2=O)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].O.NN>>[CH3:1][C:2]1[NH:3][C:4]([CH3:46])=[C:5]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH2:35])=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCCCCCCN2C(=O)c3ccccc3C2=O)C1c1cccc([N+](=O)[O-])c1
Agent: NN
Solvent: O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCCCCCCN)C1c1cccc([N+](=O)[O-])c1

Procedure:
Prepared by a method analogous to that of Example 1(b) from 18.95 g (30 mmol) of 1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-5-(11-phthalimido-undecyloxy)carbonyl-pyridine and 4.5 ml (90 mmol) of hydrazine hydrate. 15.0 g of a yellow oil which is used for further reactions without purification.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][OH:15])[CH2:9]1)=O)(C)(C)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:6][N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][OH:15])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CO)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCO[C@H](CO)C1
Reaction time: 0.25 h
Yield: 67.7 %

Procedure:
(S)-2-Hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester (Intermediate 8; 1.20 g, 5.52 mmol) in THF (5 mL) was added to a suspension of LiAlH4 (1.30 g, 34.3 mmol) in anhydrous THF (15 mL) at −10° C. and stirred under nitrogen for 15 min. The cooling bath was removed and the reaction mixture was gently heated to reflux for 4 h. The reaction mixture was quenched by careful addition of a mixture of water (4 mL) in THF (25 mL) with ice bath cooling. THF (50 mL) was added to the reaction mixture, stirred for 15 min, filtered and the solid washed with THF (50 mL). The combined filtrates were evaporated in vacuo. The residue was dissolved in DCM (50 mL), dried (MgSO4) and the solvent removed in vacuo to give (S)-(4-methylmorpholin-2-yl)-methanol (490 mg, 67%) as a colourless oil.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([C:18]3[CH:23]=[C:22]([C:24]4[O:25][C:26]([CH2:29][CH:30]([CH3:32])[CH3:31])=[N:27][N:28]=4)[CH:21]=[CH:20][C:19]=3[CH3:33])[C:7]2=[O:34])[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=[O:40]>ClCCl.C(OCC)(=O)C>[CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16]([CH3:17])=[O:40])[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([C:18]3[CH:23]=[C:22]([C:24]4[O:25][C:26]([CH2:29][CH:30]([CH3:32])[CH3:31])=[N:27][N:28]=4)[CH:21]=[CH:20][C:19]=3[CH3:33])[C:7]2=[O:34])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CSc1ncc2cc(-c3cc(-c4nnc(CC(C)C)o4)ccc3C)c(=O)n(C3CCCC3)c2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccc(-c2nnc(CC(C)C)o2)cc1-c1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 152.6 %

Procedure:
To a solution of 8-cyclopentyl-6-{5-(5-isobutyl-[1,3,4]oxadiazol-2-yl)-2-methyl-phenyl}-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (40.0 mg, 0.08 mmol) in dichloromethane (3 mL) at 0° C. was added 3-chloroperoxybenzoic acid (0.04 g, 0.19 mmol). The mixture was stirred at 0° C. for 1 hour, then was diluted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and brine, dried (magnesium sulfate), filtered and concentrated under reduced pressure to give 8-cyclopentyl-6-{5-(5-isobutyl-[1,3,4]-oxadiazol-2-yl)-2-methyl-phenyl}-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (0.06 g). The crude product was used in the next step without further purification.
Reaction SMILES: ClCC([NH:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[C:8]([F:15])[C:7]=1[CH3:16])=O.[OH-].[Na+].O1CCCC1>O>[F:15][C:8]1[C:7]([CH3:16])=[C:6]([C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=1)[NH2:5]
Reactant: Cc1c(F)ccc([N+](=O)[O-])c1NC(=O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(F)ccc([N+](=O)[O-])c1N

Procedure:
2-Chloro-N-(3-fluoro-2-methyl-6-nitrophenyl)acetamide (prepared from 47.2 g of 2-chloro-N-(3-fluoro-2-methylphenyl)acetamide, ca. 234 mmol) was suspended in water (220 ml) then treated with aqueous sodium hydroxide solution (12.5M, 110 ml, 1.37 mol). Tetrahydrofuran (110 ml) was added, then the mixture was heated to reflux for 5 hours, then evaporated (removing most of the tetrahydrofuran). The yellow solid was filtered off and washed with water until washing were non-alkaline. Drying in vacuo afforded a yellow solid (32.3 g, 81% over 2 steps) containing ˜13% isomer.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:34])=[C:21]([NH:25][S:26]([C:29]3[CH:33]=[CH:32][O:31][CH:30]=3)(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[CH3:35][Zn]C>>[F:34][C:20]1[C:19]([C:9]2[N:10]=[C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:35])[N:7]=2)=[CH:24][CH:23]=[CH:22][C:21]=1[NH:25][S:26]([C:29]1[CH:33]=[CH:32][O:31][CH:30]=1)(=[O:28])=[O:27]
Reactant: C[Zn]C
Reactant: O=S(=O)(Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1ccoc1
Product: Cc1nccc(-c2sc(C3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3ccoc3)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 25 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-furansulfonamide (200 mg, 0.384 mmol)mmol) and dimethylzinc (384 μl, 0.768 mmol) at 80° C. for 3 hours, the title compound was obtained as a solid (60 mg, 31% yield). MS (ESI): 500.8 [M+H]+
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.Cl.[F:12][C:13]1([F:19])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(N(CC)C(C)C)(C)C>C(O)C>[F:12][C:13]1([F:19])[CH2:18][CH2:17][N:16]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH2:15][CH2:14]1
Reactant: FC1(F)CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(N2CCC(F)(F)CC2)nc1
Temperature: 70 °C

Procedure:
To a slurry of 2-chloro-5-nitropyridine (5 g, 31.5 mmol) and 4,4-difluoropiperidine hydrochloride (4.97 g) in ethanol (40 mL) at ambient temperature was added N,N-diisopropylethylamine (12.00 mL, 69.4 mmol) and the mixture heated to 70° C. for 18 hours. The reaction was concentrated, partitioned between CH2Cl2 and 1M NaOH. The organic phase concentrated and purified by chromatography (elution with 2% MeOH—CH2Cl2 then 3% MeOH—CH2Cl2) to provide the title compound as a yellow oil. MS (DCI) m/z 261 (M+NH4)+.
Reaction SMILES: C([O:8][C:9]1[CH:25]=[CH:24][C:12]([CH2:13][NH:14][C:15]2[C:20]([Cl:21])=[C:19](C)[N:18]=[C:17]([CH3:23])[N:16]=2)=[CH:11][C:10]=1[O:26][CH:27]([F:29])[F:28])C1C=CC=CC=1.Cl.[CH2:31](O)C>>[Cl:21][C:20]1([CH3:31])[CH:19]=[N:18][C:17]([CH3:23])=[N:16][CH:15]1[NH:14][CH2:13][C:12]1[CH:24]=[CH:25][C:9]([OH:8])=[C:10]([O:26][CH:27]([F:28])[F:29])[CH:11]=1
Reactant: CCO
Reactant: Cc1nc(C)c(Cl)c(NCc2ccc(OCc3ccccc3)c(OC(F)F)c2)n1
Agent: Cl
Product: CC1=NC(NCc2ccc(O)c(OC(F)F)c2)C(C)(Cl)C=N1
Yield: 41 %

Procedure:
In analogy to the method described in example B1, 6.9 g (16.4 mmol) of [4-benzyloxy-3-(1.1-difluoromethoxy)benzyl](5-chloro-2,6-dimethylpyrimidin-4-yl)amine (from example A6) are reacted with 70 ml of 12.5N hydrochloric acid in 70 ml of ethanol. Extraction with ethyl acetate at a pH of 8 gives, after concentration, a solid residue. Extraction by stirring with petroleum ether and drying give 2.2 g (41%) of the title compound as a beige crystallizate. m.p.: 167-168.5° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7])#[CH:2].[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C=CC=CC=1>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([O:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])#[CH:2]
Reactant: Oc1ccccc1
Reactant: C#Cc1cccc(C(=O)Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C#Cc1cccc(C(=O)Oc2ccccc2)c1

Procedure:
Air in a 20 ml Schlenk tube was replaced by Ar gas and 1.02 g (7 mmol) of m-ethynylbenzoic acid and 5 g (42 mmol) of thionyl chloride were added to the tube and the mixture was stirred at 50° C. for 2 hours and then excess thionyl chloride was removed by distillation under reduced pressure to obtain m-ethynylbenzoyl chloride. To the m-ethynylbenzoyl chloride obtained was added a solution having 692 mg (7.35 mmol) of phenol and 3.4 ml (42 mmol) of pyridine dissolved in 7 ml of dichloromethane under ice-cooling and then the resultant mixture was stirred at room temperature for one hour. After completion of the stirring, dichloromethane was removed by distillation under reduced pressure and 35 ml of water was added to the resultant residue. The mixture was extracted with 35 ml of ethyl acetate, the extract was dried over magnesium sulfate and the solvent was removed by distillation under reduced pressure using an evaporator. The resultant crude reaction product was purified by column chromatography (Hexane/AcOEt=10/1) using silica gel to obtain 0.55 q of phenyl 3-ethynylbenzoate which is a desired product as yellow solid. (Yield: 35%)
Reaction SMILES: Cl[Si:2]([CH3:10])([CH3:9])[CH2:3][CH2:4][Si:5](Cl)([CH3:7])[CH3:6].[NH2:11][CH:12]1[C:33](=[O:34])[N:14]2[C:15]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=[O:21])=[C:16]([Cl:19])[CH2:17][S:18][C@H:13]12.C(N(CC)CC)C>C(Cl)Cl>[Cl:19][C:16]1[CH2:17][S:18][C@@H:13]2[CH:12]([N:11]3[Si:5]([CH3:7])([CH3:6])[CH2:4][CH2:3][Si:2]3([CH3:10])[CH3:9])[C:33](=[O:34])[N:14]2[C:15]=1[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)=[O:21]
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12
Reactant: C[Si](C)(Cl)CC[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[Si]1(C)CC[Si](C)(C)N1C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12
Temperature: 25 °C

Procedure:
A solution of 1,2-bis(chlorodimethylsilyl)ethane (3.2 g) in methylene chloride (20 ml) was added to a stirred mixture of p-nitrobenzyl 7-amino-3-chloro-3-cephem-4-carboxylate (5.0 g) and triethylamine (4.9 ml) in methylene chloride (25 ml) under a nitrogen atmosphere. The mixture was stirred at reflux for 16 hours, then allowed to cool to room temperature, and washed with 8% aqueous sodium hydrogen phosphate solution. The organic layer was separated, dried with magnesium sulphate, and evaporated under reduced pressure to give the title compound as a gum, nmr (CDCl3) δ0.17 (s, 12H), 0.78 (s, 4H), 3.38+3.82 (ABq, J=18 Hz, 2H), 4.76 (d, J=4 Hz, 1H), 4.93 (d, J=4 Hz, 1H), 5.28 (s, 2H), 7.3-8.1 (m, 4H).
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[CH3:19][CH:20]([C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1)=[O:25])[C:21](O)=[O:22]>>[CH3:19][CH:20]([C:21]([NH:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2)=[O:22])[C:24]([NH:26][CH2:27][C:28]1[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=1)=[O:25]
Reactant: Cc1ccc(CNC(=O)C(C)C(=O)O)cc1
Reactant: CN1C(=O)C(N)c2ccccc2-c2ccccc21
Product: Cc1ccc(CNC(=O)C(C)C(=O)NC2C(=O)N(C)c3ccccc3-c3ccccc32)cc1

Procedure:
The title compound, MS: m/e=441.2 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and 2-methyl-N-(4-methyl-benzyl)-malonamic acid.
Reaction SMILES: [OH:1][NH:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:15][C:16]1[N:17]=[C:18]([C:21]([F:24])([F:23])[F:22])[S:19][CH:20]=1>>[F:22][C:21]([F:24])([F:23])[C:18]1[S:19][CH:20]=[C:16]([CH2:15][O:1][NH:2][C:3]2[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=2[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:17]=1
Reactant: FC(F)(F)c1nc(CBr)cs1
Reactant: CCOC(=O)c1ccccc1NO
Product: CCOC(=O)c1ccccc1NOCc1csc(C(F)(F)F)n1
Yield: 52 %

Procedure:
The titled compound was prepared using similar procedure as that of Example-1 (step-2) using ethyl 2-(hydroxyamino)benzoate and product of step 3 described above in 52% yield.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([OH:12])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH:38]1[CH2:41][CH:40]([C:42]2[C:47]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[CH:46][CH:45]=[CH:44][N:43]=2)[CH2:39]1>CN(C=O)C.O>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[C:10]([N:38]1[CH2:39][CH:40]([C:42]2[C:47]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[CH:46][CH:45]=[CH:44][N:43]=2)[CH2:41]1)=[O:12]
Reactant: c1ccc(-c2cccnc2C2CNC2)cc1
Reactant: O=C(O)c1nc2ccccc2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1nc2ccccc2[nH]1)N1CC(c2ncccc2-c2ccccc2)C1
Reaction time: 0.08 h
Yield: 36.8 %

Procedure:
To a mixture of 1H-benzoimidazole-2-carboxylic acid (124 mg, 0.76 mmol) in DMF (5 mL) was added TEA (152 mg, 1.5 mmol) and HATU (347 mg, 0.92 mmol). The reaction mixture was stirred for 5 min and 2-azetidin-3-yl-3-phenyl-pyridine hydrochloride (100 mg, 0.76 mmol) was added. The reaction mixture was stirred at RT overnight. The mixture was diluted with water (10 mL), and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (5 mL) and brine (5 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by column chromatography to give (1H-benzoimidazol-2-yl)-[3-(3-phenyl-pyridin-2-yl)-azetidin-1-yl]-methanone (100 mg, 0.28 mmol, 59% yield) as a light yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:16]=2)[C:11](O)=[O:12])=[CH:5][CH:4]=1)#[N:2].[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)=[O:34])(C)(C)[CH3:29]>>[CH2:28]([O:32][C:33]([N:35]1[CH2:36][CH2:37][N:38]([C:11](=[O:12])[C:10]2[CH:14]=[C:15]([O:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=3)[CH:16]=[C:8]([O:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:27][CH:26]=3)[CH:9]=2)[CH2:39][CH2:40]1)=[O:34])[CH3:29]
Reactant: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)O)c2)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CCOC(=O)N1CCN(C(=O)c2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 79.9 %

Procedure:
Following the procedure of Example 5(c) 3,5-bis-(4-cyano-phenoxy)-benzoic acid 0.45 g (1.26 mmol) and piperazine-1-carboxylic acid tert-butyl ester (0.234 g, 1.26 mmol) were used to afford 0.5 g of the required product. 1H NMR (DMSO-d6): δ 1.18 (3H, t), 3.52 (8H, m), 4.15 (2H, q), 7.00 (2H, s), 7.07 (1H, s), 7.28 (2H, d), 7.88 (2H, d).