Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C@@:5]1([CH2:19][C:20]([CH3:22])=[CH2:21])[CH2:9][C:8](=[O:10])[N:7]([C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:18])[CH2:6]1)=[O:4]>CO.CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]([C@@:5]1([CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:9][C:8](=[O:10])[N:7]([C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:18])[CH2:6]1)=[O:4]
Reactant: C=C(C)C[C@]1(C(=O)OC)CC(=O)N(c2c(C)cccc2C)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)[C@@]1(CC(C)C)CC(=O)N(c2c(C)cccc2C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
10% Pd/C (120 mg) was added to a solution of (S)-1-(2,6-dimethyl-phenyl)-3-(2-methyl-allyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (prepared from step d, 474 mg, 1.57 mmol) in MeOH (5 mL) and resulting black suspension was stirred at room temperature overnight under H2 gas using a balloon. The reaction mixture was then diluted with EtOAc (25 mL) and filtered through celite, washed with MeOH (25 mL) and volatiles from filtrate were evaporated to obtain crude product which was purified by flash chromatography (SiO2, 20→60% EtOAc/hexanes) to obtain (S)-1-(2,6-dimethyl-phenyl)-3-isobutyl-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (450 mg, 94% yield). LC-MS: Rt (retention time): 2.55 min, MS: (ES) m/z 304.1 (M+H+).
Reaction SMILES: C(N(CC)CC)C.C(O[C:12](=[O:14])[CH3:13])(=O)C.Cl.[NH2:16][CH2:17][C:18]1[CH:34]=[CH:33][C:32]2[C:23]3[NH:24][C:25](=[O:31])[C:26]4[N:27]([CH:28]=[CH:29][N:30]=4)[C:22]=3[CH2:21][C:20]=2[CH:19]=1>CN(C)C=O>[O:31]=[C:25]1[NH:24][C:23]2[C:32]3[CH:33]=[CH:34][C:18]([CH2:17][NH:16][C:12](=[O:14])[CH3:13])=[CH:19][C:20]=3[CH2:21][C:22]=2[N:27]2[CH:28]=[CH:29][N:30]=[C:26]12
Reactant: NCc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)NCc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12
Reaction time: 18 h

Procedure:
1.1 ml of triethylamine and then 0.52 ml of acetic anhydride are added to a suspension of 0.8 g of 8-aminomethyl-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one hydrochloride in 20 ml of dimethylformamide. After reacting for 18 hours at a temperature in the region of 20° C., the reaction mixture is filtered and the solid is washed successively with dimethylformamide, distilled water and acetone and then dried under reduced pressure (1 mbar) at 50° C. 0.81 g of N-[(4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-8-yl)methyl]acetamide is thus obtained in the form of a white solid melting above 260° C. (Analysis; % Calculated C: 65.30, H: 4.79, N: 19.04; % Found C: 65.3, H: 4.8, N: 18:7).
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=O)[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.C1C[O:15]CC1>>[CH2:1]1[CH:11]([OH:15])[CH2:9][C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1
Reactant: C1CCOC1
Reactant: O=C1CCCc2ccccc21
Product: OC1CCc2ccccc2C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 97 %

Procedure:
In situ Preparation of the Compound of Formula (II) wherein R1 is ##STR10## Borane methylsulfide complex (neat, ~10M, 1.4 mL, 14 mmol) was added to a solution of cis, exo-3-amino-2-hydroxybornane [J. Chem. Soc. (C) 49 1970] (169 mg, 1 mmol) in THF (70 mL) at ambient temperature and stirred for 16 hrs. α-Tetralone (2.92 g, 19.7 mmol) as a solution in THF (10 mL) was added to the preceding solution over 1 hr, stirred for 15 min after addition was completed, cooled to 0° C., and quenched with methanol (27 mL). After stirring the quenched reaction for 18 hrs, the solvents were removed under vacuum, the residual oil was dissolved in methylene chloride (60 mL), and washed with pH 4 phosphate buffer (50 mL), water (50 mL), treated with magnesium sulfate, and the solvent was removed under vacuum to give the (R) tetralol 2.89 g (97% yield) 84% ee.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[N:13]([CH3:19])[C:14](=[O:18])[CH:15]=[C:16](O)[C:11]=3[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:16]1[C:11]2[CH:10]=[N:9][N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[C:12]=2[N:13]([CH3:19])[C:14](=[O:18])[CH:15]=1
Reactant: Cn1c(=O)cc(O)c2cnn(-c3cccc(F)c3)c21
Reactant: O=P(Cl)(Cl)Cl
Product: Cn1c(=O)cc(Cl)c2cnn(-c3cccc(F)c3)c21
Temperature: 90 °C

Procedure:
A mixture of 1-(3-fluorophenyl)-4-hydroxy-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (2.15 g, 8.27 mmol) and phosphorous oxychloride (10.0 mL, 107 mmol) was heated at 90° C. in an oil bath for 2.5 h. The excess POCl3 was removed on the rotovap and the resulting orange residue was treated with ice and solid Na2CO3 with stirring, and extracted 3×100 mL with EtOAc. The combined EtOAc layers were washed with brine, dried over MgSO4 and concentrated. Purification of the resulting crude material on an ISCO (40 g column, eluting with a gradient of 25-60% EtOAc in Hexanes) provided the title compound as a yellow crystalline solid. MS (ESI, pos.ion) m/z: 278.1 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[CH:22]2.Cl.N1C=CC=CC=1>C(OCCO)C>[NH:24]1[C:25]2[C:21](=[CH:20][C:19]([NH:18][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][C:3]=3[C:16]#[N:17])=[CH:27][CH:26]=2)[CH:22]=[CH:23]1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Nc1ccc2[nH]ccc2c1
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc2ncc(C#N)c(Nc3ccc4[nH]ccc4c3)c2cc1OC

Procedure:
Using an analogous procedure to that described in Example 141, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 158.6 mg (1.2 mmol) of 5-aminoindole and 115.6 mg (1 mmol) of pyridine hydrochloride in 10 mL of 2-ethoxyethanol was refluxed for 0.5 hr. The work up gave 338.7 mg (98.5%) of the product as a yellow solid, m.p.>250° C., mass (electrospray, m/e): M+H 344.9. HRCIMS: calcd 344.127 for C20H16N4O2 (M+), obsd 344.1277.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[OH:19][C:20]1[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22].Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[OH:19][C:20]1[C:26]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:24]=[CH:23][C:21]=1[NH:22][C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: Nc1cccc(C(F)(F)F)c1O
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cccc(C(F)(F)F)c1O
Yield: 39.3 %

Procedure:
The product is prepared according to the procedure described in example 5, using 1 g of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 978 mg of 2-hydroxy-3-(trifluoromethyl)aniline and 1.2 g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 6 ml of pyridine and 8 ml of N,N-dimethylformamide. 600 mg of N-[2-hydroxy-3-(trifluoromethyl)phenyl]-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a beige solid, the characteristics of which are the following:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[C:11]1(=[O:18])[CH:16]=[CH:15][C:14](=[O:17])[CH:13]=[CH:12]1>O.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:16]2[CH:15]=[C:14]([OH:17])[CH:13]=[CH:12][C:11]=2[OH:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(O)c1ccc(F)cc1
Reactant: O=C1C=CC(=O)C=C1
Solvent: O
Solvent: ClCCl
Product: O=S(=O)(c1ccc(F)cc1)c1cc(O)ccc1O
Reaction time: 4 h

Procedure:
A solution of the title A compound, 4-fluorobenzenesulfinic acid (3 g, 18.75 mmol) in 10 mL of water is added to a solution of 1,4 benzoquinone (1.93 g, 17.86 mmol) in 30 mL of CH2Cl2 at RT. After 4 h, the precipitated product is collected by vacuum filtration and washed with cold CH2Cl2 and dried under vacuum to afford 2-(4-fluorobenzenesulfonyl)-benzene-1,4-diol: NMR (DMSO-d6) 6.73 (d, 1H, J=9), 6.92 (dd, 1H, J=9, 3), 7.31 (d, 1H, J=3),7.41 (app t, 2H, J=9), 7.96 (dd, 2H, J=9, 5), 9.41 (s, 1H), 10.05 (s, 1H); ESI-MS 267 [M-1]−.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N:7]2[CH2:13][CH2:12][CH2:11][C:10]([C:15]([F:18])([F:17])[F:16])([OH:14])[CH2:9][CH2:8]2)=[C:5]([N+:19]([O-])=O)[CH:4]=[N:3]1.C(OC([NH:29][C:30]1[S:34][C:33]([C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])=[N:32][C:31]=1[C:43](O)=[O:44])=O)(C)(C)C>>[NH2:29][C:30]1[S:34][C:33]([C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])=[N:32][C:31]=1[C:43]([NH:19][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[N:7]1[CH2:13][CH2:12][CH2:11][C:10]([OH:14])([C:15]([F:18])([F:17])[F:16])[CH2:9][CH2:8]1)=[O:44]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCCC(O)(C(F)(F)F)CC1
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CCCC(O)(C(F)(F)F)CC1
Yield: 29 %

Procedure:
Following the procedure for Example 101 starting from 1-(1-methyl-4-nitro-1H-pyrazol-5-yl)-4-(trifluoromethyl)azepan-4-ol and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)-thiazole-4-carboxylic acid gave 405 as a pale brown solid (53 mg, 29% over three steps). 1H NMR (400 MHz, CDCl3) δ 8.95 (s, 1H), 7.94 (s, 1H), 7.39-7.28 (m, 1H), 7.02 (t, J=8.7 Hz, 2H), 6.21 (s, 2H), 3.73 (s, 3H), 3.46 (ddd, J=13.7, 8.5, 5.0 Hz, 1H), 3.29-3.18 (m, 3H), 2.95 (s, 1H), 2.15-1.97 (m, 5H), 1.87-1.77 (m, 1H). LCMS (ES+) m/z 517 (M+1)
Reaction SMILES: [NH3:1].CO.Cl[C:5]1[N:10]=[C:9]([Cl:11])[N:8]=[C:7]([CH3:12])[N:6]=1.C1(C)C=CC=CC=1>>[Cl:11][C:9]1[N:8]=[C:7]([CH3:12])[N:6]=[C:5]([NH2:1])[N:10]=1
Reactant: Cc1nc(Cl)nc(Cl)n1
Reactant: N
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1nc(N)nc(Cl)n1
Reaction time: 2.5 h
Yield: 73 %

Procedure:
A solution of ammonia, 2.0M methyl alcohol (Aldrich, St. Louis, Mo.) (36.0 mL, 72 mmol) was added dropwise at room temperature (slightly exothermic) to a stirred yellow suspension of 2,4-dichloro-6-methyl-1,3,5-triazine (from Example 7) (2.94 g, 18 mmol) in toluene (20.0 mL, 188 mmol) over 1.5 h. The resulting mixture was stirred for an additional 2.5 h, concentrated and purified (ISCO, DCM to 10% MeOH in DCM) to give the desired product 4-chloro-6-methyl-1,3,5-triazin-2-amine (1.88 g, 73%) as a yellow solid. MS (API-ES) m/z 145 (M+H)+; 1H NMR (CD3OD, 300 MHz) δ 2.32 (s, 3H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=2)O1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]([C:27]2([C:30]3[CH:40]=[CH:39][C:33]4[O:34][C:35]([F:38])([F:37])[O:36][C:32]=4[CH:31]=3)[CH2:29][CH2:28]2)=[O:26])[CH:21]=[CH:20][C:19]=1[CH3:41]>COCCOC.C([O-])([O-])=O.[Na+].[Na+].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>[F:38][C:35]1([F:37])[O:34][C:33]2[CH:39]=[CH:40][C:30]([C:27]3([C:25]([NH:24][C:22]4[CH:21]=[CH:20][C:19]([CH3:41])=[C:18]([C:9]5[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=5)[N:23]=4)=[O:26])[CH2:29][CH2:28]3)=[CH:31][C:32]=2[O:36]1
Reactant: CC1(C)OB(c2cccc(O)c2)OC1(C)C
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1cccc(O)c1
Temperature: 120 °C
Yield: 78.2 %

Procedure:
To a mixture of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (132 mg, 0.600 mmol) and N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (183 mg, 0.500 mmol) in DME (3 mL) and 2 M Na2CO3 (0.5 mL) was added Pd(PPh3)4 (29 mg, 0.025 mmol). The mixture was heated in microwave oven at 120° C. for 30 min. The mixture was partitioned between ethyl acetate and H2O, and the aqueous layer was extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography to afford 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6-(3-hydroxyphenyl)-5-methylpyridin-2-yl)cyclopropanecarboxamide (166 mg, 78%). 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J=8.4 Hz, 1H), 7.88 (s, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.24 (t, J=7.9 Hz, 1H), 7.18-7.15 (m, 2H), 6.91-6.88 (m, 2H), 6.79-6.78 (m, 1H), 6.73-6.69 (m, 2H), 2.29 (s, 3H), 1.75 (q, J=3.6 Hz, 2H), 1.15 (q, J=3.6 Hz, 2H). MS (ESI) m/e (M+H+) 426.2.
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:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[NH2:32][CH2:33][C@@H:34]([OH:36])[CH3:35].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][NH:32][CH2:33][C@@H:34]([OH:36])[CH3:35])[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:5])=[O:4])[CH3:2]
Reactant: C[C@H](O)CN
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNC[C@H](C)O)c4)cc23)CC1
Yield: 30.2 %

Procedure:
Following the general procedure of example 16, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (50 mg, 0.114 mmol), (2S)-1-amino-2-propanol (6.5 mg, 0.087 mmol) and NaBH(OAc)3 (58 mg, 0.261 mmol) were reacted to give the title compound (13.1 mg, 23%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:19](=O)[C:18]3[C:17]([C:28](OCC)=[O:29])=[CH:16][C:15]([F:33])=[CH:14][C:13]=3[NH:12]2)=[CH:7][CH:6]=1)[CH3:3].O.[NH2:35][NH2:36]>CO>[CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[NH:12][C:13]3[C:18]4[C:19](=[N:35][NH:36][C:28](=[O:29])[C:17]=4[CH:16]=[C:15]([F:33])[CH:14]=3)[CH:20]2[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:7][CH:6]=1)[CH3:3]
Reactant: NN
Reactant: CCOC(=O)c1cc(F)cc2c1C(=O)C(c1ccccc1)C(c1ccc(CN(C)C)cc1)N2
Solvent: CO
Solvent: O
Product: CN(C)Cc1ccc(C2Nc3cc(F)cc4c(=O)[nH]nc(c34)C2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 30 %

Procedure:
A mixture of compound ethyl 2-(4-((dimethylamino)methyl)phenyl)-7-fluoro-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (80 mg, 0.18 mmol) in 85% hydrazine monohydrate (1 mL) and methanol (5 mL) was stirred at room temperature for 4 h. The solvent was removed in vacuum; the crude product was purified by chromatography to obtain the title compound as a yellow solid (22 mg, yield 30%). LC-MS (ESI) m/z: 415 (M+1)+. 1H-NMR (400 MHz, DMSO-d) δ (ppm): 2.14 (s, 6H), 3.36 (s, 2H), 4.18-4.21 (d, J=8.8 Hz, 1H), 4.67-4.69 (d, J=9.2 Hz, 1H), 6.81-6.84 (m, 1H), 6.99-7.01 (m, 2H), 7.08-7.19 (m, 8H).
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([N:23]([CH2:25][C:26]([O:28]CC)=O)[CH3:24])=[O:22])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CC(C)([O-])C.[K+].Cl>C1COCC1.CN(C=O)C>[CH3:24][N:23]1[CH2:25][C:26]([OH:28])=[C:20]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:15][CH:16]=2)[C:21]1=[O:22]
Reactant: CCCCCCCCCCCCOc1ccc(CC(=O)N(C)CC(=O)OCC)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCOc1ccc(C2=C(O)CN(C)C2=O)cc1
Reaction time: 1 h
Yield: 64.3 %

Procedure:
In a mixture of THF (50 ml) and DMF (10 ml) was dissolved ethyl N-(4-dodecyloxyphenylacetyl)-N-methylaminoacetate (4.0 g, 0.01 mol.). To the solution was added at room temperature potassium tertiary butoxide (1.8 g, 1.6 mol.) and the mixture was stirred for one hour, to which was then added 2N HCl (20 ml), followed by extraction with ethyl acetate. The organic layer was washed with water, dried and concentrated under reduced pressure to give crude crystals. The crude crystals were recrystallized from IPE - ethyl acetate to give N-methyl-3-(4-dodecyloxyphenyl)-4-hydroxy-3-pyrrolin-2-one (4-b, 2.4 g, 71%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[N+:12]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)([O-:14])=[O:13]>[N+](C1C=CC=CC=1)([O-])=O>[N+:9]([C:5]1[CH:4]=[N:3][C:2]2[NH:1][C:19]([C:18]3[CH:21]=[CH:22][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=3)=[N:8][C:7]=2[CH:6]=1)([O-:11])=[O:10]
Reactant: Nc1cc([N+](=O)[O-])cnc1N
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: O=[N+]([O-])c1ccccc1
Product: O=[N+]([O-])c1ccc(-c2nc3cc([N+](=O)[O-])cnc3[nH]2)cc1
Temperature: 175 °C
Yield: 80.8 %

Procedure:
To a stirred solution of 2,3-diamino-5-nitropyridine (3) (400 mg, 2.6 mmol) in nitrobenzene (50 mL) was added 4-nitrobenzaldehyde (393 mg, 2.6 mmol) and the mixture heated at 175° C. for 24 h. The solvent was removed by distillation under reduced pressure and the resulting orange solid collected by filtration using CH3CN. The filter cake was washed with ether and air dried to give 4 as an orange solid (0.614 g, 2.1 mmol, 83%) that was used as is without further purification. 1H NMR (500 MHz, DMSO-d6) δ14.58 (br s, 1H), 9.28 (apparent d, 1H), 8.88 (br s, 1H), 8.51 (d, J=8.39 Hz, 2H), 8.45 (d, J=8.28 Hz, 2H). EIMS M−1 284.3. Rf=0.55 (silica, 19:1 DCM/MeOH)
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[Cl:9][C:10]1[S:11][C:12]([Cl:19])=[CH:13][C:14]=1[S:15](Cl)(=[O:17])=[O:16]>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:15]([C:14]1[CH:13]=[C:12]([Cl:19])[S:11][C:10]=1[Cl:9])(=[O:17])=[O:16]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1cc(Cl)sc1Cl
Product: Cc1noc(NS(=O)(=O)c2cc(Cl)sc2Cl)c1Br
Yield: 47 %

Procedure:
N-(4-Bromo-3-methyl-5-isoxazolyl)-2,5-dichlorothiophene-3-sulfonamide was prepared in the same manner as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and 2,5-dichlorothiophene-3-sulphonyl chloride in 47% yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 135°-138° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1.Cl.[C:16]1([CH3:23])[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=1>>[CH3:23][C:16]1[CH:21]=[CH:20][C:19]([C:10](=[O:11])[C:9]2[CH:13]=[CH:14][C:6]([F:5])=[CH:7][CH:8]=2)=[C:18]([CH3:22])[CH:17]=1
Reactant: Cc1cccc(C)c1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1ccc(C(=O)c2ccc(F)cc2)c(C)c1
Temperature: 5 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To a suspension of anhydrous aluminum chloride (19.5 g) dispersed in m-xylene (150 ml) was added dropwise 4-fluorobenzoyl chloride (21.1 g) under ice-cooling. The mixture was stirred at 0-10° C. for 3 hr and poured into 6N hydrochloric acid. The reaction mixture was partitioned and the obtained organic layer was washed successively with water, 10% aqueous sodium hydroxide solution and water. The solvent was evaporated to give a 96:4 mixture (30.2 g, 99%) of 1,3-dimethyl-4-(4′-fluorobenzoyl)benzene and 1,3-dimethyl-2-(4′-fluorobenzoyl)benzene as pale-yellow oil. 1,3-Dimethyl-4-(4′-fluorobenzoyl)benzene
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.[C:33](Cl)(=[O:35])[CH3:34]>>[C:33]([N:30]1[CH2:29][CH2:28][CH:27]([NH:26][C:24]([C:20]2[C:16]3[N:17]=[CH:18][N:19]=[C:14]([C:8]4[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:15]=3[NH:22][C:21]=2[CH3:23])=[O:25])[CH2:32][CH2:31]1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Agent: Cl
Product: CC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(C)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methylphenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f28) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:22])[CH2:10][C@H:11]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:12]([O:14]C)=[O:13])=[CH:4][CH:3]=1.[OH-].[Na+]>CO.C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:22])[CH2:10][C@H:11]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:12]([OH:14])=[O:13])=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](CC(=O)Nc1ccc(Cl)cc1)C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(C[C@@H](C(=O)O)C1CCCCC1)Nc1ccc(Cl)cc1
Yield: 100.9 %

Procedure:
Methyl(2R)-4-((4-chlorophenyl)amino)-2-cyclohexyl-4-oxobutanoate (0.29 g) obtained in Example 5a) and 1 N sodium hydroxide (1.0 ml) were dissolved in methanol (12 ml) and THF (3 ml), and mixed at room temperature for 1 hour. Then, the reaction solution was concentrated under reduced pressure, acidified by adding 1 N hydrochloric acid to the concentrated solution and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound as pale brown powder (0.28 g, quantitative).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6](=O)[CH2:7][CH:8]2[C:13](=O)[CH2:12][CH2:11][S:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:18][CH:19]([CH3:24])[CH2:20][N:21]([CH3:23])[CH3:22].[ClH:25]>Cl.C(O)C.CCOCC>[ClH:25].[CH3:22][N:21]([CH3:23])[CH2:20][CH:19]([N:18]1[C:6]([C:5]2[CH:16]=[CH:17][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:7][C:8]2[CH2:9][S:10][CH2:11][CH2:12][C:13]1=2)[CH3:24]
Reactant: CC(N)CN(C)C
Reactant: O=C(CC1CSCCC1=O)c1ccc(Br)cc1
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CC(CN(C)C)n1c(-c2ccc(Br)cc2)cc2c1CCSC2
Temperature: 5 °C

Procedure:
A solution of 5.5 g (0.017 mole) of 3-(4-bromophenacyl)-2,3,5,6-tetrahydrothiopyran-4-one [Example 2 (a)], 1.6 g of 2-amino-1-dimethylaminopropane, 16 ml. of ethanol, and one drop of concentrated hydrochloric acid is heated under reflux for 3 hours, cooled to 5°C, and filtered to provide a solid product. The resulting product is dissolved in ethanol, the solution is acidified with ethereal hydrogen chloride and diluted to the cloud point with ether. Upon standing, a solid separates. Recrystallization from ethanol gives off-white crystals of 1-(1-dimethylamino-2-propyl)-2-(4-bromophenyl)-1,4,6,7-tetrahydrothiopyrano[4,3-b]pyrrole hydrochloride, m.p. 237° to 238°C. dec.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([O:27][CH2:28][CH2:29][NH2:30])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([O:27][CH2:28][CH:29]([NH2:30])[S:40]([CH3:39])(=[O:42])=[O:41])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: Cc1cc(F)ccc1-c1nc(OCCN)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(F)ccc1-c1nc(OCC(N)S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
The product of Example 131 (100 mg, 0.23 mmol) in CH2Cl2 (4 mL) was stirred under Ar at 230. Triethylamine (0.1 mL) was added followed by the addition of a solution of methanesulfonyl chloride (29 mg, 0.25 mmol) in CH2Cl2 (1 mL). The solvents were removed in vacuo, and the residue was partitioned between EtOAc and H2O. The organic phase was washed with H2O, satd aq NaCl, dried over anhyd Na2SO4, filtered and evaporated to give the crude product. Flash chromatography eluted with 0-10% EtOAc/CH2Cl2 gave the title compound as a white-amorphous solid. mp 95-99°, LC MS m/z=505 (MH+). Retention time=2.02 min.