Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([CH3:12])(=[O:11])=[O:10].[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]([NH2:23])[CH3:22])[CH:17]=[C:18]([Cl:20])[CH:19]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]([NH:23][C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=2[S:9]([CH3:12])(=[O:11])=[O:10])[CH3:22])[CH:17]=[C:18]([Cl:20])[CH:19]=1
Reactant: CS(=O)(=O)c1ccc(F)cc1F
Reactant: CC(N)c1cc(Cl)cc(Cl)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1cc(F)ccc1S(C)(=O)=O)c1cc(Cl)cc(Cl)c1
Yield: 9 %

Procedure:
2,4-Difluoro-1-(methylsulfonyl)benzene (3.13 mmol), 1-(3,5-dichlorophenyl)ethanamine (3.13 mmol) and N,N-diisopropylethylamine (6.3 mmol) were stirred at 45° C. in dry acetonitrile (25 mL) for 16 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and purified by silica chromatography in 20% ethyl acetate in hexanes to collect the title compound (9% yield). 1H NMR (400 MHz, CDCl3): δ 9.23 (s, 1H), 7.87 (t, 1H), 7.28 (s, 1H), 7.19 (s, 2H), 6.41 (t, 1H), 6.11 (d, 1H), 4.51 (m, 1H), 1.62 (d, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([OH:17])=O)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH:21]1([NH2:25])[CH2:24][CH2:23][CH2:22]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:25][CH:21]3[CH2:24][CH2:23][CH2:22]3)=[O:17])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2ccc(-c3cccc(C(=O)O)c3)nc12
Reactant: NC1CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1ncnc2ccc(-c3cccc(C(=O)NC4CCC4)c3)nc12

Procedure:
Following the same reaction and purification procedure, the acid 14 (90 mg, 0.34 mmol) was reacted with cyclobutanamine (CAS-2516-34-9) (48 mg, 0.68 mmol), HATU (146 mg, 0.38 mmol) and DIPEA (0.3 mL, 1.7 mmol) in DMF (1 mL) at room temperature to provide 3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-N-cyclobutylbenzamide 19. LC/MS (ESI+): m/z 320 (M+H). 1H NMR (400 MHz, DMSO) δ 8.76 (d, J=7.4 Hz, 1H), 8.70 (s, 1H), 8.59 (t, J=12.2 Hz, 1H), 8.51 (d, J=8.9 Hz, 1H), 8.43 (s, 1H), 8.19 (d, J=8.8 Hz, 1H), 8.06 (d, J=33.2 Hz, 1H), 7.95 (d, J=7.8 Hz, 1H), 7.63 (t, J=7.8 Hz, 1H), 4.48 (dq, J=16.3, 8.2 Hz, 1H), 2.37-2.22 (m, 2H), 2.22-1.99 (m, 2H), 1.79-1.60 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([CH3:12])[CH:3]=1.[NH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(N(CC)C(C)C)(C)C>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)(=[O:10])=[O:9])=[C:4]([CH3:12])[CH:3]=1
Reactant: Cc1cc(Br)ccc1S(=O)(=O)Cl
Reactant: NCCN1CCOCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Br)ccc1S(=O)(=O)NCCN1CCOCC1
Temperature: 40 °C
Reaction time: 18 h
Yield: 99.4 %

Procedure:
A mixture of 4-bromo-2-methylbenzene sulfonyl chloride (700 mg, 2.6 mmol), 4-(2-aminoethyl)morpholine (372 mg, 2.86 mmol, 1.1 eq), and N,N-diisopropylethylamine (1.0 mL, 5.71 mmol, 2.2 eq) in anhydrous tetrahydrofuran (13 mL, 0.2 M) was stirred at 40° C. under nitrogen for 18 h. Solvent was removed at reduced pressure and the residue was partitioned between EtOAc and water. The organic phase was washed with water and brine, dried over Na2SO4, and concentrated at reduced pressure. The residue was purified by MPLC (eluting with 50% to 75% EtOAc/hexane) to give 939 mg (99%) of the desired product as a white solid. 1H-NMR (DMSO-d6) δ 7.73 (d, J=8.4 Hz, 1H), 7.68 (broad s, 1H), 7.65 (dd, J=2.1, 0.6 Hz, 1H), 7.55 (ddd, J=7.3, 2.1, 0.6 Hz, 1H), 3.41 (t, J=4.5 Hz, 4H), 2.88 (t, J=6.3 Hz, 2H), 2.56 (s, 3H), 2.19 (t,=6.6 Hz, 2H), 2.16 to 2.12 (m, 4H); MS LC-MS [M+H]+=363 & 365, RT=1.90 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[NH2:14])[CH3:2].N1C=CC=CC=1.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.Cl>ClCCl>[CH2:1]([O:3][C:4](=[O:15])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[NH:14][S:28]([C:25]1[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=1)(=[O:30])=[O:29])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)C=Cc1ccc(Cl)cc1N
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C=Cc1ccc(Cl)cc1NS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.4 %

Procedure:
To 3-(2-amino-4-chloro-phenyl)-acrylic acid ethyl ester (18.0g, 79.8 mmol) in dichloromethane (144 ml) was added pyridine (9.04 ml, 112 mmol) and p-toluenesulfonyl chloride (16.0g, 83.9 mmol). The reaction was stirred at room temperature for 18 hours and poured into 1N hydrochloric acid (150 ml). The layers were separated and the organic layer was dried over magnesium sulfate, filtered, and concentrated. The resulting solid was slurried in hexanes and filtered to afford 3-[4-chloro-2-(toluene-4-sulfonylamino)-phenyl]-acrylic acid ethyl ester (28.3g, 93%). mp=124-127° C. 1H NMR (300 MHz, CDCl3) d 1.35 (t, 3, J=7.2), 2.40 (s, 3), 4.27 (q, 2, J=7.2), 6.12 (dd, 1, J=15.9, 0.9), 7.20-7.39 (m, 4), 7.39 (d, 1, J=8.6), 7.48-7.53 (m, 2), 7.62 (d, 2, J=8.3). 13C NMR (75 MHz, CDCl3) d 15.50, 22.79, 62.24, 122.48, 127.98, 128.49, 129.34, 129.50, 131.05, 136.82, 137.00, 137.73, 138.93, 145.55, 167.59. IR 3214, 1694, 1631, 1318, 1167 cm−1. Analysis calculated for C18H18ClNO4S: C, 56.91; H, 4.78; N, 3.69. Found: C, 57.10; H, 5.08; N, 3.70.
Reaction SMILES: [Br:1]CC(C1C=C2C(=CC=1)C(=O)OCC2)=O.C(N1CCN[C@H](CO)C1)(OC(C)(C)C)=O.[CH:31]([N:34]([CH:37]([CH3:39])[CH3:38])[CH2:35][CH3:36])([CH3:33])[CH3:32]>C1COCC1>[BrH:1].[CH3:36][CH2:35][N:34]([CH:37]([CH3:39])[CH3:38])[CH:31]([CH3:33])[CH3:32]
Reactant: O=C(CBr)c1ccc2c(c1)CCOC2=O
Agent: CC(C)(C)OC(=O)N1CCN[C@H](CO)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Br
Temperature: 25 °C
Reaction time: 14 h

Procedure:
6-(Bromoacetyl)-3,4-dihydro-1H-isochromen-1-one (˜1.54 g, ˜5.72 mmol, presence of α-chloroketone was noted, ˜10%) and commercially available (S)-4-N—BOC-2-hydroxymethylpiperazine (1.24 g, 5.72 mmol) were added to a round bottom flask and diluted with THF (50 mL). Diisopropylethylamine (1.30 mL, 7.44 mmol) was then introduced and the mixture left stirring for 14 h at RT during which time a considerable amount of solid had formed (presumably HBr salt of DIPEA). The reaction mixture was diluted with EtOAc, then washed with saturated NH4Claq followed by H2O. Both aqueous layers were sequentially back extracted once with another portion of EtOAc, the organics were then combined, dried with MgSO4, filtered, and concentrated in vacuo. The recovered crude product was subjected to purification by flash chromatography (Biotage, 50% EtOAc/Hex) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([CH3:27])([CH3:26])[C:22]([O:24]C)=[O:23])=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH2:28][CH3:29])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.O[Li].O.Cl>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([CH3:26])([CH3:27])[C:22]([OH:24])=[O:23])=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH2:28][CH3:29])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCc1cc(Nc2ccc(C(C)(C)C(=O)OC)cc2)nc(-c2cccc(Cl)c2)n1
Agent: Cl
Agent: [Li]O
Solvent: C1COCCO1
Solvent: O
Product: CCc1cc(Nc2ccc(C(C)(C)C(=O)O)cc2)nc(-c2cccc(Cl)c2)n1
Temperature: 50 °C
Reaction time: 16 h
Yield: 175.8 %

Procedure:
To a solution of methyl 2-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)amino)phenyl)-2-methylpropanoate (0.100 g, 0.24 mmol) in dioxane (9 mL) and water (6 mL) was added LiOH.H2O (0.031 g, 0.73 mmol) and the reaction mixture stirred under a nitrogen atmosphere at 50° C. for 16 h. After this time, the reaction mixture was cooled and treated with 1M HCl to pH 3.0 and concentrated to afford the title compound (0.167 g, 100%) as a yellow oil. MW=395.88. 1H NMR (CDCl3, 300 MHz) δ 9.79 (s, 1H), 8.86 (s, 1H), 8.44-8.39 (m, 1H), 8.33-8.26 (m, 1H), 7.43-7.40 (m, 1H), 7.40-7.35 (m, 4H), 6.77 (s, 1H), 6.52 (s, 1H), 2.89 (q, J=7.6 Hz, 2H), 2.42-2.38 (m, 3H), 2.08-2.00 (m, 3H), 1.65-1.57 (m, 3H); APCI MS m/z 396 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:20]3[CH2:21][CH:22]([C:24]([O:26]CC)=O)[CH2:23][CH:12]2[CH2:13][C:14]2([CH2:19]3)[O:18][CH2:17][CH2:16][O:15]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:29][CH2:30][Mg+].[Br-]>CCOCC.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH:12]3[CH2:23][CH:22]([C:24]4([OH:26])[CH2:30][CH2:29]4)[CH2:21][CH:20]2[CH2:19][C:14]2([CH2:13]3)[O:15][CH2:16][CH2:17][O:18]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CC2CC3(CC(C1)N2S(=O)(=O)c1ccc(Cl)cc1)OCCO3
Reactant: CC[Mg+]
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=S(=O)(c1ccc(Cl)cc1)N1C2CC(C3(O)CC3)CC1CC1(C2)OCCO1
Temperature: -78 °C
Reaction time: 18 h

Procedure:
Ethyl 9-[(4-chlorophenyl)sulfonyl]spiro[9-azabicyclo[3.3.1]nonane-3,2′-[1,3]dioxolane]-7-carboxylate (50) (395 mg, 0.918 mmol) was dissolved in Et2O (2 mL) and the resulting solution was cooled to −78° C. Ti(O-i-Pr)4 was added followed by EtMgBr dropwise over 10 minutes. The reaction mixture was warmed to room temperature and stirred for 18 h. The resulting solution was diluted with EtOAc and washed with saturated aqueous NH4Cl. The organic phase was dried (Na2SO4), filtered, and concentrated to give 1-{9-[(4-chlorophenyl)sulfonyl]spiro[9-azabicyclo[3.3.1]nonane-3,2′-[1,3]dioxolan]-7-yl}cyclopropanol (55). MS (ESI) 414.1 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:11]1[S:15][C:14]([C:16]2[CH2:20][C:19]([C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=3)([C:21]([F:24])([F:23])[F:22])[O:18][N:17]=2)=[CH:13][C:12]=1[CH3:33].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:32][C:27]1[CH:26]=[C:25]([C:19]2([C:21]([F:22])([F:24])[F:23])[O:18][N:17]=[C:16]([C:14]3[S:15][C:11]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)=[C:12]([CH3:33])[CH:13]=3)[CH2:20]2)[CH:30]=[C:29]([Cl:31])[CH:28]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)sc1Br
Reactant: OB(O)c1ccncc1
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: C1CCOC1
Solvent: O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)sc1-c1ccncc1
Reaction time: 22 h
Yield: 40.2 %

Procedure:
Pyridine-4-boronic acid (30 mg) is added to a solution of 3-(5-bromo-4-methyl-thiophen-2-yl)-5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole (100 mg), K2CO3 (90 mg) and Pd(PPh3)4 (20 mg) in a mixture of THF and water (0.4 ml, 9:1). After 22 hours at 70° C., the reaction is quenched with water and extracted three times with ethyl acetate. The organic phases are combined, dried over MgSO4 and concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield 4-{5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophen-2-yl}-pyridine (40 mg) as a colorless oil. MS (HPLC/MS): 457 (MH+). Retention time: 5.20 min.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=[O:22])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([F:20])[C:13]=1F)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.FC1C(F)=C(F)C(F)=CC=1C(CC(OCC)=O)=O.[NH2:41][C:42]1[C:47]([F:48])=[CH:46][C:45]([F:49])=[C:44]([NH:50][C:51]([CH3:54])([CH3:53])[CH3:52])[N:43]=1.NC(=C)C([O-])=O>C(Cl)(Cl)Cl>[C:51]([NH:50][C:44]1[N:43]=[C:42]([N:41]2[C:13]3[C:12](=[CH:17][C:16]([F:18])=[C:15]([F:19])[C:14]=3[F:20])[C:11](=[O:22])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4]2)[C:47]([F:48])=[CH:46][C:45]=1[F:49])([CH3:54])([CH3:52])[CH3:53]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(F)c1F
Reactant: CC(C)(C)Nc1nc(N)c(F)cc1F
Agent: C=C(N)C(=O)[O-]
Agent: CCOC(=O)CC(=O)c1cc(F)c(F)c(F)c1F
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(-c2nc(NC(C)(C)C)c(F)cc2F)c2c(F)c(F)c(F)cc2c1=O
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
To 1 ml chloroform solution of ethyl 3-ethoxy-2-(2,3,4,5-tetrafluorobenzoyl)acrylate prepared from 0.27 g of ethyl 2,3,4,5-tetrafluorobenzoylacetate by normal process was added 2-amino-6-(t-butylamino)-3,5-difluoropyridine until completion of the conversion into the aminoacrylate form was confirmed by monitoring the reaction by TLC. The solution was concentrated under reduced pressure. To the residue were added 0.6 g of anhydrous potassium carbonate and 1 ml of N,N-dimethylformamide, and the mixture was stirred at 90° C. for 15 minutes and allowed to cool. The solution was separated by adding 30 ml of chloroform and 300 ml of distilled water, and the chloroform layer was washed twice with 300 ml of distilled water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and allowed to stand. The precipitate was collected by filtration, washed with ethanol and diisopropylether successively to obtain 0.15 g of the title compound as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:5].ClOC(C)(C)C.[CH3:23][S:24][CH2:25][C:26](OCC)=[O:27].C(N(CC)CC)C>C(Cl)Cl>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([C:4]([C:3]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:2]=2[NH:1][C:26](=[O:27])[CH:25]3[S:24][CH3:23])=[O:5])=[CH:7][CH:8]=1
Reactant: CCOC(=O)CSC
Reactant: Nc1ccccc1C(=O)c1ccc(Cl)cc1
Agent: CC(C)(C)OCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSC1C(=O)Nc2c(C(=O)c3ccc(Cl)cc3)cccc21
Temperature: -65 °C
Reaction time: 0.25 h
Yield: 33 %

Procedure:
A solution of 23.1 g. (0.1 mole) of 2-amino-4'-chlorobenzophenone in 400 ml. of methylene chloride was cooled to -65° C. and treated dropwise with 12.4 g. (0.1 mole) of t-butyl hypochlorite. After 15 min., 13.4 g. of ethyl α-(methylthio)-acetate (0.1 mole) was added dropwise maintaining -65° C. temperature. After 11/2 hr. 10.1 g. of triethylamine (0.1 mole) was added and the reaction mixture allowed to come to room temperature. The solution was then washed with water and stripped. The residue was taken into methanol and brought to reflux at which time 1 N hydrochloric acid was added and the resulting mixture refluxed overnight. The mixture was cooled, resulting precipitate filtered off and recrystallized from toluene, giving 10 g. of a cream colored solid. The product (33% yield) melted at 186°-188° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][C:9]2[N:10]=[CH:11][N:12]=[C:13](Cl)[C:8]=2[CH2:7]1)=[O:5])[CH3:2].[OH:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]=[CH:28]2.C1CCN2C(=NCCC2)CC1>CC#N>[CH2:1]([O:3][C:4]([CH:6]1[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][C:9]2[N:10]=[CH:11][N:12]=[C:13]([O:24][C:25]3[CH:26]=[C:27]4[C:31](=[CH:32][CH:33]=3)[NH:30][CH:29]=[CH:28]4)[C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1Cc2c(Cl)ncnc2CN1C(=O)OC(C)(C)C
Reactant: Oc1ccc2[nH]ccc2c1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C1Cc2c(ncnc2Oc2ccc3[nH]ccc3c2)CN1C(=O)OC(C)(C)C
Temperature: 60 °C

Procedure:
To a solution of 4-chloro-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-6,7-dicarboxylic acid 7-tert-butyl ester 6-ethyl ester (1 g, 2.93 mmol) in CH3CN (30 mL), 5-hydroxy-indole (0.779 g, 5.85 mmol) and DBU (0.88 mL, 5.85 mmol) are added. After heating at 60° C. for 5 h the reaction is evaporated and the product isolated using FCC eluting with heptane:EtOAc 1:1. MS (ESI) m/z 439.1 (M+1).
Reaction SMILES: [OH-].[K+].[SH2:3].[CH2:4]([O:6][C:7](=[O:20])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:9]([CH2:13]Cl)/[CH:10]=[CH:11]/Cl)[CH3:5]>C(O)C.O>[S:3]1[CH:11]=[CH:10][C:9]([CH:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7]([O:6][CH2:4][CH3:5])=[O:20])=[CH:13]1
Reactant: S
Reactant: CCOC(=O)C(C(=O)OCC)=C(/C=C/Cl)CCl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(C(=O)OCC)c1ccsc1
Reaction time: 1 h
Yield: 78 %

Procedure:
Potassium hydroxide (0.14 g, 2.0 mmol) in ethanol (50 ml) was saturated with hydrogen sulphide at 0° for one hour. To this was added 4-trans ethyl-2-ethoxycarbonyl-5-chloro-3-chloromethylpenta-2,4-dienoate (0.62 g, 2.45 mmol), and addition of hydrogen sulphide was continued for one hour at room temperature. The reaction mixture was stirred for a further four hours. Potassium hydroxide (0.20 g, 2.8 mmol) was added and hydrogen sulphide passed for thirty minutes. The reaction mixture was stirred at room temperature for sixteen hours, diluted with water (50 ml) and extracted with ether (3×50 ml). The extracts were washed with saturated brine, N sodium bicarbonate solution, saturated brine, dried (Na2SO4) and evaporated to give the title compound (78% yield) purified by distillation, b.p. 119°-127°/0.5 mm. δ (CDCl3) 1.27 (6H, t, J 7 Hz, CH3), 4.20 (4H, q, J 7 Hz, OCH2), 4.75 (1H, s, CH), 7.20-7.43 (3H, m, thienyl protons), νmax (film) 1730 cm-1, λmax (ethanol) 234 nm. C11H14O4S requires M, 242.0649. Found M+, 242.0609.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][C:5](=[O:7])[CH3:6].[H][H]>[Hg]>[CH3:1][CH:2]([CH:2]([CH3:1])[CH2:3][CH2:4][C:5](=[O:7])[CH3:6])[CH2:3][CH2:4][C:5](=[O:7])[CH3:6]
Reactant: C=CCCC(C)=O
Reactant: [H][H]
Agent: [Hg]
Product: CC(=O)CCC(C)C(C)CCC(C)=O
Yield: 70 %

Procedure:
25 g. of 1-hexene-5-one were passed in a 15 ml/min flow of hydrogen into the reactor tube while the tube was irradiated for 17.5 hours inside a photoreactor equipped with sixteen 8 W low pressure mercury lamps. During irradiation the temperature inside the quartz tube averaged 65.C. The crude reaction mixture was evaporated under reduced pressure to give 8.2 g. of involatile product containing the title compound, in about 70% yield. 250 MHZ 13 C NMR (CDCl3) 208.4, 41.3, 36.5, 35.7, 29.3, 28.1, 26.2, 15.6, 13.6.
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:5])[CH3:4].[CH2:18]([C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33]Br)=[CH:28][CH:27]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].OS(O)(=O)=O>CN(C)C=O.O>[C:3]([NH:6][C:7]([CH2:33][CH2:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:31][CH:30]=1)([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:5])[CH3:4]
Reactant: CCCCCCCCc1ccc(CCBr)cc1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCc1ccc(CCC(NC(C)=O)(C(=O)OCC)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
60% NaH in oil (9.65 g) is added portionwise to a solution of diethyl acetamidomalonate (58.5 g) in dimethylformamide (240 ml) at such a rate to keep the temperature below 10° C. The resulting mixture is stirred for 90 min., the temperature being allowed to increase to room temperature. To this mixture is added dropwise within 15 min. a solution of 2-(4-octylphenyl)ethyl bromide (19) (40 g) in dimethylformamide (40 ml). The reaction mixture is heated to ca. 80° C. within ca. 25 min. and further stirred for ca. 3-5 hrs. After cooling to room temperature, water (280 ml) is added and the resulting mixture is further stirred until a beige precipitate is formed. The mixture is adjusted to pH 7 with 10% H2SO4. After cooling to ca. 2° C., the residue is filtered, washed with 200 ml water and then recrystallized in heptane to yield compound (8) as colorless crystals. The resulting compound (8) exhibits the same physico-chemical characteristics as indicated in Example 7.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[NH2:2].[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([C:22]3([C:25]([NH:27][C:28]4[CH:29]=[N:30][C:31]([CH3:35])=[C:32](Br)[CH:33]=4)=[O:26])[CH2:24][CH2:23]3)=[CH:21][C:16]=2[O:15][CH2:14]1.O1C2C=CC(C3(C(NC4C=NC(C)=C(C5C=CC=CC=5)C=4)=O)CC3)=CC=2OC1>>[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([C:22]3([C:25]([NH:27][C:28]4[CH:33]=[C:32]([C:6]5[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=5)[C:1]([NH2:2])=[O:3])[C:31]([CH3:35])=[N:30][CH:29]=4)=[O:26])[CH2:24][CH2:23]3)=[CH:21][C:16]=2[O:15][CH2:14]1
Reactant: Cc1ncc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1Br
Reactant: NC(=O)c1cccc(B(O)O)c1
Agent: Cc1ncc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccccc1
Product: Cc1ncc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1cccc(C(N)=O)c1

Procedure:
3-(5-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2-methylpyridin-3-yl)benzamide was prepared from 3-carbamoylphenylboronic acid and 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-bromo-6-methylpyridin-3-yl)cyclopropanecarboxamide in a manner analogous to that of 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-5-phenylpyridin-3-yl)cyclopropanecarboxamide.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:14]([N:17]([CH:21]([CH3:23])[CH3:22])[CH2:18][CH2:19][NH2:20])([CH3:16])[CH3:15]>>[CH3:15][CH:14]([N:17]([CH:21]([CH3:23])[CH3:22])[CH2:18][CH2:19][NH:20][S:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:12])=[O:11])[CH3:16]
Reactant: CC(C)N(CCN)C(C)C
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Product: CC(C)N(CCNS(=O)(=O)c1ccc([N+](=O)[O-])cc1)C(C)C

Procedure:
p-Nitrobenzenesulfonyl chloride was reacted with N,N-diisopropyl ethylene diamine to give N-[2-[bis(1-methylethyl)amino]ethyl]-4-nitrobenzene sulfonamide as the free base, m.r. 86°-88° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:22][CH:23]2[CH2:27][CH2:26][C:25](=O)[CH2:24]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].Cl.[CH3:30][O:31][NH2:32]>CO.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:22][CH:23]2[CH2:27][CH2:26][C:25](=[N:32][O:31][CH3:30])[CH2:24]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CON
Reactant: CS(=O)(=O)c1ccc(C(CC2CCC(=O)C2)C(=O)Nc2cnccn2)cc1Cl
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CON=C1CCC(CC(C(=O)Nc2cnccn2)c2ccc(S(C)(=O)=O)c(Cl)c2)C1
Temperature: 25 °C
Yield: 79.8 %

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-oxo-cyclopentyl)-N-pyrazin-2-yl-propionamide (prepared as in Example 45, 73.5 mg, 0.17 mmol) and methoxyamine hydrochloride (21.8 mg, 0.26 mmol) in methanol (512 μL) and pyridine (512 μL) was heated under reflux for 5 h. The reaction mixture was allowed to cool to 25° C. and was then concentrated in vacuo. The resulting residue was diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The organic layers were washed with a saturated aqueous sodium chloride solution (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 70% ethyl acetate/hexanes) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-methoxyimino-cyclopentyl)-N-pyrazin-2-yl-propionamide (61.2 mg, 78%) as a white foam: mp 85–87° C.; (ES)+-HRMS m/e calcd for C20H23ClN4O4S (M+H)+ 451.1202 found 451.1207.