Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:6]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])[C:5](=[O:12])[CH2:4][S:3]1.[Cl:13][C:14]1[CH:32]=[CH:31][C:17]([CH2:18][N:19]2[C:27]3[C:22](=[C:23]([F:30])[C:24]([CH:28]=O)=[CH:25][CH:26]=3)[CH:21]=[N:20]2)=[C:16]([C:33]([F:36])([F:35])[F:34])[CH:15]=1>>[Cl:13][C:14]1[CH:32]=[CH:31][C:17]([CH2:18][N:19]2[C:27]3[C:22](=[C:23]([F:30])[C:24](/[CH:28]=[C:4]4/[C:5](=[O:12])[N:6]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])[C:2](=[O:1])[S:3]/4)=[CH:25][CH:26]=3)[CH:21]=[N:20]2)=[C:16]([C:33]([F:34])([F:35])[F:36])[CH:15]=1
Reactant: CS(=O)(=O)NN1C(=O)CSC1=O
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1F
Product: CS(=O)(=O)NN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2F)C1=O

Procedure:
N-[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-4-fluoro-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]methanesulfonamide was prepared from N-(2,4-dioxothiazolidin-3-yl)methanesulfonamide (from Example 360) and [4-Chloro-2-(trifluoromethyl)benzyl]-4-fluoro-1H-indazol-5-carbaldehyde (from Example 347) following General Procedure E.
Reaction SMILES: C[Si]([NH:5][C:6]1[N:11]=[C:10]([O:12][Si](C)(C)C)[N:9]=[CH:8][N:7]=1)(C)C.C(O[C@@H:21]1[O:43][C@H:42]([CH2:44][O:45]C(=O)C2C=CC=CC=2)[C@@H:32]([O:33]C(=O)C2C=CC=CC=2)[C@H:22]1[O:23]C(=O)C1C=CC=CC=1)(=O)C.CC#N.S(O)(C(F)(F)F)(=O)=O>CS(C)=O>[CH:8]1[N:9]([C@@H:21]2[O:43][C@H:42]([CH2:44][OH:45])[C@@H:32]([OH:33])[C@H:22]2[OH:23])[C:10](=[O:12])[N:11]=[C:6]([NH2:5])[N:7]=1
Reactant: C[Si](C)(C)Nc1ncnc(O[Si](C)(C)C)n1
Reactant: CC(=O)O[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CC#N
Solvent: CS(C)=O
Product: Nc1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Temperature: 55 °C
Reaction time: 0.58 h
Yield: 71 %

Procedure:
A mixture of 2-[(trimethylsilyl)amino]-4-[(trimethylsilyl)oxy]-s-triazine (4.5 Kg), 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (8.8 Kg), anhydrous MeCN (34.6 Kg) and TfOH (600 g) were heated at 55° C. for 12.5 hours. The reaction mixture was cooled to 45° C., DMSO (29 Kg) was added, and the MeCN was evaporated at an internal temperature of <50° C. under vacuum until about 54 L of the solution. The solution was cooled to 23° C. MeOH (13.9 Kg) was added followed by a solution of 30% NaOMe in MeOH solution (2.5 Kg) that was pre-diluted with MeOH (7.0 Kg). The solution was stirred at 23° C. for 35 minutes. When the reaction was complete MeOH (90.4 Kg) was added and the resulting slurry was stirred at 22° C. for 3 hours and 10 minutes and was then filtered and washed three times with MeOH (7.0 Kg each). The cake was dried under vacuum at below 70° C. for 9 hours and 20 minutes to give 3.2 Kg of 98.89% purity crude azacitidine (71% yield based on 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose).
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[N:13][C:6]=2[N:5]([CH2:14][CH2:15][CH3:16])[C:4]2[N:17]=[C:18](OS(C(F)(F)F)(=O)=O)[CH:19]=[CH:20][C:3]1=2.[NH:29]1[CH:33]=[CH:32][CH:31]=[N:30]1>>[CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[N:13][C:6]=2[N:5]([CH2:14][CH2:15][CH3:16])[C:4]2[N:17]=[C:18]([C:32]3[CH:33]=[N:29][NH:30][CH:31]=3)[CH:19]=[CH:20][C:3]1=2
Reactant: c1cn[nH]c1
Reactant: CCCN1c2ncccc2C(=O)N(C)c2ccc(OS(=O)(=O)C(F)(F)F)nc21
Product: CCCN1c2ncccc2C(=O)N(C)c2ccc(-c3cn[nH]c3)nc21

Procedure:
The title compound (mp 206°-207° C.) was prepared from 5,11-dihydro-5-methyl-11-n-propyl-2-trifluoromethanesulfonyloxy-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and 4-stannyl)pyrazole in a manner analogous to that described in Example 1.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:12]([CH3:16])=[C:13]([CH3:15])[N:14]=2)[CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:7]=1.[O:17]1[CH:19]2[CH2:20][C:21]3[C:26]([CH:18]12)=[CH:25][CH:24]=[CH:23][CH:22]=3>O1CCOCC1.O>[OH:17][C@@H:19]1[CH2:20][C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:18]1[NH:1][C:2]1[C:3]2[N:4]([C:12]([CH3:16])=[C:13]([CH3:15])[N:14]=2)[CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:7]=1
Reactant: COC(=O)c1cc(N)c2nc(C)c(C)n2c1
Reactant: c1ccc2c(c1)CC1OC21
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(N[C@@H]2c3ccccc3C[C@H]2O)c2nc(C)c(C)n2c1
Temperature: 100 °C
Reaction time: 60 h
Yield: 77.2 %

Procedure:
10.0 g (45.7 mmol) methyl 8-amino-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxylate and 18.1 g (137 mmol) 1,2-epoxyindane are suspended in 300 ml dioxane and 100 ml water. The reaction mixture is stirred at 100° C. for 2.5 d. After cooling down in an ice bath, the precipitate is collected and washed with water. The product is suspended in a mixture of 2-propanol and acetone (1:1) and filtered by suction. After drying in vacuo at 50° C., 12.4 g (77%) of the title compound are isolated as a colourless solid (m.p. 261-262° C.).
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[CH2:27]1[O:40][C:39]2[CH:38]=[CH:37][C:31]([CH:32]=[CH:33][C:34](O)=[O:35])=[CH:30][C:29]=2[O:28]1>>[CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:34](=[O:35])[CH:33]=[CH:32][C:31]1[CH:37]=[CH:38][C:39]2[O:40][CH2:27][O:28][C:29]=2[CH:30]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: O=C(O)C=Cc1ccc2c(c1)OCO2
Reactant: CC(C)CN([C@@H](CCCCN)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Product: CC(C)CN([C@@H](CCCCNC(=O)C=Cc1ccc2c(c1)OCO2)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Yield: 76 %

Procedure:
Nα-isobutyl-Nα-(4-nitrobenzenesulfonyl)-L-lysine was reacted with 3,4-methylenedioxycinnamic acid under the conditions described in example 86 to yield 76% of the desired product.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:25])[C@H:7]([CH3:24])[NH:8][C:9](=[O:23])[C@@H:10]([NH:16][C@@H:17]([C:19]([O:21]C)=[O:20])[CH3:18])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:2][CH2:3][CH3:4].[OH-].[Na+].C(O)(=O)C>CO>[CH2:1]([NH:5][C:6](=[O:25])[C@H:7]([CH3:24])[NH:8][C:9](=[O:23])[C@@H:10]([NH:16][C@@H:17]([C:19]([OH:21])=[O:20])[CH3:18])[CH2:11][C:12]([CH3:15])([CH3:13])[CH3:14])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)[C@H](C)NC(=O)[C@H](CC(C)(C)C)N[C@H](C)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CCCCNC(=O)[C@H](C)NC(=O)[C@H](CC(C)(C)C)N[C@H](C)C(=O)O
Yield: 48 %

Procedure:
N-[2-(S)-N(1-(R)-Methoxycarbonylethyl)amino-4,4-dimethylpentanoyl]-L-alanine N-butylamide (65 mg) in methanol (30 ml) was treated with IN-sodium hydroxide (3 ml) at 20° for 6 h. Excess acetic acid was then added and the solvent evaporated in vacuo. The residue was chromatographed on reverse phase silica (RF 18) in a gradient of 20%-80% methanol in water. Elution in 70% methanol in water afforded the title compound (30 mg) as a freeze-dried powder, m.p. 137°-138°; (Found: [m+1]+ =344.2548. C17H34N3O4 requires [m+1]+ =344.2549); δ(D2O) 0.9 (3H, t, J=6 Hz, CH2CH3); 0.94 (9H, s, C(CH3)3); 1.2-1.8 (6H, m, (CH2)2 and CH2); 1.4 (3H, d, J=8 Hz, CH3 ); 1.52 (3H, d, J=7 Hz, CH3); 3.18 (2H, t, J=6 Hz, NHCH2); 3.66 (1H, q, J=5 Hz, CHCO); 3.88 (1H, d, J=10 Hz, CHCH2) and 4.38 (1H, q, J=5 Hz, CHCH3).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([O:29][CH3:30])[CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(=[O:7])=[O:6].[I-:31].[Na+]>C(C(C)=O)C>[CH2:13]([O:12][CH2:11][CH:10]([O:29][CH3:30])[CH2:9][NH:8][S:5]([CH2:4][CH2:3][CH2:2][I:31])(=[O:7])=[O:6])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: [I-]
Reactant: CCCCCCCCCCCCCCCCOCC(CNS(=O)(=O)CCCCl)OC
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCCCCCCCCCCCCCCCOCC(CNS(=O)(=O)CCCI)OC
Yield: 77 %

Procedure:
To a solution of 3.845 (8.18 mM) of 3-(3-chloropropylsulfonylamino)-1-hexadecyloxy-2-methoxypropane IIIa3 in 30 ml of methyl ethyl ketone is added 2.45 g (16.36 mM) of sodium iodide and the mixture is refluxed for 3 hours with stirring. After the solvent is evaporated, the residue is purified by the column chromatography on silica gel with a n-hexane-ethyl acetate (4:1) mixture as an eluent. The product is recrystallied from methanol to give 3.556 g (6.332 mM) of 1-hexadecyloxy-3-(3-iodopropylsulfonylamino)-2-methoxypropane IIa3 in 77% yield.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=3[C:6]=2[CH:5]=[C:4]([S:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:34]>ClCCl>[Cl:1][C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=3[C:6]=2[CH:5]=[C:4]([S:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:34])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3c(Cl)cc(Sc4ccccc4)cc3c2C1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2oc3c(Cl)cc(S(=O)c4ccccc4)cc3c2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.3 %

Procedure:
To a solution of the product of Example 91, step A (50 mg, 0.12 mmol) in dichloromethane (2.0 mL) at −10° C. was added a solution of m-chloroperoxybenzoic acid (18 mg, 0.108 mmol) in dichloromethane (1.0 mL) drop wise. The reaction mixture was stirred at ambient temperature for 2 h, concentrated in vacuo and purified by column chromatography (SiO2, 4:1 hexanes/ethyl acetate) providing tert-butyl 6-chloro-8-(phenylsulfinyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (30 mg, 58%) as an off-white solid: 1H NMR (CDCl3, 400 MHz) δ 7.68-7.63 (m, 3H), 7.51-7.45 (m, 4H), 4.55 (s, 2H), 3.86-3.77 (m, 2H), 2.93-2.85 (m, 2H), 1.50 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31](O)=[O:32])[C:25]=1[CH3:34])(=[O:12])=[O:11].[F:35][CH:36]1[CH2:41][CH2:40][CH2:39][N:38]([CH2:42][CH2:43][NH2:44])[CH2:37]1>>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31]([NH:44][CH2:43][CH2:42][N:38]2[CH2:39][CH2:40][CH2:41][CH:36]([F:35])[CH2:37]2)=[O:32])[C:25]=1[CH3:34])(=[O:12])=[O:11]
Reactant: NCCN1CCCC(F)C1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)NCCN1CCCC(F)C1

Procedure:
{5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetic acid was coupled with 2-(3-fluoro-piperidin-1-yl)-ethylamine to give the titled compound.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH3:12])[C:6]2[O:10][CH:9]=[CH:8][C:7]=2[CH:11]=1.C([O-])([O-])=O.[K+].[K+].[Si](I)(C)(C)C>C(#N)C.CCOC(C)=O>[CH3:12][C:5]1[C:6]2[O:10][CH:9]=[CH:8][C:7]=2[CH:11]=[C:3]([OH:2])[CH:4]=1
Reactant: COc1cc(C)c2occc2c1
Agent: C[Si](C)(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1cc(O)cc2ccoc12
Temperature: 25 °C
Yield: 26 %

Procedure:
To a mixture of the product from Step D (850 mg, 5.2 mmol) and K2CO3 in acetonitrile (10 mL) was added TMSI (1.1 mL). The mixture was refluxed for 2 hrs. The reaction was cooled to room temperature. The mixture was diluted with EtOAc (100 mL) and washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE:EtOAc=5:1) to afford the title compound (200 mg, 25%) as an oil.
Reaction SMILES: [N+](C(C)C)([O-])=[O:2].[Na].[F:8][C:9]1[C:18]([CH2:19]Br)=[CH:17][C:16]2[C:15]([CH3:22])([CH3:21])[CH2:14][CH2:13][C:12]([CH3:24])([CH3:23])[C:11]=2[CH:10]=1>C(O)C>[F:8][C:9]1[C:18]([CH:19]=[O:2])=[CH:17][C:16]2[C:15]([CH3:22])([CH3:21])[CH2:14][CH2:13][C:12]([CH3:24])([CH3:23])[C:11]=2[CH:10]=1
Reactant: CC1(C)CCC(C)(C)c2cc(CBr)c(F)cc21
Reactant: CC(C)[N+](=O)[O-]
Agent: [Na]
Solvent: CCO
Product: CC1(C)CCC(C)(C)c2cc(C=O)c(F)cc21
Yield: 58 %

Procedure:
5.26 g (59.0 mmol) of 2-nitropropane was added to a solution prepared by dissolving 1.04 g (45.4 mmol) of sodium in 60 mL of ethanol. The resulting solution was added to a solution of 16.9 g (45.4 mmol) of crude 2-fluoro-3-bromomethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene in 60 mL of ethanol. After 5 hours the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with 1M aqueous sodium hydroxide, water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The product was purified by flash chromatography on silica gel (1% ethyl acetate/hexane) to afford 6.17 g (58%) of 3-fluoro-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthaldehyde (m.p.=119.4-120.0° C.).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([C:10]([NH:12][NH2:13])=[O:11])[CH:7]=[CH:6][C:5]=12.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24](O)=O)=[CH:18][C:17]=1[C:27]([F:30])([F:29])[F:28]>>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]2[O:11][C:10]([C:8]3[CH:7]=[CH:6][C:5]4[N:4]([CH:3]=[CH:2][N:1]=4)[CH:9]=3)=[N:12][N:13]=2)=[CH:18][C:17]=1[C:27]([F:28])([F:30])[F:29]
Reactant: COc1ccc(CCC(=O)O)cc1C(F)(F)F
Reactant: NNC(=O)c1ccc2nccn2c1
Product: COc1ccc(CCc2nnc(-c3ccc4nccn4c3)o2)cc1C(F)(F)F
Yield: 38 %

Procedure:
In the same manner as in Example 14 and using imidazo[1,2-a]pyridine-6-carbohydrazide instead of 1H-benzotriazole-5-carbohydrazide and 3-[4-methoxy-3-(trifluoromethyl)phenyl]propionic acid instead of 3-(3-cyanophenyl)propionic acid, the title compound (yield 38%) was obtained as colorless crystals.
Reaction SMILES: [CH2:1]([O:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH:11][CH2:12][CH2:13][CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][OH:19])[CH2:2][CH2:3][CH2:4][CH3:5].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.C(OCC)C>ClCCl>[CH2:1]([O:6][CH:7]1[C:18](=[O:19])[CH2:17][CH2:16][CH:15]=[CH:14][CH2:13][CH2:12][CH:11]=[CH:10][CH2:9][CH2:8]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCOCCCC=CCCC=CCCCO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCCOC1CCC=CCCC=CCCC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
8.8 g of diatomaceous earth and a solution of 5.39 g of 12-pentyloxy-4,8-dodecadien-1-ol in 50 ml of dichloromethane were charged into a 250 ml flask. 8.8 g of PCC were then added in small portions and the mixture was stirred for 2 h at room temperature. Ethyl ether was added to the reaction mixture to precipitate the chromium salts, and the mixture was then filtered on SiO2, concentrated and distilled in a bulb-to-bulb apparatus. 4 g of 12-pentyloxy-4,8-cyclododecadien-1-one were obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:12][C:13]1[C:18]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:17][C:16](B2OC(C)(C)C(C)(C)O2)=[CH:15][N:14]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O.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>[Cl:12][C:13]1[C:18]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:17][C:16]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][N:10]=3)[N:5]=[CH:4][CH:3]=2)=[CH:15][N:14]=1
Reactant: CC1(C)OB(c2cnc(Cl)c(NS(=O)(=O)c3ccc(F)cc3)c2)OC1(C)C
Reactant: Clc1ccnc2cccnc12
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: O
Solvent: C1COCCO1
Product: O=S(=O)(Nc1cc(-c2ccnc3cccnc23)cnc1Cl)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 45.6 %

Procedure:
(Some starting materials may be obtained from Aldrich, St. Louis, Mo.) To a 50 mL round-bottomed flask was added 4-chloro-1,5-naphthyridine (40 mg, 243 μmol), N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide (100 mg, 243 μmol), tetrakis(triphenylphosphine)palladium (28 mg, 24 μmol), sodium carbonate (243 μl, 486 μmol), dioxane (2 mL). The reaction mixture was stirred at 100° C. for 5 h. The mixture was cooled down to room temperature. The reaction mixture was diluted with water (3 mL) and extracted with EtOAc (2×30 mL). The organic extract was washed with saturated NaCl (3 mL), dried over Na2SO4, filtered and concentrated in vacuo and the residue was purified by silica gel chromatography, eluting with 70% EtOAc/hexanes to give N-(2-chloro-5-(1,5-naphthyridin-4-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide (46 mg, 46% yield) as a white solid. MS (ESI pos. ion) m/z calc'd for C19H12ClFN4O2S: 414.0; found 415.0. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 7.09 (s, 1 H) 7.13-7.23 (m, J=8.33 Hz, 2 H) 7.68 (d, J=4.38 Hz, 1 H) 7.75 (dd, J=8.55, 4.17 Hz, 1 H) 7.97 (dd, J=8.99, 4.90 Hz, 2 H) 8.49-8.56 (m, J=2.85, 2.85 Hz, 2 H) 8.58 (d, J=2.05 Hz, 1 H) 9.01 (dd, J=4.17, 1.68 Hz, 1 H) 9.10 (d, J=4.38 Hz, 1 H)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[CH:24]=O)[CH:7]=1)[CH3:2].[CH2:27]([NH2:29])[CH3:28].C([BH3-])#N.[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[CH2:24][NH:29][CH2:27][CH3:28])[CH:7]=1)[CH3:2]
Reactant: CCN
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc([N+](=O)[O-])cc2C=O)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Product: CCNCc1cc([N+](=O)[O-])ccc1Oc1cc(CC(=O)OCC)ccc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
[3-(2-Formyl-4-nitro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester (1.0 g, 2.79 mmol), ethylamine (2M in THF; 2.8 mL, 5.6 mmol), and sodium cyanoborohydride (0.26 g, 4.2 mmol) were combined in CH2Cl2 (30 mL), and the reaction was stirred at room temperature for 3 hours. After work-up, the mixture was concentrated to give the title compound.
Reaction SMILES: CO.[OH-].[Na+].[NH2:5][C:6]1[C:11]([C:12]2[O:16][N:15]=[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[CH:13]=2)=[CH:10][CH:9]=[CH:8][N:7]=1.Cl[CH2:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][N:28]=1>CN(C)C=O>[CH3:33][C:31]1[CH:30]=[CH:29][N:28]=[C:27]([CH2:26][O:24][C:21]2[CH:22]=[CH:23][C:18]([CH2:17][C:14]3[CH:13]=[C:12]([C:11]4[C:6]([NH2:5])=[N:7][CH:8]=[CH:9][CH:10]=4)[O:16][N:15]=3)=[CH:19][CH:20]=2)[CH:32]=1
Reactant: Cc1ccnc(CCl)c1
Reactant: Nc1ncccc1-c1cc(Cc2ccc(O)cc2)no1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1ccnc(COc2ccc(Cc3cc(-c4cccnc4N)on3)cc2)c1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 29.7 %

Procedure:
Methanol (3 mL) and 1 N aqueous sodium hydroxide solution (0.18 mL) were added to 4-(5-(2-amino-pyridine-3-yl)isoxazole-3-ylmethyl)-phenol (50 mg, 0.19 mmol) described in Manufacturing Example 5-1-1, which was then dissolved by irradiating ultrasonic wave. This solution was concentrated under a reduced pressure. To the resulting residue were added 2-chloromethyl-4-methyl-pyridine (31.8 mg, 0.22 mmol) described in Manufacturing Example 11-1-4 and N,N-dimethylformamide (2 mL), which was stirred for 10 minutes at 60° C. The reaction solution was partitioned into water and ethyl acetate. The organic layer was separated, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (21 mg, 30.2%).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8]([NH:11][CH2:12][CH2:13][CH3:14])[CH2:9][CH3:10]>ClCCl>[CH2:8]([N:11]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:12][CH2:13][CH3:14])[CH2:9][CH3:10]
Reactant: CCCNCCC
Reactant: O=C1CCCCC1
Solvent: ClCCl
Product: CCCN(CCC)C1CCCCC1

Procedure:
Cyclohexanone (0.415 cm3, 4.0 mmol), di-n-propylamine (0.548 cm3, 4.0 mmol) and [Ir(COD)(dppb)][PF6] (0.070 g, 2 mol %) were reacted in dichloromethane at 20° C. for 24 hrs, at approx. 1 bar H2. The yield of N,N-di-n-propylcyclohexylamine obtained was 43.5%.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:20]([C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][CH:27]=[C:26]2[CH2:32][CH2:33][CH2:34]O)([O-:22])=[O:21].C(Br)(Br)(Br)[Br:37]>C(#N)C>[N+:20]([C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][CH:27]=[C:26]2[CH2:32][CH2:33][CH2:34][Br:37])([O-:22])=[O:21]
Reactant: BrC(Br)(Br)Br
Reactant: O=[N+]([O-])c1ccc2[nH]cc(CCCO)c2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: O=[N+]([O-])c1ccc2[nH]cc(CCCBr)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.2 %

Procedure:
To a solution of triphenylphosphine (6.70 g, 0.025 mol) in 80 mL of acetonitrile was added a solution of 5-nitro-3-(3-hydroxypropyl)indole (4.30 g, 0.020 mol) in 75 mL of acetonitrile, followed by a solution of CBr4 (9.00 g, 0.027 mol) in 25 mL of acetonitrile, at 0° C. under Ar. The mixture was stirred at room temperature for 3 h and then it was evaporated and the residue was chromatographed (SiO2 /EtOAc-hexane, 1;9 then 1:4) to give the title compound (4.60 g, 84%) as a solid, m.p. 92°-95° C.
Reaction SMILES: [O-]CC.[Na+].Cl.[C:6]([NH2:14])(=[NH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:15](=[C:22]([C:28]([O-])=[O:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[O:29]=[C:28]1[CH:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:14]=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:13]1
Reactant: N=C(N)c1ccccc1
Reactant: CCOC(=O)C(=Cc1ccccc1)C(=O)[O-]
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1C(=O)NC(c2ccccc2)=NC1c1ccccc1
Reaction time: 2 h
Yield: 76.7 %

Procedure:
To a mixture of a 20% solution of sodium ethoxide in ethanol (44.9 g) and ethanol (200 ml) is added benzamidine hydrochloride (10.3 g) at room temperature. The mixture is stirred at the same temperature for two hours, and thereto is added ethyl benzalmalonate (14.0 g), and the mixture is refluxed for three hours. The reaction mixture is concentrated under reduced pressure, and to the residue is added ice-water. To the mixture is added dropwise conc. hydrochloric acid until the pH value of the mixture is adjusted to pH 4. The precipitates are collected by filtration, and washed with water to give crude ethyl 3,4,5,6-tetrahydro-4-oxo-2,6-diphenylpyrimidine-5-carboxylate (15.8 g).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]=[C:16]2[O:26][CH3:27])=[CH:10][C:3]=1[C:4]([O:6]C(C)C)=[O:5].S(=O)(=O)(O)O>C(Cl)Cl>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:23])([F:25])[F:24])[N:17]=[C:16]2[O:26][CH3:27])=[CH:10][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COc1nc(C(F)(F)F)cc(=O)n1-c1cc(C(=O)OC(C)C)c(Cl)cc1F
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: COc1nc(C(F)(F)F)cc(=O)n1-c1cc(C(=O)O)c(Cl)cc1F
Temperature: 0 °C

Procedure:
A solution of 5 g of isopropyl 2-chloro-4-fluoro-5-[2-methoxy-6-oxo-4-trifluoromethyl-1(6H) pyrimidinyl]-benzoate in 20 ml of methylene chloride is treated with 25 ml of concentrated sulphuric acid while stirring and cooling at 20°-25° C. The reaction mixture is stirred at room temperature for a further 20 minutes and poured on to 100 g of ice. The organic phase is separated, the aqueous phase is extracted twice with 15 ml of ethyl acetate each time and the combined organic phases are washed to neutrality with water. The solution is subsequently dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The resinous residue is recrystallized from diethyl ether/n-hexane. There is obtained 2-chloro-4-fluoro-5-[2 -methoxy-6-oxo-4-trifluoromethyl-1(6H)-pyrimidinyl]-benzoic acid, m.p. 205°-210° C.