Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([C@@H:12]1[C@:29]2([CH3:30])[C@H:15]([C:16]3[C@H:26]([CH2:27][CH2:28]2)[C@:24]2([CH3:25])[C:19]([CH2:20][C@@H:21]([O:36][C:37]([O:39][CH3:40])=[O:38])[CH2:22][C@@H:23]2[O:31][C:32]([O:34][CH3:35])=[O:33])=[CH:18][CH:17]=3)[CH2:14][CH2:13]1)[CH2:3][S:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[OH:41]O>CO.O>[CH3:1][CH:2]([C@@H:12]1[C@:29]2([CH3:30])[C@H:15]([C:16]3[C@H:26]([CH2:27][CH2:28]2)[C@:24]2([CH3:25])[C:19]([CH2:20][C@@H:21]([O:36][C:37]([O:39][CH3:40])=[O:38])[CH2:22][C@@H:23]2[O:31][C:32]([O:34][CH3:35])=[O:33])=[CH:18][CH:17]=3)[CH2:14][CH2:13]1)[CH2:3][S:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:41])=[O:5]
Reactant: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)CS(=O)c5ccccc5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Reactant: OO
Solvent: O
Solvent: CO
Product: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)CS(=O)(=O)c5ccccc5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 29 mg of 20-methyl-1α,3β-bis(methoxycarbonyloxy)-21-phenylsulfinylpregna-5,7-diene in 1 ml of methanol was added 0.5 ml of a 30% aqueous solution of hydrogen peroxide and the mixture was stirred at ambient temperature for 6 hours. The reaction mixture was diluted with water and the methanol was distilled off under reduced pressure. The residue was extracted with methylene chloride, the extract was washed with an aqueous solution of sodium thiosulfate, water and an aqueous solution of sodium chloride, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give 13 mg of 20-methyl-1α,3β-bis(methoxycarbonyloxy)-21-phenylsulfonylpregna-5,7-diene, whose 1H NMR spectrum was identical with that obtained in Example 5.
Reaction SMILES: [CH2:1]([CH:8]([CH2:12][C:13](=[O:26])[C@@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:27][C@@H:28]([CH2:49][C:50]1[N:51]=[CH:52][NH:53][CH:54]=1)[C:29]([NH:31][C@@H:32]([CH2:42][CH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1)[C@@H:33]([OH:41])[CH2:34][C@@H:35]([CH:38]([CH3:40])[CH3:39])[CH:36]=[CH2:37])=[O:30]>>[CH:43]1([CH2:42][C@H:32]([NH:31][C:29]([C@@H:28]([NH:27][C:9]([C@H:8]([CH2:12][C:13]([C@@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])=[O:26])[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:11])[CH2:49][C:50]2[N:51]=[CH:52][NH:53][CH:54]=2)=[O:30])[C@@H:33]([OH:41])[CH2:34][C@@H:35]([CH:38]([CH3:40])[CH3:39])[CH:36]=[CH2:37])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)CC(Cc1ccccc1)C(=O)O
Reactant: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@@H](N)Cc1c[nH]cn1)C(C)C
Product: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](CC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)Cc1ccccc1)C(C)C

Procedure:
In a manner analogous to that described in Example 27, by condensing (αRS,S)-α-benzyl-1-t-butoxycarbonyl-γ-oxo-2-pyrrolidinebutyric acid with (S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamide and subsequent epimer separation by chromatography, there were obtained t-butyl (S)-2-[[(S)-α-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]acetyl]-1-pyrrolidinecarboxylate (less polar isomer) and t-butyl (S)-2-[[(R)-γ-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]phenethyl]acetyl]-1-pyrrolidinecarboxylate. MS: 734 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]([F:28])([F:27])[C:13]1[N:18]=[CH:17][C:16]([C:19]2([CH2:25][NH2:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:15][N:14]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:26][CH2:25][C:19]1([C:16]2[CH:17]=[N:18][C:13]([C:12]([F:28])([F:27])[F:11])=[N:14][CH:15]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:6]
Reactant: O=C(O)c1ccccc1Cl
Reactant: NCC1(c2cnc(C(F)(F)F)nc2)CCOCC1
Product: O=C(NCC1(c2cnc(C(F)(F)F)nc2)CCOCC1)c1ccccc1Cl

Procedure:
From 2-chlorobenzoic acid and (4-(2-(trifluoromethyl)pyrimidin-5-yl)tetrahydro-2H-pyran-4-yl)methanamine. LCMS (MH+): m/z=400.1, tR (minutes, Method F)=2.15
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3I)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:19]([OH:22])[C:20]#[CH:21]>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:21]#[C:20][CH2:19][OH:22])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C#CCO
Reactant: CN1Cc2c(I)ncn2-c2cccc(Cl)c2C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: CN1Cc2c(C#CCO)ncn2-c2cccc(Cl)c2C1=O

Procedure:
5.20 g (14 mmol) of 7-chloro-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one were heated to boiling under reflux for 4 hours with 1.04 g (18.5 mmol) of propargyl alcohol, 70 mg of bis-(triphenyl -phosphine)-palladium(II) dichloride and 10 mg of copper(I) iodide in 35 ml of diethylamine. The reaction mixture was evaporated and the residue was suspended in methylene chloride. The suspension was suction filtered and the suction filter cake was washed with ethyl acetate. After two successive recrystallizations from ethanol and, respectively, N,N-dimethylformamide there was obtained 7-chloro-4,5-dihydro-3-(3-hydroxy-1-propynyl)-5-methyl-6H -imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 250-252°.
Reaction SMILES: [CH2:1](N(CC)CC)C.IC.[OH:10][CH:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]2[CH:26]=[C:25]3[C:20]([CH:21]=[C:22]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[N:34]4[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]4)[NH:23][C:24]3=[O:27])=[CH:19][CH:18]=2)[CH2:12]1>C(#N)C>[OH:10][CH:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]2[CH:26]=[C:25]3[C:20]([CH:21]=[C:22]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[N:34]4[CH2:39][CH2:38][N:37]([CH3:1])[CH2:36][CH2:35]4)[NH:23][C:24]3=[O:27])=[CH:19][CH:18]=2)[CH2:12]1
Reactant: O=c1[nH]c(-c2ccccc2N2CCNCC2)cc2ccc(N3CCCC(O)C3)cc12
Reactant: CCN(CC)CC
Solvent: CI
Solvent: CC#N
Product: CN1CCN(c2ccccc2-c2cc3ccc(N4CCCC(O)C4)cc3c(=O)[nH]2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.3 %

Procedure:
0.0185 ml (0.133 mmol) of triethylamine and 0.00665 ml (0.107 mmol) of iodomethane were added to an acetonitrile solution (0.4 ml) containing 3.6 mg (0.0089 mmol) of the 7-(3-hydroxypiperidin-1-yl)-3-(2-piperazin-1-ylphenyl)-2H-isoquinolin-1-one obtained in Example 102. The obtained mixture was stirred at a room temperature for 4 hours. Thereafter, the solvent was distilled away under reduced pressure. The obtained residue was developed and purified by thin-layer chromatography (NH2 F254s, Merck, developing solvent; dichloromethane:methanol=10:1, Rf value: 0.8), so as to obtain 1.8 mg (48%) of 7-(3-hydroxypiperidin-1-yl)-3-[2-(4-methylpiperazin-1-yl)phenyl]-2H-isoquinolin-1-one in the form of a yellow solid.
Reaction SMILES: [C:1]([NH:4][NH2:5])([NH2:3])=[NH:2].Cl.[CH3:7][S:8]([OH:11])(=[O:10])=[O:9].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19]1[CH2:28][C:27]2[N:26]=[CH:25][CH:24]=[C:23]([O:29][CH3:30])[C:22]=2[C:21](=O)[CH2:20]1>CO>[CH3:7][S:8]([OH:11])(=[O:10])=[O:9].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19]1[CH2:28][C:27]2[N:26]=[CH:25][CH:24]=[C:23]([O:29][CH3:30])[C:22]=2[C:21](=[N:5][NH:4][C:1]([NH2:3])=[NH:2])[CH2:20]1
Reactant: COc1ccnc2c1C(=O)CC(c1ccccc1Cl)C2
Reactant: N=C(N)NN
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CO
Product: COc1ccnc2c1C(=NNC(=N)N)CC(c1ccccc1Cl)C2
Temperature: 60 °C
Reaction time: 16 h
Yield: 103.6 %

Procedure:
To a solution of aminoguanidine hydrochloride (0.048 g) in methanol (20 ml) was added methanesulfonic acid (0.042 g), and the mixture was refluxed for 1 hour. To the mixture were added 7-(2-chlorophenyl)-4-methoxy-5,6,7,8-tetrahydroquinolin-5-one (0.12 g) and methanesulfonic acid (0.042 g), and the mixture was stirred at 50° C. for 9 hours and at 60° C. for 16 hours. Under reduced pressure, the solvent was evaporated. To the residue was added water, and the mixture was washed with ethyl acetate. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from water-ethanol to give 7-(2-chlorophenyl)-5-guanidinoimino-4-methoxy-5,6,7,8-tetrahydroquinoline methanesulfonate (Compound 79) (0.19 g) as colorless crystals.
Reaction SMILES: Cl.[N:2]1[N:6]2[CH:7]=[CH:8][N:9]=[CH:10][C:5]2=[C:4]([C:11](=[NH:13])[NH2:12])[CH:3]=1.CN(C)/[CH:16]=[C:17](\[N+:23]([O-:25])=[O:24])/[C:18](OCC)=[O:19].C(N(CC)CC)C>C(O)C>[N+:23]([C:17]1[C:18]([OH:19])=[N:13][C:11]([C:4]2[CH:3]=[N:2][N:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:5]=23)=[N:12][CH:16]=1)([O-:25])=[O:24]
Reactant: CCOC(=O)/C(=C/N(C)C)[N+](=O)[O-]
Reactant: N=C(N)c1cnn2ccncc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=[N+]([O-])c1cnc(-c2cnn3ccncc23)nc1O
Temperature: 90 °C
Reaction time: 22 h
Yield: 48.9 %

Procedure:
A mixture of crude pyrazolo[1,5-a]pyrazine-3-carboximidamide hydrochloride (Preparation 24c, 4.88 g), (Z)-ethyl 3-(dimethylamino)-2-nitroacrylate (8.04 g, 42.7 mmol) and triethylamine (6.25 mL, 44.8 mmol) in ethanol (165 mL) was stirred and heated to 90° C. in a sealed tube. After 22 hours, the reaction mixture was cooled and the precipitate was filtered, washed with ethanol and diethyl ether and dried to give the title compound (3.12 g, 66%) as a yellow solid.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:25]2[CH:33]=[C:32]3[C:28]([CH2:29][C:30](=[O:34])[NH:31]3)=[CH:27][CH:26]=2)[CH:22]=[CH:23][CH:24]=1>>[CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=[C:29]1[C:28]2[C:32](=[CH:33][C:25]([C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([O:18][CH3:17])[CH:20]=3)=[CH:26][CH:27]=2)[NH:31][C:30]1=[O:34])([CH3:3])[CH3:2]
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Reactant: COc1cccc(-c2ccc3c(c2)NC(=O)C3)c1
Product: COc1cccc(-c2ccc3c(c2)NC(=O)C3=Cc2cc(C(C)C)c(OC)c(C(C)C)c2)c1

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 6-(3-methoxyphenyl)-2-oxindole to give 0.4 g of 3-(3,5-diisopropyl-4-methoxybenzylidene)-6-(3-methoxyphenyl)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.[NH2:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][N:30]=1>>[CH3:21][S:18]([CH:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:8][C:6]3[N:7]=[C:2]([C:32]4[CH:31]=[N:30][C:29]([NH2:28])=[N:34][CH:33]=4)[N:3]=[C:4]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:5]=3[CH:10]=2)[CH2:13][CH2:14]1)(=[O:20])=[O:19]
Reactant: Nc1ncc(B(O)O)cn1
Reactant: CS(=O)(=O)C1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Product: CS(=O)(=O)C1CCN(Cc2cc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3s2)CC1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperidin-1-ylmethyl)-4-morpholin-4-yl-thieno[2,3-d]pyrimidine was reacted with 2-aminopyrimidine-5-boronic acid in General Procedure A. Purification on silica gave 283. NMR (400 MHz, CDCl3): 1.88-2.00 (2H, m), 2.04-2.20 (4H, m), 2.83-2.86 (4H, m), 3.13-3.20 (2H, m), 3.81 (2H, s), 3.88-3.90 (4H, m), 3.92-3.96 (4H, m), 5.25 (2H, br, s), 7.18 (1H, s),9.37 (1H, s). (M+H)+ 490
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH2:11][CH:10]([C:24]([OH:26])=O)[CH2:9]1)=[O:7].O[N:28]=[C:29]([CH:31]1[CH2:33][CH2:32]1)[NH2:30]>>[CH:31]1([C:29]2[N:30]=[C:24]([CH:10]3[CH2:11][CH:12]([C:14]4[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=4)[CH2:13][N:8]([C:6]([NH:5][CH2:4][CH2:3][O:2][CH3:1])=[O:7])[CH2:9]3)[O:26][N:28]=2)[CH2:33][CH2:32]1
Reactant: COCCNC(=O)N1CC(C(=O)O)CC(c2ccc(C(F)(F)F)cc2)C1
Reactant: NC(=NO)C1CC1
Product: COCCNC(=O)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(C3CC3)no2)C1
Yield: 38.8 %

Procedure:
100 mg (0.267 mmol) of the compound from Example 105A and 54 mg (0.534 mmol) of N′-hydroxycyclopropanecarboximidamide were reacted according to the General Method 2. Diastereomer separation of 64 mg of the cis/trans isomer mixture according to Method 14C gave 45.4 mg of the title compound and 5.5 mg of the trans isomer.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][S:9][CH3:10])[C:3]=1[NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14].ClC1C=C(C=CC=1)C(OO)=O.[O-2:29].[Al+3].[O-2:31].[O-2].[Al+3]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][S:9]([CH3:10])(=[O:31])=[O:29])[C:3]=1[NH:11][C:12](=[O:17])[C:13]([F:15])([F:16])[F:14]
Reactant: [O-2]
Reactant: CSCc1cccc(Cl)c1NC(=O)C(F)(F)F
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Al+3]
Solvent: ClCCl
Product: CS(=O)(=O)Cc1cccc(Cl)c1NC(=O)C(F)(F)F

Procedure:
The crude solid N-(2-chloro-6-methylsulfanylmethyl-phenyl)-2,2,2-trifluoro-acetamide from Step 2 was redissolved in methylene chloride (300 ml) and treated at 0° C. with meta-chloroperoxybenzoic acid (39.88 g, 0.177 mole) in portions with stirring. After 90 minutes the entire reaction mixture was poured onto a column of deactivated aluminum oxide (6% water) and the product was washed free of the acid by eluting with 1:1 ethyl acetate:hexane to afford 22.28 g of N-(2-Chloro-6-methanesulfonylmethyl-phenyl)-2,2,2-trifluoro-acetamide, a crystalline product (86%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[CH:11](O)[CH2:12][C:13]1[CH:22]=[N:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1.O=S(Cl)[Cl:26]>>[Cl:26][CH:11]([C:2]1[CH:3]=[N:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)[CH2:12][C:13]1[CH:22]=[N:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1
Reactant: O=S(Cl)Cl
Reactant: OC(Cc1cnc2ccccc2n1)c1cnc2ccccc2n1
Product: ClC(Cc1cnc2ccccc2n1)c1cnc2ccccc2n1

Procedure:
A solution of 1,2-di(quinoxalin-2-yl)ethanol (0.05 g, 0.166 mmol) in SOCl2 (2 mL) was stirred at room temperature for 1 hour. The solution was then concentrated to afford 2,2′-(1-chloroethane-1,2-diyl)diquinoxaline (0.05 g) as a yellow solid. MS (ESI) m/z 321.1 (M+H+).
Reaction SMILES: C[C:2]1[CH:7]=[CH:6]C=C[C:3]=1[S:8]([N:11]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:20]=[O:21])[C:14]=2[CH:13]=[CH:12]1)(=[O:10])=[O:9].[S:22]1C=CC=C1S(N1C2C(=C(C=C)C=CC=2)C=C1)(=O)=O.N1C(C)=CC=CC=1C.I([O-])(=O)(=O)=O.[Na+]>O=[Os](=O)(=O)=O>[S:22]1[CH:6]=[CH:7][CH:2]=[C:3]1[S:8]([N:11]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:20]=[O:21])[C:14]=2[CH:13]=[CH:12]1)(=[O:10])=[O:9]
Reactant: Cc1ccccc1S(=O)(=O)n1ccc2c(C=O)cccc21
Reactant: C=Cc1cccc2c1ccn2S(=O)(=O)c1cccs1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: Cc1cccc(C)n1
Product: O=Cc1cccc2c1ccn2S(=O)(=O)c1cccs1

Procedure:
The experimental for Intermediate 16 was followed using 1-(2-thienylsulfonyl)-4-vinyl-1H-indole (333 mg, 1.15 mmol; Intermediate 21), OsO4 (15 mg, 0.06 mmol), 2,6-lutidine (268 μL, 2.30 mmol) and sodium periodate (0.984 g, 4.60 mmol). The title compound was obtained (306 mg, 91%, still some dioxane according to HNMR) as a black gum. MS (ESI+) for C13H9NO3S2 m/z 292 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[Cl:7][C:8]1[CH:9]=[C:10]([CH2:14][C:15](O)=[O:16])[CH:11]=[CH:12][CH:13]=1>>[Cl:7][C:8]1[CH:9]=[C:10]([CH2:14][C:15]([NH:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3])=[O:16])[CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)Cc1cccc(Cl)c1
Reactant: C[C@H](N)C(=O)O
Product: C[C@H](NC(=O)Cc1cccc(Cl)c1)C(=O)O

Procedure:
The title compound was prepared using L-alanine (Nova Biochem) and 3-chlorophenyl acetic acid (Aldrich) by following General Procedures BF or BG, followed by hydrolysis using General Procedure BD.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[NH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([F:32])[CH:23]=1>>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:20]=[CH:19][C:16]([CH2:17][NH:21][C:22]3[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([F:32])[CH:23]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)c1ccc(N)cc1F
Reactant: CCCCc1ccc(C#Cc2ccc(C=O)cc2)cc1
Product: CCCCc1ccc(C#Cc2ccc(CNc3ccc(C(=O)OC)c(F)c3)cc2)cc1

Procedure:
The titled compound was prepared following the procedure A using 4-[(4-butylphenyl)ethynyl]benzaldehyde and methyl 4-amino-2-fluorobenzoate as a beige powder (63%). M− (ESI): 414.1; M+ (ESI): 416.9. HPLC, Rt: 5.58 min (Purity: 96.9%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](O)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[CH3:11][C@@H:12]([OH:16])[CH2:13][O:14][CH3:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([O:16][C@@H:12]([CH3:11])[CH2:13][O:14][CH3:15])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COC[C@@H](C)O
Reactant: COc1cc(O)cc(Br)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC[C@H](C)Oc1cc(Br)cc(OC)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.6 %

Procedure:
3-Bromo-5-methoxyphenol (7.60 g, 37.4 mmol) synthesized in Example (1a) was dissolved in toluene (100 mL), and R-(−)-1-methoxy-2-propanol (4.40 mL, 44.9 mmol) and triphenylphosphine (13.8 g, 52.6 mmol) were added, followed by dropwise addition of diethyl azodicarboxylate (2.2 mol/l toluene solution, 24 mL, 52.8 mmol) at 0° C. and stirring at room temperature for 1.5 hours under nitrogen atmosphere. The solvent was distilled off under reduced pressure, diethyl ether (100 mL) was added, and the deposit was filtered to be removed. The mother liquor was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=10%-20%) to afford the desired compound (9.22 g, yield 89%) as a colorless liquid.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10](=[O:29])[CH2:11][CH2:12][C:13]([O:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]CC1C=CC=CC=1)=[O:20])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H][H]>[Pd].C(O)C>[C:1]([NH:8][CH2:9][C:10](=[O:29])[CH2:11][CH2:12][C:13]([O:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)NCC(=O)CCC(=O)OCCCC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCC(=O)CCC(=O)OCCCC(=O)O
Yield: 102.7 %

Procedure:
This compound was prepared from the product of 5a (5.40 g; 13.2 mmol), 10% palladium on activated carbon (250 mg), hydrogen gas, and 96% ethanol (100 mL) as described in Example 2c. 4.30 g product was obtained (yellowish oil) which was used in 5c without any further workup.
Reaction SMILES: [CH:1]([CH:4]1[N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7][N:6]2[C:17]3[CH:23]=[C:22]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[CH:20][C:18]=3[N:19]=[C:5]12)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]([CH:4]1[NH:9][CH2:8][CH2:7][N:6]2[C:17]3[CH:23]=[C:22]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:21]=[CH:20][C:18]=3[N:19]=[C:5]12)([CH3:3])[CH3:2]
Reactant: CC(C)C1c2nc3ccc(S(C)(=O)=O)cc3n2CCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C1NCCn2c1nc1ccc(S(C)(=O)=O)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 136.3 %

Procedure:
To a solution of tert-butyl 1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazine-2(1H)-carboxylate (20 mg, 0.05 mmol) in CH2Cl2 (1 mL) was added TFA (0.3 mL) under N2. The mixture was stirred at rt for 1 h. The mixture was concentrated to afford 1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine (20 mg, TFA salt, 100% yield) as a yellow solid, which was used for the next step without further purification. LC-MS m/z 352.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].[CH2:10]([O:12][C:13]([C:15]1([CH2:29]I)[CH2:19][CH2:18][N:17]([C:20](=[O:28])[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:16]1)=[O:14])[CH3:11]>>[CH2:10]([O:12][C:13]([C:15]1([CH2:29][O:9][C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:19][CH2:18][N:17]([C:20](=[O:28])[C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[CH2:16]1)=[O:14])[CH3:11]
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccc(F)cc2)C1
Reactant: Oc1ccc(F)c(Cl)c1
Product: CCOC(=O)C1(COc2ccc(F)c(Cl)c2)CCN(C(=O)c2ccc(F)cc2)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 3-chloro-4-fluoro-phenol and 1-(4-fluoro-benzoyl)-3-iodomethyl-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 12) to afford the racemate as a white solid (153 mg, 69%) ES m/z 424 [MH]+
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[N:3]=1.[CH:24]([O:27][C:28]1[CH:34]=[C:33]([CH:35]2[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]2)[C:32]([CH3:42])=[CH:31][C:29]=1[NH2:30])([CH3:26])[CH3:25].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)(C)C>[Cl:8][C:6]1[C:5]([C:9]#[N:10])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[N:3]=[C:2]([NH:30][C:29]2[CH:31]=[C:32]([CH3:42])[C:33]([CH:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]3)=[CH:34][C:28]=2[O:27][CH:24]([CH3:26])[CH3:25])[N:7]=1
Reactant: Cc1cc(N)c(OC(C)C)cc1C1CCN(C)CC1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)nc(Cl)c1C#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: Cc1cc(Nc2nc(Cl)c(C#N)c(Nc3ccccc3S(=O)(=O)C(C)C)n2)c(OC(C)C)cc1C1CCN(C)CC1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To a solution of 2,4-dichloro-6-(2-(isopropylsulfonyl)phenylamino)pyrimidine-5-carbonitrile (0.5 mmol) and 2-isopropoxy-5-methyl-4-(1-methylpiperidin-4-yl)aniline (0.5 mmol) in 3 mL of isopropanol, was added 4-methylbenzenesulfonic acid (0.5 mmol). The suspension was stirred at 120° C. for 2 hours. Product was obtained after work-up and prep-HPLC. MS (ES+): 597.23 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([CH2:16][C:17]([O:20][CH2:21][CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])([CH3:19])[CH3:18])[C:14]([CH2:27][O:28][CH2:29][CH3:30])=[N:13][C:7]=3[C:8]([NH2:12])=[N:9][C:10]=2[CH:11]=1.B1([C:37]2[CH:42]=[CH:41][CH:40]=[N:39][CH:38]=2)OCCCO1>>[CH2:29]([O:28][CH2:27][C:14]1[N:15]([CH2:16][C:17]([O:20][CH2:21][CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])([CH3:19])[CH3:18])[C:6]2[C:5]3[CH:4]=[CH:3][C:2]([C:37]4[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=4)=[CH:11][C:10]=3[N:9]=[C:8]([NH2:12])[C:7]=2[N:13]=1)[CH3:30]
Reactant: c1cncc(B2OCCCO2)c1
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CC(C)(C)OCCS(C)(=O)=O
Product: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CC(C)(C)OCCS(C)(=O)=O
Yield: 58.6 %

Procedure:
7-Bromo-2-ethoxymethyl-1-{2-[2-(methanesulfonyl)ethoxy]-2-methylpropyl}-1H-imidazo[4,5-c]quinolin-4-amine (1.2 g, 2.4 mmol) and pyridine-3-boronic acid 1,3-propanediol cyclic ester (0.47 g, 2.9 mmol) were coupled according to the method described in Part J of Example 1. The work-up procedure used in Part F of Examples 125–135 was followed. The crude product was purified by column chromatography on silica gel (eluting sequentially with 95:5 and 90:10 dichloromethane:methanol) followed by recrystallization from acetonitrile (52 mL/g). The crystals were isolated by filtration, washed with acetonitrile, and dried for four hours under vacuum at 65° C. to provide 0.70 g of 2-ethoxymethyl-1-{2-[2-(methanesulfonyl)ethoxy]-2-methylpropyl}-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as white, crystalline plates, mp 202–204° C.