Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(=O)(O)[O-].[Na+]>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([S:24]([CH3:23])(=[O:26])=[O:25])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
1-(4-Nitrophenyl)piperazine (2.79 g, 13.5 mmol) was dissolved in dichloromethane (100 ml). Triethylamine (2.25 ml, 16.2 mmol) was added and the reaction was cooled to 0° C. Methanesulfonyl chloride (1.15 ml, 14.9 mmol) was added dropwise and the reaction was stirred at 0° C. for 1 h. Saturated sodium bicarbonate was added and the reaction was extracted (×3) with dichloromethane, dried (MgSO4), filtered and concentrated in vacuo to give 4-(4-nitrophenyl)-1-methylsulfonylpiperazine as a yellow solid (3.83 g, quantitative yield). GC/MS (EI, M+) m/z=285.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]([N:5]1[C:9]2=[N:10][CH:11]=[C:12]([Br:14])[CH:13]=[C:8]2[C:7]([CH:15]=[O:16])=[CH:6]1)=[O:4].S([CH2:28][N+:29]#[C-:30])(C1C=CC(C)=CC=1)(=O)=O.C1CCN2C(=NCCC2)CC1>COCCOC>[CH3:1][N:2]([CH3:17])[C:3]([N:5]1[C:9]2=[N:10][CH:11]=[C:12]([Br:14])[CH:13]=[C:8]2[C:7]([C:15]2[O:16][CH:30]=[N:29][CH:28]=2)=[CH:6]1)=[O:4]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CN(C)C(=O)n1cc(C=O)c2cc(Br)cnc21
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: CN(C)C(=O)n1cc(-c2cnco2)c2cc(Br)cnc21
Temperature: 90 °C
Yield: 29.5 %

Procedure:
To aldehyde 20 (2.00 g, 6.75 mmol) in 1,2-dimethoxyethane (70 mL) was added tosylmethyl isocyanide (1.58 g, 8.10 mmol) followed by DBU (1.44 g, 9.46 mmol), and the reaction mixture heated at 90° C. overnight. After cooling, sorbent (HM-N, Jones Chromatography) was added and the solvent evaporated. The product was purified by silicagel chromatography using ethyl acetate:hexane (4:6) (gradient elution) to give product 21 as a light orange solid (667 mg, 29%); 1H NMR (400 MHz, CDCl3) δ 3.40-2.90 (bs, 6H), 7.32 (s, 1H), 7.86 (s, 1H), 7.96 (s, 1H), 8.32 (d, J=2.2 Hz, 1H), 8.48 (d, J=2.2 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][NH:10][C@@H:11]2[C:20]3[N:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH2:14][CH2:13][CH2:12]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:21][O:22][C:23](=[O:34])[C:24]1[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[CH:26][C:25]=1[CH2:32]Br.CCN(C(C)C)C(C)C>CC#N>[CH3:21][O:22][C:23](=[O:34])[C:24]1[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[CH:26][C:25]=1[CH2:32][N:10]([CH2:9][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=1)[CH:11]1[C:20]2[N:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:14][CH2:13][CH2:12]1
Reactant: Cc1cnc(CN[C@H]2CCCc3cccnc32)c(C)c1
Reactant: COC(=O)c1cc(C#N)ccc1CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1cc(C#N)ccc1CN(Cc1ncc(C)cc1C)C1CCCc2cccnc21

Procedure:
Using General Procedure A: Reaction of (S)-(3,5-dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine in CH3CN with 2-Bromomethyl-5-cyano-benzoic acid methyl ester, DIPEA and KI gave 5-cyano-2-{[(3,5-dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8yl)amino]-methyl}-benzoic acid methyl ester as a red oil. 1H NMR (CDCl3) δ 1.76 (m, 1H), 2.06 (m, 2H), 2.16 (s, 3H), 2.27 (s, 3H), 2.28 (m, 1H), 2.75 (m, 2H), 3.86 (m, 2H), 3.90 (s, 3H), 4.15 (m, 1H), 4.29 (m, 2H), 6.99 (d, 2H, J=15.8 Hz), 7.35 (d, 1H, J=6.6 Hz), 7.46 (d, 1H, J=7.9 Hz), 7.88 (s, 1H), 8.01 (s, 2H), 8.51 (s, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH2:8][C@H:9]3[CH2:21][C@H:10]3[C:11]=2[N:12]([C:14]2[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][N:15]=2)[N:13]=1)=[O:5])C.[OH-].[Na+]>C1COCC1.CO>[Br:20][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([N:12]2[C:11]3[C@@H:10]4[CH2:21][C@@H:9]4[CH2:8][C:7]=3[C:6]([C:4]([OH:5])=[O:3])=[N:13]2)[CH:19]=1
Reactant: CCOC(=O)c1nn(-c2cc(Br)ccn2)c2c1C[C@H]1C[C@@H]21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1nn(-c2cc(Br)ccn2)c2c1C[C@H]1C[C@@H]21
Temperature: 23 °C
Reaction time: 2 h
Yield: 100.5 %

Procedure:
To a solution of (1aR,5aR)-2-(4-bromo-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ethyl ester (9.0 g, 25.8 mmol) in THF (50 mL) and MeOH (50.0 mL) was added a 2.0 M aqueous solution of sodium hydroxide (25.8 mL, 51.7 mmol). The reaction was stirred at 23° C. for 2 h then concentrated to remove the organic solvents. The remaining residue was diluted to 150 mL with water. This solution was filtered to remove trace insoluble impurities then acidified to pH ˜3 with 6 M HCl. The resulting precipitate was collected by filtration, rinsed with water, then dried under vacuum to give the title compound (8.3 g) as a white solid. LCMS m/z=320.0 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH:10]([O:13]C)OC.C([Li])CCC.Br[CH2:21][CH2:22][CH2:23][CH:24]=[CH2:25].Cl>C1COCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:25][CH2:24][CH2:23][CH:22]=[CH2:21])=[C:3]([CH:4]=1)[CH:10]=[O:13]
Reactant: COc1ccc(Br)c(C(OC)OC)c1
Reactant: C=CCCCBr
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCCCc1ccc(OC)cc1C=O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
Step AH (3): To a solution of 1-bromo-2-(dimethoxymethyl)-4-methoxybenzene (688.5 mg, 2.637 mmol) in THF (7.0 mL) at −78° C. was added n-butyl lithium (3.46 mL, 5.538 mmol). The resulting mixture was stirred at −78° C. for 15 min. 5-Bromopent-1-ene (0.31 mL, 2.637 mmol) was added by drops. The reaction mixture was warmed to rt and stirred overnight. Aqueous hydrochloric acid solution (1N) was added and the reaction mixture was stirred at rt for 3 h. The reaction was extracted with DCM. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography to give 5-methoxy-2-(pent-4-enyl)benzaldehyde (538.6 mg, 100%) as colorless oil. LC-MS (M+H)+=205.36. 1H NMR (CDCl3, 500 MHz) δ 10.30 (s, 1H) 7.35 (d, J=3.0 Hz, 1H) 7.17 (m, 1H) 7.06 (m, 1H) 5.82 (m, 1H) 5.05-4.98 (m, 2H) 3.84 (s, 3H) 2.12 (m, 2H) 1.69 (m, 2H) 1.57 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[CH2:10][C:11]([OH:13])=[O:12].I[CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[CH2:10][C:11]([O:13][CH2:15][CH3:16])=[O:12]
Reactant: CCI
Reactant: O=C(O)Cc1c(F)cc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)Cc1c(F)cc(F)cc1F
Temperature: 50 °C
Reaction time: 3 h
Yield: 88.7 %

Procedure:
A mixture of 2,4,6-trifluorophenylacetic acid (570 mg, 3.0 mmol), iodoethane (1.56 g, 10 mmol), and potassium carbonate (1.38 g, 10 mmol) in 5 mL of dimethylsulfoxide is stirred at 50° C. for 3 h, and cooled to room temperature. The mixture is partitioned between diethyl ether and water. The organic layer is washed with water and saturated sodium chloride, dried over magnesium sulfate, and filtered through hydrous magnesium silicate. The filtrate is concentrated to give ethyl 2,4,6-trifluorophenylacetate as a light yellow oil (581 mg, 2.66 mmol).
Reaction SMILES: [C@H:1]12[NH:8][CH2:7][C@H:6]1[CH2:5][CH2:4][N:3]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:2]2.[CH3:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[C:19]([N:26]2[CH:30]=[CH:29][N:28]=[N:27]2)[N:18]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.O>C(Cl)Cl>[CH3:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([N:8]2[C@H:1]3[C@H:6]([CH2:5][CH2:4][N:3]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:2]3)[CH2:7]2)=[O:22])=[C:19]([N:26]2[CH:30]=[CH:29][N:28]=[N:27]2)[N:18]=1
Reactant: Cc1ccc(C(=O)O)c(-n2ccnn2)n1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2CN[C@@H]2C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(C(=O)N2C[C@H]3CCN(C(=O)OC(C)(C)C)C[C@H]32)c(-n2ccnn2)n1
Yield: 98 %

Procedure:
To a mixture of Intermediate 24 (570 mg, 2.69 mmol), 6-methyl-2-(1H-1,2,3-triazol-1-yl)nicotinic acid (603 mg, 2.95 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1200 mg, 2.69 mmol) in DCM (15 mL) was added TEA (1.1 mL, 8.06 mmol). The resulting mixture was stirred for 5 h at ambient temperature at which time water (30 mL) was added. The aqueous layer was extracted with DCM (15 mL) three times. The organic layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by FCC (SiO2, ethyl acetate/hexanes, 0-40%) to yield (1S,6R)-tert-butyl 8-(6-methyl-2-(1H-1,2,3-triazol-1-yl)nicotinoyl)-3,8-diazabicyclo[4.2.0]octane-3-carboxylate (1.05 g, 98%). MS (ESI) mass calcd. for C20H26N6O3, 398.2; m/z found, 399.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.48-8.38 (m, 1H), 7.82-7.79 (m, 1H), 7.77-7.64 (m, 1H), 7.33-7.23 (m, 1H), 4.53-4.27 (m, 2H), 4.06-3.89 (m, 1H), 3.80-3.36 (m, 4H), 3.01-2.90 (m, 1H), 2.62-2.58 (m, 3H), 2.03-1.76 (m, 2H), 1.53-1.42 (m, 9H).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[C:8]3[C:13]([N:14]=[CH:15][C:6]2=[N:5][CH:4]=[C:3]1[C:16]([OH:18])=O)=[CH:12][CH:11]=[CH:10][CH:9]=3.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:31][C:32]1[NH:36][N:35]=[N:34][N:33]=1.O>CN(C)C=O>[NH:33]1[C:32]([NH:31][C:16]([C:3]2[C:2](=[O:1])[N:7]3[C:8]4[C:13]([N:14]=[CH:15][C:6]3=[N:5][CH:4]=2)=[CH:12][CH:11]=[CH:10][CH:9]=4)=[O:18])=[N:36][N:35]=[N:34]1
Reactant: Nc1nnn[nH]1
Reactant: O=C(O)c1cnc2cnc3ccccc3n2c1=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1nnn[nH]1)c1cnc2cnc3ccccc3n2c1=O
Reaction time: 1 h
Yield: 75.1 %

Procedure:
A mixture of 250 mg of 1-oxo-1H-pyrimido[1,2-a]quinoxaline-2-carboxylic acid and 200 mg of carbonyldiimidazole in 5 ml of dry dimethylformamide was heated over a steam bath for 15 minutes and then 100 mg of 5-aminotetrazole were added thereto. The mixture obtained was heated over a steam bath for another 30 minutes and was then poured into water and left at room temperature for 1 hour. The solid obtained was filtered off, was washed with water and ether and dried to obtain 240 mg (61% yield) of N-(5-tetrazolyl)-1-oxo-1H-pyrimido[1,2-a]quinoxaline-2-carboxamide melting above 300°.
Reaction SMILES: [CH:1](=[C:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([OH:12])[C:6]=2[CH2:5][CH2:4]1)[CH3:2].[H][H]>CO.CCOC(C)=O.[Pd]>[CH2:1]([CH:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([OH:12])[C:6]=2[CH2:5][CH2:4]1)[CH3:2]
Reactant: [H][H]
Reactant: CC=C1CCc2c(O)cccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCC1CCc2c(O)cccc21

Procedure:
A mixture of 1-ethylidene-indan-4-ol (37 mg, 0.23 mmol) and 10% Pd/C (12 mg, 10% weight) in methanol (4 ml) was hydrogenated under 50 psi hydrogen atmosphere for 1 hour. The mixture was dissolved in EtOAc, filtered through a celite pad. The filtrate was concentrated under reduced pressure, and dried to 1-ethyl-indan-4-ol (36 g, 97%)
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]=1[CH3:9].C(N(CC)CC)C.CS([Cl:28])(=O)=O>C(Cl)Cl>[Cl:28][CH2:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(-c2ccc(C)c(CO)c2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(-c2ccc(C)c(CCl)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-hydroxymethyl-4,4'-dimethylbiphenyl (1.3 g) and triethylamine (0.8 g) in methylene chloride (50 ml) was cooled to 0° C., and methanesulfonyl chloride (0.84 g) in methylene chloride was added dropwise. The mixture was allowed to warm to room temperature, and was stirred overnight. Ice/water was then added, the organic layer separated, the aqueous layer washed with methylene chloride, the organic layer washed with brine, dried over sodium sulfate, and the solvent evaporated under reduced pressure, to yield 3-chloromethyl-4,4'-dimethylbiphenyl as an oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:33]=[CH:34][CH:35]=1)[CH2:8][N:9]1[C:13](=[O:14])[C:12]2([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[N:11]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:10]1)=[O:4].O.[OH-].[Li+]>CO.O>[C:23]([O:22][C:20]([N:17]1[CH2:18][CH2:19][C:12]2([N:11]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:10][N:9]([CH2:8][C:7]3[CH:6]=[C:5]([CH:35]=[CH:34][CH:33]=3)[C:3]([OH:4])=[O:2])[C:13]2=[O:14])[CH2:15][CH2:16]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: COC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)N(Cc1cccc(C(=O)O)c1)CN2c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.8 %

Procedure:
To a solution of tert-Butyl 3-(3-(methoxycarbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (2 g, 4.17 mmol) in methanol (28 mL) was added lithium hydroxide monohydrate (0.35 g, 8.34 mmol) in water (14 mL). After stirring at room temperature for 18 h, the reaction mixture was concentrated in vacuo, acidified with dilute citric acid, extracted with dichloromethane. The organic extracts were washed with brine, dried over MgSO4, filtered and concentrated to obtain 3-((8-(tert-butoxycarbonyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid (1.88 g, 97%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[N:2]1.Br[C:14]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:15]=1[C:16]([OH:18])=[O:17].C(=O)([O-])[O-].[K+].[K+]>[Cu]=O>[C:16]([C:15]1[C:19]([O:23][CH3:24])=[CH:20][CH:21]=[CH:22][C:14]=1[N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[N:2]1)([OH:18])=[O:17]
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: COc1cccc(Br)c1C(=O)O
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cccc(-n2nc(C(=O)O)c3ccccc32)c1C(=O)O
Yield: 36.5 %

Procedure:
3-Indazolecarboxylic acid (1.16 g), 0.81 g of 2-bromo-6-methoxybenzoic acid [described in Chem. Ber., 107, 3874 (1974)], 0.79 g of potassium carbonate and 0.04 g of copper(II) oxide were subjected to reaction in the same manner as in Example 1 to obtain 0.40 g (25.6%) of 1-(2-carboxy-3-methoxyphenyl)-3-indazolecarboxylic acid.
Reaction SMILES: OC1C=C(N2C3C(=NC=CC=3)N=C2)SC=1C(OC)=O.[OH:20][C:21]1[CH:25]=[C:24]([N:26]2[C:30]3=[N:31][CH:32]=[CH:33][CH:34]=[C:29]3[N:28]=[CH:27]2)[S:23][C:22]=1[C:35]([O:37][CH3:38])=[O:36].C([O-])([O-])=O.[K+].[K+].Br[CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[C:53]([F:56])([F:55])[F:54]>CN(C)C=O>[N:28]1[C:29]2[C:30](=[N:31][CH:32]=[CH:33][CH:34]=2)[N:26]([C:24]2[S:23][C:22]([C:35]([O:37][CH3:38])=[O:36])=[C:21]([O:20][CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[C:53]([F:54])([F:55])[F:56])[CH:25]=2)[CH:27]=1
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: COC(=O)c1sc(-n2cnc3cccnc32)cc1O
Agent: COC(=O)c1sc(-n2cnc3ncccc32)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-n2cnc3cccnc32)cc1OCc1ccccc1C(F)(F)F

Procedure:
In a similar manner as described for example B3, 12.49 g of an isomeric mixture of methyl 3-hydroxy-5-(1H-imidazo[4,5-b]pyridin-1-yl)thiophene-2-carboxylate and methyl 3-hydroxy-5-(3H-imidazo[4,5-b]pyridin-3-yl)thiophene-2-carboxylate (example C8) and 7.45 g of K2CO3 and 12.91 g of 1-(bromomethyl)-2-(trifluoromethyl)benzene in 200 ml N,N-dimethylformamide yield compound B5a and compound B5b.
Reaction SMILES: [OH:1][C@:2]1([C:14]2[S:15][C:16]([C:19]3[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[C:21]([CH2:28][OH:29])[CH:20]=3)=[CH:17][N:18]=2)[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[C:4]([CH3:13])([CH3:12])[CH2:3]1.[C:30](Cl)(=[O:32])[CH3:31].C(N(CC)CC)C>ClCCl>[C:30]([O:29][CH2:28][C:21]1[CH:20]=[C:19]([C:16]2[S:15][C:14]([C@@:2]3([OH:1])[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[C:4]([CH3:13])([CH3:12])[CH2:3]3)=[N:18][CH:17]=2)[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)Cl
Reactant: COC(=O)[C@H]1CC[C@](O)(c2ncc(-c3cc(CO)cc([N+](=O)[O-])c3)s2)CC1(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H]1CC[C@](O)(c2ncc(-c3cc(COC(C)=O)cc([N+](=O)[O-])c3)s2)CC1(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 84.8 %

Procedure:
To a solution of the product of Step 4 (194 mg, 0.46 mmol) dissolved in dichloromethane (1.8 mL) at −20° C. was added acetyl chloride (34 μL, 0.48 mmol) and triethylamine (129 μL, 0.92 mmol). The reaction was warmed to room temperature and stirred for 2.5 h. The reaction was quenched with saturated aqueous sodium bicarbonate, and extracted with dichloromethane (3×). The combined organic layers were washed with brine, then dried over sodium sulfate, filtered, and concentrated to afford methyl(1S,4R)-4-(5-{3-[(acetyloxy)methyl]-5-nitrophenyl}-1,3-thiazol-2-yl)-4-hydroxy-2,2-dimethylcyclohexanecarboxylate (203 mg, 0.39 mmol, 86% yield) as a yellow foam. MS ESI: [M+H]+ m/z 463.1.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[CH2:12][CH3:13])[CH2:8][CH:7]([NH2:14])[CH2:6]2)[CH3:2].C(N(CC)CC)C.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl>[CH2:12]([C:11]1[CH:10]=[C:9]2[C:5](=[CH:4][C:3]=1[CH2:1][CH3:2])[CH2:6][CH:7]([NH:14][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:8]2)[CH3:13]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCc1cc2c(cc1CC)CC(N)C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cc2c(cc1CC)CC(NC(=O)c1ccccc1)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5,6-Diethyl-indan-2-ylamine (4.10 g) is dissolved in dichloromethane (DCM) (150 mL) and triethylamine (2.41 g) is added. Benzoyl chloride (3.20 g) is then added dropwise and the reaction mixture is stirred at room temperature. The reaction is shown to be complete by TLC after 1 hour. The solution is washed with 0.2M HCl (100 mL), water (100 mL) and brine (100 mL). The organic layer is dried over MgSO4, filtered and the solvent is removed in vacuo. Crystallised from ethyl acetate. TLC. (silica, dichloromethane I methanol 10:1 Rf=0.85).
Reaction SMILES: [CH:1]([C:4]([C:7]([C:10]([C:13]([C:16]([CH2:19][S:20]([OH:22])=[O:21])([F:18])[F:17])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[OH2:23].BrBr>C(O)(=O)C>[CH:1]([C:4]([C:7]([C:10]([C:13]([C:16]([CH2:19][S:20]([OH:23])(=[O:22])=[O:21])([F:17])[F:18])([F:15])[F:14])([F:11])[F:12])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: O=S(O)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)F
Reactant: O
Agent: BrBr
Solvent: CC(=O)O
Product: O=S(=O)(O)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)F
Reaction time: 12 h

Procedure:
H(CF2)6CH2SO2H (1.00 g, 2.63 mmol) was put in a 100 ml flask, and was dissolved in acetic acid (20 ml) in the air. After the reaction system was dipped in ice bath and water (1.0 ml) was added thereto, bromine (1.1 g, 6.84 mmol) was added and stirring was continued at room temperature for 12 hours. After completion of the reaction, the inside of the system was brought to reduced pressure, and after removing the solvent and bromine, the reaction product was dried in vacuo at 60° C. for 12 hours to obtain H(CF2)6CH2SO3H (1.04 g, 2.63 mmol).
Reaction SMILES: [N:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[S:3][C:2]=1[C:10]1([C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[CH3:25][C:26](OC(C)=O)=[O:27]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:26]([N:6]1[CH2:7][CH2:8][C:9]2[N:1]=[C:2]([C:10]3([C:16]4[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=4)[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)[S:3][C:4]=2[CH2:5]1)(=[O:27])[CH3:25]
Reactant: O=C(O)c1ccc(C2(c3nc4c(s3)CNCC4)CCOCC2)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)N1CCc2nc(C3(c4ccc(C(=O)O)cc4)CCOCC3)sc2C1

Procedure:
4-[4-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-tetrahydro-pyran-4-yl]-benzoic acid (40 mg, 0.116 mmol) in pyridine, catalytic amount of 4-dimethylaminopyridine (DMAP), and excess Ac2O were mixed together at room temperature. After the reaction was complete, the mixture was evaporated, washed with water, and extracted with EtOAc. The organic phase was dried and evaporated to give 4-[4-(5-acetyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-tetrahydro-pyran-4-yl]-benzoic acid. Similar HATU coupling procedure from Example 9 was followed to obtain the title compound. MS found for C26H28N4O3S as (M+H)+ 477.58. 1H NMR (400 MHz, dmso-d6): δ: 9.53 (s, 1H), 7.89 (d, J=8.4 Hz, 2H), 7.51 (t, J=8.4 Hz, 2H), 7.10 (d, J=7.2 Hz, 1H), 6.92 (t, J=7.6 Hz, 1H), 6.72 (d, J=8.0 Hz, 1H), 6.54 (t, J=7.6 Hz, 1H), 4.84 (s, 2H), 4.61-4.57 (m, 2H), 3.69-3.57 (m, 6H), 2.80-2.29 (m, 6H), 2.05-1.98 (m, 3H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH3:11])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O.O>[C:18]([N:2]([CH3:1])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH3:11])=[CH:6][CH:5]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CNCc1ccc(SC)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CSc1ccc(CN(C)C(=O)c2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
N-Methyl-N-(4-methylthiobenzyl)amine (4.2 g) and potassium carbonate (5.2 g) are dissolved in a mixture of acetone (20 ml) and water (20 ml), and thereto is added dropwise benzoyl chloride (3.7 ml) gradually under ice cooling. After the mixture is stirred at the same temperature for 30 minutes, the reacting mixture is poured into water, and then extracted with dichloromethane. The extract is washed with aqueous sodium chloride solution, and dried over magnesium sulfate. Dichloromethane is distilled off to give N-benzoyl-N-methyl-N-(4-methylthiobenzyl)amine (6.8 g).
Reaction SMILES: [F:1][CH:2]([F:28])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19](C)=[N:20][C:21](O)=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:27])[CH3:26])=[O:4].C(N(CC)CC)C.CS(Cl)(=O)=O.[CH2:41]([Cl:43])Cl>>[Cl:43][CH2:41][C:21]1[N:20]=[CH:19][C:18]([C:15]2[CH:16]=[CH:17][C:12]([C@H:8]3[O:7][C:6]([CH3:26])([CH3:27])[N:5]([C:3](=[O:4])[CH:2]([F:28])[F:1])[C@@H:9]3[CH2:10][F:11])=[CH:13][CH:14]=2)=[CH:23][CH:22]=1
Reactant: ClCCl
Reactant: Cc1nc(O)ccc1-c1ccc([C@H]2OC(C)(C)N(C(=O)C(F)F)[C@@H]2CF)cc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CC1(C)O[C@H](c2ccc(-c3ccc(CCl)nc3)cc2)[C@@H](CF)N1C(=O)C(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A stirred solution of 2,2-Difluoro-1-{(4S,5R)-4-fluoromethyl-5-[4-(6-hydroxy-methyl-pyridin-3-yl)-phenyl]-2,2-dimethyl-oxazolidin-3-yl}-ethanone (1660 mg, 4.2 mmol) and triethylamine (0.88 ml, 6.31 mmol) in CH2Cl2 (30 ml) is treated with methanesulfonyl chloride (0.49 ml, 6.31 mmol) and stirred at ambient temperature for 16 hours. The reaction mixture is concentrated to dryness to afford the title compound as a red oil (1.53 g): 1H NMR (400 MHz, CDCl3) 1.60-1.77 (m, 6H), 4.53-4.84 (m, 5H), 5.25-5.31 (m, 1H), 6.12 (t, 1H), 7.58 (d, 2H), 7.65 (d, 2H), 7.68 (d, 1H), 8.03-8.07 (m, 1H), 8.86-8.90 (m, 1H). m/z M+H 413.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:63]([N:65]([CH2:74][CH3:75])[C:66]([CH:68]1[CH2:73][CH2:72][CH2:71][CH2:70][NH:69]1)=[O:67])[CH3:64]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:69]1[CH2:70][CH2:71][CH2:72][CH2:73][CH:68]1[C:66]([N:65]([CH2:74][CH3:75])[CH2:63][CH3:64])=[O:67])=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CCN(CC)C(=O)C1CCCCN1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCN(CC)C(=O)C1CCCCN1C(=O)c1cc2ncnc(NC(C)c3nc4cc(Cl)ccc4[nH]3)c2cc1Cl

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 2-diethylaminocarbonyl-piperidine in DMSO at ambient temperature.