Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCOCC1.Cl.Cl[C:9]1[C:14]([C:15]2[N:20]=[C:19]([CH3:21])[N:18]=[C:17]([NH2:22])[N:16]=2)=[CH:13][C:12]([O:23][CH3:24])=[CH:11][N:10]=1.[NH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[N:30][CH:31]=1>>[CH3:24][O:23][C:12]1[CH:13]=[C:14]([C:15]2[N:20]=[C:19]([CH3:21])[N:18]=[C:17]([NH2:22])[N:16]=2)[C:9]([NH:25][C:26]2[CH:31]=[N:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[N:10][CH:11]=1
Reactant: COc1ccc(N)cn1
Reactant: COc1cnc(Cl)c(-c2nc(C)nc(N)n2)c1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cnc(Nc2ccc(OC)nc2)c(-c2nc(C)nc(N)n2)c1
Temperature: 140 °C

Procedure:
1,4-dioxane (0.1 mL, 1.169 mmol) and 2N HCl (0.219 mL, 0.437 mmol) was added to a mixture of 4-(2-chloro-5-methoxypyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (110 mg, 0.437 mmol) and 5-amino-2-methoxypyridine (Aldrich, St. Louis, Mo.) (81 mg, 0.656 mmol) in a microwave reaction vessel and the mixture was sealed and heated at 140° C. for 60 min in a Personal Chemistry microwave unit under microwave irradiation. After cooling, the resulting dark mixture was concentrated. Flash column chromatographic purification (short column, SiO2, pure DCM to 5% MeOH in DCM) provided the title compound mixed with starting material. This was washed with methanol several times and finally the solid was recrystallized from MeOH to give 4-(5-methoxy-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (21 mg, 0.062 mmol, 14.16% yield) as a yellow-green powder. LCMS (API-ES) m/z 340 (M+H)+; 1H NMR (400 MHz, d6-DMSO) δ 11.47 (s, 1H) 8.52 (d, J=2.74 Hz, 1H) 8.39 (d, J=3.33 Hz, 1H) 8.13-8.18 (m, 1H) 8.12 (d, J=3.13 Hz, 1H) 7.86 (br s., 1H) 7.73 (br. s., 1H) 6.79 (d, J=8.80 Hz, 1H) 3.83 (s, 3H) 3.82 (s, 3H) 2.44 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](O)=[N:6][CH:7]=1.P(Cl)([Cl:21])(OC1C=CC=CC=1)=O>>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([Cl:21])=[N:6][CH:7]=1
Reactant: O=P(Cl)(Cl)Oc1ccccc1
Reactant: O=[N+]([O-])c1cc(Br)cnc1O
Product: O=[N+]([O-])c1cc(Br)cnc1Cl
Temperature: 180 °C

Procedure:
A suspension of 5-bromo-2-hydroxy-3-nitro-pyridine (19.2 g; ex. Maybridge) in phenyl dichlorophosphate (40 ml) was heated at 180° C. for 30 minutes to give a red oil. The reaction mixture was then purified as described in Example 1 Method 1(a) to give the title compound as a pale yellow solid (20.4 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:29][CH3:30])[C:16]2[C:17]([CH2:27][CH3:28])=[C:18]([CH:23]=[C:24]([Cl:26])[CH:25]=2)[C:19]([O:21]C)=[O:20])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:29][CH3:30])[C:16]2[C:17]([CH2:27][CH3:28])=[C:18]([CH:23]=[C:24]([Cl:26])[CH:25]=2)[C:19]([OH:21])=[O:20])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1c(C(=O)OC)cc(Cl)cc1N(CC)C1CCC(NC(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1c(C(=O)O)cc(Cl)cc1N(CC)C1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 50 °C
Reaction time: 17 h
Yield: 92.8 %

Procedure:
To a stirred solution of methyl 3-[(4-{[(tert-butoxy)carbonyl]amino}cyclohexyl)(ethyl)amino]-5-chloro-2-ethylbenzoate (156 mg, 0.36 mmol) in THF (4.0 ml) and MeOH (0.29 ml), was added a solution of 4M NaOH (aq) (2.7 ml, 10.7 mmol). The resulting solution was stirred at 50° C. for 17 hours. The reaction mixture was treated with 4M NaOH (aq) (0.5 ml, 2.0 mmol) and stirring was continued at 50° C. for 32 hours. The heat was removed and the reaction mixture was left to stir at room temperature for 65 hours. The reaction mixture was treated with 4M NaOH (aq) (1.0 ml, 4.0 mmol) and heated back up to 50° C. for 24 hours. The organic solvents were removed in-vacuo and the aqueous phase was treated with a solution of 0.5M citric acid (20 ml) to adjust the pH to 4/5. The product was extracted with ethyl acetate (3×25 ml). The combined organic phases were washed with brine (30 ml), dried (MgSO4), filtered and concentrated in-vacuo and then further dried on the high vac line for 4 hours to give the title compound (142 mg, 92%) as a white solid and a mixture of cis/trans isomers. LC-MS 98%, 5.49 min (7 minute LC-MS method), m/z=425.1, 427.1. 1H NMR shows a mixture of cis/trans isomers.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]([Cl:16])=[CH:4][N:3]=1.[Br:17][CH2:18][C:19](Br)=[O:20].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[C:8]([C:7]1[C:2]([NH:1][C:19](=[O:20])[CH2:18][Br:17])=[N:3][CH:4]=[C:5]([Cl:16])[N:6]=1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1ncc(Cl)nc1C(=O)c1ccccc1
Reactant: O=C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CBr)Nc1ncc(Cl)nc1C(=O)c1ccccc1

Procedure:
2-Amino-3-benzoyl-5-chloropyrazine (0.9 g or 4 mmol) was reacted as described in Example 5 with 8.1 g. (0.04 mol) of 2-bromoacetyl bromide in 25 ml. methylene chloride and 25 ml. of 10% aqueous sodium carbonate solution. The same work up yielded 1 g. (71%) of the above-named product with a melting point of 120°-125° dec. Recrystallization from methylene chloride/petroleum ether afforded colorless needles with a melting point of 124°-126° dec.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:17]([C:18]#[C:19][CH2:20][N:21]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:16][N:15]([CH2:30][C:31]3[C:36]([CH3:37])=[C:35]([O:38][CH3:39])[C:34]([CH3:40])=[CH:33][N:32]=3)[C:4]=2[N:5]=[C:6]([NH:8]C(=O)C(C)(C)C)[N:7]=1>[Cl-].[Cl-].[Zn+2]>[Cl:1][C:2]1[C:3]2[C:17]([C:18]#[C:19][CH2:20][N:21]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:16][N:15]([CH2:30][C:31]3[C:36]([CH3:37])=[C:35]([O:38][CH3:39])[C:34]([CH3:40])=[CH:33][N:32]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1
Reactant: COc1c(C)cnc(Cn2cc(C#CCN(CC(C)C)CC(C)C)c3c(Cl)nc(NC(=O)C(C)(C)C)nc32)c1C
Agent: [Cl-]
Agent: [Zn+2]
Product: COc1c(C)cnc(Cn2cc(C#CCN(CC(C)C)CC(C)C)c3c(Cl)nc(N)nc32)c1C

Procedure:
The title compound was prepared by cleaving the pivaloyl protecting group of N-[4-chloro-5-(3-diisobutylamino-prop-1-ynyl)-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-2,2-dimethyl-propionamide with ZnCl2 according to the General Procedure B. tR: 5.23 min. 1H-NMR (CDCl3) δ 8.23 (s, 1H), 7.08 (s, 1H), 5.31 (s, 2H), 4.99 (s, 1H), 3.76 (s, 3H), 3.56 (s, 2H), 2.29 (s, 31H), 2.27 (d, 4H), 2.21 (s, 31H), 1.74 (m, 2H), 0.90 (d, 12H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[Br:28]N1C(=O)CCC1=O>C1COCC1.O>[Br:28][CH:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)Cc1cccnc1
Reactant: O=C1CCC(=O)N1Br
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(Br)c1cccnc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
Ethyl 3-pyridylacetate (1.0 g, 1.0 eq) was dissolved in THF (50 mL) and cooled to −78° C. Lithium bis (trimethylsilyl) amide (6.66 mL, 1.1 eq) was added to the reaction and stirred for 20 minutes. Chlorotrimethylsilane (1.44 mL, 1.875 eq) was added at −78° C. and stirred for 20 minutes. N-bromosuccinimide (1.09 g, 1.01 eq) was added to the reaction mixture. The reaction mixture was allowed to stir and warm to room temperature overnight. The reaction mixture was diluted with H2O. The organic layer was extracted with ethyl acetate. The organic phase was dried over sodium sulfate and the solvent was evaporated to give a yellow oil. The resulting oil was chromatographed on silica gel using hexanes and ethyl acetate (1:1) to give ethyl 2-bromo-2(3-pyridyl)acetate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1[O:12][CH2:13][C:14]([O:16][CH3:17])=[O:15].C(O)(=O)C.N#N>CO.[Pd]>[C:3]([OH:18])(=[O:2])[CH3:4].[NH2:11][CH2:10][C:8]1[CH:7]=[CH:6][C:5]([O:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[C:4]([CH:9]=1)[C:3]([O:2][CH3:1])=[O:18]
Reactant: COC(=O)COc1ccc(C#N)cc1C(=O)OC
Agent: [Pd]
Agent: N#N
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)COc1ccc(CN)cc1C(=O)OC
Reaction time: 24 h
Yield: 71.8 %

Procedure:
To a solution of methyl-5-cyano-2-(2-methoxy-2-oxoethoxy)benzoate (5 g, 0.02 mol) in methanol (1 L) was added glacial acetic acid (1.1 g, 0.02 mol) and passed N2 for 30 min. To this was added Pd/C (1.5 g, 35%) and hydrogenated under 2.5 Kg of pressure for 24 h. The reaction mixture was filtered and filtrate concentrated under vacuum (temp. 38° C. under N2). To the crude residue was added 100 mL of EtOAc and again removed under vacuum at same temp. The solid was treated with 100 mL EtOAc, stirred for 2 h, filtered and dried to give the title compound as a white powder (2.25 g, 35%). TLC: chloroform/methanol, 9:1, Rf: 0.15
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:23][C:24]1[CH:25]=[C:26]([C:30]2[S:34][C:33]([CH3:35])=[N:32][C:31]=2[C:36]([OH:38])=O)[CH:27]=[CH:28][CH:29]=1.[C@H:39]12[CH2:44][C@H:43]1[CH2:42][C@@H:41]([CH2:45][NH:46][C:47](=[O:52])[C:48]([F:51])([F:50])[F:49])[NH:40]2.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:51][C:48]([F:49])([F:50])[C:47]([NH:46][CH2:45][C@@H:41]1[CH2:42][C@H:43]2[C@H:39]([CH2:44]2)[N:40]1[C:36]([C:31]1[N:32]=[C:33]([CH3:35])[S:34][C:30]=1[C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([F:23])[CH:25]=1)=[O:38])=[O:52]
Reactant: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1)C(F)(F)F
Reactant: Cc1nc(C(=O)O)c(-c2cccc(F)c2)s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc(C(=O)N2[C@H](CNC(=O)C(F)(F)F)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
TBTU (3.22 mmol, 1.05 eq) is added to a solution of 5-(3-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid (3.07 mmol, 1.0 eq), N-[(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-2,2,2-trifluoro-acetamide (3.07 mmol, 1.0 eq) and DIPEA (9.20 mmol, 3.0 eq) in DCM (15 mL). After 2 h the mixture is washed twice with water, once with sat. aqueous NaHCO3 solution, once with hydrochloric acid (0.2 M) and three times with water. The organic layer is dried over Na2SO4, the solvents are removed in vacuo and the residue is purified by flash chromatography (gradient: DCM to DCM/MeOH 19/1) and preparative TLC (DCM/MeOH 19/1) to give the desired product as an orange foam. LC-MS (acidic): tR=0.97 min; [M+H]+=428.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11](=[O:22])[NH:12][C:13](=[O:21])[C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[F:23][C:24]([F:29])([F:28])[CH2:25][CH2:26]O.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[C:11](=[O:22])[N:12]([CH2:26][CH2:25][C:24]([F:29])([F:28])[F:23])[C:13](=[O:21])[C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(NC2=C(c3ccccc3)C(=O)NC2=O)cc1
Reactant: OCCC(F)(F)F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(NC2=C(c3ccccc3)C(=O)N(CCC(F)(F)F)C2=O)cc1
Temperature: 130 °C
Yield: 76.9 %

Procedure:
To a solution of 3-[(4-methoxyphenyl)amino]-4-phenyl-1H-pyrrole-2,5-dione (0.17 mmol, 50 mg), 3,3,3-trifluoropropan-1-ol (0.19 mmol, 21 mg), diethyl azodicarboxylate (0.19 mmol, 33 mg) in dry THF (1 mL) was added triphenylphosphine (0.19 mmol, 49 mg) in dry THF (1 mL). The mixture was heated in a microwave reactor at 130° C. for six min. After cooling, the reaction mixture was purified by HPLC (95% 0.1M ammonium acetate buffer: 5% CH3CN→100% CH3CN) to give 51 mg (77%) of the title compound. 1H NMR (400 MHz, CDCl3) δ 7.27 (bs, 1H), 7.17-7.06 (m, 3H), 7.00-6.95 (m, 2H), 6.64-6.55 (m, 4H), 3.89 (t, J=7.3 Hz, 2H), 3.70 (s, 3H), 2.61-2.48 (m, 2H).
Reaction SMILES: [C:1]1([CH2:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]32[CH2:19][C:18](=[O:20])[NH:17][C:16]2[CH:21]=[CH:22][CH:23]=[CH:24][C:15]=2[S:14]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:33])C=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[C:1]1([CH2:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]32[CH2:19][C:18](=[O:20])[NH:17][C:16]2[CH:21]=[CH:22][CH:23]=[CH:24][C:15]=2[S:14]3=[O:33])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C1CC2(CCCCC2Cc2ccccc2)Sc2ccccc2N1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C1CC2(CCCCC2Cc2ccccc2)S(=O)c2ccccc2N1

Procedure:
To a solution of 2'-phenylmethyl-4,5-dihydro-4-oxospiro[1,5-benzothiazepine-2(3H), 1'-cyclohexane] (5.0 g) in methylene chloride (150 ml) was added 80% m-chloroperbenzoic acid (3.9 g) at 0° C. After fifteen minutes, a saturated aqueous solution (150 ml) of sodium sulfite was added to the solution. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with diisopropyl ether to give 2'-phenylmethyl-4,5-dihydro-4-oxospiro[1,5-benzothiazepine-2(3H), 1'-cyclohexane] 1-oxide
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[N:19][CH3:20])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].O1CCCC1.[H][H]>[Ni].ClC1C=CC=CC=1Cl>[CH3:20][NH:19][C@@H:12]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[C@H:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:10][CH2:11]1
Reactant: [H][H]
Reactant: CN=C1CCC(c2ccc(Cl)c(Cl)c2)c2ccccc21
Agent: [Ni]
Solvent: Clc1ccccc1Cl
Solvent: C1CCOC1
Product: CN[C@H]1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Yield: 0.75 %

Procedure:
N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H) naphthalenylidene]methanamine (Ketimine) (50 g), tetrahydrofuran (300 ml), Raney Nickel (0.15 g wet basis) and o-dichlorobenzene (25 ml) are charged into a reaction vessel. The mixture is hydrogenated at 5 to 6 kg/cm2 over pressure of hydrogen for 6 to 7 hrs at about 28 to 30° C. The catalyst is removed by filtration and the cake is washed with 50 ml tetrahydrofuran. The cis to trans ratio is 85 to 87/15 to 13. The amount of dehalogenated byproduct is <0.1%. Sertraline racemate free base thus formed is treated with hydrochloric acid (24 ml, 33%) and predominantly isomer of sertraline HCl racemate is filtered [Cis>95%, trans<5%, dehalogenation product<0.1%, yield 0.75 to 0.78%].
Reaction SMILES: Cl[C:2]1[C:3]([F:22])=[CH:4][C:5]2[C:6]([CH:21]=1)=[N:7][C:8]1[N:9]([CH2:19][CH3:20])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>N1C=CC=CC=1>[CH2:19]([N:9]1[C:8]2[N:7]=[C:6]3[CH:21]=[C:2]([N:27]4[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]4)[C:3]([F:22])=[CH:4][C:5]3=[CH:14][C:13]=2[C:12](=[O:15])[C:11]([C:16]([OH:18])=[O:17])=[CH:10]1)[CH3:20]
Reactant: CN1CCNCC1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCN(C)CC4)cc3nc21

Procedure:
1-Ethyl-7-fluoro-8-(4-methyl-1-piperazinyl)-4-oxo- 1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is prepared under the conditions of Example 5 but starting from 1.6 g of 8-chloro-1-ethyl-7-fluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid and 4.5 g of 4-methylpiperazine in 16 cm3 of pyridine. After recrystallizing 4 times from, in total, 120 cm3 of dimethylformamide, 1.2 g of 1-ethyl-7-fluoro-8-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid melting at 285°-286° C. solvated with 1% of water.
Reaction SMILES: [CH3:1][C:2]1([OH:13])[CH2:11][CH2:10][CH2:9][CH:8]2[CH:3]1[CH:4]1[CH2:12][CH:7]2[CH:6]=[CH:5]1.[C:14]([O-])([O-])=[O:15].[Na+].[Na+]>>[CH:14]([O:13][C:2]1([CH3:1])[CH2:11][CH2:10][CH2:9][CH:8]2[CH:3]1[CH:4]1[CH2:12][CH:7]2[CH:6]=[CH:5]1)=[O:15]
Reactant: O=C([O-])[O-]
Reactant: CC1(O)CCCC2C3C=CC(C3)C21
Agent: [Na+]
Product: CC1(OC=O)CCCC2C3C=CC(C3)C21
Temperature: 25 °C
Reaction time: 72 h
Yield: 58 %

Procedure:
7.4 g (0.042 mole) of 3-methyl-tricyclo[6.2.1.02,7 ]undec-9-en-3-ol--see Example 1--were then added to the above mixture, and the whole mixture was stirred for 3 days at room temperature. The obtained mixture was then decomposed by the addition of 100 ml of a saturated aqueous solution of Na2CO3, extracted with ether (3×50 ml), washed with water (3×50 ml) and dried over Na2SO4. After evaporation 8 g of crude material were obtained which, by distillation at 0.02 Torr, provided the desired compound in a 58% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22](O)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH2:33])=[C:28]([N:34]2[CH:38]=[N:37][C:36]([CH3:39])=[N:35]2)[CH:27]=1>>[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH:33][C:22]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:19])[C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:21])[CH3:20])=[O:23])=[C:28]([N:34]2[CH:38]=[N:37][C:36]([CH3:39])=[N:35]2)[CH:27]=1
Reactant: Cc1ncn(-c2cc(F)ccc2CN)n1
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Product: Cc1ncn(-c2cc(F)ccc2CNC(=O)c2nc3n(c(=O)c2OCc2ccccc2)CCOC3(C)C)n1

Procedure:
The title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid and intermediate 85, (4-fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)methanamine. White crystals; mp 203° C. (ethyl acetate). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.65 (6H, s, 2×CH3), 2.50 (3H, s, CH3), 4.03 (4H, m, 2×CH2), 4.46 (2H, d, J=6.6 Hz, NCH2), 5.31 (2H, s, OCH2), 7.06 (1H, dd, J=3 Hz and J=8.6 Hz, aromatic), 7.16 (1H, m, aromatic), 7.30-7.34 (3H, m, aromatics), 7.50 (2H, m, aromatics), 7.74 (1H, dd, J=6.0 Hz and J=8.6 Hz, aromatic), 8.28 (1H, s, CH), 8.45 (1H, broad t, NH). Anal. Calcd for C27H27FN6O4: C, 62.54; H, 5.25; N, 16.21. Found: C, 62.48; H, 5.31; N, 16.29.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][NH:13][C:12](=[O:16])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>CN(C)C=O>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[C:12](=[O:16])[CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(CCO[Si](C)(C)C(C)(C)C)C(=O)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
Sodium hydride (0.35 g, 8.6 mmol, 60% in mineral oil) was added to a solution of 4-tert-butyloxycarbonyl-piperazin-2-one (0.86 g, 4.3 mmol) in dimethylformamide (20.0 mL) at 0° C. The reaction was stirred at 0° C. for 0.5 h. To this mixture was added 2-bromoethoxy-tert-butyldimethylsilane (2.3 mL, 10.8 mmol) and the reaction was stirred for 2 h at room temperature. The reaction mixture was quenched with a dilute aqueous solution of sodium bicarbonate and extracted with methylene chloride. The organic extracts were washed with brine and dried over anhydrous sodium sulfate. Purification of the crude residue by flash column chromatography (silica gel, eluting with 20% ethyl acetate in hexanes) gave 4-tert-butyloxycarbonyl-1-[2-(tert-butyldimethylsilyloxy)ethyl]-piperazin-2-one (1.17 g, 76%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:22]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[N:25]=3)=[CH:17][N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>CO.O1CCCC1.[C].[Pd]>[F:29][C:26]([F:27])([F:28])[C:24]1[N:25]=[C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)=[N:16][CH:17]=2)[N:22]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:35])[CH3:36])[CH:23]=1
Reactant: [H][H]
Reactant: C[Si](C)(C)CCOCn1cc(C(F)(F)F)nc1-c1ccc(-c2ccc(OCc3ccccc3)cc2)nc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cc(C(F)(F)F)nc1-c1ccc(-c2ccc(O)cc2)nc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 95.9 %

Procedure:
In methanol (8 mL) and tetrahydrofuran (6 mL) was dissolved 2-[4-(benzyloxy)-phenyl]-5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridine (0.77 g), and after adding palladium carbon (0.154 g) under nitrogen atmosphere, the atmosphere was replaced by hydrogen, and the mixture was stirred at room temperature for 5 hours. Insoluble material was filtered off by using a membrane filter, and the filtrate was concentrated under reduced pressure. The concentrate was diluted with methanol, activated charcoal was added thereto, and the mixture was filtered by using Celite. The filtrate was concentrated under reduced pressure and crystallized to obtain 4-{5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)-ethoxy]methyl}-1H-imidazol-2-yl]pyridin-2-yl}phenol (0.612 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1S(C)(=O)=O.[OH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26]3=[N:27][CH:28]=[CH:29][CH:30]=[C:25]3[N:24]([CH2:31][CH2:32][CH3:33])[C:23]2=[O:34])=[CH:18][CH:17]=1.[H-].[Na+]>CN(C=O)C.CO>[CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1[O:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[C:26]3=[N:27][CH:28]=[CH:29][CH:30]=[C:25]3[N:24]([CH2:31][CH2:32][CH3:33])[C:23]2=[O:34])=[CH:20][CH:21]=1
Reactant: CCCn1c(=O)n(-c2ccc(O)cc2)c2ncccc21
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCCn1c(=O)n(-c2ccc(Oc3nc4cccnc4n3C)cc2)c2ncccc21
Temperature: 180 °C
Yield: 50.4 %

Procedure:
3-Methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (320 mg) was added to a solution of 3-(4-hydroxyphenyl)-1-propyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (400 mg) and NaH (65.3 mg) in DMF (5 mL) at 100° C. The mixture was heated at 180° C. for 30 min under microwave irradiation. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0%-50% EtOAc in hexane) to give 3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1-propyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (300 mg) as white crystals.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][SH:7])(=[O:3])[CH3:2].[OH-].[K+:9].[C:10](=[S:12])=[S:11]>C(O)C>[C:1]([NH:4][CH2:5][CH2:6][S:7][C:10](=[S:11])[S-:12])(=[O:3])[CH3:2].[K+:9]
Reactant: CC(=O)NCCS
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)NCCSC(=S)[S-]
Reaction time: 0.5 h

Procedure:
A solution of 1.708 g (14.35 mmole) of 2-acetylaminoethyl mercaptan in 2 ml of absolute ethanol is added dropwise over the course of 0.5 hours, while stirring and cooling to 10°-15°, to a solution of 0.80 g (14.35 mmole) of potassium hydroxide in 5 ml of absolute ethanol. After a further half hour, a solution of 1.09 g (14.35 mmole) of carbon disulphide in 3 ml of absolute ethanol is added, the temperature being maintained at 10°-15°. The reaction mixture is further stirred for 3 hours at room temperature and cooled in an ice bath for 20 minutes. The yellow crystalline precipitate is filtered off, washed once with absolute ethanol and yields potassium (2-acetylaminoethyl)-trithiocarbonate having a melting point of 171°-174°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.Cl[S:11]([N:14]=[C:15]=[O:16])(=[O:13])=[O:12].[Cl-].[Al+3].[Cl-].[Cl-]>>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]2[NH:7][C:15](=[O:16])[NH:14][S:11](=[O:13])(=[O:12])[C:5]=2[CH:4]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C=NS(=O)(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc2c(c1)S(=O)(=O)NC(=O)N2

Procedure:
Commercially available 4-methoxyaniline can be treated with chlorosulfonyl isocyanate followed by aluminum chloride to give the corresponding 7-methoxy-1,1-dioxo-1,4-dihydro-2H-1λ6-benzo[1,2,4]thiadiazin-3-one. Opening of the cyclic urea with a strong acid (e.g., sulfuric acid) gives the desired 2-amino-5-methoxy-benzenesulfonamide intermediate.