Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][CH:10]2[CH2:12][O:11]2)=[CH:6][CH:5]=1)[CH3:2].[Cl:15][C:16]1[CH:32]=[CH:31][CH:30]=[CH:29][C:17]=1[CH2:18][N:19]1[C:23]([CH3:24])=[C:22]([CH2:25][NH:26][CH3:27])[C:21]([CH3:28])=[N:20]1.O1CC1>CO>[Cl:15][C:16]1[CH:32]=[CH:31][CH:30]=[CH:29][C:17]=1[CH2:18][N:19]1[C:23]([CH3:24])=[C:22]([CH2:25][N:26]([CH3:27])[CH2:12][CH:10]([OH:11])[CH2:9][O:8][C:7]2[CH:13]=[CH:14][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=2)[C:21]([CH3:28])=[N:20]1
Reactant: CCOc1ccc(OCC2CO2)cc1
Reactant: CNCc1c(C)nn(Cc2ccccc2Cl)c1C
Solvent: CO
Solvent: C1CO1
Product: CCOc1ccc(OCC(O)CN(C)Cc2c(C)nn(Cc3ccccc3Cl)c2C)cc1
Temperature: 68 °C
Yield: 61.4 %

Procedure:
2-((4-Ethoxyphenoxy)methyl)oxirane (0.06 g, 0.32 mmol) and 1-(1-(2-chlorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-N-methylmethanamine (0.10 g, 0.38 mmol) were dissolved in methanol (0.32 ml), warmed to 68° C. and stirred until the oxirane was consumed as observed by TLC. The solution was cooled to room temperature and the solvent removed under reduced pressure. The resulting oil was purified using flash column chromatography with 1:2:0.01 ethyl acetate:hexanes:triethylamine as the eluting solvent to yield 0.09 g (63%) of 1-(((1-(2-chlorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)methyl)(methyl)amino)-3-(4-ethoxyphenoxy)propan-2-ol as a clear liquid. 1H NMR (500 MHz, CDCl3) δ 7.35 (dd, J=7.8, 1.2, 1H), 7.17 (td, J=7.7, 1.3, 1H), 7.12 (td, J=7.5, 1.2, 1H), 6.85-6.79 (m, 4H), 6.48 (dd, J=7.6, 0.9, 1H), 5.28 (s, 2H), 4.12-4.04 (m, 1H), 3.97 (q, J=7.0, 2H), 3.90 (d, J=4.9, 2H), 3.47 (d, J=13.2, 1H), 3.34-3.29 (m, 1H), 2.60 (dd, J=12.2, 9.7, 1H), 2.48 (dq, J=12.2, 3.9, 1H), 2.26 (s, 3H), 2.24 (s, 3H), 2.11 (s, 3H), 1.38 (t, J=9.1, 3H). 13C NMR (75 MHz, CDCl3) δ 153.47, 153.04, 148.04, 138.67, 135.31, 131.92, 129.43, 128.79, 127.58, 127.50, 115.63, 115.63, 115.53, 115.53, 113.71, 71.25, 66.37, 64.14, 59.51, 51.70, 50.28, 42.09, 15.13, 12.36, 9.82. HRMS (m/z): [MNa]+ calc for C25H32ClN3O3Na+, 480.20. found 480.2030.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][OH:8])(=[O:4])[CH:2]=[CH2:3].C(N(C(C)C)CC)(C)C.[S:18](Cl)([C:21]1[C:33]2[CH:32]=[CH:31][CH:30]=[C:26]([N:27]([CH3:29])[CH3:28])[C:25]=2[CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19]>C(Cl)Cl>[C:1]([O:5][CH2:6][CH2:7][O:8][S:18]([C:21]1[C:33]2[C:25](=[C:26]([N:27]([CH3:29])[CH3:28])[CH:30]=[CH:31][CH:32]=2)[CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])(=[O:4])[CH:2]=[CH2:3]
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: C=CC(=O)OCCO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)OCCOS(=O)(=O)c1cccc2c(N(C)C)cccc12
Yield: 56.5 %

Procedure:
To a solution of 2-hydroxyethyl acrylate (25.8 mg, 0.2 mmol) in 2 ml of freshly distilled CH2Cl2 was added diisopropylethylamine (DIPEA, 0.35 ml, 0.2 mmol) dropwise at 0° C. Dansyl chloride (50.0 mg, 0.19 mmol) was then added dropwise, and the resultant mixture was stirred at room temperature until TLC indicated the disappearance of starting material. The reaction was quenched with a 5% solution of NH4Cl and extracted (3×20 ml) with CH2Cl2. The combined organic layers were dried over anhydrous MgSO4 and purified with column chromatography on silica gel (1:4, EtOAc:hexanes) to give 37.5 mg (56%) of 2-(5-dimethylamino-naphthalene-1-sulfonyloxy)-ethyl acrylate as a yellow semi solid. 1H NMR (250 MHz) δ 8.61 (d, J=8.6 Hz, 1H), 8.26 (t, J=6.3 Hz, 2H), 7.56 (m, 2H), 7.20 (d, J=7.7 Hz, 1H), 6.19 (dd, J=16.5, 2.5 Hz, 1H), 5.80 (dd, J=16.5, 10.3 Hz, 1H), 5.71 (dd, J=16.5, 10.3 Hz, 1H), 4.25 (m, 4H), 2.88 (s, 6H). 13C NMR (63 MHz) δ 158.0, 151.7, 131.8, 131.5, 130.9, 130.6, 129.8, 128.8, 127.3, 123.0, 119.4, 115.6, 67.8, 61.5, 45.4.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([Cl:22])[CH:17]=2)=[C:6]([CH:14]=1)[C:7]([N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[O:8].[N:23]1[CH:28]=[C:27](B(O)O)[CH:26]=[N:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.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:22][C:18]1[CH:17]=[C:16]([O:15][C:5]2[CH:4]=[CH:3][C:2]([C:27]3[CH:28]=[N:23][CH:24]=[N:25][CH:26]=3)=[CH:14][C:6]=2[C:7]([N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[O:8])[CH:21]=[CH:20][N:19]=1
Reactant: OB(O)c1cncnc1
Reactant: CCN(CC)C(=O)c1cc(Br)ccc1Oc1ccnc(Cl)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: O
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1cc(-c2cncnc2)ccc1Oc1ccnc(Cl)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A resealable tube was charged with a mixture of 5-bromo-2-(2-chloropyridin-4-yloxy)-N,N-diethylbenzamide (2.500 g, 6.52 mmol), pyrimidin-5-ylboronic acid (2.018 g, 16.29 mmol), and potassium carbonate (4.50 g, 32.6 mmol) in THF (40.0 mL) and water (10.0 mL). Tetrakis(triphenylphosphine)palladium(0) (0.376 g, 0.326 mmol) was added, the system was purged with argon, and the tube was sealed. The reaction mixture was stirred at 100° C. for 4.0 h. The reaction mixture was partitioned between EtOAc and water. The aqueous phase was separated and extracted with EtOAc. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a brown solid. This material was purified via column chromatography on silica gel (RediSep 120 g column, gradient elution with 50-100% ethyl acetate-hexane) to afford 2-(2-chloropyridin-4-yloxy)-N,N-diethyl-5-(pyrimidin-5-yl)benzamide as an off-white solid. MS m/z=383.2 [M+H]+. Calcd for C20H19ClN4O2: 382.1.
Reaction SMILES: [CH2:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH2:4][CH2:3][CH:2]1[NH2:14].[C:15](Cl)(=[O:18])[CH2:16][CH3:17].C(N(CC)CC)C>O1CCCC1>[CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:14][C:15](=[O:18])[CH2:16][CH3:17]
Reactant: NC1CCc2oc3ccccc3c2C1
Reactant: CCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(=O)Nc1ccc2oc3c(c2c1)CCCC3
Yield: 18.9 %

Procedure:
Following the procedure of Example 1, tetrahydro-dibenzofuran-2-ylamine (0.94 g, 5.0 mmol), propionyl chloride (0.47 mL, 5.3mmol), and triethylamine (2.1 mL, 15 mmol) in tetrahydrofuran (20 mL) provided N-(6,7,8,9-tetrahydro-dibenzofuran-2-yl)-propionamide (0.23 g). Mp 164-165° C.; Anal. Calcd. for C15H17NO2: C, 74.05; H, 7.04; N, 5.76; Found: C, 74.09; H, 7.09; N, 5.78.
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)=O.[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[CH2:22]2.N1CCCCC1>CCO>[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[C:22]2=[CH:1][C:3]1[O:7][C:6]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([NH2:17])(=[O:15])=[O:16])=[CH:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: NS(=O)(=O)c1ccc(-c2ccc(C=O)o2)cc1
Reactant: O=C1Cc2cc(Cl)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: NS(=O)(=O)c1ccc(-c2ccc(C=C3C(=O)Nc4ccc(Cl)cc43)o2)cc1
Temperature: 70 °C

Procedure:
To 4-(5-formylfuran-2-yl)benzenesulfonamide (30 mg, 0.120 mmol) in EtOH was added 5-chlorooxindole (20 mg, 0.120 mmol) and piperidine (12 μL, 0.120 mmol). The mixture was stirred at 70° C. for several hours. The solid formed was isolated by filtration and air dried to yield 4-(5-((5-chloro-2-oxoindolin-3-ylidene)methyl)furan-2-yl)benzenesulfonamide. LC-MS (M+1=401).
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]2[NH:7][C:6]3[C:13]([C:25]([O:27]C)=O)=[CH:14][C:15]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)=[N:16][C:5]=3[C:4]=2[CH:3]=1.[NH3:29]>CO>[Cl:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]2[NH:7][C:6]3[C:13]([C:25]([NH2:29])=[O:27])=[CH:14][C:15]([C:17]4[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=4)=[N:16][C:5]=3[C:4]=2[CH:3]=1
Reactant: N
Reactant: COC(=O)c1cc(-c2ccc(OC)cc2)nc2c1[nH]c1cc(OC)c(Cl)cc12
Solvent: CO
Product: COc1ccc(-c2cc(C(N)=O)c3[nH]c4cc(OC)c(Cl)cc4c3n2)cc1
Temperature: 80 °C

Procedure:
A suspension of methyl 8-chloro-7-methoxy-2-(4-methoxyphenyl)-5H-pyrido[3,2-b]indole-4-carboxylate (29 mg, 0.073 mmol) in a 7 N solution of ammonia in MeOH (7 mL) in a sealed microwave vial was heated at 80° C. for 24 hr. The solvents were removed and preparative HPLC (100×30 mm Luna C18 column, gradient elution with A:B=30:70 to A:B=0:100 [A=10 mM NH4OAc in 5% aqueous CH3CN; B=10 mM NH4OAc in 95% aqueous CH3CN] over 20 min) afforded 8-chloro-7-methoxy-2-(4-methoxyphenyl)-5H-pyrido[3,2-b]indole-4-carboxamide (16 mg) as a yellow solid. MS (ESI) m/z 380.1 (M+H). 1H NMR (MeOD) δ ppm 8.36 (1H, s), 8.13 (1H, s), 8.06 (2H, d, J=8.85 Hz), 7.31 (1H, s), 7.10 (2H, d, J=8.85 Hz), 4.03 (3H, s), 3.90 (3H, s).
Reaction SMILES: Br[C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22].C([Li])CCC.[CH2:33]([S:40]C#N)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O1CCCC1.CCCCCC>[CH2:33]([S:40][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: N#CSCc1ccccc1
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(Br)c1S(=O)(=O)C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(SCc2ccccc2)c1S(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.7 %

Procedure:
A solution of 5-bromo-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylsulphonylpyrazole (3.0 g) in dry tetrahydrofuran (32 ml), stirred under nitrogen at -78° C., was treated with a solution of n-butyllithium in hexane (2.8 ml of a 2.5M solution) over a period of 5 minutes. After 1 hour at -78° C., a solution of benzyl thiocyanate (0.95 g) in tetrahydrofuran (2 ml) was added. The stirred mixture was allowed to warm slowly to room temperature during 16 hours, then poured onto ice/water (50 ml) and extracted with ether (3×50 ml). The combined extracts were dried over anhydrous magnesium sulphate, evaporated in vacuo, and purified by chromatography, eluting with ethyl acetate/hexane (2:98). The product was triturated with hexane to give 5-benzylthio-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylsulphonylpyrazole (0.25 g), as a white solid, m.p. 117°-119° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12]([C:14]2[N:19]=[C:18]([NH:20][C@H:21]([CH3:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:17]([N+:27]([O-])=O)=[CH:16][CH:15]=2)=[C:11]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[N:10]=1.O.O.[Sn](Cl)Cl.[N:42]#[C:43]Br>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12]([C:14]2[N:19]=[C:18]3[N:20]([C@H:21]([CH3:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:43]([NH2:42])=[N:27][C:17]3=[CH:16][CH:15]=2)=[C:11]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[N:10]=1
Reactant: N#CBr
Reactant: C[C@@H](Nc1nc(-c2[nH]c(-c3c(F)cccc3F)nc2-c2ccc(F)cc2)ccc1[N+](=O)[O-])C(C)(C)C
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: C[C@@H](n1c(N)nc2ccc(-c3[nH]c(-c4c(F)cccc4F)nc3-c3ccc(F)cc3)nc21)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.1 %

Procedure:
Dissolve {6-[2-(2,6-difluoro-phenyl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-3-nitro-pyridin-2-yl}-(1(R),2,2-trimethyl-propyl)-amine (673 mg, 1.4 mmol) in 100% ethanol (15 mL) and add tin(II) dichloride dihydrate (1.5 g, 6.8 mmol, 5 equiv). Heat the reaction mixture until starting material is consumed. Cool the reaction solution to room temperature, quench slowly with saturated aqueous NaHCO3. Add Celite® to the quenched reaction and filter the suspension on a Celite® pad, washing with water and ethyl acetate. Separate the layers and wash the organic layer with saturated aqueous NaCl. Dry the organic layer with Na2SO4, filter, and concentrated under reduced pressure. Add 10% aqueous ethanol (14 mL) and cyanogen bromide (216 mg, 2.04 mmol, 1.5 equiv) to the residue and stir overnight. Quench with saturated aqueous NaHCO3 (20 mL). Add ethyl acetate and water to dissolve all solids. Wash the organic layer is with saturated aqueous NaCl, dry with Na2SO4, filter, and concentrate under reduced pressure. Subject the residue to medium pressure silica gel chromatography eluting with a gradient of 1.5-3% (2M ammonia in MeOH)/CH2Cl2 to provide 5-[2-(2,6-difluoro-phenyl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-3-(1(R),2,2-trimethyl-propyl)-3H-imidazo[4,5-b]pyridin-2-ylamine as a tan glass (289 mg, 43% yield).
Reaction SMILES: N[C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[C:3]([OH:5])=O.[CH:14]1([NH:21][C:22]([NH2:24])=[S:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH:14]1([NH:21][C:22]2[S:23][CH:2]([CH2:6][C:7]3[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=3)[C:3](=[O:5])[N:24]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: NC(=S)NC1CCCCCC1
Product: O=C1N=C(NC2CCCCCC2)SC1Cc1ccc(O)cc1

Procedure:
Synthesis was performed from (2S)-2-amino-3-(4-hydroxyphenyl)propanoic acid and N-cycloheptylthiourea according to Method E and C.
Reaction SMILES: [O:1]=[C:2]1CCC[C:8]2NC(=S)C(C#N)=C[C:3]1=2.[NH2:15][C:16]1[CH2:21][C:20]([CH3:23])([CH3:22])[CH2:19][C:18](=[O:24])[CH:17]=1.C(OCC)(=O)C#C>>[CH3:22][C:20]1([CH3:23])[CH2:21][C:16]2[NH:15][C:2](=[O:1])[CH:3]=[CH:8][C:17]=2[C:18](=[O:24])[CH2:19]1
Reactant: N#Cc1cc2c([nH]c1=S)CCCC2=O
Reactant: CC1(C)CC(=O)C=C(N)C1
Agent: C#CC(=O)OCC
Product: CC1(C)CC(=O)c2ccc(=O)[nH]c2C1
Yield: 78.5 %

Procedure:
In analogy to (Pettit, G. R.; Fleming, W. C.; Paull, K. D. J. Org. Chem. 1968, 33 (3) 1089-1092), 3-amino-5,5-dimethylcyclohex-2-en-1-one was reacted with ethyl propio-late to give the title compound as a light brown solid in 78.5% yield.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][OH:7])=[CH:2]1.[H-].[Na+].[Cl:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13](Cl)[N:12]=1>O1CCCC1>[Cl:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([O:7][CH2:6][C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[N:12]=1
Reactant: Cc1cc(Cl)nc(Cl)c1
Reactant: OCc1ccsc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Cl)nc(OCc2ccsc2)c1

Procedure:
To a solution containing 3-thiophenemethanol (0.78 g, 0.0062×1.1 mol) and sodium hydride (0.26 g, (ca.60% in mineral oil), 0.0062×1.05 mol) in tetrahydrofuran, 2,6-dichloro-4-methylpyridine (1.0 g, 0.0062 mol) was added, and the resultant solution was refluxed for about 1 hour.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH2:13]([O:20][C:21]1[C:22](=[O:30])[N:23]([CH3:29])[C:24]([CH2:27][OH:28])=[N:25][CH:26]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O[N:32]1[C:36](=[O:37])[C:35]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:34]2[C:33]1=[O:42].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CC(N(C)C)=O>[CH2:13]([O:20][C:21]1[C:22](=[O:30])[N:23]([CH3:29])[C:24]([CH2:27][O:28][N:32]2[C:33](=[O:42])[C:34]3=[CH:41][CH:40]=[CH:39][CH:38]=[C:35]3[C:36]2=[O:37])=[N:25][CH:26]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cn1c(CO)ncc(OCc2ccccc2)c1=O
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Product: Cn1c(CON2C(=O)c3ccccc3C2=O)ncc(OCc2ccccc2)c1=O
Temperature: 0 °C
Reaction time: 16 h
Yield: 93.7 %

Procedure:
Diethyl azodicarboxylate (4.8 g) (20 mmol) are added dropwise at 0° C. while stirring to a mixture of 3.69 g (15 mmol) of 5-(benzyloxy)-2-(hydroxymethyl)-3-methyl-4(3H)-pyrimidinone, 3.26 g (20 mmol) of N-hydroxyphthalimide and 5.24 g (20 mmol) of triphenylphosphine in 100 ml of absolute dimethylacetamide. The mixture is stirred at 0° C. for 2 hours and at room temperature for 16 hours. Subsequently, the solvent is removed in a high vacuum at room temperature. The residue is crystallized from ethanol/diethyl ether. After drying in a high vacuum for 18 hours at room temperature there are obtained 5.5 g of N-[[5-(benzyloxy)-3,4-dihydro-3-methyl-4-oxo-2-pyrimidinyl]methoxy]phthalimide as white crystals of m.p. 170° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][C:21]=2[F:22])[N:18]([CH3:23])[C:17](=[O:24])[CH2:16][CH2:15]3)[CH:9]=[N:10][CH:11]=1.[CH3:25][C:26]1[C:30]([C:31](O)=[O:32])=[C:29]([CH3:34])[O:28][N:27]=1>>[F:22][C:21]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][C:17](=[O:24])[N:18]2[CH3:23])=[CH:13][C:12]=1[C:8]1[CH:7]=[C:6]([O:5][CH2:4][CH2:3][NH:2][C:31]([C:30]2[C:26]([CH3:25])=[N:27][O:28][C:29]=2[CH3:34])=[O:32])[CH:11]=[N:10][CH:9]=1
Reactant: Cc1noc(C)c1C(=O)O
Reactant: CN1C(=O)CCc2cc(-c3cncc(OCCN)c3)c(F)cc21
Agent: Cl
Product: Cc1noc(C)c1C(=O)NCCOc1cncc(-c2cc3c(cc2F)N(C)C(=O)CC3)c1

Procedure:
In analogy to the procedure described for the preparation of example 219, 6-[5-(2-amino-ethoxy)-pyridin-3-yl]-7-fluoro-1-methyl-3,4-dihydro-1H-quinolin-2-one hydrochloride (example 238) has been coupled with 3,5-dimethyl-isoxazole-4-carboxylic acid to give the title compound as a colorless solid. MS: 439.4 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=[C:15](Br)Br)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH2:23]([Sn:27](Cl)([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH3:26].C(OCC)(=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][Sn:27]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N1CCC(C=C(Br)Br)CC1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC[Sn](C#CC1CCN(C(=O)OC(C)(C)C)CC1)(CCCC)CCCC
Reaction time: 1 h
Yield: 86.6 %

Procedure:
A mixture of 23.199 g (62.85 mmole) 1-(t-butoxycarbonyl)-4-(2,2-dibromoethen-1-yl)piperidine (prepared as in Step B3 above) and 600 mL anhydrous THF was cooled with dry ice acetone bath under nitrogen. To this mixture was added 88 mL of a 1.6 M butyl lithium solution in hexanes dropwise with stirring and cooling over 50 minutes. After one hour, the flask was transferred into an ice bath. After another hour, a solution of 28.64 g (87.99 mmole) tributyltin chloride in 100 mL THF was added with stirring and cooling over 35 minutes. After three h, the mixture was concentrated under vacuum to remove some THF, and the residue was partitioned between 600 mL ice water and 800 mL ether. The organic layer was washed with 200 mL of water (1×), 2% sodium bicarbonate (1×), water (2×), and saturated brine (1×), dried over sodium sulfate and concentrated under vacuum to give 30.104 g crude product as a green-yellowish liquid. FC on 275 g silica gel using cold 2.5˜15% ethyl acetate in hexanes as quickly as possible to give 27.115 g title compound as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]O)=[CH:4][CH:3]=1.CN(C)C(=O)C.S(Cl)([Cl:19])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][Cl:19])=[CH:4][CH:3]=1
Reactant: OCCc1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Product: ClCCc1ccc(Cl)cc1
Temperature: 67.5 °C
Reaction time: 2 h

Procedure:
Into a 250-mL round-bottom flask equipped with magnetic stirring, a thermocouple, a condenser, and a nitrogen bubbler vented to caustic scrubber, was charged 2-(4-chlorophenyl)ethanol (25.011 g, 160 mmol), N,N-dimethylacetamide (0.748 mL, 7.99 mmol), and toluene (73 mL). The mixture was heated to 65 to 70° C. and then thionyl chloride (12.24 mL, 168 mmol) was added over 1 h. The reaction was stirred at 60 to 68° C. for 2 h to give a dark-brown solution. This solution was cooled to 45° C., washed with water (2×27 mL) and saturated aqueous sodium bicarbonate (3×27 mL) at 40 to 45° C., and then cooled room temperature and allowed to stir overnight.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:28]([NH2:30])=[O:29])[CH:17]=[C:18]([C:21]4[CH:25]=[C:24]([CH:26]=O)[S:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH3:31][NH:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O.C(O)(=O)C>[NH2:30][C:28]([C:16]1[CH:17]=[C:18]([C:21]2[CH:25]=[C:24]([CH2:26][N:32]([CH3:31])[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[S:23][CH:22]=2)[CH:19]=[C:20]2[C:15]=1[NH:14][CH:13]=[C:12]2[CH:9]1[CH2:10][CH2:11][N:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH2:7][CH2:8]1)=[O:29]
Reactant: CCOC(=O)CNC
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(C=O)c4)cc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)CN(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Reaction time: 8 h
Yield: 30.2 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1H-indole-7-carboxamide (45 mg, 100 μmol) in dimethyl sulfoxide (1.0 mL) was added ethyl N-methylglycinate (320 μmol) and 2 to 3 drops of glacial acetic acid. The resulting mixture is agitated overnight. After 18 h, sodium triacetoxyborohydride (200 mg, 1000 μmol) is added. This mixture is agitated for 1.5 h followed by purification by Gilson Preparatory HPLC to give 16.5 mg of the title compound (30.0%).
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)=[N+:2]=[N-:3].C([O-])([O-])=[O:15].[K+].[K+].OO>CO.O>[N:1]([CH2:4][CH2:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]([NH2:11])=[O:15])=[CH:8][CH:7]=1)=[N+:2]=[N-:3]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(CCN=[N+]=[N-])cc1
Agent: OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: [N-]=[N+]=NCCc1ccc(C(N)=O)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 95.9 %

Procedure:
To a solution of 4-(2-azidoethyl)benzonitrile (1.0 g, 5.81 mmol) in a 5:1 mixture of MeOH/H2O (100 mL), K2CO3 (4.41 g. 31.94 mmol) was added and the resulting solution cooled to 0° C. Then 15.4 mL of a 30% H2O2 solution was added and the reaction was allowed to warm to room temperature. After stirring at room temperature for approximately three hours, the crude reaction mixture was concentrated under reduced pressure to remove MeOH and then extracted with EtOAc (3×100 mL). Combined organics were dried over sodium sulfate, filtered, and concentrated in vacua. Crude product was subjected to silica gel purification eluting with 1% MeOH in CH2Cl2 to give 1.06 g (96%) of 4-(2-azidoethyl)benzamide.
Reaction SMILES: [S:1](=[O:4])(=[O:3])=[O:2].[C:5]1(=[O:11])[O:10][C:8](=[O:9])[CH:7]=[CH:6]1>>[S:1]([C:7]1[C:8]([O:10][C:5](=[O:11])[CH:6]=1)=[O:9])([OH:4])(=[O:3])=[O:2]
Reactant: O=C1C=CC(=O)O1
Reactant: O=S(=O)=O
Product: O=C1C=C(S(=O)(=O)O)C(=O)O1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
The reagent was prepared using the sulfonation procedure of U.S. Pat. No. 3,987,043 (cited previously). Liquid sulfur trioxide (100 mole %) was added slowly to the agitated maleic anhydride powder while heating to maintain the temperature at 60° C. After the exothermic reaction was complete, the reaction temperature was raised to 100°-110° C. and the mixture was held for 3 hours. After cooling to room temperature, the viscous dark brown oil crystallized to solid sulfomaleic anhydride.