Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])[CH:2]=[CH2:3].CN(P(N(C)C)(N(C)C)=O)C>>[CH2:3]=[C:2]([CH2:3][CH2:2][C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])[C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4]
Reactant: C=CC(=O)OCc1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=C(CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 92.5 %

Procedure:
Benzyl acrylate (500 g, 3.0 mol) was heated in an oil bath to 100° C. Heating was stopped and HMPT (10 g, 61 mmol) was added dropwise while maintaining an internal temperature below 140° C. Once addition was complete, the mixture was stirred and cooled to room temperature. A slurry of silica (5:1 Hexane/EtOAc) was added and the mixture was placed in a column containing a plug of dry silica. The column was washed with 1:1 Hexane/EtOAc and the fractions were combined and evaporated to give 450 g of clear light golden liquid. The liquid was distilled under high vacuum (200 μHg) at 185° C. to give 212 g (42%) of a cl and colorless liquid.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][C:7](=[O:9])[CH:6]([C:10](=[O:26])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:5](=[O:27])[CH2:4]1)=O.[NH2:28]OS(O)(=O)=O>O>[O:27]=[C:5]1[CH:6]([C:10](=[O:26])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:7](=[O:9])[CH2:8][CH:3]([C:1]#[N:28])[CH2:4]1
Reactant: CCCCCCCCCCCCCCCC(=O)C1C(=O)CC(C=O)CC1=O
Reactant: NOS(=O)(=O)O
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)C1C(=O)CC(C#N)CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
43 g (0.12 mol) of 5-formyl-2-palmitoylcyclohexane-1,3-dione were suspended in 150 ml of distilled water. To this were added 15.7 g (0.14 mol) of hydroxylamine-O-sulfonic acid dissolved in 50 ml of water. The heterogeneous reaction mixture was stirred at room temperature overnight. The resulting solid was filtered off with suction, washed with water and dried. 37.7 g (86% of theory) of 3,5-dioxo-4-palmitoylcyclohexanecarbonitrile were isolated (melting point 66° to 69° C.).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:5]([C:14](OC)=[O:15])[CH2:4][O:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(OCC)C>[OH:15][CH2:14][C@H:5]1[CH2:4][O:3][C:2]([CH3:1])([CH3:18])[N:6]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: COC(=O)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1[C@@H](CO)COC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
A solution of (R)-3-tert-butyl 4-methyl 2,2-dimethyloxazolidine-3,4-dicarboxylate (5 g, 19.3 mmol) in anhydrous diethyl ether was chilled in an ice bath and 1 M LiAlH4 in diethyl ether (38 mL, 38.6 mmol) was added dropwise under an N2 atmosphere. The reaction was allowed to warm to room temperature with stirring overnight. The reaction was quenched by slowly adding saturated aqueous Na2SO4 (5 mL). The slurry was filtered through a pad of Celite. The Celite pad was rinsed with EtOAc and the solution was dried in vacuo to yield (S)-tert-butyl 4-(hydroxymethyl)-2,2-dimethyloxazolidine-3-carboxylate (2.77 g, 12 mmol) as a clear oil. [M+H] calc'd for C11H21NO4, 232. found, 232.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]=[C:12]=[S:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]1([CH:20]([O:27][C:28]([C:30]2[N:31]=[CH:32][N:33]([C@@H:36]3[O:48][C@H:47]([CH2:49][O:50][C:51](=[O:53])[CH3:52])[C@@H:42]([O:43][C:44](=[O:46])[CH3:45])[C@H:37]3[O:38][C:39](=[O:41])[CH3:40])[C:34]=2[NH2:35])=[O:29])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[C:14]1([CH:20]([O:27][C:28]([C:30]2[N:31]=[CH:32][N:33]([C@@H:36]3[O:48][C@H:47]([CH2:49][O:50][C:51](=[O:53])[CH3:52])[C@@H:42]([O:43][C:44](=[O:46])[CH3:45])[C@H:37]3[O:38][C:39](=[O:41])[CH3:40])[C:34]=2[NH:35][C:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])=[S:13])=[O:29])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(N=C=S)OCc1ccccc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)OC(c3ccccc3)c3ccccc3)c2N)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)OC(c3ccccc3)c3ccccc3)c2NC(=S)NC(=O)OCc2ccccc2)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 46 h
Yield: 98 %

Procedure:
Four portions of benzyloxycarbonyl isothiocyanate (Caution: stench, handle in a well ventilated hood only, crude, 2.0 g each, total 41 mmol) were added to a solution of 5-amino-1-(2,3,5-tris-O-acetyl-β-D-ribofuranosyl)-1H-imidazole-4-carboxylic acid diphenylmethyl ester (1.1 g, 2 mmol) in CH2Cl2 (10 mL) at 0 h, 6 h, 22 h and 30 h. The reaction mixture was stirred at room temperature under an argon atmosphere for a total of 46 h after the addition of the first portion of benzyloxycarbonyl isothiocyanate, then chromatographed on silica gel (100 g, column packed in CH2Cl2, 100-mL fractions), with CH2Cl2 (100 mL), followed by 25% EtOAc in CH2Cl2 as the eluant. Fractions 6 to 11 were combined, concentrated, and pumped under reduced pressure to give 1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-5-[[[[(phenylmethoxy)carbonyl]amino]thioxomethyl]amino]-1H-imidazole-4-carboxylic acid diphenylmethyl ester as a pale yellow foam: 1.46 g (98% yield); IR (CHCl3) 3405, 3250, 3200, 1750, 1738, 1600, and 1505 cm-1 ; HRMS [(+) FAB] m/z found 767.2060 [calcd for C37H36N4NaO11S, 767.1999 (M+Na+)], 745.2297 [calcd for C37H37N4O11S, 745.2180 (M+H+)]; NMR (CDCl3)δ2.04 (s, 3), 2.10 (s, 3), 2.13 (s, 3), 4.33 (m, 2), 4.39 (m, 1), 5.10 (s, 2), 5.35 (m, 1), 5.52 (m, 1), 5.87 (m, 1), 7.10 (s, 1), 7.32 (m, 15), 7.87 (s, 1), 8.16 (s, 1), 10.95 (s, 1); UV max (95% C2H5OH) 215 nm (sh, ε35000), 266 (13850).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([NH2:9])[CH:3]=1.[C:10]1(=O)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[O:11]1.C([O-])(O)=O.[Na+]>C(O)(=O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([N:9]2[C:10](=[O:11])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:19])[CH:3]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Cc1cnc(N)cc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cnc(N2C(=O)c3ccccc3C2=O)cc1C
Temperature: 90 °C
Yield: 33.7 %

Procedure:
To a solution of 4,5-dimethylpyridin-2-amine (2.1 g, 0.02 mol) in acetic acid (40 mL) was added isobenzofuran-1,3-dione (2.5 g, 0.02 mol) at the room temperature. The mixture was heated at 90° C. overnight. The resulting solution was basified by saturated solution of NaHCO3 and extracted with ethyl acetate (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated under vacuum to give 2-(4,5-dimethylpyridin-2-yl)-isoindoline-1,3-dione (1.7 g, 40%) 1H NMR (300 MHz, DMSO) δ 8.33 (s, 1H), 7.97-7.91 (m, 4H), 7.32 (s, 1H), 2.30 (s, 3H), 2.27 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:19][CH:20]([OH:25])[C:21]([O:23][CH3:24])=[O:22])[CH:15]=2)[N:10]=1.[Cl:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:28]=1[C:29](Cl)=[O:30].C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[Cl:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:28]=1[C:29]([O:25][CH:20]([CH2:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:3]1[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[CH:18]=[CH:17]2)[C:21]([O:23][CH3:24])=[O:22])=[O:30]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: COC(=O)C(O)Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COC(=O)C(Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)OC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of methyl 3-[2-(2,6-dichlorophenyl)-6-quinolinyl]-2-hydroxypropanoate 55 (0.104 g) in pyridine (1 ml) is added 2,6-dichlorobenzoyl chloride (0.2 ml). The solution is stirred for 6 h at room temperature. A saturated solution of NaHCO3 (10 ml) is added. The aqueous phase is extracted with AcOEt (3×10 ml). The organic phases are washed with brine, dried over MgSO4 and evaporated. The residue is purified twice over silica gel using AcOEt/petroleum ether (10/90 to 20/80) as eluent.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH:4]([CH2:9][C:10]1[C:11]([NH:23][C:24]2[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=2[CH3:32])=[N:12][C:13]([CH3:22])=[CH:14][C:15]=1[O:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])C(OC)=O>O>[CH2:18]([CH:17]([O:16][C:15]1[CH:14]=[C:13]([CH3:22])[N:12]=[C:11]([NH:23][C:24]2[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=2[CH3:32])[C:10]=1[CH2:9][CH2:4][C:3]([OH:33])=[O:2])[CH2:20][CH3:21])[CH3:19]
Reactant: CCC(CC)Oc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1CC(C(=O)OC)C(=O)OC
Solvent: O
Product: CCC(CC)Oc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1CCC(=O)O

Procedure:
Hydrolysis of 2-[4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-ylmethyl]-malonic acid dimethyl ester with phosphoic/water at reflux to give the title compound as a white foam. Anal. For C23H32N2O3. ¾H2O calc.: C,69.40; H, 8.48; N, 7.04; found: C, 69.17; H, 8.62; N, 6.90.
Reaction SMILES: Cl[C:2]1[C:3]2[C:19]([CH3:20])=[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[S:17][C:4]=2[N:5]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)[N:7]=1.NC(N)=[S:28].C(O)C>O>[Cl:16][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[Cl:15])[CH2:8][C:6]1[NH:7][C:2](=[S:28])[C:3]2[C:19]([CH3:20])=[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[S:17][C:4]=2[N:5]=1
Reactant: CCOC(=O)c1sc2nc(Cc3ccc(Cl)c(Cl)c3)nc(Cl)c2c1C
Reactant: NC(N)=S
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1sc2nc(Cc3ccc(Cl)c(Cl)c3)[nH]c(=S)c2c1C
Temperature: 25 °C
Reaction time: 35 h
Yield: 94 %

Procedure:
A mixture of 1.23 g of ethyl 4-chloro-2-(3,4-dichlorobenzyl)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate, 594 mg of thiourea and 50 mL of ethanol was stirred at room temperature for 35 hours. Then 50 mL of water was added, followed by 30 minutes' stirring. Crystals were recovered by filtration and washed with water. Drying the same under aeration, 1.15 g of the title compound was obtained.
Reaction SMILES: C[O:2][C:3]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[N:22]=[C:21]([NH:23][C:24]3[NH:25][N:26]=[C:27]([CH3:29])[CH:28]=3)[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)=[CH:8][C:7]=1[CH3:30])=[O:4].[OH-].[Na+].Cl>O.CCO>[C:3]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[N:22]=[C:21]([NH:23][C:24]3[NH:25][N:26]=[C:27]([CH3:29])[CH:28]=3)[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)=[CH:8][C:7]=1[CH3:30])([OH:4])=[O:2]
Reactant: COC(=O)Cc1ccc(Nc2nc(Nc3cc(C)n[nH]3)c3ccccc3n2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(Nc2nc(Nc3ccc(CC(=O)O)c(C)c3)nc3ccccc23)[nH]n1
Temperature: 70 °C
Yield: 95.3 %

Procedure:
A solution of [2-(4-methoxycarbonylmethyl-3-methylphenylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (IIc-64, 200 mg, 0.5 mmol) in a mixture of methanol/water (3/1, 8 mL) was treated with 1M NaOH (2 mL, 2 mmol). The mixture was heated at 70° C. for 2 hours and then neutralised with 1M HCl (2 mL, 2 mmol). The solid that formed was collected by filtration to afford the title compound (185 mg, 95%) as a pale yellow solid, mp 245° C. (dec.); 1H NMR (DMSO) δ2.27 (6H, 2×s), 3.55 (2H, s), 6.49 (1H, s), 7.13 (1H, d), 7.26 (1H, t), 7.50 (1H, d), 7.62-7.78 (3H, m), 8.42 (1H, d), 9.34 (1H,d), 10.26 (1H, s), 12.36 (1H, s); IR (solid) 1660, 1590, 1562, 1504, 1427, 1385, 810, 776, 751, 693; MS 389.4 (M+H)+
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:13][CH2:12]1
Reactant: CN1CCNCC1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(C=O)cc2)CC1
Temperature: 130 °C

Procedure:
20 g (161 mmol) of 4-fluorobenzaldehyde, 48.4 g (483 mmol) of 1-methylpiperazine and 22.3 g (161 mmol) of potassium carbonate were added to 50 ml of dimethylformamide, and the mixture was heated at 130° C. for 36 hours. The mixture was subsequently concentrated under reduced pressure. The residue was partitioned between ethyl acetate and 2 M hydrochloric acid. The aqueous phase was separated off and made alkaline using aqueous sodium bicarbonate solution. This aqueous phase was extracted with ethyl acetate, and the organic phase was separated off, dried and concentrated under reduced pressure. This gave 48.7 g of the intermediate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=2)=[CH:16][CH:15]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCc1ccc(Br)cc1[N+](=O)[O-]
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: COCCOC
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1[N+](=O)[O-]
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 104.7 %

Procedure:
To 4-bromo-1-ethyl-2-nitrobenzene (20.0 g, 0.087 mol) in 150 ml 1,2-dimethoxyethane is added, at room temperature, 4-chlorophenylboronic acid (14.98 g, 0.096 mol) and tetrakis(triphenylphosphine)palladium(0) (2.0 g, 0.00174 mol) and nitrogen gas is bubbled through the mixture. After stirring for 10 minutes at 20° C., a solution of sodium carbonate (73.8 g, 0.696 mol) in water (350 ml) is added and mixture is refluxed for 16 hours. The reaction mixture is cooled to room temperature, filtered through diatomaceous earth, washing with 200 ml of ethyl acetate. The mixture is poured into a separating funnel and the two phases are separated. The aqueous phase is extracted with ethyl acetate. The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated in vacuo to give 4′-chloro-4-ethyl-3-nitrobiphenyl (23.84 g) as a brown oil used without further purification in the next step.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[F:15][C:16]([F:33])([F:32])[C:17]1[CH:18]=[C:19]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH:20]=[CH:21][C:22](O)=O>>[F:15][C:16]([F:32])([F:33])[C:17]1[CH:18]=[C:19]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)/[CH:20]=[CH:21]/[C:22]1[NH:1][C:2]2[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=2[N:8]=1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: O=C(O)C=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CCn1c(=O)c2[nH]c(/C=C/c3cc(C(F)(F)F)cc(C(F)(F)F)c3)nc2n(CC)c1=O
Yield: 60.7 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 3.00 g (15.1 mmol) of 5,6-diamino-1,3-diethyluracil and 4.73 g (16.7 mmol) of 3,5-bis(trifluoromethyl)cinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane to give 4.09 g (yield 61%) of Compound 148 as pale yellow needles.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6]Br)(=[O:3])[CH3:2].[NH2:8][C:9]1[N:13]([CH2:14][CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[N:12]=[C:11]([OH:24])[C:10]=1[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:1]([O:4][CH2:5][CH2:6][O:24][C:11]1[C:10]([C:25]2[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=2)=[C:9]([NH2:8])[N:13]([CH2:14][CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[N:12]=1)(=[O:3])[CH3:2]
Reactant: Cc1ccc(-c2c(O)nn(CCO[Si](C)(C)C(C)(C)C)c2N)cc1
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)OCCOc1nn(CCO[Si](C)(C)C(C)(C)C)c(N)c1-c1ccc(C)cc1
Reaction time: 8 h
Yield: 46.8 %

Procedure:
2-Bromoethyl acetate (0.29 g) was added dropwise over 1 minute to a stirred suspension of 5-amino-1-{2-[(tert-butyl)dimethylsilyl]oxyethyl}-4-(4-methylphenyl)-1-H-pyrazol-3-ol (0.60 g) (Preparation 31) and caesium carbonate (1.69 g) in anhydrous dimethylformamide (10 ml), under a nitrogen atmosphere, at room temperature. The resulting mixture was stirred overnight. The reaction was quenched by adding 1.0M citric acid (40 ml) and the resulting aqueous mixture was extracted with ethyl acetate (2×50 ml). The combined organic extracts were washed with water (40 ml), brine (40 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography using a Biotage Flash™ 40 column at 10 psi, with a step gradient of ethyl acetate/hexane (1:3 to 1:2) to give the title compound as a yellow oil (0.35 g).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C@@H:8]1[CH2:12][N:11]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C@H:10]([C:21]([OH:23])=O)[CH2:9]1.[N:34]1([C:40]2[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=2[C:42]#[N:43])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[F:29][C:28]([F:31])([F:30])[C:26]1[CH:25]=[C:5]([CH:4]=[C:3]([C:2]([F:32])([F:1])[F:33])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C@@H:8]1[CH2:12][N:11]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[C@H:10]([C:21]([N:37]2[CH2:36][CH2:35][N:34]([C:40]3[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=3[C:42]#[N:43])[CH2:39][CH2:38]2)=[O:23])[CH2:9]1
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@H]1C[C@@H](C(=O)O)N(Cc2ccc(Cl)cc2)C1
Reactant: N#Cc1ccccc1N1CCNCC1
Product: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@H]1C[C@@H](C(=O)N2CCN(c3ccccc3C#N)CC2)N(Cc2ccc(Cl)cc2)C1
Yield: 9 %

Procedure:
As described for Example 64e, (2S,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-methyl-amino]-1-(4-chloro-benzyl)-pyrrolidine-2-carboxylic acid (1 mmol) was converted, using 2-piperazin-1-yl-benzonitrile instead of 2-cyclohexyl-1,3,8-triaza-spiro[4.5]dec-1-en-4-one, to the title compound (60 mg) in 9% yield as colorless oil. MS m/e=665.1 [M+H]+.
Reaction SMILES: [OH:1][CH:2]([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:9]=1)[CH2:3][NH2:4].[CH2:21]([O:23][C:24]1[C:28](OCC)=[N:27][S:26](=[O:32])[N:25]=1)[CH3:22]>C(O)C>[OH:1][CH:2]([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:9]=1)[CH2:3][NH:4][C:28]1[C:24]([O:23][CH2:21][CH3:22])=[N:25][S:26](=[O:32])[N:27]=1
Reactant: CCOC1=NS(=O)N=C1OCC
Reactant: NCC(O)COCc1cccc(CN2CCCCC2)c1
Solvent: CCO
Product: CCOC1=NS(=O)N=C1NCC(O)COCc1cccc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 2.78 g (0.01 mol) of 2-hydroxy-3-[3-(1-piperidylmethyl)benzyloxy]propylamine in 10 ml of ethanol is added dropwise over a period of 30 minutes to a solution of 1.90 g (0.01 mol) of 3,4-diethoxy-1,2,5-thiadiazole-1-oxide in 10 ml of ethanol and the mixture is stirred at room temperature for 4 hours. The title compound obtained after concentration of the reaction solution by evaporation is reacted without further purification.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:14](O)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[NH2:24][C:25]1[S:26][C:27]([N:30]2[CH:34]=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:32]=[N:31]2)=[CH:28][N:29]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1>C(Cl)Cl>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:14]([NH:24][C:25]3[S:26][C:27]([N:30]4[CH:34]=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:32]=[N:31]4)=[CH:28][N:29]=3)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cnn(-c2cnc(N)s2)c1
Reactant: O=C(O)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCOC(=O)c1cnn(-c2cnc(NC(=O)C(OC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)s2)c1
Yield: 49.7 %

Procedure:
The compound of example A5 was obtained by similar method described in example A1 using 2-(4-cyclopropanesulfonyl-phenyl)-2-[(tetrahydro-pyran-4-yloxy)]-acetic acid (Preparation 4; 1.1 g, 3.23 mmol), ethyl 1-(2-aminothiazol-5-yl)pyrazole-4-carboxylate (Preparation 41; 0.924 g, 3.88 mmol), HOBt (0.524 g, 3.88 mmol), and EDCl (0.741 g, 3.88 mmol), N-methyl morpholine (0.815 g, 0.88 mmol) in DCM (20 mL) to provide the title compound (0.9 g).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([O:13][CH2:14][CH3:15])[C:6]([CH3:12])=[N:7]2.[CH3:16][O:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.[OH-].[Na+]>O>[OH2:13].[CH2:14]([O:13][C:5]1[C:6]([CH3:12])=[N:7][C:8]2[C:3]([CH:4]=1)=[C:2]([NH:22][C:21]1[CH:23]=[CH:24][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1)[CH:11]=[CH:10][N:9]=2)[CH3:15]
Reactant: COc1ccc(N)cc1
Reactant: CCOc1cc2c(Cl)ccnc2nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOc1cc2c(Nc3ccc(OC)cc3)ccnc2nc1C

Procedure:
The mixture of 5-chloro-3-ethoxy-2-methyl-1,8-naphthyridine (5.0 g), 4-methoxyaniline (2.77 g) and IMS (40 ml) was boiled under reflux for 2.5 hours. The mixture was cooled and filtered. The solid obtained was dissolved in boiling IMS (50 ml) and 5M sodium hydroxide solution (4.0 ml) was added. The mixture was heated under reflux for 1 hour and then cooled and water (100 ml) was added. The mixture was filtered to give 3-ethoxy-5-(4-methoxyanilino)-2-methyl-1,8-naphthyridine hydrate, m.p. 228°-231° C.
Reaction SMILES: N([O-])=O.[Na+].[Br:5][C:6]1[C:11](N)=[CH:10][C:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:8][N:7]=1.[BrH:20]>O>[Br:5][C:6]1[C:11]([Br:20])=[CH:10][C:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:8][N:7]=1
Reactant: Nc1cc(-c2ccc(Cl)cc2)cnc1Br
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Clc1ccc(-c2cnc(Br)c(Br)c2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 0.33 g (4.85 mmol) of sodium nitrite in 1.9 mL of water was added at 0° C. with vigorous stirring to a suspension of 1.25 g (4.41 mmol) of 2-bromo-5-(4-chlorophenyl)pyridin-3-ylamine in 9.90 mL (88.16 mmol) of 48% aqueous HBr and 9.90 mL of water and stirred for a further 10 minutes at 0° C. Subsequently a solution of 0.95 g (6.61 mmol) of CuBr in 3.47 mL of 48% aqueous HBr was added and the mixture was stirred for I hour at 60° C. The reaction mixture was diluted with water and exhaustively extracted with EtOAc. The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution and water, dried over magnesium sulfate, and evaporated down in vacuo. The residue was purified by column chromatography (silica gel, PE/DCM 1:1). Yield: 1.00 g (65% of theoretical); C11H6Br2ClN (M=347.433); calc.: molpeak (M+H)+:346/348/350/352 (2BrCl); found: molpeak (M+H)+: 346/348/350/352 (2BrCl).