Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:7][N:6]([CH:8]([CH3:10])[CH3:9])[C:5](=[O:11])[C:4]1([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH:24][C:25]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.[C:37](=[O:40])([O-:39])[O-].[K+].[K+]>C(O)C>[C:5]([OH:24])(=[O:11])/[CH:4]=[CH:18]\[C:37]([OH:39])=[O:40].[C:18]1([C:4]2([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:3]([CH2:2][N:28]3[CH2:27][CH2:26][C:25]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)([OH:24])[CH2:30][CH2:29]3)[CH2:7][N:6]([CH:8]([CH3:10])[CH3:9])[C:5]2=[O:11])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)N1CC(CCl)C(c2ccccc2)(c2ccccc2)C1=O
Reactant: OC1(c2ccccc2)CCNCC1
Agent: [K+]
Solvent: CCO
Product: CC(C)N1CC(CN2CCC(O)(c3ccccc3)CC2)C(c2ccccc2)(c2ccccc2)C1=O
Product: O=C(O)/C=C\C(=O)O

Procedure:
A mixture of 15 g. (0.046 mole) of 4-chloromethyl-3,3-diphenyl-1-isopropyl-2-pyrrolidinone, 8.1 g. (0.046 mole) of 4-hydroxy-4-phenylpiperidine, 8.2 g. (0.06 mole) of potassium carbonate and 200 ml. of ethanol was heated in a steel bomb at 200° C. for 48 hours. The cooled mixture was partitioned between water and isopropyl ether. The dried isopropyl ether layer (sodium sulfate) was concentrated. The residual material (19 g.) was dissolved in 150 ml. of isopropyl alcohol to which solution was added 7.0 g of maleic acid and 50 ml. of isopropyl ether. The maleate salt was collected and recrystallized from isopropyl alcohol-water. The dried salt weighed 8.0 g and melted at 207°-208° C.
Reaction SMILES: [CH:1]([NH:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([O:23][CH3:24])[C:17]=2[Cl:25])=[C:10]([OH:27])[CH:9]=1)=[O:7])([CH3:3])[CH3:2].C[O-].[Na+].C1([O-])C=CC=CC=1.[Na+].[C:39](Cl)(=[O:44])[CH2:40][CH:41]([CH3:43])[CH3:42]>>[CH:1]([NH:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([O:23][CH3:24])[C:17]=2[Cl:25])=[C:10]([O:27][C:39](=[O:44])[CH2:40][CH:41]([CH3:43])[CH3:42])[CH:9]=1)=[O:7])([CH3:3])[CH3:2]
Reactant: COc1c(C)ccc(C(=O)Oc2ccc(C(=O)CNC(C)C)cc2O)c1Cl
Reactant: CC(C)CC(=O)Cl
Agent: C[O-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Product: COc1c(C)ccc(C(=O)Oc2ccc(C(=O)CNC(C)C)cc2OC(=O)CC(C)C)c1Cl

Procedure:
Following a procedure similar to that described in Example 2A above, when 3-hydroxy-4-(2-chloro-3-methoxy-4-methylbenzoyloxy)phenyl isopropylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted with isovaleryl chloride there is obtained 3-(isovaleryloxy)-4-(2-chloro-3-methoxy-4-methylbenzoyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using a procedure similar to that described above in Example 2B, there is obtained 3-(isovaleryloxy)-4-(2-chloro-3-methoxy-4-methylbenzoyloxy)-alpha-(isopropylaminomethyl)benzyl alcohol hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[N:11]=2)=[CH:5][CH:4]=1.[C:24](O)(=[O:27])[CH:25]=[CH2:26]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:27])[CH:25]=[CH2:26])=[CH:19][CH:18]=3)[N:11]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(Sc2ccnc(Nc3ccc(N)cc3)n2)cc1
Reactant: C=CC(=O)O
Product: C=CC(=O)Nc1ccc(Nc2nccc(Sc3ccc(OC)cc3)n2)cc1
Yield: 55.1 %

Procedure:
In a procedure analogous to Example 15, reaction of N1-(4-(4-methoxyphenylthio)pyrimidin-2-yl)benzene-1,4-diamine (80 mg, 0.23 mmol) and acrylic acid (24 μL, 0.46 mmol) furnished the product (48 mg, 55%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[CH:6][C:7]=1[OH:8].[C:10](=O)([O:16]C(C)(C)C)[O:11][C:12]([CH3:15])([CH3:14])[CH3:13]>C(Cl)Cl>[C:12]([O:11][C:10](=[O:16])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[CH:6][C:7]=1[OH:8])([CH3:15])([CH3:14])[CH3:13]
Reactant: Cc1ccc(N)c(O)c1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: ClCCl
Product: Cc1ccc(NC(=O)OC(C)(C)C)c(O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.4 %

Procedure:
To a stirred solution of 6-amino-m-cresol (5 g, 40.6 mmol) in DCM (100 mL) was added di-tert-butyl carbonate (9.4 ml, 40.6 mmol), under an argon atmosphere. The resulting mixture was stirred for 18 h at RT, quenched by addition of a saturated aqueous solution of NaHCO3 and extracted with DCM. The organic phase was washed with a saturated aqueous solution of NaHCO3, dried (Na2SO4), filtered and concentrated to afford 9.1 g of the title compound as a black oil which was used as a crude material. HPLC: LtRet=4.86 min; LC-MS: m/z 224.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21]1>CCCCO>[Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:21]2)=[C:4]2[C:10]([NH:11][C:12]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)C1CCCC1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)C4CCCC4)c23)C1
Temperature: 160 °C
Reaction time: 18 h
Yield: 22 %

Procedure:
A solution of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopentanecarboxamide (205 mg, 0.629 mmol) in n-BuOH (5 mL) was treated with (R)-tert-butyl piperidin-3-ylcarbamate (629 mg, 3.14 mmol) and stirred at 160° C. for 18 hours in a sealed tube. The solvent was removed in vacuo, and the residue was dissolved in EtOAc (50 mL) and washed with water (2×10 mL). The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 5-80% CH3CN/water gradient; 25 CV) to yield a solid, which was crystallized from CH3CN to provide (R)-tert-butyl 1-(5-bromo-3-(cyclopentanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (70 mg, 22% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 11.56 (s, 1H), 9.36 (s, 1H), 8.14 (s, 1H), 7.64 (br s, 1H), 6.90 (br s, 1H), 3.56-3.47 (m, 1H), 3.20-3.11 (m, 2H), 3.04-2.97 (m, 1H), 2.81-2.74 (m, 1H), 1.91-1.80 (m, 4H), 1.78-1.70 (m, 3H), 1.67-1.59 (m, 3H), 1.55-1.50 (m, 2H), 1.42-1.34 (m, 1H); LCMS (APCI+) m/z 407.9 [(M-Boc)+H]+, Retention time=4.03 minutes (Method 2).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[C:11]([OH:18])[CH:10]=1.CCN(C(C)C)C(C)C.CN1CCCC1=O>O>[NH2:1][C:2]1[CH:7]=[C:6]([O:18][C:11]2[CH:10]=[CH:9][C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: Nc1cc(Cl)ccn1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1
Temperature: 160 °C
Reaction time: 15 h

Procedure:
A mixture of 15.88 g of 2-amino-4-chloropyridine 34.5 g of p-nitrophenol, 52 ml of Hunig's base and 100 ml of 1-methyl-2-pyrrolidinone was stirred at 160° C. for 15 hours. Water was added, extraction was performed with ethyl acetate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=1:1) using NH type silica gel to obtain 3.24 g of the target substance as a light yellow solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([NH:14][C:15]([CH2:21][CH3:22])([CH2:19][CH3:20])[C:16]([OH:18])=O)=[O:13])[CH:9]=[CH:8][C:7]=2[N:23]2[CH2:26][C:25]([F:28])([F:27])[CH2:24]2)[CH2:3][CH2:2]1.[F:29][C:30]1([F:34])[CH2:33][NH:32][CH2:31]1>>[F:29][C:30]1([F:34])[CH2:33][N:32]([C:16]([C:15]([NH:14][C:12]([C:10]2[CH:9]=[CH:8][C:7]([N:23]3[CH2:24][C:25]([F:28])([F:27])[CH2:26]3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:13])([CH2:21][CH3:22])[CH2:19][CH3:20])=[O:18])[CH2:31]1
Reactant: CCC(CC)(NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)C(=O)O
Reactant: FC1(F)CNC1
Product: CCC(CC)(NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)C(=O)N1CC(F)(F)C1

Procedure:
In analogy to the procedure described in Example 293, 2-(6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinamido)-2-ethylbutanoic acid and 3,3-difluoroazetidine (CAN 679431-52-8) were condensed to the title product. MS (EI): m/e=471.4 [M−H]−.
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][S:8][CH3:9])[C:3]([OH:5])=[O:4].C.[CH2:11](O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].S([O-])(O)(=O)=O.[Na+]>O.C1(C)C=CC=CC=1>[OH:1][CH:2]([CH2:6][CH2:7][S:8][CH3:9])[C:3]([O:5][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:4]
Reactant: CCCCCCCCCCO
Reactant: CSCCC(O)C(=O)O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCCOC(=O)C(O)CCSC
Temperature: 25 °C

Procedure:
To a 4 neck 1 L round bottom flask fitted with a reflux condenser, dean stark trap, thermocouple, and mechanical overhead stirrer was added 2-hydroxy-4-(methylthio)butanoic acid (125 g, 832.2 mmol, obtained for example by stirring Alimet over activated charcoal, filtering and concentrating in a rotovap), 1-decanol (238 mL, 1248 mmol), sodium hydrogen sulfate (1.998 g, 16.64 mmol), and toluene (625 mL). The reaction was heated to reflux with removal of water (16 mL) during the course of about 6 hours and the reaction was monitored by GC analysis. The reaction was cooled to room temperature overnight and the organic layer was washed with saturated NaHCO3 (1×300 mL), DI water (1×300 mL) and brine (2×300 mL), dried over sodium sulfate, filtered and evaporated to give an amber oil (395.5 g). The oil was purified by kugelrohr distillation at 110° C. and 0.1 Torr vacuum to give an oil (105.23 g, 43.5%). m/z 313 (MNa+);
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([OH:17])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.Cl.[CH3:59][NH:60][O:61][CH3:62]>C(Cl)Cl>[CH3:62][O:61][N:60]([CH3:59])[C:15]([CH:11]1[CH2:12][CH2:13][CH2:14][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10]1)=[O:17]
Reactant: CC(C)(C)OC(=O)NC1CCCC(C(=O)O)C1
Reactant: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)C1CCCC(NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.4 %

Procedure:
To a cold (0° C.) solution of 3-[(tert-butoxycarbonyl)amino]-cyclohexanecarboxylic acid (5.00 g, 20.6 mmol) in CH2Cl2 (50 mL) including triethylamine (3.1 mL, 22.2 mmol) were added benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (10.7 g, 20.6 mmol), N,O-dimethylhydroxyamine hydrochloride (2.21 g, 20.6 mmol) and Et3N (3.2 mL, 23.0 mmol) successively. The resulting mixture was allowed to warm to room temperature, and the stirring was continued for 18 hrs. The reaction mixture was diluted with CH2Cl2 and washed with 1N HCl, saturated aqueous NaHCO3 solution, and brine, successively. The organic phase was dried over Na2SO4, filtered, and evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=1:1) to give tert-butyl 3-{[methoxy(methyl)amino]carbonyl}cyclohexylcarbamate as a colorless oil (5.39 g, yield; 92%).
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][NH:14][CH3:15])[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[CH2:26][CH2:27]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][N:14]([CH2:27][CH2:26][C:25]2[CH:29]=[CH:30][CH:31]=[C:23]([CH3:22])[CH:24]=2)[CH3:15])[C:8]([NH2:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cccc(CCBr)c1
Reactant: CNCCCC(C(N)=O)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cccc(CCN(C)CCCC(C(N)=O)(c2ccccc2)c2ccccc2)c1

Procedure:
A mixture containing 2,2-diphenyl-5-methylaminopentanamide (0.3 g--see Preparation 3), 3-methylphenethyl bromide (0.21 g), anhydrous potassium carbonate (0.5 g) and acetonitrile (20 ml) was heated under reflux for 8 hours. The mixture was partitioned between dichloromethane (30 ml) and 10% aqueous sodium carbonate (30 ml), the layers separated and the aqueous layer extracted with dichloromethane (2×20 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with dichloromethane containing methanol (5%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as an oil, yield 0.23 g.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([OH:14])=O)[CH:7]=2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.ClC(OC)=O.[NH:32]1[CH:36]=[CH:35][C:34]([C:37]2[CH:38]=[C:39]([CH:41]=[CH:42][CH:43]=2)[NH2:40])=[N:33]1>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:40][C:39]3[CH:41]=[CH:42][CH:43]=[C:37]([C:34]4[CH:35]=[CH:36][NH:32][N:33]=4)[CH:38]=3)=[O:14])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Nc1cccc(-c2cc[nH]n2)c1
Reactant: CCCN(CC1CC1)c1cc(C(=O)O)ncn1
Agent: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2cccc(-c3cc[nH]n3)c2)ncn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A cooled (0° C.) solution of 6-(cyclopropylmethyl(propyl)amino)pyrimidine-4-carboxylic acid (Intermediate 21, 112 mg; 0.45 mmol) in DCM was treated with diisopropylethylamine (78.4 mL; 0.52 mmol) and methyl chloroformate (36.2 mL; 0.47 mmol). After stirring at 0° C. for 15 minutes, 3-(1H-pyrazol-3-yl)aniline (Apollo, 107 mg; 0.67 mmol) was added and the mixture stirred for 72 hours. The solvent was evaporated and the compound purified by preparative HPLC to give the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.[CH:9]1[C:17]2[C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[S:14][C:13]=2[C:12](B(O)O)=[CH:11][CH:10]=1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>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>[Br:8][C:4]1[CH:3]=[C:2]([C:21]2[C:15]3[S:14][C:13]4[CH:12]=[CH:11][CH:10]=[CH:9][C:17]=4[C:16]=3[CH:18]=[CH:19][CH:20]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: OB(O)c1cccc2c1sc1ccccc12
Reactant: Brc1cccc(Br)c1
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: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1cccc(-c2cccc3c2sc2ccccc23)c1
Temperature: 25 °C
Yield: 39.2 %

Procedure:
A nitrogen flushed mixture of 1,3-dibromobenzene (18.63 g, 78.92 mmol), dibenzo{b,d}thiophen-4-ylboronic acid (6.0 g, 26.3 mmol), Pd(PPh3)4 (304 mg, 0.414 mmol), toluene (200 mL) and a slurry of K2CO3 (10.9 g, 78.92 mmol) in water (20 mL) were refluxed for 23 h. After the mixture cooled to room temperature the organic layer was washed with water, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by vacuum distillation (Kugelrohr) followed by flash chromatography on silica (hexane:dichloromethane) to give 4-(3-bromophenyl)dibenzo[b,d]thiophene (3.5 g 39.2%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:11](=[O:21])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:22][N:23]=[C:24]=[O:25].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:22][NH:23][C:24](=[O:25])[O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][C:11](=[O:21])[N:12]2[CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)=[CH:4][CH:3]=1
Reactant: CN=C=O
Reactant: O=C1CCC(c2ccc(O)cc2)N1CCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CNC(=O)Oc1ccc(C2CCC(=O)N2CCN2CCOCC2)cc1
Yield: 52.3 %

Procedure:
To a solution of 5-(4-hydroxyphenyl)-1-[2-(4-morpholinyl)ethyl]pyrrolidin-2-one (0.99 g) in dry tetrahydrofuran (50 ml) was added methyl isocyanate (0.22 ml) at ambient temperature, with stirring, over ten mins. Milled potassium carbonate (0.565 g) was added, the reaction mixture was stirred for 2 days and filtered through a pad of celite. The filter cake was washed with ethyl acetate, and the combined filtrates were concentrated. The residue was purified by flash column chromatography (silica gel, 1% triethylamine/1-10% methanol/ether) and (silica gel, 5% methanol/ether). The appropriate fractions were collected and concentrated to afford 0.62 g (52.3%) of product. Recrystallization from absolute ethanol/ether gave the analytical sample, mp 119°-120° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]([Br:14])[N:7]=1>S(=O)(=O)(O)O>[Br:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([N+:1]([O-:4])=[O:2])=[C:8]([Br:14])[N:7]=1
Reactant: COc1ccc(Br)nc1Br
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COc1cc([N+](=O)[O-])c(Br)nc1Br
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To 150 ml of concentrated sulfuric acid were added at 0° C. 150 ml fuming nitric acid. 40.0 g of 2,6-dibromo-3-methoxypyridine (example E2) were added portionwise to this mixture at 0° C. The reaction mixture was stirred for 45 minutes at 0° C. and then heated to 65° C. for 2 h. The mixture was poured into 2 l of crushed ice and stored at 0° C. overnight. The resulting precipitate was filtered, washed with water and dried under vacuum to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[NH:7][C:8]([CH2:12][C:13]([N:15]([CH3:17])[CH3:16])=[O:14])=[N:9]2)=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[Br:24]Br.O>C(O)(=O)C>[Br:24][CH:12]([C:8]1[NH:7][C:6](=[O:18])[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1)[C:13]([N:15]([CH3:17])[CH3:16])=[O:14]
Reactant: CN(C)C(=O)Cc1nc2cc(Cl)ccc2c(=O)[nH]1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CN(C)C(=O)C(Br)c1nc2cc(Cl)ccc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-(7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-N,N-dimethylacetamide and sodium acetate (930 mg, 3 eq.) in acetic acid (15 ml), was added bromine (190 ul, 1 eq.). The reaction mixture was stirred at room temperature overnight. Water was added and the product was extracted into ethyl acetate. The ethyl acetate layer was washed several times with water, saturated sodium bicarbonate, saturated sodium chloride, dried over magnesium sulfate, filtered, and concentrated to give 2-bromo-2-(7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-N,N-dimethylacetamide (0.95 g) as a brown solid.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:24]C(C)([O-])C.[K+].[Si:30]([O:37][C:38]1[CH:39]=[CH:40][CH:41]=[C:42]2[C:47]=1[N:46]=[C:45](C=O)[CH:44]=[CH:43]2)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]>C1COCC1>[Si:30]([O:37][C:38]1[CH:39]=[CH:40][CH:41]=[C:42]2[C:47]=1[N:46]=[C:45](/[CH:24]=[CH:4]/[O:3][CH3:2])[CH:44]=[CH:43]2)([C:33]([CH3:34])([CH3:36])[CH3:35])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc2ccc(C=O)nc12
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CO/C=C/c1ccc2cccc(O[Si](C)(C)C(C)(C)C)c2n1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 95.1 %

Procedure:
Methoxymethyl triphenylphosphonium chloride (3.94 g, 11.5 mmol) was suspended in anhydrous THF (25 mL) under an atmosphere of dry N2. After cooling to 0° C., potassium tert-butoxide (1.41 g, 12.5 mmol) was added. The solution was stirred at 0° C. for 5 minutes, then warmed to ambient temperature. After 15 minutes 8-(tert-butyldimethylsilyloxy)quinoline-2-carbaldehyde (3.00 g, 10.4 mmol) was added. The reaction was stirred at ambient temperature overnight, and then concentrated under vacuum. Diethyl ether (200 mL) was added, and the mixture was stirred at ambient temperature for 1 hour and then filtered. The precipitate was washed with diethyl ether and the filtrate was collected and concentrated under vacuum. The resulting residue was dissolved in diethyl ether (50 mL) to which hexanes (50 mL) was added. The mixture was stirred for 1 hour and then filtered. The filtrate was concentrated under vacuum to give 3.12 g, 95% of the desired product as a mixture of cis-trans isomers.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[CH:14]=[N:15][CH:16]=[C:17]([O:19][C@H:20]4[CH2:24][CH2:23][NH:22][CH2:21]4)[CH:18]=3)=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:4]1=[O:25].[CH2:26]([O:28][C:29](Cl)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([N:22]1[CH2:23][CH2:24][C@H:20]([O:19][C:17]2[CH:16]=[N:15][CH:14]=[C:13]([C:9]3[CH:8]=[C:7]4[C:12](=[CH:11][CH:10]=3)[N:3]([CH3:2])[C:4](=[O:25])[CH2:5][CH2:6]4)[CH:18]=2)[CH2:21]1)=[O:30])[CH3:27]
Reactant: CN1C(=O)CCc2cc(-c3cncc(O[C@H]4CCNC4)c3)ccc21
Reactant: CCOC(=O)Cl
Agent: Cl
Product: CCOC(=O)N1CC[C@H](Oc2cncc(-c3ccc4c(c3)CCC(=O)N4C)c2)C1

Procedure:
In analogy to the procedure described in example 76, 1-methyl-6-[5-((S)-pyrrolidin-3-yloxy)-pyridin-3-yl]-3,4-dihydro-1H-quinolin-2-one hydrochloride (example 60) has been reacted with chloroformic acid ethyl ester to give the title compound as a light yellow amorphous solid. MS: 396.5 (M+H+).
Reaction SMILES: [CH3:1][C:2]1N=CN2[C:10]=1C=NNC2=S.CI.[CH2:14]([C:17]1[N:21]2[C:22](=[S:26])[NH:23][N:24]=[CH:25][C:20]2=[C:19]([CH3:27])[N:18]=1)[CH2:15][CH3:16].C(I)(C)C>>[CH2:14]([C:17]1[N:21]2[C:22]([S:26][CH:2]([CH3:10])[CH3:1])=[N:23][N:24]=[CH:25][C:20]2=[C:19]([CH3:27])[N:18]=1)[CH2:15][CH3:16]
Reactant: CCCc1nc(C)c2cn[nH]c(=S)n12
Reactant: Cc1ncn2c(=S)[nH]ncc12
Solvent: CC(C)I
Solvent: CI
Product: CCCc1nc(C)c2cnnc(SC(C)C)n12

Procedure:
The general procedure of Example 32 is repeated but replacing the 8-methyl-imidazo[1,5-d]-as-triazine-4(3H)-thione and methyl iodide employed in that example with 6-n-propyl-8-methyl-imidazo[1,5-d]-as-triazine-4(3H)-thione and isopropyl iodide.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:12][CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][C:15]3=[O:19])[CH:7]=[N:6][C:5]=2[S:4][C:3]=1[C:20]([O:22]C)=[O:21].O[Li].O>C1COCC1.CO.O>[CH3:1][C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:12][CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][C:15]3=[O:19])[CH:7]=[N:6][C:5]=2[S:4][C:3]=1[C:20]([OH:22])=[O:21]
Reactant: COC(=O)c1sc2ncn(CCN3CCCC3=O)c(=O)c2c1C
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1c(C(=O)O)sc2ncn(CCN3CCCC3=O)c(=O)c12
Temperature: 25 °C
Yield: 60.2 %

Procedure:
Methyl 5-methyl-4-oxo-3-(2-(2-oxopyrrolidin-1-yl)ethyl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate (0.5 g, 1.5 mmol) was dissolved in a mixture of THF-MeOH—H2O (10 mL-3 mL-3 mL) followed by the addition of LiOH—H2O (0.250 g). The mixture was stirred at RT over night. The solvent evaporated and the residue was dissolved in 4 mL of water and then acidified with 2N HCl to pH˜3. The solid was filtered off, dried to gave 0.290 g of 5-methyl-4-oxo-3-(2-(2-oxopyrrolidin-1-yl)ethyl)-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid, in 60% yield.