Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:20])=[C:16](Cl)[N:17]=2)[C:12](=[O:21])[C:11]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10]1.Cl.[N:28]1([CH:33]2[CH2:37][CH2:36][NH:35][CH2:34]2)[CH:32]=[CH:31][N:30]=[N:29]1.C1CCN2C(=NCCC2)CC1>CC#N.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:20])=[C:16]([N:35]3[CH2:36][CH2:37][CH:33]([N:28]4[CH:32]=[CH:31][N:30]=[N:29]4)[CH2:34]3)[N:17]=2)[C:12](=[O:21])[C:11]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10]1
Reactant: c1cn(C2CCNC2)nn1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(Cl)c(F)cc2c1=O
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(N3CCC(n4ccnn4)C3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of ethyl 1-(2,4-difluorophenyl)-7-chloro-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (91 mg, 0.5 mmol), 3-(1,2,3-triazol-1-yl)pyrrolidine hydrochloride (259 mg, 1.5 mmol), and DBU (380 mg, 2.5 mmol) in CH3CN (20 ml) was heated under reflux for 2 h, cooled to r.t. and stirred further for 18 h, diluted with water. Unreacted starting materials were removed by extraction with chloroform. The water layer was concentrated to give a yellow oil. Yield: 150 mg, 62%. 1H NMR (CDCl3) δ: 1.3 (t, 3H), 2.5 (m, 2H), 3.9 (m, 4H), 4.4 (q, 2H), 5.3 (m, 1H), 7.3 (m, 4H), 7.8 (d, 1H), 8.0 (d, 1H), 8.4 (s, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[S:3]([C:6]1[O:7][C:8]2[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:9]=2[CH:10]=1)(=[O:5])=[O:4].[Br:18]N1C(=O)CCC1=O>C(#N)C>[CH3:1][N:2]([CH3:17])[S:3]([C:6]1[O:7][C:8]2[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[C:11]([Br:18])[C:9]=2[CH:10]=1)(=[O:5])=[O:4]
Reactant: COc1cccc2cc(S(=O)(=O)N(C)C)oc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COc1ccc(Br)c2cc(S(=O)(=O)N(C)C)oc12
Yield: 93.4 %

Procedure:
Prepared from 7-methoxybenzofuran-2-sulfonic acid dimethylamide (0.82 g) and N-bromosuccinimide (0.57 g) in acetonitrile (50 ml). Purification by column chromatography eluting with 50% ethyl acetate in hexane afforded the desired product as a pale yellow solid (1.0 g).
Reaction SMILES: C([O:3][C:4](=[O:33])[CH:5]=[C:6]([C:8]1[O:12][C:11]2[C:13]([C:17]3[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[CH:20]=[C:19]([CH:26]([CH3:28])[CH3:27])[C:18]=3[O:29][CH2:30][CH2:31][CH3:32])=[CH:14][CH:15]=[CH:16][C:10]=2[CH:9]=1)[CH3:7])C.C1COCC1.[Li+].[OH-]>CO>[CH2:30]([O:29][C:18]1[C:19]([CH:26]([CH3:28])[CH3:27])=[CH:20][C:21]([CH:23]([CH3:24])[CH3:25])=[CH:22][C:17]=1[C:13]1[C:11]2[O:12][C:8]([C:6]([CH3:7])=[CH:5][C:4]([OH:33])=[O:3])=[CH:9][C:10]=2[CH:16]=[CH:15][CH:14]=1)[CH2:31][CH3:32]
Reactant: CCCOc1c(-c2cccc3cc(C(C)=CC(=O)OCC)oc23)cc(C(C)C)cc1C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCOc1c(-c2cccc3cc(C(C)=CC(=O)O)oc23)cc(C(C)C)cc1C(C)C
Temperature: 25 °C

Procedure:
A mixture of 0.450 mmol of 3-[7-(2-propoxy-3,5-diisopropylphenyl)-benzo[b]furan-2-yl]-but-2-enoic acid ethyl ester, 3 mL of THF, 3 mL of methanol and 1 mL of LiOH (2N aqueous) was refluxed for 2 hours. After cooling at room temperature, the mixture was acidified to pH=2 and extracted with ethyl acetate. The organic layer was dried over MgSO4 and after evaporation of the solvents, the crude acid was recrystallized from acetonitrile. 3-[7-(2-Propoxy-3,5-diisopropylphenyl)-benzo[b]furan-2-yl]-but-2-enoic acid was isolated as a white solid. 1H-NMR (400 MHz, CDCl3) δ 7.55 (m, 2H, Ar—H), 7.54 (s, 1H, Ar—H), 7.28 (t, J=7.6 Hz, 1H, Ar—H), 7.10 (s, 1H, furan-H), 6.94 (s, 1H, Ar—H), 6.62 (s, 1H, C═C—H), 4.06 (q, J=6.9 Hz, 2H, O—CH2—CH3), 2.56 (s, 3H, C═C—CH3), 1.74 (s, 4H, ring-CH2), 1.37 (s, 6H, ring-CH3), 1.33 (s, 6H, ring-CH3), 1.27 (t, J=6.9 Hz, 3H, O—CH2—CH3).
Reaction SMILES: Cl[C:2]1C=CC=C(C(OO)=O)C=1.[CH:12]1([C:15]2[O:19][N:18]=[CH:17][C:16]=2[C:20](=[O:30])[C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[C:23](SC)[CH:22]=2)[CH2:14][CH2:13]1.[S:31](S([O-])=O)([O-:34])(=O)=[O:32].[Na+].[Na+]>ClCCl>[CH:12]1([C:15]2[O:19][N:18]=[CH:17][C:16]=2[C:20](=[O:30])[C:21]2[CH:22]=[CH:23][C:24]([CH3:27])=[C:25]([S:31]([CH3:2])(=[O:34])=[O:32])[CH:26]=2)[CH2:13][CH2:14]1
Reactant: CSc1cc(C(=O)c2cnoc2C2CC2)ccc1C
Reactant: O=S([O-])S(=O)(=O)[O-]
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(C(=O)c2cnoc2C2CC2)cc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Chloroperbenzoic acid (about 50%, 2.5 g) was added to a solution of 5-cyclopropyl-4-(4-methyl-3-methylsulphenylbenzoyl)isoxazole (0.8 g) in dichloromethane and the mixture was stirred at room temperature overnight. An aqueous solution of sodium metabisulphite was added and the mixture was stirred for 20 minutes. The solid was filtered and the filtrate layers separated. The organic phase was washed with aqueous sodium acetate, brine, dried and filtered. The filtrate was evaporated and the residue triturated with ether and filtered to give 5-cyclopropyl-4-(4-methyl-3-methylsulphonylbenzoyl)isoxazole (0.65 g) as a white solid, m.p. 126.4°-127.7° C.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([C@@H:13]2[O:17]C(=O)[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:35]=[C:34]([CH:36]([CH3:38])[CH3:37])[CH:33]=[CH:32][C:31]=3[O:39][CH3:40])[C@H:14]2[CH3:41])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O.[OH-].[K+].CCOC(C)=O>CCO>[F:1][C:2]([F:42])([F:43])[C:3]1[CH:4]=[C:5]([C@H:13]([OH:17])[C@@H:14]([NH:15][CH2:19][C:20]2[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[CH:22][C:21]=2[C:30]2[CH:35]=[C:34]([CH:36]([CH3:37])[CH3:38])[CH:33]=[CH:32][C:31]=2[O:39][CH3:40])[CH3:41])[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN[C@@H](C)[C@@H](O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 75 °C

Procedure:
To a solution of (4S,5S)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (147.7 mg, 0.239 mmol) in EtOH (7.5 mL) was added H2O (1.5 mL) and KOH (150 mg, 2.67 mmol). The solution was heated to 75° C. for 30 h and then cooled to room temperature. EtOAc (75 mL) was added and the organic layer was washed with H2O (15 mL) and brine (2×15 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography to afford (1S,2S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-({[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)propan-1-ol. Rf=0.44 (40% EtOAc/hexanes). LCMS=594.2 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 6.93-7.78 (m, 9H), 3.51-4.20 (m, 6H), 2.91 (m, 1H), 2.49 (m, 1H), 1.22-1.26 (m, 6H), 0.79-0.81 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][O:10][C:9]3[CH:12]=[C:13]4[O:18][CH2:17][O:16][C:14]4=[CH:15][C:8]=3[C:7](=[O:19])[C:6]=2[CH:20]=1.[CH3:21][N:22](C)C=O.C(Cl)(Cl)Cl.[C-]#N.[Na+]>O>[CH2:17]1[O:18][C:13]2[C:14](=[CH:15][C:8]3[C:7](=[O:19])[C:6]4[CH:20]=[C:2]([C:21]#[N:22])[CH:3]=[CH:4][C:5]=4[CH2:11][O:10][C:9]=3[CH:12]=2)[O:16]1
Reactant: CN(C)C=O
Reactant: O=C1c2cc(Br)ccc2COc2cc3c(cc21)OCO3
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc2c(c1)C(=O)c1cc3c(cc1OC2)OCO3

Procedure:
Heat a mixture of 9.26 gm. (0.0278 mole) of 9-bromo-6,11-dihydro-2,3-methylenedioxy-11-oxodibenz[b,e]oxepin, 5.23 (0.0584 mole) of cuprous cyanide and 33 ml. of dimethylformamide under reflux for 9 hours with vigorous stirring. Cool the reaction mixture and shake with a mixture of 45 ml. of chloroform, 32 ml. of saturated sodium cyanide solution and 32 ml. of water until all solids have dissolved. Separate the organic layer, wash with aqueous sodium cyanide solution and water and dry over anhydrous magnesium sulfate. Remove the solvent under vacuum to obtain the title product (yield 7.76 gm., m.p. 217°-220° C.). Recrystallize from acetic acid to obtain pure product as tan prisms [m.p. 224°-225° C., pmr (CDCl3) 5.03 (2H,s, CH2O), 617(2H,s,OCH2O--)].
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH:6]([CH3:11])[CH:7]([CH3:10])[CH2:8][N:9]=1.[Cl-:12].[NH4+:13]>CO>[ClH:12].[CH3:11][CH:6]1[CH:7]([CH3:10])[CH2:8][NH:9][C:3](=[NH:13])[CH2:4][CH2:5]1
Reactant: COC1=NCC(C)C(C)CC1
Reactant: [Cl-]
Reactant: [NH4+]
Solvent: CO
Product: CC1CCC(=N)NCC1C
Product: Cl

Procedure:
The product of EXAMPLE 124 in MeOH is reacted with ammonium chloride by the method of EXAMPLE 27 to generate the title material.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([C:8]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].CO[CH:20](OC)[N:21]([CH3:23])[CH3:22]>C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([C:10](=[CH:20][N:21]([CH3:23])[CH3:22])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9])=[CH:16][CH:17]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: COC(OC)N(C)C
Solvent: c1ccccc1
Product: CCOC(=O)C(=CN(C)C)C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 85.2 %

Procedure:
To a solution of ethyl 4-nitrobenzoylacetate (11.9 g) in benzene (100 ml) was dropwise added N,N-dimethylformamide dimethylacetal (9.5 g) dissolved in benzene (50 ml) during a period of 0.5 hour, under stirring at room temperature. The mixture was refluxed for 4 hours. The reaction mixture was evaporated under reduced pressure. The resulting oil was recrystallized from ether-hexane to give 12.5 g of ethyl 2-(4-nitrobenzoyl)-3-dimethylaminopropenoate.
Reaction SMILES: N1CCC(C2N=CNC=2)CC1.[CH:12]1([NH:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C1(CCCCC([Cl:37])=O)CCCCC1>C(#N)C.ClCCl>[Cl-:37].[CH:19]1([NH2+:18][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: C1CCC(NC2CCCCC2)CC1
Reactant: O=C(Cl)CCCCC1CCCCC1
Agent: c1nc(C2CCNCC2)c[nH]1
Solvent: CC#N
Solvent: ClCCl
Product: C1CCC([NH2+]C2CCCCC2)CC1
Product: [Cl-]
Temperature: 60 °C
Yield: 68 %

Procedure:
To a mixture of 755 mg (5.00 mmol) 4-(4-piperidyl)1-H-imidazole and 942 mg (5.20 mmol) of ##STR7## dicyclohexylamine in 10 ml anhydrous acetonitrile at 25° C. was slowly added 1.06 g (5.20 mmol) cyclohexanevaleroyl chloride in 2 ml of dichloromethane over a period of 10 min with stirring; then the reaction mixture was heated at 60° C. for 1.5 h. After cooling to ambient temperature, the solid side product that was obtained (dicyclohexylammonium chloride) was filtered off and the filtrate was concentrated in vacuo to remove acetonitrile. The resulting crude oil was crystallized with methanol: anhydrous diethyl ether to give 1.085 mg of analytically pure product as a yellow powder. Yield: 68%; M.P.: 159° C.; MS: m/e=317 (M+); 1H NMR (CDCl3): imidazole H: δ 7.65 (s, 1 H), 6.75 (s, 1 H); cyclohexylbutyl: δ 2.20 (m, 8 H), 1.20 (m, 11 H); piperidyl: 4.65 (d, 2 H), 3.95 (d, 2 H), 3.10 (d, 2 H), 2.84 (m, 1 H), 2.20 (m, 2 H).
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:7]=[N:8][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:11]=1)[CH2:3][CH2:4][OH:5]>CCCCCC.CCO>[NH2:1][C@H:2]([C:6]1[CH:7]=[N:8][C:9]([C:12]([F:15])([F:13])[F:14])=[CH:10][CH:11]=1)[CH2:3][CH2:4][OH:5].[NH2:1][C@@H:2]([C:6]1[CH:7]=[N:8][C:9]([C:12]([F:15])([F:13])[F:14])=[CH:10][CH:11]=1)[CH2:3][CH2:4][OH:5]
Reactant: NC(CCO)c1ccc(C(F)(F)F)nc1
Solvent: CCO
Solvent: CCCCCC
Product: N[C@@H](CCO)c1ccc(C(F)(F)F)nc1
Product: N[C@H](CCO)c1ccc(C(F)(F)F)nc1

Procedure:
Racemic 3-amino-3-(6-(trifluoromethyl)pyridin-3-yl)propan-1-ol (1.10 g, 5.00 mmol) was resolved by chiral HPLC (conditions: CHIRALPAK AD-H column, 20×250 mm, hexane/EtOH [88:12] at 20 mL/min, UV at 230 nm) to give (S)-3-amino-3-(6-(trifluoromethyl)pyridin-3-yl)propan-1-ol and (R)-3-amino-3-(6-(trifluoromethyl)pyridin-3-yl)propan-1-ol. Analytical chiral HPLC: CHIRALPAK AD-H column, 250×4.6 mm, hexane/EtOH [90:10] at 1.0 mL/min, UV at 230 nm); retention time for (S)-isomer: 18.68 min (>99% ee); retention time for (R)-isomer: 23.56 min (>99% ee).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][OH:23])[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:30].[Na+].O1CCCC1>CO.C(#N)C>[NH2:30][CH:12]([C:10]1[C:9]([N:15]2[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][OH:23])[CH2:17][CH2:16]2)=[C:8]2[C:3]([CH:4]=[CH:5][CH:6]=[N:7]2)=[C:2]([Cl:1])[CH:11]=1)[CH3:13]
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCC(CCO)CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CO
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCC(CCO)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-{5-chloro-8-[4-(2-hydroxyethyl)piperidin-1-yl]quinolin-7-yl}ethanone (0.0948 g, 0.285 mmol) and ammonium acetate (0.220 g, 2.85 mmol) in methanol (1 mL) and acetonitrile (1 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.71 mL, 0.71 mmol). The reaction was heated at 65° C. overnight. The resulting mixture was cooled to room temperature, quenched with sat. NaHCO3 solution and extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C18H25ClN3O (M+H)±: m/z=334.2; Found: 334.2.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:8][C:6](=[O:7])[C@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1.[CH3:12][C:13]([CH:15]=[CH2:16])=[O:14].C1C=CC=CC=1.C([O-])(=O)C.[Na+]>O.C(O)(=O)C>[CH3:1][CH:2]1[CH2:3][CH2:4][CH:5]([CH:9]([CH3:11])[CH3:10])[C:6](=[O:7])[CH:8]1[CH2:16][CH2:15][C:13](=[O:14])[CH3:12]
Reactant: CC(C)[C@@H]1CC[C@@H](C)CC1=O
Reactant: C=CC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)CCC1C(=O)C(C(C)C)CCC1C

Procedure:
A mixture of 19.6 g of the pyrrolidine-enamine of p-menthone, 10 ml of methylvinyl ketone and 150 ml of anhydrous benzene is refluxed under nitrogen for 20 hours. The mixture is then cooled and treated with 6 g of sodium acetate in 12 ml of water as well as with 12 ml of acetic acid. The mixture is again refluxed for 4 hours. Then, the product is extracted with benzene and the solvent evaporated. The residue is fractionated in vacuo and there is obtained 1-methyl-4-isopropyl-2-(3'-oxobutyl)-cyclohexan-3-one with a boiling point of 88°-90°C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH:11]=O)=[C:8]([CH3:13])[C:6]=2[N:7]=1.C(O)(=O)C(O)=O.[OH:26][C@@H:27]([CH3:36])[C:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:29].CN1CCOCC1.COC(OC)OC.B.C(C1C=CC(C)=NC=1)C>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][N:33]3[CH2:32][CH2:31][N:30]([C:28](=[O:29])[C@@H:27]([OH:26])[CH3:36])[CH2:35][CH2:34]3)=[C:8]([CH3:13])[C:6]=2[N:7]=1
Reactant: Cc1c(C=O)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: C[C@H](O)C(=O)N1CCNCC1
Agent: B
Agent: CCc1ccc(C)nc1
Agent: O=C(O)C(=O)O
Solvent: COC(OC)OC
Solvent: CN1CCOCC1
Solvent: CO
Product: Cc1c(CN2CCN(C(=O)[C@H](C)O)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Temperature: 57.5 °C
Reaction time: 4 h
Yield: 81 %

Procedure:
2-Chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde IV (15.0 g, 50 mmol) was charged to a suitably sized reactor, followed by methanol (306 mL), (S)-2-hydroxy-1-(piperazin-1-yl)propan-1-one oxalate V (18.8 g, 75 mmol), N-methyl morpholine (10.2 g, 100 mmol) and trimethylorthoformate (53.1 g, 500 mmol). The slurry was heated to 55-60° C. and stirred for 4 hrs. 5-Ethyl-2-methylpyridine borane (8.7 g, 60.0 mmol) were slowly added and the solution was stirred for 2 h. The reaction mixture was partially concentrated under reduced pressure. Me-THF (350 mL) was added and the reaction mixture was concentrated under reduced pressure to an end volume of 300 mL. The mixture was cooled to 5° C. 3.3% Sulfuric acid in water (401 g) was added and pH 1.6 was reached. The organic phase was removed. The pH of the aqueous phase was adjusted to 7.9 with 10% aqueous sodium carbonate solution (300 g) at 0-5° C. The mixture was warmed to 25° C. and the organic phase was separated. The organic phase was concentrated under reduced pressure to 75 mL. The solution was warmed to 35° C. and seeded with 41 mg (S)-1-(4-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one II. The suspension was cooled to 0° C. and n-heptane (200 g) was added. The resulting slurry was aged at −5° C., filtered and washed with n-heptane. The cake was dried at 70° C. under reduced pressure to afford (S)-1-(4-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one II (17.8 g, 81% yield)
Reaction SMILES: Cl.[N:2]1([CH2:8][CH:9]2[C:14](=[O:15])[N:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]3=[N:11][C:10]2=[O:20])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.CC(C)([O-])C.[K+].Cl[CH2:28][N:29]1[C:39](=[O:40])[C:38]2[C:33](=[CH:34][C:35]([O:44][CH3:45])=[CH:36][C:37]=2[CH:41]([CH3:43])[CH3:42])[S:30]1(=[O:32])=[O:31]>CN(C)C=O.O>[N:2]1([CH2:8][C:9]2[C:14](=[O:15])[N:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]3=[N:11][C:10]=2[O:20][CH2:28][N:29]2[C:39](=[O:40])[C:38]3[C:33](=[CH:34][C:35]([O:44][CH3:45])=[CH:36][C:37]=3[CH:41]([CH3:43])[CH3:42])[S:30]2(=[O:31])=[O:32])[CH2:3][CH2:4][O:5][CH2:6][CH2:7]1
Reactant: O=C1N=C2C=CC=CN2C(=O)C1CN1CCOCC1
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CCl)C2=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COc1nc3ccccn3c(=O)c1CN1CCOCC1)C2=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 47.1 %

Procedure:
A mixture of 3-(4-morpholinylmethyl)pyrido[1,2-a]pyrimidine-2,4-dione hydrochloride (0.6 g) and potassium t-butoxide (0.49 g) in dimethylformamide (20 mL) was stirred at room temperature for five minutes. 2-Chloromethyl-4-isopropyl-6-methoxysaccharin (0.61 g) was added and stirring was continued at room temperature for one hour. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (3×200 mL). The dichloromethane extract was dried over sodium sulfate and stripped of volatiles, finally under high vacuum. The crude product (780 mg) was combined with that (0.65 g) from another run at the same scale using sodium hydride (60% dispersion in mineral oil, 0.19 g) instead of potassium t-butoxide and purified by column chromatography on silica gel with dichloromethane-methanol (95:5) as eluant affording 2-[3-(4-morpholinylmethyl)-4-oxo-4-H-pyrido[1,2-a]pyrimidin-2yl]oxymethyl-4-isopropyl-6-methoxysaccharin (500 mg, 23% yield), part of which was recrystallized from ethanol (m.r. 177°-180° C.).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[C:4]([CH3:15])[C:3]=1[C:16]([F:19])([F:18])[F:17].[C:20]([Cu])#[N:21]>CN1CCCC1=O>[C:20]([C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[C:4]([CH3:15])[C:3]=1[C:16]([F:19])([F:18])[F:17])#[N:21]
Reactant: Cc1c(NC(=O)C(C)(C)C)ccc(Cl)c1C(F)(F)F
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: Cc1c(NC(=O)C(C)(C)C)ccc(C#N)c1C(F)(F)F
Temperature: 25 °C
Yield: 93.2 %

Procedure:
A suspension of N-(4-chloro-2-methyl-3-trifluoromethylphenyl)-2,2-dimethylpropionamide (8.36 g, 28.5 mmol) and CuCN (4.33 g, 65.5 mmol) in anhydrous N-methylpyrrolidinone (85 mL) was refluxed for 38 h. After cooling to rt, the suspension was poured into ice water with stirring. The resulting solid was filtered, washed with water and dried to yield an 85:15 mixture (7.55 g) of compound 841C and 841D. The resulting mixture was used in the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([CH3:11])=[C:9]([CH3:12])[NH:8][C:5]2=[N:6][CH:7]=1.BrC1[N:19]=[C:18]2NC(C)=C(C)C2=CC=1.C([Cu])#N.Cl>O.N1C=CC=CC=1>[C:18]([C:2]1[CH:3]=[C:4]2[C:10]([CH3:11])=[C:9]([CH3:12])[NH:8][C:5]2=[N:6][CH:7]=1)#[N:19]
Reactant: Cc1[nH]c2ncc(Br)cc2c1C
Reactant: Cc1[nH]c2nc(Br)ccc2c1C
Agent: N#C[Cu]
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: Cc1[nH]c2ncc(C#N)cc2c1C
Temperature: 220 °C
Yield: 40 %

Procedure:
An autoclave was charged with 5-bromo-2,3-dimethyl-pyrrolo[2,3-b]pyridine (prepared in a similar manner as 6-bromo-2,3-dimethyl-pyrrolo[2,3-b]pyridine (247 mg, 1.1 mmol) and CuCN (135 mg. 1.5 mmol). The mixture was covered with pyridine and heated to 220° C. for 12 h. After cooling the raction mixture was poured into a mixture of FeCl3 hexahydrate (0.9 g), conc HCl (0.5 ml), and water (10 ml). The mixture was heated to 80° C. for 1 h and extracted with CH2Cl2. The organic layer was washed four times with 2M HCl, dried over MgSO4 and evaporated leaving 77 mg (40%) 5-cyano-2,3-dimethyl-pyrrolo[2,3-b]pyridine.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].C(=O)([O-])[O-].[Na+].[Na+].[Br:13][C:14]1([C:17](Cl)=[O:18])[CH2:16][CH2:15]1.[OH-].[Na+]>O.C(Cl)Cl>[CH3:5][C:2]([NH:1][C:17]([C:14]1([Br:13])[CH2:16][CH2:15]1)=[O:18])([CH3:6])[CH2:3][OH:4]
Reactant: CC(C)(N)CO
Reactant: O=C(Cl)C1(Br)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(CO)NC(=O)C1(Br)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
1.69 g of 2-amino-2-methyl-1-propanol is introduced into 85 ml of methylene chloride under nitrogen at room temperature, and 2.38 g of sodium carbonate is added to 38 ml of water and then 3.6 g of acid chloride 107. It is stirred overnight at room temperature and then treated with methanolic 2N sodium hydroxide solution. The organic phase is separated, dried on sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with ethyl acetate/hexane, whereby 3.83 g of 1-bromocyclopropanecarboxylic acid-1,1-dimethyl-2-hydroxy-ethylamide 108 is obtained as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]2[NH:8][N:9]=[N:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].C(O)C.[N+]([O-])([O-])=O.[Ag+:20]>O>[Ag:20].[N+:1]([C:4]1[CH:12]=[CH:11][C:7]2[NH:8][N:9]=[N:10][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: O=[N+]([O-])c1ccc2[nH]nnc2c1
Solvent: O
Solvent: CCO
Product: [Ag]
Reaction time: 0.5 h

Procedure:
Solution was prepared by dissolving 18.0 g (0.11 mole) of 5-nitrobenzotriazole into 300 ml of ethanol and whereto a solution prepared by dissolving 16.9 g (0.10 mole) of silver nitrate into 100 ml of water was dropped and the mixture thereof was stirred for 30 minutes. The crystals thus produced were filtrated and were then washed with 100 ml of ethanol, and thus, 26.4 g of 5-nitrobenzotriazole silver were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[OH:9].[H-].[Na+].B(OCC)(OCC)OCC.[S:22](Cl)([C:25]1[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=1)(=[O:24])=[O:23]>CN(C)C=O.C(OCC)(=O)C>[CH3:29][C:28]1[CH:30]=[CH:31][C:25]([S:22]([O:8][C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([OH:9])[CH:4]=2)(=[O:24])=[O:23])=[CH:26][CH:27]=1
Reactant: Oc1ccc(O)c(O)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CCOB(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)Oc2ccc(O)c(O)c2)cc1
Reaction time: 1 h
Yield: 50.2 %

Procedure:
1.37 g of 1,2,4-trihydroxy benzene and 40 ml of anhydrous dimethylformamide were mixed together under an inert gas atmosphere and then 0.984 g of sodium hydride in suspension at 53% in oil were added slowly at 15°-20° C. The mixture was stirred for one hour and then 1.906 ml of triethyl borate were added, followed by stirring for one hour. Then, a solution of 2.072 g of tosyl chloride in 15 ml of dimethylformamide were added over 2 hours and the mixture was stirred for 4 hours at ambient temperature. The mixture was poured into a water-ice-hydrochloric acid mixture and extraction took place with ethyl acetate followed by evaporating to dryness. The crude residue was washed with petroleum ether and after chromatography on silica and eluting with a cyclohexane-ethyl acetate (1-1) mixture, 1.53 g of the expected product were obtained which was crystallized from a flugene-isopropyl ether mixture.