Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=3[F:28])[N:18]=[C:17]3[N:29](C4CCCCO4)[N:30]=[C:31]([CH3:32])[C:16]=23)[CH:10]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[F:28][C:22]1[CH:23]=[C:24]([OH:27])[CH:25]=[CH:26][C:21]=1[C:19]1[N:18]=[C:17]2[NH:29][N:30]=[C:31]([CH3:32])[C:16]2=[C:15]([CH2:14][N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH:10]2[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:20]=1
Reactant: Cc1nn(C2CCCCO2)c2nc(-c3ccc(O)cc3F)cc(CN3CCN(C(=O)OC(C)(C)C)CC3c3ccccc3)c12
Agent: Cl
Solvent: C1COCCO1
Product: Cc1n[nH]c2nc(-c3ccc(O)cc3F)cc(CN3CCNCC3c3ccccc3)c12
Yield: 51 %

Procedure:
178 mg 4-[6-(2-fluoro-4-hydroxy-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-ylmethyl]-3-phenyl-piperazine-1-carboxylic acid tert-butyl ester were dissolved in 3 ml dry 1,4-dioxane and 2 ml HCl (4N in 1,4-dioxane) was added. After stirring the reaction at r.t. for 30 min the volatiles were removed in vacuo and the resulting residue was purified by preparative HPLC (C18 column, acetonitrile/water gradient). 63 mg (51%) of the title compound were obtained.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[CH:6]=[N:7][OH:8].[F:13][C:14]1[C:15]([NH2:24])=[N:16][C:17](S(C)(=O)=O)=[N:18][CH:19]=1>O1CCCC1>[NH2:24][C:15]1[C:14]([F:13])=[CH:19][N:18]=[C:17]([O:8][N:7]=[CH:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[Cl:3])[N:16]=1
Reactant: ON=Cc1ccccc1Cl
Reactant: CS(=O)(=O)c1ncc(F)c(N)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1nc(ON=Cc2ccccc2Cl)ncc1F
Reaction time: 1 h
Yield: 49.5 %

Procedure:
To a suspension of 60% NaH (0.063 g, 1.57 mmol) in anhydrous tetrahydrofuran (THF; 5 mL) was added in portions a solution of 2-chlorobenzaldehyde oxime (0.254 g, 1.64 mmol in 1 mL of THF) at room temperature, and the resulting frothy mixture was stirred for 1 h. To the resulting tan mixture was added 5-fluoro-2-methanesulfonylpyrimidin-4-ylamine (0.25 g, 1.31 mmol), at which point the reaction mixture turned orange and most of the solids dissolved. Within minutes of the addition a new solid had precipitated, and the resulting orange mixture was stirred at room temperature for 16 h. The entire reaction mixture was adsorbed to Celite (2.5 g) and the adsorbed material was purified by flash chromatography (24 g SiO2; 0→100% EtOAc/hexanes) to give 2-chlorobenzaldehyde O-(4-amino-5-fluoropyrimidin-2-yl)oxime (0.173 g, 50%) as a white solid: mp 220-230° C. dec; 1H NMR (400 MHz, DMSO-d6) δ 8.83 (s, 1H), 8.05 (d, J=3.1 Hz, 1H), 7.92 (dd, J=7.8, 1.5 Hz, 1H), 7.54 (m, 5H); ESIMS m/z 267 ([M+H]+), 265 ([M−H]−).
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1([N:30]2[C:34](=[O:35])[CH:33]=[CH:32][C:31]2=[O:36])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[C:27](=[O:28])[CH:26]=[CH:25][C:24]1=[O:29]>>[CH2:10]([N:8]([O:9][CH:25]1[CH2:26][C:27](=[O:28])[N:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:30]2[C:34](=[O:35])[CH2:33][CH:32]([O:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:31]2=[O:36])[C:24]1=[O:29])[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ON(Cc1ccccc1)Cc1ccccc1
Reactant: O=C1C=CC(=O)N1c1ccccc1N1C(=O)C=CC1=O
Product: O=C1CC(ON(Cc2ccccc2)Cc2ccccc2)C(=O)N1c1ccccc1N1C(=O)CC(ON(Cc2ccccc2)Cc2ccccc2)C1=O
Yield: 67.9 %

Procedure:
The procedure of Example 1 is repeated using 5.33 g (25 mmole) of N,N-dibenzylhydroxylamine and 3.35 g (12.5 mmole) of N,N'-ortho-phenylenedimaleimide. The residue is purified by preparative HPLC (Silica gel: 7:3 heptane:ethyl acetate eluent) to give 5.9 g (34%) of a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:24][CH3:25])=[CH:11][C:12]([C:18]2[N:22]=[C:21]([CH3:23])[O:20][N:19]=2)=[C:13]([CH:17]=1)[C:14](Cl)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-].[CH2:27]([Zn+])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(C)C=CC=CC=1.Cl>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.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:10]([O:24][CH3:25])=[CH:11][C:12]([C:18]2[N:22]=[C:21]([CH3:23])[O:20][N:19]=2)=[C:13]([C:14](=[O:15])[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [Zn+]Cc1ccccc1
Reactant: COc1cc(-c2noc(C)n2)c(C(=O)Cl)cc1OCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc(-c2noc(C)n2)c(C(=O)Cc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 5-benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)benzoyl chloride, benzylzinc bromide (0.5 mol/L, tetrahydrofuran solution, 4.4 mL), dichlorobis-(triphenylphosphine)palladium(II) (153 mg) and toluene (6 mL) was stirred at room temperature under an argon atmosphere for 5 hours. Ethyl acetate and 2 mol/L hydrochloric acid were added to the mixture. The separated organic layer was washed with water, an aqueous solution of sodium bicarbonate and brine successively, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 5%-20% ethyl acetate/hexane, gradient elution) to give the title compound (307 mg).
Reaction SMILES: [O:1]=[C:2]1[CH2:18][C@H:6]2[O:7][C:8]3[CH:13]=[C:12]([CH2:14][CH:15]=[CH2:16])[C:11]([OH:17])=[CH:10][C:9]=3[C@@H:5]2[CH2:4][CH2:3]1>C(OCC)(=O)C.[Pd]>[O:1]=[C:2]1[CH2:18][C@H:6]2[O:7][C:8]3[CH:13]=[C:12]([CH2:14][CH2:15][CH3:16])[C:11]([OH:17])=[CH:10][C:9]=3[C@@H:5]2[CH2:4][CH2:3]1
Reactant: C=CCc1cc2c(cc1O)[C@@H]1CCC(=O)C[C@H]1O2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1cc2c(cc1O)[C@@H]1CCC(=O)C[C@H]1O2
Reaction time: 1 h
Yield: 99.5 %

Procedure:
A suspension of 0.250 g (1.02 mmol) of the product of Example 12, Step I and 50 mg of 5% Pd/C in 5 mL of ethyl acetate was shaken under 40 psi H2 for 1 h. The solution was filtered through Celite and the filtrate was concentrated to afford 0.250 g (100%) of a white powder.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].S(O[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([O:45][CH3:46])=[O:44])(C1C=CC(C)=CC=1)(=O)=O>CN(C)C=O>[C:1]1(=[O:11])[N:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([O:45][CH3:46])=[O:44])[C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COC(=O)CCCCCCCCCCCCCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Agent: [K]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCCCCCCCCCCCCCN1C(=O)c2ccccc2C1=O
Temperature: 110 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
A mixture of potassium phthalimide (5.59 g, 30.2 mmoles) and 200 ml of dried N,N-dimethylformamide was heated to 110° C. To this mixture was added dropwise methyl 20-tosyloxyeicosanoate (10.0 g, 20.1 mmoles) dissolved in 300 ml of N,N-dimethylformamide and the resulting mixture was heated at 110° C. with stirring for 2 hours. After the completion of the reaction, the reaction mixture was treated in the same manner as in Reference Example 2 to give methyl 20-phthalimidoeicosanoate (8.97 g, 95%) having the following properties.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[C:5]([C:7]2[CH:16]=[CH:15][C:14]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[CH:8]=2)[N:6]=1.[Br:17]Br.C(=O)([O-])O.[Na+]>ClCCl>[Br:17][C:4]1[O:3][C:2]([CH3:1])=[N:6][C:5]=1[C:7]1[CH:16]=[CH:15][C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=1
Reactant: Cc1nc(-c2ccc3c(c2)CCCC3)co1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nc(-c2ccc3c(c2)CCCC3)c(Br)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a solution of 2-methyl-4-(5,6,7,8-tetrahydronaphthalen-2-yl)oxazole (9.0 g) in dichloromethane (90 mL) was added dropwise a solution of bromine (2.2 mL) in dichloromethane (5 mL) at room temperature. After stirring the mixture at room temperature for 30 min, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give 5-bromo-2-methyl-4-(5,6,7,8-tetrahydronaphthalen-2-yl)oxazole (11.7 g, yield 95%) as crystals. Recrystallization from ethanol gave colorless plate crystals. melting point: 97–98° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6])#[CH:2].[CH3:10][S:11](Cl)(=[O:13])=[O:12]>N1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([NH:6][S:11]([CH3:10])(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)#[CH:2]
Reactant: CS(=O)(=O)Cl
Reactant: C#Cc1cccc(N)c1
Solvent: c1ccncc1
Product: C#Cc1cccc(NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-ethynyl aniline (1.05 mL, 10.0 mmol) in pyridine (5 mL) was added methanesulfonyl chloride (857 μL, 1.10 eq.) at a temperature of 0° C. The resulting mixture was stirred overnight at room temperature and was then evaporated. The residue was treated with 2 N aq. HCl (25 mL) and subsequently extracted with ethyl acetate (2×30 mL). The combined organic layers were dried over MgSO4 and evaporated to give the desired methanesulfonamide in quantitative yield. It was used without further purification.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]2[N:17]=[CH:18][C:19]([C:20]#[N:21])=[C:6]12)=[O:4].[CH2:22]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[C:11]1([C:8]2[N:7]3[N:17]=[CH:18][C:19]([C:20]#[N:21])=[C:6]3[N:5]([C:3](=[O:4])[CH2:2][N:32]3[CH2:33][CH2:34][N:29]([CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:30][CH2:31]3)[CH2:10][CH:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N#Cc1cnn2c1N(C(=O)CCl)CC=C2c1ccccc1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#Cc1cnn2c1N(C(=O)CN1CCN(Cc3ccccc3)CC1)CC=C2c1ccccc1

Procedure:
A mixture of 3.8 g of 4-(chloroacetyl)-4,5-dihydro-7-phenylpyrazolo[1,5-a]pyrimidine-3-carbonitrile, 2.5 ml of N-benzylpiperazine and 1.6 g of sodium carbonate in 165 ml of toluene was reacted as described in Example 146, giving 4 g of the desired product, mp 156-158.
Reaction SMILES: [F:1][CH2:2][C@H:3]1[CH2:8][NH:7][CH2:6][C@@H:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:4]1.Cl[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25]>>[F:1][CH2:2][C@H:3]1[CH2:8][N:7]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2[N+:24]([O-:26])=[O:25])[CH2:6][C@@H:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH2:4]1
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNC[C@H](CF)C1
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](CF)CN(c2ccncc2[N+](=O)[O-])C1

Procedure:
Method 1 of example 1 was followed using cis (+/−)-tert-butyl 5-(fluoromethyl)piperidin-3-ylcarbamate and 4-chloro-3-nitropyridine yielding cis (+/−)-tert-butyl 5-(fluoromethyl)-1-(3-nitropyridin-4-yl)piperidin-3-ylcarbamate. LCMS (m/z): 355.1 (MH+); LC Rt=2.41 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[CH:12]2.[OH-].[K+].[I:20]I.O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2[I:20]
Reactant: II
Reactant: Fc1cccc(F)c1-c1ccc2[nH]ncc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cccc(F)c1-c1ccc2[nH]nc(I)c2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 72.4 %

Procedure:
To a solution of 5-(2,6-difluoro-phenyl)-1H-indazole (40.8 g, 176.46 mmol) in DMF (441.1 mL) was added KOH (14.8 g, 246.69 mmol) and I2 (98.5 g, 388.21 mmol) at RT. The reaction mixture was stirred for 6 h at RT. Water was added to the reaction mass and extracted with EtOAc (2×500 mL). Organic layer was washed with brine and dried over Na2SO4. The organic layer was concentrated and purified by column using silica (100-200 mesh) and 0-15 EtOAc-hexane to provide 5-(2,6-difluoro-phenyl)-3-iodo-1H-indazole (45.5 g, 72.4% yield). MS (ESI, pos. ion) m/z: 357.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[O:11][CH3:12]>[Fe].CC(O)=O.O>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1ccc([N+](=O)[O-])cc1Br
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(N)cc1Br
Temperature: 80 °C
Yield: 86 %

Procedure:
A mixture of 670 mg (2.9 mmol) of 2-bromo-4-nitroanisole and 1.20 g (21.1. mmol) of iron powder in 10 mL of 1:1 v/v HOAc/H2O was heated at 80° C. for 1.5 h. The mixture was cooled and filtered onto a pad of Celite. The flask and filtered solids were rinsed with 100 mL of EtOAc and 100 mL of H2O. The filtrate was transfered to a separatory fumel and the layers were separated. The organic layer was washed with 50 mL of sat'd NaHCO3, 50 mL sat'd NaCl, dried over MgSO4 and concentrated in vacuo. Flash chromatography on 25 g of silica gel using 3:2 v/v hexanes/ether as the eluant afforded 504 mg (86%) of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH3:29])=[N:13][C:14]=1[CH2:15][CH3:16].N1C=CN=C[C:33]=1N>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:33][CH2:20][C@@H:19]2[O:27][CH2:28][CH3:29])=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: Nc1cnccn1
Product: CCO[C@H]1CCc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (cis)-2-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl]pyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 1.14, 1.20, 1.29, 1.95, 2.31, 2.45, 2.73, 2.82, 3.12, 3.48, 3.74, 3.99, 5.42, 5.75, 7.12–7.21, 7.36, 7.51; HRMS (FAB) calcd for C25H27Cl2N3O+H 456.1609, found 456.1617.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10]([O:13]/[N:14]=C(/OCC)\C)(=[O:12])=[O:11]>O1CCOCC1.O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10]([O:13][NH2:14])(=[O:11])=[O:12]
Reactant: CCO/C(C)=N/OS(=O)(=O)c1c(C)cc(C)cc1C
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl (1E)-N-(2,4,6-trimethylphenyl)sulfonyloxyethanimidate (14 g, 49.12 mmol) in 1,4 dioxane (25 mL) is added HClO4 (7.0 mL, 70% in water) at 0° C. and the reaction mixture is stirred at room temperature for 1 hour. The reaction mixture is diluted with water and extracted with DCM (2×50 mL). The combined organic extracts are dried over sodium sulphate and filtered. The crude material is used without further purification (10 g, theoretical yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:21])=[C:4]([C:13]([NH:15][C:16]([CH3:20])([CH3:19])[CH2:17][OH:18])=[O:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([OH:9])=[O:8].[C:22](Cl)(=[O:24])[CH3:23]>CC(N(C)C)=O>[C:22]([NH:1][C:2]1[C:3]([I:21])=[C:4]([C:13]([NH:15][C:16]([CH3:19])([CH3:20])[CH2:17][OH:18])=[O:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([OH:9])=[O:8])(=[O:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: CC(C)(CO)NC(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1c(I)c(C(=O)O)c(I)c(C(=O)NC(C)(C)CO)c1I

Procedure:
Analogously to Example 3, 63.0 g. (100 mmol) of 5-amino-N-(2-hydroxy-1,1-dimethylethyl)-2,4,6-triiodoisophthalamic acid is reacted in 120 ml. of dimethylacetamide with 17 ml. of acetyl chloride and worked up. Yield: 64.0 g. (95%), m.p. 279°-281° C., with decomposition.
Reaction SMILES: O1CCCC1.[CH2:6]([O:8][CH:9]([O:15][CH2:16][CH3:17])[C:10]1([CH:13]=[O:14])[CH2:12][CH2:11]1)[CH3:7].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O>[CH2:16]([O:15][CH:9]([O:8][CH2:6][CH3:7])[C:10]1([CH2:13][OH:14])[CH2:11][CH2:12]1)[CH3:17]
Reactant: CCOC(OCC)C1(C=O)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(OCC)C1(CO)CC1
Reaction time: 0.67 h
Yield: 90.5 %

Procedure:
A tetrahydrofuran (190 mL) solution of 1-(diethoxymethyl)cyclopropane carboaldehyde (37.78 g) was cooled to 0° C. Lithium aluminum hydride (2 g, 52.7 mmol) was added and the mixture was stirred for 40 minutes. Water was added to terminate the reaction, followed by extraction with chloroform. The organic layer was washed with water and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, whereby 34.60 g (91%) of the title compound was obtained as a colorless oil.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([S:20][CH2:21][CH2:22][CH3:23])[N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:21]([S:20][C:16]1[N:15]=[C:14]([C:12]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:13]=2)[CH:19]=[CH:18][CH:17]=1)[CH2:22][CH3:23]
Reactant: COC(=O)c1ccccc1S
Reactant: CCCSc1cccc(C#N)n1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCSc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 36.6 %

Procedure:
A mixture of methyl thiosalicylate (0.67 g, 4.0 mmol), 2-cyano-6-propylthiopyridine (0.72 g, 4.0 mmol), triethylamine (0.84 ml, 6.0 mmol) and toluene (50 ml) was refluxed for 48 hrs as described in Example 1. The reaction mixture was concentrated under reduced pressure and the residue was recrystallized from ethanol to give the titled compound (0.46 g, 37%) as crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH2:13][CH2:14][CH2:15][C@@H:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][S:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:18][C@@H:17]1[C:31]([O:33]C)=[O:32].[ClH:35]>>[ClH:35].[ClH:35].[ClH:35].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH2:13][CH2:14][CH2:15][C@@H:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][S:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:18][C@@H:17]1[C:31]([OH:33])=[O:32]
Reactant: COC(=O)[C@H]1CN(CCSc2ccccn2)CC[C@H]1CCCc1ccnc2ccc(OC)cc12
Agent: Cl
Product: COc1ccc2nccc(CCC[C@@H]3CCN(CCSc4ccccn4)C[C@@H]3C(=O)O)c2c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A solution of 0.5 g of methyl (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(pyridin-2-ylthio)ethyl]piperidine-3-carboxylate in 7.8 cm3 of 6N hydrochloric acid was heated with stirring at a temperature in the region of 100° C. for 2 hours. After concentrating the reaction mixture to dryness under reduced pressure (5 kPa) at a temperature in the region of 80° C. the residue obtained was triturated in 10 cm3 of diisopropyl ether. The insoluble material was filtered off and then dried under reduced pressure (13 kPa) at a temperature in the region of 60° C. 0.55 g of (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(pyridin-2-ylthio)ethyl]piperidine-3-carboxylic acid trihydrochloride was obtained in the form of a solid with a cream color which melts with softening in the region of 165° C.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:12])[N:4]([CH3:11])[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[NH2:8].[CH3:13][O:14][C:15]1[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:16]=1[CH:17]=[CH:18][C:19](O)=O>>[CH3:13][O:14][C:15]1[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:16]=1/[CH:17]=[CH:18]/[C:19]1[NH:1][C:2]2[C:3](=[O:12])[N:4]([CH3:11])[C:5](=[O:10])[N:6]([CH3:9])[C:7]=2[N:8]=1
Reactant: Cn1c(N)c(N)c(=O)n(C)c1=O
Reactant: COc1cccc(C=CC(=O)O)c1OC
Product: COc1cccc(/C=C/c2nc3c([nH]2)c(=O)n(C)c(=O)n3C)c1OC

Procedure:
Substantially the same procedure as in Example 7 was repeated using 2.50 g (14.7 mmol) of 5,6-diamino-1,3-dimethyluracil and 3.37 g (16.2 mmol) of 2,3-dimethoxycinnamic acid. Then, the resultant crude crystals were recrystallized from ethanol/water to give 1.03 g (yield of Compound 88 as pale yellow needles.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[O:32]=[C:33]1[N:39]([CH:40]2[CH2:45][CH2:44][N:43]([C:46]3[N:51]=[CH:50][N:49]=[C:48]([C:52](O)=[O:53])[CH:47]=3)[CH2:42][CH2:41]2)[CH2:38][CH2:37][C:36]2[CH:55]=[CH:56][CH:57]=[CH:58][C:35]=2[NH:34]1.C(N(CC)CC)C>CN(C=O)C.CO.O>[N:1]1([C:52]([C:48]2[N:49]=[CH:50][N:51]=[C:46]([N:43]3[CH2:44][CH2:45][CH:40]([N:39]4[CH2:38][CH2:37][C:36]5[CH:55]=[CH:56][CH:57]=[CH:58][C:35]=5[NH:34][C:33]4=[O:32])[CH2:41][CH2:42]3)[CH:47]=2)=[O:53])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cc(N2CCC(N3CCc4ccccc4NC3=O)CC2)ncn1
Reactant: c1ccc2c(c1)CCN2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1cc(N2CCC(N3CCc4ccccc4NC3=O)CC2)ncn1)N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
34 μL (0.30 mmol) 2,3-dihydro-1H-indole and 90.0 mg (0.28 mmol) TBTU was added to 100 mg (0.27 mmol) 6-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid and 42 μL (0.30 mmol) triethylamine in 4.0 mL DMF. The mixture was stirred for 1 h at RT and then poured onto 40 mL water. The precipitated product was suction filtered. The solid was stirred with methanol, suction filtered and dried.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7](=[O:32])[N:8]2[C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]3[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[C:21]([F:27])[C:20]=3[F:28])[C:14]([O:29][CH3:30])=[CH:13][C:12]=2[Cl:31])=[C:4]([O:33][CH3:34])[N:3]=1.C(N(CC)C(C)C)(C)C.C([O:47][CH2:48][C:49](Cl)=[O:50])(=O)C.Cl>C(OCC)(=O)C>[Cl:31][C:12]1[CH:13]=[C:14]([O:29][CH3:30])[C:15]([O:17][CH2:18][C:19]2[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[C:21]([F:27])[C:20]=2[F:28])=[CH:16][C:11]=1[N:8]1[C:7](=[O:32])[NH:6][C:5]2[C:9]1=[N:10][C:2]([NH:1][C:48](=[O:47])[CH2:49][OH:50])=[N:3][C:4]=2[O:33][CH3:34]
Reactant: COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)nc(N)nc32)cc1OCc1c(OC)ccc(F)c1F
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)nc(NC(=O)CO)nc32)cc1OCc1c(OC)ccc(F)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-amino-9-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-6-methoxy-7,9-dihydro-8H-purin-8-one (40 mg) and N,N-diisopropyl-ethylamine (0.15 mL) in ethyl acetate (4 mL) was added acetoxyacetyl chloride (0.078 mL), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in methanol (1 mL)-tetrahydrofuran (2 mL). To the solution was added sodium methoxide (28% methanol solution, 0.05 mL), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 1 mol/L hydrochloric acid, and the mixture was poured into a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1−ethyl acetate) to give the title compound (4 mg).