Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[C:6]2[NH:7][C:8]([CH2:10][C:11]([O:13]CC)=[O:12])=[N:9][C:5]=2[CH:4]=1.C1COCC1.O.[OH-].[Li+:31]>C1COCC1>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[C:6]2[NH:7][C:8]([CH2:10][C:11]([O-:13])=[O:12])=[N:9][C:5]=2[CH:4]=1.[Li+:31]
Reactant: CCOC(=O)Cc1nc2cc(C(F)(F)F)cc(C(F)(F)F)c2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C([O-])Cc1nc2cc(C(F)(F)F)cc(C(F)(F)F)c2[nH]1
Reaction time: 8 h
Yield: 114.7 %

Procedure:
A solution of ethyl 2-(5,7-bis(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)acetate (250 mg, 0.74 mmol) in 4:1 THF/water (4 mL) was treated with lithium hydroxide (21 mg, 0.88 mmol), and the mixture was stirred overnight. Analysis by LC/MS indicated that the reaction was not complete, so additional lithium hydroxide (5 mg, 0.21 mmol) was added, and the mixture was stirred for 6 h. Analysis by LC/MS indicated that the reaction was still not complete, so additional lithium hydroxide (15 mg, 0.63 mmol) was added, and the mixture was stirred overnight. Analysis by LC/MS indicated that the reaction was complete. The THF was stripped in-vacuo at room temperature, and the aqueous was freeze-dried to yield 270 mg of yellow powder. This material was used as-is in the next step. 1H NMR (500 MHz, CD3OD) δ ppm 3.72 (s, 2H) 7.54 (s, 1 H) 7.96 (s, 1 H).
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][CH2:20][CH2:21][O:22]C2CCCCO2)[CH:13]=1.Cl.C(OCC)(=O)C>C(O)C>[OH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][CH2:20][CH2:21][OH:22])[CH:13]=1
Reactant: c1cc(CCCCOC2CCCCO2)cc(CCCCOC2CCCCO2)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: OCCCCc1cccc(CCCCO)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 56.4 %

Procedure:
To a solution of, 822 mg of 1,3-bis[4-(2-tetrahydropyranyloxy)butyl]benzene in 3 ml of ethanol was added 1.5 ml of 6N hydrochloric acid, and after stirring at a room temperature for 7 hours, 30 ml of ethyl acetate and 10 ml of ice water were added. The separated organic layer was washed with 5% sodium bicarbonate aqueous solution, water and a saturated sodium chloride, dried over magnesium sulfate, and evaporated under a reduced pressure to remove the solvent. The resulting oily residue was applied to a silica gel column and eluted with chloroform/methanol (100:1) to obtain 264 mg of the title compound as a colorless liquid.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:16]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[CH:32]=[C:31]([F:33])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[CH2:22][C@@H:21]1[OH:34])=[O:17])[CH:13]([CH3:15])[CH3:14])=O)C1C=CC=CC=1.[ClH:35].C(O)(C)C.[H][H]>C(O)(C)C.[C].[Pd]>[ClH:35].[NH2:11][C@H:12]([C:16]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[CH:32]=[C:31]([F:33])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[CH2:22][C@@H:21]1[OH:34])=[O:17])[CH:13]([CH3:14])[CH3:15]
Reactant: [H][H]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1O
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Product: CC(C)[C@H](N)C(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1O
Yield: 84.2 %

Procedure:
To a solution of 1.70 g (3.55 m-mol) of 5'-O-(N-benzyloxycarbonylvalyl)-2'-deoxy-5-fluorouridine obtained in Example 26 in 50 ml of isopropyl alcohol were added 10% palladium-carbon (750 mg) and a solution of 16.0% hydrogen chloride-isopropyl alcohol (810 mg). The mixture was stirred for 3.5 hours in a stream of hydrogen under normal pressure at ordinary temperature. The catalyst was filtered off and the solvent was distilled off under reduced pressure from the reaction mixture and the residue was dissolved in isopropyl alcohol (5 ml). A small amount of ether was added to this solution and the resultant white precipitate was collected by filtration in a stream of dry nitrogen whereby 1.14 g (yield: 84.1%) of 5'-O-(valyl)-2'-deoxy-5-fluorouridine hydrochloride was obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH2:24][CH3:25])[C:13]3[C:18]([C:19]=2[C:20]#[N:21])=[CH:17][CH:16]=[C:15]([O:22][CH3:23])[CH:14]=3)=[CH:7][CH:6]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>N1C=CC=CC=1>[C:20]([C:19]1[C:18]2[C:13](=[CH:14][C:15]([O:22][CH3:23])=[CH:16][CH:17]=2)[N:12]([CH2:24][CH3:25])[C:11]=1[C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:1][S:27]([CH3:26])(=[O:29])=[O:28])=[CH:6][CH:7]=1)#[N:21]
Reactant: CCn1c(-c2ccc(OCCN)cc2)c(C#N)c2ccc(OC)cc21
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCn1c(-c2ccc(OCCNS(C)(=O)=O)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
2-[4-(2-Aminoethoxy)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (30 mg, 0.09 mmol), prepared in step B, above, is dissolved in pyridine (300 μL). Methanesulfonyl chloride (8 μL, 0.1 mmol) is added. This is stirred at room temperature for 45 minutes. More methansulfonyl chloride (4 μL, 0.05 mmol) is added. Stirring continues for another hour. The reaction mixture is partitioned between EtOAc and aqueous HCl. The organic layer is dried and concentrated. Purification by silica gel chromatography (1/1 CH2Cl2/EtOAc) yields N-{2-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)phenoxy]ethyl}methanesulfonamide, compound 268 (32 mg, 86%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)([O-])=O.[C:14](OC(=O)C)(=[O:16])[CH3:15]>C(O)(=O)C.[Fe]>[C:14]([NH:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)(=[O:16])[CH3:15]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)OC(C)=O
Agent: [Fe]
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
150 g (0.83 mole) of 4-nitrophenylacetic acid are heated to 95° C. in 1.5 liters of glacial acetic acid. With vigorous stirring, 160 g (2.86 moles) of iron powder are added in portions in such a manner that the internal temperature does not rise above 105° C. Towards the end of the reaction, the reaction mixture clears up. 200 ml of acetic anhydride are added, and stirring is afterwards continued for a further 30 minutes at 100° C. Cooling to room temperature is allowed to take place; this is followed by suction filtration from formed iron salts, concentration to half the volume, and dilution with 1.5 liters of water. Extraction is effected three times with, in each case, one liter of ethyl acetate. This is followed by washing the organic phase with water and then concentrating it to dryness to obtain 133 g (83.1% of theory) of 4-acetamidophenylacetic acid (m.p. 168° to 170° C.).
Reaction SMILES: C(OC([N:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:17]([CH2:18][CH2:19][O:20][CH2:21][C:22]3[O:23][CH:24]=[CH:25][CH:26]=3)[C:16]3[CH:27]=[CH:28][CH:29]=[CH:30][C:15]=3[N:14]=2)[CH2:8][CH2:7]1)=O)C.[OH-].[K+].C(O)(C)C>O>[O:23]1[CH:24]=[CH:25][CH:26]=[C:22]1[CH2:21][O:20][CH2:19][CH2:18][N:17]1[C:16]2[CH:27]=[CH:28][CH:29]=[CH:30][C:15]=2[N:14]=[C:13]1[N:9]1[CH2:10][CH2:11][CH2:12][NH:6][CH2:7][CH2:8]1
Reactant: CCOC(=O)N1CCCN(c2nc3ccccc3n2CCOCc2ccco2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: c1coc(COCCn2c(N3CCCNCC3)nc3ccccc32)c1
Reaction time: 18 h

Procedure:
Combine 1-ethoxycarbonyl-4-(1-(2-(fur-2-ylmethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (1 mmol), potassium hydroxide (1.2 mmol), and isopropanol (20 mL). Heat to reflux. After 18 hours, evaporate in vacuo to give a residue. Combine the residue and water. Extract with dichloromethane. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:18][CH:17]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.C(O[C:35]1(O[Si](C)(C)C)[CH2:37][CH2:36]1)C.C([BH3-])#N.[Na+]>CO>[CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[NH:15][C:16]2[CH:17]=[CH:18][C:19]([N:22]4[CH2:27][CH2:26][N:25]([CH:35]5[CH2:37][CH2:36]5)[CH2:24][CH2:23]4)=[CH:20][CH:21]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(Nc3ccc(N4CCNCC4)cc3)c3ccccc3nc2c1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: c1ccc2c(Nc3ccc(N4CCN(C5CC5)CC4)cc3)c3ccccc3nc2c1
Temperature: 25 °C
Yield: 2 %

Procedure:
35 mg (0.10 mmol) of 9-[4-(piperazin-1-yl)phenyl]aminoacridine (Example 16) was dissolved in 1 ml of methanol. 57 μl (1.0 mmol) of acetic acid, 22 μl (0.11 mmol) of (1-ethoxycyclopropyloxy)-trimethylsilane and a small amount of 3 Å molecular sieves were added. The reaction mixture was stirred at room temperature under nitrogen atmosphere. After 30 min 28 mg (0.45 mmol) of sodium cyanoborohydride was added and the reaction mixture was heated at 50° C. over night. The solvents were removed under vacuum, and the residue was purified by chromatography (silica gel column, eluent chloroform/methanol 6:1) to obtain 3.8 mg (10%, overall yield 2%) of the title compound.
Reaction SMILES: [Cl-:1].[NH2:2][C@H:3]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:4][N+:5]([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C.[O-]S(C(F)(F)F)(=O)=O.[N:29]1([S:34](N2C=C[N+](C)=C2)(=[O:36])=[O:35])[CH:33]=[CH:32][N:31]=[CH:30]1>CC#N>[Cl-:1].[N:29]1([S:34]([NH:2][C@H:3]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:4][N+:5]([CH3:8])([CH3:6])[CH3:7])(=[O:36])=[O:35])[CH:33]=[CH:32][N:31]=[CH:30]1
Reactant: C[n+]1ccn(S(=O)(=O)n2ccnc2)c1
Reactant: COC(=O)C[C@@H](N)C[N+](C)(C)C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)C[C@H](C[N+](C)(C)C)NS(=O)(=O)n1ccnc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of (R)-2-amino-4-methoxy-N,N,N-trimethyl-4-oxobutan-1-aminium chloride (35 mg) in anhydrous MeCN (5 mL) is treated with triethyl amine (2.5 equiv.) and 3-(Imidazole-1-sulfonyl)-1-methyl-3H-imidazol-1-ium triflate (1.5 equiv.). The reaction mixture is stirred at ambient temperature for 16 h then concentrated under reduced pressure and the resulting residue is purified on silica gel using MeOH/DCM (0->80%).
Reaction SMILES: [CH3:1][N:2]([C:4]([CH2:6][C:7]1[CH:28]=[CH:27][C:26]2[C:12]3[NH:13][C:14](=[O:25])[C:15]4[N:16]([CH:17]=[C:18]([C:20]([O:22]CC)=[O:21])[N:19]=4)[C:11]=3[CH2:10][C:9]=2[CH:8]=1)=[O:5])[CH3:3].O1CCOCC1.[OH-].[Na+]>O>[CH3:1][N:2]([C:4]([CH2:6][C:7]1[CH:28]=[CH:27][C:26]2[C:12]3[NH:13][C:14](=[O:25])[C:15]4[N:16]([CH:17]=[C:18]([C:20]([OH:22])=[O:21])[N:19]=4)[C:11]=3[CH2:10][C:9]=2[CH:8]=1)=[O:5])[CH3:3]
Reactant: CCOC(=O)c1cn2c3c([nH]c(=O)c2n1)-c1ccc(CC(=O)N(C)C)cc1C3
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CN(C)C(=O)Cc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nc(C(=O)O)cn12
Yield: 72 %

Procedure:
The preparation is carried out as in Example 25 but from 0.3 g of ethyl 8-(N,N-dimethylaminocarbonylmethyl)-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-2-carboxylate, 15 ml of dioxane, 15 ml of water and 2.3 ml of 1N sodium hydroxide solution. 0.2 g of 8-(N,N-dimethylaminocarbonylmethyl)-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-2-carboxylic acid is obtained in the form of an ochre solid melting above 260° C. (Analysis C18H16N4O4 ; % Calculated C: 61.36, H: 4.58, N: 15.90, O: 18.16; % Found C: 61.1, H: 4.5, N: 15.6, O: 18.0).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:13][O:14][C:15]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18].O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][S:9]([NH:18][CH2:17][C:16]2[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:15]=2[O:14][CH3:13])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: O=S(=O)(Cl)Cc1cccc(Cl)c1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CNS(=O)(=O)Cc2cccc(Cl)c2)c(OC)c1
Reaction time: 0.5 h

Procedure:
At room temperature, 1.06 g of 3-chlorophenylmethanesulfonyl chloride were initially charged in 30 ml of dichloromethane, and 1.42 ml of 2,4-dimethoxybenzylamine were added dropwise. The reaction mixture was stirred for 30 minutes. Then the mixture was admixed with 50 ml of water and 50 ml of water, and then the aqueous phase was washed once more with 30 ml of ethyl acetate. The combined organic phases were washed with 1 N aqueous hydrochloric acid, dried over MgSO4 and concentrated by rotary evaporation. The residue (1.65 g) was used in the next reaction without further purification.
Reaction SMILES: [C:1]([Si:5]([O:8][CH:9]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH2:41][CH3:42])([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[C:27]([CH3:40])[CH:26]=2)[CH2:23][CH3:24])=[CH:18][C:17]=1[CH3:43])[C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[CH2:44]([O:46][C:47](=[O:55])[CH2:48][C:49]1[N:50]=[C:51](Br)[S:52][CH:53]=1)[CH3:45].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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.O>[CH2:44]([O:46][C:47](=[O:55])[CH2:48][C:49]1[N:50]=[C:51]([C:28]2[CH:29]=[CH:30][C:25]([C:22]([C:19]3[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][CH:9]([O:8][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:6])[CH3:7])[C:10]([CH3:13])([CH3:12])[CH3:11])=[C:17]([CH3:43])[CH:18]=3)([CH2:23][CH3:24])[CH2:41][CH3:42])=[CH:26][C:27]=2[CH3:40])[S:52][CH:53]=1)[CH3:45]
Reactant: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: CCOC(=O)Cc1csc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)Cc1csc(-c2ccc(C(CC)(CC)c3ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c3)cc2C)n1
Temperature: 100 °C
Reaction time: 12 h
Yield: 82.3 %

Procedure:
Degassed N,N-dimethylformamide (0.53 mL) was added to t-butyl-(1-{2-[4-(1-ethyl-1-{4-[4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy)dimethylsilane (Example 24-(1); 50.4 mg, 0.083 mmol), 2-bromothiazole-4-acetic acid ethyl ester (Example 42; 37.8 mg, 0.151 mmol), tetrakis(triphenylphosphine)palladium (0) (12.7 mg, 0.011 mmol) and potassium phosphate (50 mg, 0.24 mmol). After replacement with nitrogen, the mixture was heated while stirring at an external temperature of 96 to 104° C. for 12 hours. Water was added to the reaction mixture, followed by extraction with diethyl ether. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/dichloromethane=1/2) to give the title compound (44.4 mg, 82%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([NH:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH:14]=1)[NH:11][C:10]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:9]2)=[O:5])C.O.[OH-].[Na+]>CO>[CH:16]1([NH:15][C:13]2[CH:14]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[C:8]3[C:12]=2[NH:11][C:10]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:9]3)[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: CCOC(=O)c1cc(NC2CCCC2)c2[nH]c(-c3ccccc3)cc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(NC2CCCC2)c2[nH]c(-c3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
7-(Cyclopentyl)amino-2-phenyl-1H-indole-5-carboxylic acid ethyl ester (5 g, 14.3 mmol) prepared in Example 28 was added to a solvent mixture of MeOH (20 mL) and water (20 mL). NaOH (1.3 g, 33.8 mmol) was added thereto, and the mixture was stirred for 4 h at room temperature. After completion of the reaction, MeOH was removed under reduced pressure, and 1N HCl was added to the residue. The resulting mixture was extracted with EtOAc, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under reduced pressure, and the residue was recrystallized from EtOAc and n-Hex to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[O:9])=[CH:6][N:5]=[C:4](S(CC)(=O)=O)[N:3]=1.[NH2:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1>>[C:33]([O:32][C:30]([N:27]1[CH2:28][CH2:29][CH:24]([NH:23][C:4]2[N:3]=[C:2]([NH2:1])[C:7]([C:8](=[O:9])[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[O:16][CH3:17])=[CH:6][N:5]=2)[CH2:25][CH2:26]1)=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CCS(=O)(=O)c1ncc(C(=O)c2ccccc2OC)c(N)n1
Product: COc1ccccc1C(=O)c1cnc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc1N
Yield: 94.8 %

Procedure:
The same procedure was used as described in Example 9 starting from (4-amino-2-ethanesulfonylpyrimidin-5-yl)-(2-methoxyphenyl)-methanone (125.4 mg, 0.3902 mmol, Example 6) and 4-amino-1-Boc-piperidine (101.0 mg, 0.484 mmol, Astatech) to give 4-[4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (158.2 mg, 95% yield). HRMS, observed: 428.2296; Calcd for (M+H)+: 428.2293.
Reaction SMILES: B(F)(F)F.CCOCC.[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][S:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][C:26]([C@@H:28]1[CH2:32][CH2:31][CH2:30][N:29]1[C:33](=O)[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1)=O.[BH4-].[Na+]>O1CCCC1>[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][S:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][CH2:26][C@@H:28]1[CH2:32][CH2:31][CH2:30][N:29]1[CH2:33][CH2:34][C:35]1[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=1
Reactant: COc1ccc(CC(=O)N2CCC[C@H]2C(=O)Nc2ccccc2SCc2ccccc2Br)cc1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(CCN2CCC[C@H]2CNc2ccccc2SCc2ccccc2Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
Boron trifluoride etherate (1531 g, 1327 ml) was added over ten minutes to a stirred, ice-cooled solution of (2S)-(N-[2-(2-bromophenylmethylthio)phenyl])carbamoyl-1-(4-methoxyphenylacetyl)pyrrolidine (see Preparation 23) (1750 g) and sodium borohydride (306.2 g) in tetrahydrofuran (8.73 L). The mixture was stirred at room temperature for one hour, heated under reflux for two hours, cooled, evaporated under reduced pressure to reduced volume to remove the tetrahydrofuran, quenched by the cautious addition of water and further evaporated under reduced pressure. The residue was treated with 40% aqueous sodium hydroxide solution (5 L) and the mixture was heated under reflux for two hours, cooled to room temperature by the addition of ice, acidified to pH 6-7 with concentrated hydrochloric acid and extracted with dichloromethane. The combined organic extracts were washed with 1M aqueous sodium hydroxide solution followed by water, dried over magnesium sulphate and evaporated under reduced pressure to give the desired compound (1589 g, 96%) as a brown oil which was characterised by 1H-NMR spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH3:10].[Br:11]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][Br:11])[C:3]=1[O:9][CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1c(Cl)ccnc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1c(Cl)ccnc1CBr

Procedure:
4-Chloro-3-methoxy-2-methyl-pyridine (6.12 g) is dissolved in carbon tetrachloride (80 ml) then N-bromo-succinimide (7.12 g) and benzoyl peroxide (1 g) are added. The reaction mixture is refluxed under UV irradiation for 1.5 hour. The solid is filtered after cooling and the solvent evaporated. The desired product is purified by chromatography on silica gel.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:11][C:12]1[C:13](F)=[C:14]([CH:17]=[CH:18][CH:19]=1)[C:15]#[N:16]>CN(C=O)C>[CH2:3]([O:10][C:13]1[C:12]([Br:11])=[CH:19][CH:18]=[CH:17][C:14]=1[C:15]#[N:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: N#Cc1cccc(Br)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cccc(Br)c1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.5 %

Procedure:
To a flask containing sodium hydride (1.44 g, 60.0 mmol) suspended in DMF (60 mL, 800 mmol) at 0° C. was added benzyl alcohol (6.21 mL, 60.0 mmol) over 5 min. The reaction mixture was stirred at 0° C. for 30 min and then 3-bromo-2-fluorobenzonitrile (10.0 g, 50.0 mmol) in DMF (20 mL) was added. The reaction mixture was warmed to room temperature and stirred at 80° C. for 2 h, cooled to room temperature, and extracted with ethyl acetate (150 mL) and water (150 mL) The organic layer was washed with water (150 mL) and brine (150 mL), collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was suspended with ethyl acetate:hexanes (1:3; 50 mL). The resulting suspension was stirred vigorously for 1 h, filtered, and dried. The mother liquor was concentrated and recrystallized. The crystals were combined and dried under vacuum to give the title compound (10.3 g). 1H NMR (DMSO-d6, 300 MHz) δ (ppm): 8.04 (dd, J=1.6, 8.2 Hz, 1H), 7.87 (dd, J=1.6, 7.6 Hz, 1H), 7.56-7.51 (m, 2H), 7.47-7.37 (m, 3H), 7.29 (t, J=7.9 Hz, 1H), 5.20 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=O)[CH2:7][CH2:6]1)=[O:4].C([N:16](CC)CC)C.ClC(OCC)=O.[OH-].[NH4+]>O1CCCC1.O>[C:11]([C@H:8]1[CH2:9][CH2:10][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6][CH2:7]1)(=[O:13])[NH2:16]
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)[C@H]1CC[C@H](C(N)=O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a cooled (−10° C.) solution of trans-4-(methoxycarbonyl)cyclohexane-1-carboxylic acid (1.01 g, 5.43 mmol) in tetrahydrofuran (25 mL) was sequentially added triethylamine (1.50 mL, 10.9 mmol) and ethyl chloroformate (0.60 mL, 6.2 mmol) under a nitrogen atmosphere and the reaction mixture stirred at room temperature for 3 h. The reaction was then cooled to −10° C., ammonium hydroxide (5.0 mL, 33 mmol) was added and the reaction mixture warmed to room temperature and stirred overnight whereupon the mixture was diluted with water and extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried and concentrated to give the title compound (0.84 g, 84%) as a white solid.
Reaction SMILES: CN(C=O)C.[OH:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19]2[C:14](=[C:15]([CH2:20][CH:21]3[S:25][C:24](=[O:26])[NH:23][C:22]3=[O:27])[CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][C:11]1=[O:28].C(=O)([O-])[O-].[K+].[K+].[C:35]1([C:41](Cl)([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O>[OH:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19]2[C:14](=[C:15]([CH2:20][CH:21]3[S:25][C:24](=[O:26])[N:23]([C:41]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)([C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)[C:22]3=[O:27])[CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][C:11]1=[O:28]
Reactant: O=C1NC(=O)C(Cc2cccc3c2CCC(=O)N3CCCO)S1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCc2c(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cccc2N1CCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.6 %

Procedure:
A DMF solution (10 ml) of 1.0 g (2.99 mmol) of 5-[1-(3-hydroxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl]thiazolidine-2,4-dione and 0.455 g (3.29 mmol) of potassium carbonate was cooled with ice, and 0.876 g (3.04 mmol) of triphenylmethylchloride was added thereto, followed by stirring at room temperature overnight. Water was added to the reaction liquid and the mixture was extracted with ethyl acetate. The organic layer was washed twice with water and once with saturated sodium chloride solution, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1→ethyl acetate). The purified product was concentrated under reduced pressure and evaporated to dryness, giving 700 mg (40.6% yield) of 5-[1-(3-hydroxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl]-3-tritylthiazolidine-2,4-dione as a colorless amorphous solid.