Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([O:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=2[CH:26]=O)[CH:7]=1)[CH3:2].C(OC(=O)CC1C=C(C(F)(F)F)C=C(OC2C=CC([N+]([O-])=O)=CC=2CO)C=1)C.[F:57][C:58]([F:62])([F:61])[CH2:59][SH:60]>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:13])[F:14])[CH:9]=[C:8]([O:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=2[CH2:26][S:60][CH2:59][C:58]([F:62])([F:61])[F:57])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cc(Oc2ccc([N+](=O)[O-])cc2C=O)cc(C(F)(F)F)c1
Reactant: FC(F)(F)CS
Agent: CCOC(=O)Cc1cc(Oc2ccc([N+](=O)[O-])cc2CO)cc(C(F)(F)F)c1
Product: CCOC(=O)Cc1cc(Oc2ccc([N+](=O)[O-])cc2CSCC(F)(F)F)cc(C(F)(F)F)c1

Procedure:
[3-(2-Formyl-4-nitro-phenoxy)-5-trifluoromethyl-phenyl]acetic acid ethyl ester was reduced to [3-(2-hydroxymethyl-4-nitro-phenoxy)-5-trifluoromethyl-phenyl]-acetic acid ethyl ester according to the procedure described in Example 21, Step 6 and then brominated as described in Example 21, Step 7 and then treated with 2,2,2-trifluoroethanethiol to give {3-[4-Nitro-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-5-trifluoromethyl-phenyl}-acetic acid ethyl ester. The amine was reduced as described in Example 21, Step 9, and then treated with pivaloyl chloride as described in Example 21, Step 10 to provide {3-[4-(2,2-Dimethyl-propionylamino)-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-5-trifluoromethyl-phenyl}-acetic acid ethyl ester. Hydrolysis of the ester as described in Example 21, Step 11 provided the acid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[N:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:13][N:12]=2)[CH:7]=[CH:8][C:9]=1Br)([O-:3])=[O:2].BrC1C=CC([C:29]#[N:30])=CC=1.[N+](C1C=C(C=CC=1Br)C#N)([O-])=O>CN1CCCN(C)C1=O>[N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[N:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:13][N:12]=2)[CH:7]=[CH:8][C:9]=1[C:29]#[N:30])([O-:3])=[O:2]
Reactant: N#Cc1ccc(Br)cc1
Reactant: CCCCCCCc1cnc(-c2ccc(Br)c([N+](=O)[O-])c2)nc1
Agent: N#Cc1ccc(Br)c([N+](=O)[O-])c1
Solvent: CN1CCCN(C)C1=O
Product: CCCCCCCc1cnc(-c2ccc(C#N)c([N+](=O)[O-])c2)nc1

Procedure:
A mixture of 37.8 g of 2-(3-nitro-4-bromophenyl)-5-n-heptylpyrimidine (obtainable by nitration of 4-bromobenzonitrile, converting the 3-nitro-4-bromobenzonitrile into the corresponding amidine hydrochloride and heating the latter together with n-heptylmalondialdehydtetramethylacetale), 18 g of Cu-(I)-cyanide and 100 ml of 1,3-dimethyltetrahydro-2(1H)pyrimidinon (DMPU) is heated at 150° for 3 hours. After cooling the mixture is filtered, the filtrate and the residue are extracted with methylene chloride and the organic phase is evaporated. 2-(3-Nitro-4-cyanophenyl)-5-n-heptylpyrimidine (F. 73°) is obtained by purification by chromatography. The obtained material is heated together with 33.4 g of CsF in 120 ml of DMPU at 110° for 4 hours. After cooling the mixture is poured onto 600 ml of ice water. After extraction with methylene chloride and purification by chromatography 2-(3-fluoro-4-cyanophenyl)-5-n-heptylpyrimidine (m.p. 43°, clp. 0°, Δε=-37) is obtained
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:4]=[C:5]2[S:12][CH:11]=[N:10][N:6]2[C:7](=[O:9])[CH:8]=1.S(Cl)([Cl:16])(=O)=O>ClC(Cl)C>[Cl:16][C:8]1[C:7](=[O:9])[N:6]2[N:10]=[CH:11][S:12][C:5]2=[N:4][C:3]=1[CH2:2][Cl:1]
Reactant: O=c1cc(CCl)nc2scnn12
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(Cl)Cl
Product: O=c1c(Cl)c(CCl)nc2scnn12
Temperature: 60 °C
Reaction time: 2 h

Procedure:
7-chloromethyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-5-one (10 g), prepared according to Example 1, was reacted with sulfuryl chloride (7.5 g) in dichloroethane (150 ml) under stirring at 60° C. for 2 hours. After cooling the precipitate was filtered then was suspended in water (500 ml) and neutralized by treatment with 35% NaOH. Filtration and washings with water gave 6-chloro-7-chloromethyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-5-one, m.p. 193°-195° C. (7.5 g), which was reacted with triphenylphosphine (9.1 g) in acetonitrile (125 ml) under stirring at reflux temperature for 20 hours. After cooling the precipitate was filtered and washed with ethyl acetate to give (6-chloro-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-7-yl)-methyl-triphenylphosphonium chloride (16 g), which was suspended in dimethylsulphoxide (60 ml) and treated dropwise with potassium terbutoxide (3.6 g) dissolved in dimethylsulphoxide (30 ml) at a temperature of about 20° C. The solution of the ylide so obtained was then reacted with benzaldehyde (6 g) at 80° C. for 8 hours. After cooling the solution was diluted with ice water and the precipitate was filtered and washed with water. Crystallization from chloroform-ethanol gave 3.4 g of 6-chloro-7-trans-(2-phenyl-ethenyl)-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-5-one, m.p. 265°-270° C. dec., N.M.R. (CF3COOD) δ p.p.m.: 7.45 (m) (3H, C-3, C-4 and C-5 phenyl protons), 7.53 (d) (1H, β-ethenyl proton), 7.66 (dd) (2H, C-2 and C-6 phenyl protons), 8.05 (d), (1H, α-ethenyl proton), 9.02 (s) (1H, C-2 proton); JHα↑Hβ =16 Hz.
Reaction SMILES: [CH2:1]([C:8]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:27])[CH2:9][O:10][CH2:11][C:12]1[CH:17]=[C:16]([N:18]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:19][CH2:20][CH3:21])[N:15]=[C:14](Cl)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36](=[O:39])([O-])[O-:37].[Na+].[Na+]>C(O)CCC.C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl>[C:31]([O:30][C:29]([NH:28][C:8]([CH3:27])([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][O:10][CH2:11][C:12]1[CH:17]=[C:16]([N:18]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:19][CH2:20][CH3:21])[N:15]=[C:14]([C:36]([O:37][CH2:8][CH2:1][CH2:2][CH3:3])=[O:39])[CH:13]=1)=[O:35])([CH3:34])([CH3:33])[CH3:32]
Reactant: O=C([O-])[O-]
Reactant: CCCN(c1cc(COCC(C)(Cc2ccccc2)NC(=O)OC(C)(C)C)cc(Cl)n1)S(C)(=O)=O
Agent: Cl[Pd]Cl
Agent: [Na+]
Solvent: CCCCO
Solvent: N#Cc1ccccc1
Product: CCCCOC(=O)c1cc(COCC(C)(Cc2ccccc2)NC(=O)OC(C)(C)C)cc(N(CCC)S(C)(=O)=O)n1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A suspension of tert-butyl [1-benzyl-2-({2-chloro-6-[(methylsulfonyl)(propyl)amino]pyridin-4-yl}methoxy)-1-methylethyl]carbamate (115 mg, 0.22 mmol, intermediate VI), sodium carbonate (70 mg, 0.66 mmol), PdCl2(PhCN)2 (2 mg, 0.004 mmol), 4A sieves and 1-[2-(dicyclohexylphasphanyl)ferrocenyl]ethyldicyclohexylphosphane (11 mg, 0.017 mmol, STREM) in n-butanol (2 ml, degassed with Argon), was purged with CO and stirred at 100° C. for 16 h under 1 atm of CO. The reaction mixture was diluted with dichloromethane, washed with water and brine, dried over sodium sulfate, concentrated in vacuo, azeothroped with toluene, and purified by flash chromatography (silica, 0-35% EtOAc/hexanes) to provide butyl 4-({2-[(tert-butoxycarbonyl)amino]-2-methyl-3-phenylpropoxy}methyl)-6-[(methylsulfonyl)(propyl)amino]pyridine-2-carboxylate as a yellow oil which was dissolved in 1:1 THF:MeOH (1.6 mL) and treated with aq LiOH (0.38 mL, 0.38 mmol, 1N) for 2 h at rt. The reaction mixture was acidified to pH 3-4 with 1N HCl, extracted with dichloromethane, dried over sodium sulfate, concentrated in vacuo, azeothroped with toluene to give 4-({2-[(tert-butoxycarbonyl)amino]-2-methyl-3-phenylpropoxy}methyl)-6-[(methylsulfonyl)(propyl)amino]pyridine-2-carboxylic acid as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.71 (s, 1H), 7.34-7.13 (m, 5H), 4.67 (s, 2H), 4.49 (s, 1H), 3.93 (t, J=7.6 Hz, 2H), 3.72 (A of AB, d, J=9.2 Hz, 1H), 3.62 (B of AB, d, J=9.2 Hz, 1H), 3.17 (A of AB, d, J=13.6 Hz, 1H), 3.05 (s, 3H), 2.90 (13 of AB, d, J=13.6 Hz, 1H), 1.70-1.55 (m, 2H), 1.46 (s, 9H), 1.27 (s, 3H), 0.96 (t, J=7.6 Hz, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=3[F:28])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:29]([NH:33][S:34]([C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1)(=[O:36])=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([NH:33][S:34]([C:37]1[CH:38]=[CH:39][CH:40]=[C:41]([C:2]2[CH:7]=[C:6]([C:8]3[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=4[F:28])[N:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:42]=1)(=[O:36])=[O:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Fc1cc(C(F)(F)F)ccc1-c1cc(C(F)(F)F)nc(-c2ccnc(Cl)c2)n1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4F)cc(C(F)(F)F)n3)ccn2)c1

Procedure:
N-tert-Butyl-3-{4-[6-(2-fluoro-4-trifluoromethyl-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonamide was prepared from 2-(2-chloro-pyridin-4-yl)-6-(2-fluoro-4-trifluoromethyl-phenyl)-4-trifluoromethyl-pyrimidine (example E.107) (0.32 g, 0.76 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.23 g, 0.91 mmol) according to the general procedure VI. Obtained as an off-white solid (0.24 g), which was subsequently deprotected.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][C:5]1[N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C.Cl[C:22]([O:24][CH3:25])=[O:23]>C(Cl)Cl>[CH3:25][O:24][C:22]([NH:1][CH2:2][CH2:3][S:4][C:5]1[N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1)=[O:23]
Reactant: NCCSc1cccc2nccn12
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NCCSc1cccc2nccn12
Yield: 66.9 %

Procedure:
To a solution of 5-[2-(amino)ethylthio]imidazo[1,2-a]pyridine (1.93 g, 10 mmoles) and triethylamine (1.53 ml, 11 mmoles) in methylene chloride (30 ml) was added methyl chloroformate (0.77 ml, 10 mmoles) under ice-cooling with stirring and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was washed in turn with an aqueous sodium bicarborate solution and water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: ethanol/ethyl acetate=1:10) to obtain 1.68 g of the desired product (66.9%, colorless crystals).
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][CH2:22][C:23]([OH:25])=[O:24]>>[C:1]([NH:21][CH2:22][C:23]([OH:25])=[O:24])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCC(=O)O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: O=C(O)CNC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 90 %

Procedure:
N-tritylglycine was prepared in 90% yield from trityl chloride and glycine according to the procedure of Zervas et al., J. Am. Chem. Soc. 78:1359 (1956).
Reaction SMILES: FC(F)(F)C([N:5]([C@@H:14]1[CH2:18][CH2:17][C@@:16]([C:22]([N:24]2[CH2:29][C@@H:28]3[C@H:30](O)[C@H:25]2[CH2:26][N:27]3[C:32]2[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][N:33]=2)=[O:23])([CH:19]([CH3:21])[CH3:20])[CH2:15]1)[C@H:6]1[CH2:11][CH2:10][O:9][CH2:8][C@H:7]1[O:12][CH3:13])=O.CCN(S(F)(F)[F:50])CC>C(Cl)Cl>[F:50][CH:30]1[C@@H:28]2[N:27]([C:32]3[CH:37]=[C:36]([C:38]([F:41])([F:39])[F:40])[CH:35]=[CH:34][N:33]=3)[CH2:26][C@H:25]1[N:24]([C:22]([C@@:16]1([CH:19]([CH3:20])[CH3:21])[CH2:17][CH2:18][C@@H:14]([NH:5][C@H:6]3[CH2:11][CH2:10][O:9][CH2:8][C@H:7]3[O:12][CH3:13])[CH2:15]1)=[O:23])[CH2:29]2
Reactant: CO[C@@H]1COCC[C@@H]1N(C(=O)C(F)(F)F)[C@@H]1CC[C@@](C(=O)N2C[C@@H]3[C@H](O)[C@H]2CN3c2cc(C(F)(F)F)ccn2)(C(C)C)C1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CO[C@@H]1COCC[C@@H]1N[C@@H]1CC[C@@](C(=O)N2C[C@@H]3C(F)[C@H]2CN3c2cc(C(F)(F)F)ccn2)(C(C)C)C1
Reaction time: 8 h
Yield: 53.1 %

Procedure:
2,2,2-trifluoro-N-((1R,3S)-3-((1R,4R,7S)-7-hydroxyl-2-(4-(trifluoromethyl)pyridin-2-yl)-2,5-diaza-bicyclo[2.2.1]heptane-5-carbonyl)-3-isopropylcyclopentyl)-N-((3S,4S)-3-methoxy-tetrahydro-2H-pyran-4-yl)acetamide (30 mg, 0.057 mmol) in CH2Cl2 (2 ml) was cooled to 0° C. and DAST (0.025 ml, 0.086 mmol) was added to the solution. The reaction mixture was stirred overnight and purified by chromatography (10% EtOAc to 100% MeOH) to yield desired product (16 mg, 32%). LC/MS (M+H)=529.2802 exp, 529.3112 obs; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.67-0.78 (m, 5H) 0.82 (d, J=6.59 Hz, 3H) 1.23 (br. s., 1H) 1.50 (d, J=3.66 Hz, 3H) 1.75 (d, J=4.39 Hz, 2H) 1.94-2.03 (m, 1H) 2.24-2.32 (m, 1H) 2.98 (s, 1H) 3.12 (br. s., 1H) 3.18-3.23 (m, 4H) 3.31-3.34 (m, 1H) 3.40 (d, J=10.98 Hz, 1H) 3.62 (d, J=12.08 Hz, 1H) 3.72 (d, J=10.62 Hz, 3H) 3.80-3.92 (m, 1H) 4.87 (br. s., 1H) 4.90-4.96 (m, 1H) 5.31 (d, J=1.83 Hz, 1H) 5.40-5.46 (m, 1H) 6.86-6.94 (m, 2H) 8.31 (d, J=5.49 Hz, 1H)
Reaction SMILES: [CH3:1][O:2][C:3]1[S:7][C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.S(O)(O)(=O)=O.Cl[C:22]1[NH:23][CH2:24][CH2:25][N:26]=1>C(#N)C.ClCCl>[CH3:1][O:2][C:3]1[S:7][C:6]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:22]3[NH:26][CH2:25][CH2:24][N:23]=3)=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cc2ccc(N)cc2)s1
Reactant: ClC1=NCCN1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CC#N
Product: COc1ccc(Cc2ccc(NC3=NCCN3)cc2)s1
Temperature: 80 °C
Yield: 69.6 %

Procedure:
To a solution of [4-(5-methoxythien-2-ylmethyl)-phenylamine (145 mg, 0.66 mmol) in acetonitrile (10 ml) was added 2-chloro-2-imidazoline sulfate (155 mg, 0.76 mmol) at 20-25° C. under nitrogen. The resulting suspension was heated at 80° C. for 1.5 hours. The mixture was diluted with dichloromethane and washed with 10% sodium hydroxide, water, dried (Na2SO4), and concentrated to dryness. Purification by preparative TLC, eluting with ethyl acetate/methyl alcohol/isoprolpylamine, gave 2-[4-(5-methoxythien-2-ylmethyl)phenyl]amino-imidazoline (132 mg, 70%) as a yellow oil; 1H NMR (300 MHz, CDCl3) δ 7.12 (d,J=8.4 Hz, 2H), 6.93 (d,J=8.4 Hz, 2H), 6.39 (dt, J=3.7, 1.1 Hz, 1H), 5.98 (d,J=3.7 Hz, 1H), 3.92 (bs, 2H), 3.82 (S,3H), 3.52 (S,4H), 3.15-3.35 (broad, 2H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[C:10]([S:12][CH3:13])[N:9]=[C:8]([NH2:14])[N:7]=1.[Br:15]N1C(=O)CCC1=O>C(O)(=O)C>[Br:15][C:11]1[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[N:7][C:8]([NH2:14])=[N:9][C:10]=1[S:12][CH3:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: CSc1cc(-c2ccco2)nc(N)n1
Solvent: CC(=O)O
Product: CSc1nc(N)nc(-c2ccco2)c1Br
Reaction time: 48 h
Yield: 34.2 %

Procedure:
To a stirred solution of 197 mg (0.95 mmol) 4-furan-2-yl-6-methylsulfanyl-pyrimidin-2-ylamine in 15 ml acetic acid was added 178 mg (1.00 mmol) N-bromosuccinimide and stirring continued at room temperature for 48 h. The reaction mixture was then concentrated in vacuo and the residue partitioned between ether and water. The organic phase was dried over, sodium sulfate and concentrated in vacuo. Chromatography (ethyl acetate/hexane 1/2) followed by trituration in ether/hexane then afforded 93 mg (34%) 5-bromo-4-furan-2-yl-6-methylsulfanyl-pyrimidin-2-ylamine as a yellow crystalline solid. EI-MS m/e (%): 287 (M{81Br}+, 44), 285 (M{79Br}+, 42), 206 ([M—Br]+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:19])C=1>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH+:8]([O-:19])[C:5]2=[N:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Clc1cnc2[nH]ccc2c1
Solvent: CCOC(C)=O
Product: [O-][NH+]1C=Cc2cc(Cl)cnc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 23.6 %

Procedure:
To 5-chloro-1H-pyrrolo[2,3-b]pyridine (10.0 g, 65.6 mmol) in EtOAc (70 mL) at 0° C. was added dropwise over 15 h a solution of m-chloroperbenzoic acid (57%, 17.9 g, 104 mmol) in EtOAc (80 mL). The reaction mixture was stirred for 20 h at RT. Then, the mixture was cooled to −40° C. and the solids were filtered off and rinsed with cold EtOAc. The solid was taken up in water (70 mL) and treated dropwise with 30% aq. K2CO3 until pH was 11. The solution was warmed for 30 min, cooled to 0° C., filtered and dried in vacuo. Analysis (NMR) indicated the presence of m-chloroperbenzoic acid. The solid was taken up in 10% MeOH in DCM and washed with 30% aq. K2CO3 until all m-chlorobenzoic acid was removed. The organic layer was dried over Na2SO4, filtered and concentrated to provide 2.61 g (24% yield) of 5-chloro-1H-pyrrolo[2,3-b]pyridine-N-oxide (C). The combined mother liquors were concentrated. Flash chromatography (5% MeOH-DCM) provided and additional 1.49 g (13% yield) contaminated with ˜10% of the benzoic acid. LC/MS (M+H+) 168.76.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1.[O:18]1[CH2:22][CH2:21][CH:20]([CH2:23][OH:24])[CH2:19]1>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:3]2[C:2]([O:24][CH2:23][CH:20]3[CH2:21][CH2:22][O:18][CH2:19]3)=[N:7][CH:6]=[C:5]([CH:4]=2)[C:8]([OH:10])=[O:9])=[CH:12][CH:13]=1
Reactant: O=C(O)c1cnc(Cl)c(-c2ccc(Cl)cc2)c1
Reactant: OCC1CCOC1
Product: O=C(O)c1cnc(OCC2CCOC2)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example CI using 6-chloro-5-(4-chlorophenyl)-3-pyridine carboxylic acid (CAN 1012792-56-1) and tetrahydro-3-furanmethanol (CAN 15833-61-1) as starting materials; LC-MS (UV peak area/ESI) 91.6%, 334.0833 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[C:7]([C:9]3[N:10]=[CH:11][N:12]4[C:18]=3[CH2:17][N:16](CC3C=CC(OC)=CC=3OC)[C:15](=[O:30])[C:14]3[CH:31]=[C:32]([Br:35])[CH:33]=[CH:34][C:13]4=3)[O:6][N:5]=2)[CH2:3][CH2:2]1.FC(F)(F)S(O)(=O)=O>C(Cl)Cl.FC(F)(F)C(O)=O>[CH:1]1([C:4]2[N:8]=[C:7]([C:9]3[N:10]=[CH:11][N:12]4[C:18]=3[CH2:17][NH:16][C:15](=[O:30])[C:14]3[CH:31]=[C:32]([Br:35])[CH:33]=[CH:34][C:13]4=3)[O:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(CN2Cc3c(-c4nc(C5CC5)no4)ncn3-c3ccc(Br)cc3C2=O)c(OC)c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NCc2c(-c3nc(C4CC4)no3)ncn2-c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
3-(3-Cyclopropyl-[1,2,4]oxadiazol-5-yl)-5-(2,4-dimethoxy-benzyl)-8-bromo-4,5-dihydro-2,5,10b-triaza-benzo[e]azulene-6-one (1.1 g, 2.0 mmol) was suspended in CH2Cl2 (6 mL), cooled in ice, and diluted slowly with trifluroacetic acid (4.7 mL). The resulting solution was treated at 5° C. with trifluoromethanesulfonic acid (266 μL, 3.0 mmol). The red solution was stirred at room temperature for 1.5 h. The mixture was then evaporated and dissolved in CH2Cl2 (10 mL), washed with sodium hydrogen carbonate (sat., 10 mL) and the organic layer was dried (Na2SO4) and evaporated. Trituration with EtOAc. Yield: 772 mg (100%). m/z 385/387 (M—H−).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[CH2:10]([O:12][P:13]([O:17]CC)[O:14][CH2:15][CH3:16])[CH3:11]>CCCCCC.C(OC(=O)C)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][P:13](=[O:17])([O:14][CH2:15][CH3:16])[O:12][CH2:10][CH3:11])=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CCOP(OCC)OCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOP(=O)(Cc1ccc(Br)cc1)OCC
Reaction time: 24 h
Yield: 81.4 %

Procedure:
4-bromobenzylbromide (10.0 g, 40.0 mmol) was dissolved in triethylphosphite (8.4 mL, 48.0 mmol) under a nitrogen atmosphere, and the reaction solution was refluxed and stirred for 24 hours. The reaction solution was passed through a silica gel column by using hexane-ethylacetate 7:3 as an eluant. After the solvent was removed, the residue material was dried in vacuum to thereby obtain pale yellow oil (10.0 g, yield: 81%).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][S:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)=[O:12])C.[NH2:21][OH:22].[OH-].[K+].CO>C1COCC1>[OH:22][NH:21][C:4](=[O:3])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][S:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)=[O:12]
Reactant: NO
Reactant: CCOC(=O)CCCCCCS(=O)c1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(CCCCCCS(=O)c1ccc(Cl)cc1)NO
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
To a solution of 7-(4-chloro-benzenesulfinyl)-heptanoic acid ethyl ester (0.5 g, 1.6 mmol) in distilled THF (10 mL) containing 50% aqueous hydroxylamine (0.9 mL, 13.6 mmol) was added at 0° C. a solution of potassium hydroxide in methanol (2.5 mL, 1M, 2.5 mmol) in a dropwise manner. After stirring at 0° C. for 1 h, distilled water (10 mL) was added and the mixture was made neutral by dropwise addition of concentrated hydrochloric acid (10 M) at 0° C. The aqueous solution was extracted with ethyl acetate (2×25 mL) and the combined extracts were washed with brine (25 mL), dried over anhydrous MgSO4, filtered and evaporated to dryness. The residue was recrystallised from ethyl acetate to give the title compound (0.4 g, 83%) as a white powder, mp 103-105° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=O)[C:8]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:9]=2[NH:10][N:11]=1)=[O:5])[CH3:2].N1C=CC=CC=1.C1(C)C=CC(S([Cl:33])(=O)=O)=CC=1>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[N:10][C:9]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:8]=2[C:7]=1[Cl:33])=[O:5])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)c1n[nH]c2c(c1=O)CCCCC2
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1nnc2c(c1Cl)CCCCC2
Yield: 22.3 %

Procedure:
To a solution of 4-oxo-4,5,6,7,8,9-hexahydro-1H-cyclohepta[c]pyridazine-3-carboxylic acid ethyl ester (2.7 g) and pyridine (0.93 ml) in dichloromethane (150 ml) was added p-toluenesulphonyl chloride (2.2 g). The reaction mixture was heated at reflux for 20 h. The reaction mixture was washed with 1M potassium carbonate solution, brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure to give an oil. The oil was purified by flash chromatography using a gradient elution: CH2Cl2 (500 ml), CH2Cl2/MeOH 99:1 (500 ml), CH2Cl2/MeOH 98:2 (500 ml), CH2Cl2/MeOH 97:3 (500 ml), CH2Cl2/MeOH 96:4 (500 ml). The appropriate fractions were combined and evaporated under reduced pressure to give a solid (0.65 g, 22%). C12H15ClN2O2 requires C, 56.58; H, 5.93; N, 11.00. Found C, 56.52; H, 6.06; N, 11.01%. δH (360 MHz; CDCl3) 1.44 (3H, t, J=7 Hz, CH3), 1.70 (2H, m, CH2), 1.77 (2H, m, CH2), 1.92 (2H, m, CH2), 3.06 (2H, m, CH2), 3.32 (2H, m, CH2), 4.51 (2H, t, J=7 Hz, CH2), m/z (ESP+) 255/257 (MH+).
Reaction SMILES: Br[C:2]1[C:3]([Cl:14])=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[CH:8]=[CH:7]2.[C:15](OCC)(=O)[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[CH2:20]([O:19][C:17](=[O:18])[C:16]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[N:10]=2)[N:5]=[CH:4][C:3]=1[Cl:14])=[CH2:15])[CH3:21]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COc1ccc2ncc(Cl)c(Br)c2n1
Product: C=C(C(=O)OCC)c1c(Cl)cnc2ccc(OC)nc12

Procedure:
Starting from 8-bromo-7-chloro-2-methoxy-[1,5]naphthyridine (41.75 g, 152.6 mmol) and diethyl malonate (70.2 mL, 3 eq.), the title compound was obtained as a white solid (31.35 g, 107.2 mmol) using the procedures reported in WO 2007/071936 for the analogous methyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][C:12]([NH:14][CH:15]([C:19](OCC)=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13].[OH-].[Na+]>C(O)C.O>[OH:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][C:12]([NH:14][C:15](=[C:19]=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13]
Reactant: CCOC(=O)C(NC(=O)Nc1ccc([N+](=O)[O-])cc1O)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)C(=C=O)NC(=O)Nc1ccc([N+](=O)[O-])cc1O
Temperature: 25 °C
Yield: 49.7 %

Procedure:
To a solution of N-(2-Hydroxy-4-nitrophenyl)-N'-[1-(ethoxycarbonyl)-2-methylpropyl)urea (200 mg, 0.62 mmol) in ethanol/water (10 mL/1 mL), sodium hydroxide (123 mg, 3.1 mmol) was added. The reaction mixture was stirred at reflux temperature for 16 hours. Then the reaction mixture was cooled to room temperature and all the solvent was evaporated. 3N of HCl was added to pH=1. A yellow solid precipitated, it was filtered to give desired product (86 mg, 47%). EI-MS m/z 298.3 (M+). mp: 168.4-169.2° C.