Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)=[CH2:2].[NH:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[CH2:14][N:15]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH2:19][S:18][C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]1=2>>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:1][CH2:2][N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[CH2:14][N:15]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH2:19][S:18][C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]1=2
Reactant: c1ccc2c(c1)CSc1ccccc1N2C[C@@H]1CCCN1
Reactant: C=Cc1ccccn1
Product: c1ccc(CCN2CCC[C@H]2CN2c3ccccc3CSc3ccccc32)nc1
Temperature: 120 °C
Yield: 58.3 %

Procedure:
A mixture of 2-vinylpyridine (250 mg) and (S)-5,11-dihydro-5-(2-pyrrolidinylmethyl)dibenzo[b,e][1,4]thiazepine (see Preparations 13 and 14) (166 mg) was heated at 120° C. for 2 hours, cooled to room temperature and purified by chromatography on silica gel using ethyl acetate/methanol (10:1) as eluant. Appropriate fractions were combined and evaporated under reduced pressure to give the title compound as a pale brown gum, (131 mg, 58%).
Reaction SMILES: [OH:1][CH:2]([CH2:20][OH:21])[CH2:3][NH:4][C:5](=[O:19])[C:6]1[CH:11]=[C:10](Cl)[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17].[NH:22]1[CH2:24][CH2:23]1>CCOC(C)=O>[OH:1][CH:2]([CH2:20][OH:21])[CH2:3][NH:4][C:5](=[O:19])[C:6]1[CH:11]=[C:10]([N:22]2[CH2:24][CH2:23]2)[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17]
Reactant: C1CN1
Reactant: O=C(NCC(O)CO)c1cc(Cl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Product: O=C(NCC(O)CO)c1cc(N2CC2)c([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 84.5 %

Procedure:
A solution of N-(2,3-dihydroxypropyl)-5-chloro-2,4-dinitrobenzamide (Friedlos et al., J. Med. Chem., 1997, 40, 1270-1275) (0.50 g, 1.56 mmol) and aziridine (1.00 g, 0.023 mol) in EtOAc (100 mL) was stirred at room temperature for 18 h. After washing with water the solution was worked up to give 2 (0.43 g, 84%): mp (EtOAc/petroleum ether) 145-147° C., 1H NMR [(CD3)2SO] δ8.74 (t, J=5.7 Hz, 1H, NH), 8.64 (s, 1H, H-3), 7.43 (s, 1H, H-6), 4.85 (d, J=4 9 Hz, 1H, OH), 4.58 (t, J=5 7 Hz, 1H, OH), 3 62 (m, 1H, CHOH), 3.44-3.36 (m, 2H, CH2OH), 3.39-3.36 (m, 1H, CONHCHH), 3.16-3.09 (m, 1H, CONHC), 2 48 (s, 4H, aziridine-H); 13C NMR δ164.19 (s), 152.98 (s), 139.70 (s), 138.89 (s), 137 53 (s), 124 57 (d), 122.58 (d), 70.02 (d), 63.70 (t), 42.73 (t), 29.91 (t). Anal. Calcd. for C12H14N4O7. C, 44.18;H, 4.33; N, 17.17%. Found: C, 44.22; H, 4.25; N, 17 40%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[C:12]([O:17][CH2:18][CH2:19][CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)[CH:5]=[CH:4][N:3]=1.Cl.[CH2:26]([O:28][C:29]([CH:31]1[CH2:36][CH2:35][CH:34]([NH2:37])[CH2:33][CH2:32]1)=[O:30])C.C([O-])([O-])=O.[K+].[K+].O>CN1C(=O)CCC1>[CH3:26][O:28][C:29]([CH:31]1[CH2:36][CH2:35][CH:34]([NH:37][C:2]2[N:7]=[C:6]([N:8]3[C:16]4[C:11](=[C:12]([O:17][CH2:18][CH2:19][CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:13]=[CH:14][CH:15]=4)[CH:10]=[CH:9]3)[CH:5]=[CH:4][N:3]=2)[CH2:33][CH2:32]1)=[O:30]
Reactant: CS(=O)(=O)CCCOc1cccc2c1ccn2-c1ccnc(Cl)n1
Reactant: CCOC(=O)C1CCC(N)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)C1CCC(Nc2nccc(-n3ccc4c(OCCCS(C)(=O)=O)cccc43)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
1-(2-Chloro-pyrimidin-4-yl)-4-(3-methanesulfonyl-propoxy)-1H-indole (300 g), 4-amino-cyclohexanecarboxylic acid ethyl ester HCl salt (155 g), and K2CO3(170 g) in NMP (2.35 L) were stirred at 80° C. for 5 h and then stirred overnight at room temperature. The reaction mixture was then stirred on an ice bath, and 2.5 L water was slowly added while stirring, and cooling continued until completion of the exothermic reaction. Upon cooling, the mixture was filtered, and resulting solid was rinsed with H2O and dried in vacuo overnight to yield 4-{4-[4-(3-methanesulfonyl-propoxy)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexanecarboxylic acid methyl ester (97%).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:31]1[S:35][N:34]=[CH:33][N:32]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:12][C:11]=1[F:30])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:30][C:11]1[CH:12]=[C:13]([O:17][C@@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:14]([F:16])=[CH:15][C:10]=1[S:7]([NH:6][C:31]1[S:35][N:34]=[CH:33][N:32]=1)(=[O:9])=[O:8]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(O[C@@H]3CCCC[C@@H]3c3ccccc3)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Nc1ncns1)c1cc(F)c(O[C@@H]2CCCC[C@@H]2c2ccccc2)cc1F
Yield: 112.2 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1R*,2R*)-2-phenylcyclohexyl]oxy}-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (53.0 mg, 0.088 mmol) prepared in Example 3a, triethylsilane (0.10 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (44.6 mg, 99%) as a colorless solid.
Reaction SMILES: [NH2:1][CH:2]([CH2:7][NH2:8])[C:3]([O:5][CH3:6])=[O:4].[OH-].[K+].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:20]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)=O)=O)=[CH:14][CH:13]=1>CO.C(Cl)Cl>[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:8]=[CH:7][C:2]([C:3]([O:5][CH3:6])=[O:4])=[N:1][C:20]=2[C:22]2[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=2)=[CH:14][CH:13]=1
Reactant: COC(=O)C(N)CN
Reactant: Cc1ccc(C(=O)C(=O)c2ccc(C)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cnc(-c2ccc(C)cc2)c(-c2ccc(C)cc2)n1
Temperature: 65 °C

Procedure:
Methyl 2,3-diaminopropionate example 1A (2.4 g, 12.6 mmol) was shaken vigorously for 5 min in a solution of KOH (2.1 g, 37.7 mmol) in 20 mL of MeOH. The resulting milky solution was filtered to remove the solids, and the filtrate was added to a solution of 4,4′-dimethylbenzil (4.48 g, 18.8 mmol) in 20 mL of MeOH. The resulting mixture was heated to 65° C. for 14 h with a reflux condenser open to air. Solvent was evaporated and the residue was dissolved in 300 mL of EtOAc and 200 mL of 1N HCl. The layers were extracted and the organic layer was evaporated to give a thick oil that was redissolved in 5 mL of CH2Cl2 and this solution was loaded onto dry 120 g silica cartridge. The solvent was evaporated with a stream of N2, and the desired product example 1B was eluted with a gradient of 0-40% EtOAc/hexanes to give 1.71 g of a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH3:16])=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:7]=2[CH:24]=1)#[CH:2].Br[C:26]1[CH:27]=[N:28][CH:29]=[N:30][CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:8]1[C:7]2[CH:24]=[C:3]([C:1]#[C:2][C:26]3[CH:27]=[N:28][CH:29]=[N:30][CH:31]=3)[CH:4]=[CH:5][C:6]=2[N:12]2[C:13]([CH3:16])=[N:14][N:15]=[C:11]2[CH2:10][N:9]=1
Reactant: C#Cc1ccc2c(c1)C(c1ccccc1F)=NCc1nnc(C)n1-2
Reactant: Brc1cncnc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nnc2n1-c1ccc(C#Cc3cncnc3)cc1C(c1ccccc1F)=NC2
Reaction time: 24 h

Procedure:
A mixture of 316 mg (1 mmol) of 8-ethynyl-6-(2-fluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine 200 mg (1.25 mmol) of 5-bromopyrimidine, 45 mq of triphenylphosphine, 10 mg of cuprous iodide, 0.5 ml of triethylamine and 10 ml of dimethylformamide was stirred and degassed for 10 minutes by a slow stream of argon. Palladium acetate, 15 mg, was then added and stirring under argon was continued for 24 hours. The reaction mixture was partitioned between aqueous sodium bicarbonate solution and methylene chloride. The organic layer was washed with water, dried and evaporated, at the end azeotropically with xylene. The residue was chromatographed over 20 g of silica gel (Merck 70-230 mesh) using 5% of ethanol in methylene chloride. The combined clean fractions were evaporated and the residue was crystallized from ethyl acetate to give off-white crystals of the title compound with m.p. 143°-146° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([N:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][C:22]([OH:28])=[CH:23][CH:24]=2)[CH2:19]1)=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:29]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([CH2:45]Br)[CH2:41][CH2:40]1)=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[OH-].[Na+].O>CS(C)=O>[CH2:29]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([CH2:45][O:28][C:22]2[CH:21]=[C:20]3[C:25]([CH2:26][CH2:27][N:18]([C:9](=[N:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:19]3)=[CH:24][CH:23]=2)[CH2:41][CH2:40]1)=[O:38])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(OCc1ccccc1)N1CCC(CBr)CC1
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCc2ccc(O)cc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCc2ccc(OCC3CCN(C(=O)OCc4ccccc4)CC3)cc2C1
Temperature: 25 °C
Reaction time: 17 h
Yield: 69.1 %

Procedure:
To a solution of N,N′-di-tert-butoxycarbonyl-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine (50 mg) and 4-bromomethylpiperidine-1-carboxylic acid benzyl ester (120 mg) in dimethyl sulfoxide (1 ml) was added 4N aqueous sodium hydroxide solution (0.13 ml), and the mixture was stirred at room temperature for 17 hours. After completion of the reaction, water was added, and the mixture was extracted with ethyl acetate and washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane:acetone=5:1) and dried under reduced pressure to give the title compound (55 mg).
Reaction SMILES: [CH2:1]([O:4][NH:5][C@@H:6]1[CH:11]=[CH:10][C@@H:9]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[NH:8][CH2:7]1)[CH:2]=[CH2:3].C(N(C(C)C)C(C)C)C.[C:30](=O)(OC(Cl)(Cl)Cl)[O:31]C(Cl)(Cl)Cl>C(#N)C>[CH2:1]([O:4][N:5]1[C:30](=[O:31])[N:8]2[CH2:7][C@H:6]1[CH:11]=[CH:10][C@H:9]2[CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16])[CH:2]=[CH2:3]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C=CCON[C@@H]1C=C[C@@H](CO[Si](C)(C)C(C)(C)C)NC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C=CCON1C(=O)N2C[C@H]1C=C[C@H]2CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 188.6 %

Procedure:
To a stirred solution of O-allyl-N-((3R,6S)-6-((tert-butyldimethylsilyloxy)methyl)-1,2,3,6-tetrahydropyridin-3-yl)hydroxylamine (Intermediate 128, 2.0 g, 6.70 mmol) in acetonitrile (560 mL), N-ethyl-N-isopropylpropan-2-amine (4.67 ml, 26.80 mmol) was added. Bis(trichloromethyl) carbonate (0.795 g, 2.68 mmol) dissolved in 40 mL CH3CN was added via a syringe pump (at a rate 0.1 ml/min) at 0° C. The reaction mixture was stirred at 0° C. for 1 hr. It was then allowed to stir at room temperature overnight. The mixture was then concentrated and diluted with EtOAc (50 mL). The organic layer was washed with water, brine, dried over MgSO4, filtered and concentrated. The residue was purified by silica gel column (12 g, 0-25% Hex/EA) to give the desired product as a colorless oil (1.64 g).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:10](=O)[CH2:9][CH2:8][N:7]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6]1)=[O:4].[BH4-].[Na+].[OH-].[NH4+:22]>>[CH3:1][O:2][C:3]([C:5]1[CH2:6][N:7]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:9][C:10]=1[NH2:22])=[O:4]
Reactant: [NH4+]
Reactant: COC(=O)C1CN(Cc2ccccc2)CCC1=O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)C1=C(N)CCN(Cc2ccccc2)C1
Temperature: 50 °C
Reaction time: 18 h
Yield: 25 %

Procedure:
rac-1-Benzyl-4-oxo-piperidine-3-carboxylic acid methyl ester (25 g) was suspended in 100 ml ammonium hydroxide 25% and heated at 50° C. during 18 h. The mixture was cooled with ice and then, NaBH4 (1 g) was added in several portions. Stirring was continued for 18 h at ambient temperature and the mixture was diluted with water/ice, with cooling, and extracted with AcOEt. The organic extract was washed with brine and dried over sodium sulfate. Removal of the solvent under reduced pressure gave a brown oil which was purified by column chromatography (silica gel, heptane/AcOEt, 1/1) and precipitated (AcOEt/heptane) to give 12.1 g (56%) of the title compound as white solid and 6 g (25%) of the title compound as its borane salt.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]1[CH2:11][C:12](=[O:15])[CH2:13][CH2:14][C:8]1=[C:7]2[CH2:16][C:17]([O:19][CH2:20][CH2:21][CH3:22])=[O:18].[CH3:23][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]1[CH:11]([CH3:23])[C:12](=[O:15])[CH2:13][CH2:14][C:8]1=[C:7]2[CH2:16][C:17]([O:19][CH2:20][CH2:21][CH3:22])=[O:18]
Reactant: CCCOC(=O)Cc1c2n(c3c(F)cccc13)CC(=O)CC2
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CCCOC(=O)Cc1c2n(c3c(F)cccc13)C(C)C(=O)CC2
Reaction time: 0.17 h

Procedure:
A solution of propyl (4-fluoro-7-oxo-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl)acetate in THF (0.17 M) was treated at −78° C. with a 1.0 M solution of NaHMDS in THF (1.2 eq.). After stirring for 10 min, MeI (2.0 eq.) was added. The cooling bath was removed and the mixture stirred for 1 hour, concentrated to dryness and the residue purified by chromatography on SiO2 (0-100% EtOAc/hexanes).
Reaction SMILES: [CH2:1]([NH:8][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]1([O:16][CH2:17][CH:18]2[O:20][CH2:19]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)(C)C>[CH2:1]([N:8]([CH2:19][CH:18]([OH:20])[CH2:17][O:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ONCc1ccccc1
Reactant: c1ccc(OCC2CO2)cc1
Solvent: CC(C)O
Product: OC(COc1ccccc1)CN(O)Cc1ccccc1
Yield: 35 %

Procedure:
The procedure of Example 1 is repeated using 3.5 g of N-benzylhydroxylamine and 6.16 g of phenylglycidyl ether in 50 ml of isopropanol. Purification by liquid chromatography affords the title compound in 35% yield as a colorless oil.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:12]2[C:8]=1[CH2:9][NH:10][C:11]2=[O:39])(=O)=O.[CH3:42][NH:43][CH2:44][C:45]#[CH:46]>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)I>[CH3:42][NH:43][CH2:44][C:45]#[C:46][C:7]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:36])[CH3:37])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:12]2[C:8]=1[CH2:9][NH:10][C:11]2=[O:39]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)C(F)(F)F)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: C#CCNC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Product: CNCC#Cc1ccc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Yield: 47.1 %

Procedure:
In a similar manner to Step 2 of Example 161, 4-trifluoromethanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (80.0 mg, 0.135 mmol) was dissolved in diethylamine (4.0 mL), and the solution was treated with bis(triphenylphosphine)dichloropalladium (14.3 mg, 0.203 mmol), copper iodide (11.6 mg, 0.0608 mmol) and N-methylpropargylamine (0.114 mL, 1.35 mmol), followed by purification by preparative thin-layer chromatography (chloroform/methanol=5/1 to 3/1) to obtain 4-(3-methylamino-1-propinyl)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (32.6 mg, yield 47%).
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:22](Cl)(=[O:24])[CH3:23].Cl>ClC(Cl)C>[OH:17][C:13]1[CH:14]=[CH:15][C:16]([C:22](=[O:24])[CH3:23])=[C:11]([NH:10][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:8])=[O:9])[CH:12]=1
Reactant: CC(=O)Cl
Reactant: O=S(=O)(Nc1cccc(O)c1)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CC(=O)c1ccc(O)cc1NS(=O)(=O)c1ccccc1

Procedure:
To 100 ml of dichloroethane were added 12.5 g of m-benzenesulfonamidophenol and 13.3 g of aluminum chloride and the resultant mixture was heated to 60° C. with stirring. To the mixture was added dropwise a solution of 3.6 ml of acetyl chloride dissolved in dichloroethane over a period of 2 hours followed by further heating to the same temperature for 2 hours. After allowing to cool, the mixture was placed in a hydrochloric acid acqueous solution and extracted with ethyl acetate. The extract was dried, concentrated and recrystallized from a mixture of hexane and ethyl acetate to provide 8.5 g of 4'-hydroxy-2'-benzenesulfonamidoacetophenone.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([C:10]#[N:11])[C:8]#[N:9].O.[NH2:13][NH2:14]>CCO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:10]([NH2:11])=[N:13][NH:14][C:8]=1[NH2:9]
Reactant: NN
Reactant: N#CC(C#N)c1ccccn1
Solvent: O
Solvent: CCO
Product: Nc1n[nH]c(N)c1-c1ccccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.2 %

Procedure:
A mixture of 2-pyridin-2-yl-malononitrile (0.65 g, 4.59 mmol) and hydrazine hydrate (225 μL, 4.59 mmol) in EtOH (5 mL) was heated to reflux and stirred for 16 hours. The reaction mixture was cooled down to room temperature and filtered. The resulting solid was washed with Et2O to provide the title compound as a light tan solid (0.42 g, 52%). The filtrate was evaporated to dryness and purified by silica gel chromatography eluting with NH4OH:MeOH:CH2Cl2 (0.5:5:95) to give a further 63.3 mg (8%) of the desired product. MS (ES+) 176, (ES−) 174. δH (DMSO-d6) 5.45 (4H, br s), 6.98 (1H, t), 7.57 (1H, d), 7.69 (1H, t), 8.46 (1H, d), 10.55 (1H, br s).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH2:9])=[CH:3][CH:2]=1.[C:10]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11].[BH4-].[Na+].O>CO>[C:10]([C:14]1[CH:15]=[CH:16][C:17]([CH2:18][NH:9][CH2:8][CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:20][CH:21]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: NCCc1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)c1ccc(CNCCc2ccncc2)cc1
Temperature: 25 °C
Yield: 91.3 %

Procedure:
1.22 g (10 mmol) of 2-(4-pyridyl)-ethyl amine and 1.62 g (10 mmol) of 4-tert-butyl benzaldehyde were dissolved in 20 ml methanol and stirred at rt over night. 555 mg (15 mmol) of sodium borohydride were added in portions under cooling. After complete addition the reaction mixture was stirred for 1 h at rt. Water was added and methanol was evaporated. The reaction mixture was extracted twice with diethyl ether. The combined organic layers were washed with water, dried over sodium sulfate, filtered and the solvent was evaporated to yield 2.45 g (91%) product as a light yellow oil. 1H NMR (DMSO-d6, 300 MHz): δ 8.49 (d, 2H), 7.34 (d, 2H) 7.21 (d, 2H), 7.13 (d, 2H), 3.77 (s, 2H), 2.93 (t, 2H), 2.81 (t, 2H), 1.31 (s, 9H).
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)[C:8](=[O:16])[NH:7][C:6]1=[O:17])([OH:3])=[O:2].S(=O)(=O)(O)O.[CH2:23](O)[CH3:24]>>[Cl:15][C:12]1[CH:13]=[C:14]2[C:9]([C:8](=[O:16])[NH:7][C:6](=[O:17])[N:5]2[CH2:4][C:1]([O:3][CH2:23][CH3:24])=[O:2])=[CH:10][CH:11]=1
Reactant: O=C(O)Cn1c(=O)[nH]c(=O)c2ccc(Cl)cc21
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cn1c(=O)[nH]c(=O)c2ccc(Cl)cc21
Yield: 82 %

Procedure:
To a suspension of 1-carboxymethyl-7-chloro-2,4(1H, 3H)-quinazolinedione (I) (5 g) in ethanol (50 ml) was added concentrated sulfuric acid (0.96 g) at room temperature, and the reaction solution was refluxed for 19 hours. After the reaction solution was concentrated suitablely to half, water (25 ml) was added, 10% potassium bicarbonate solution (25 g) was further added to adjust to pH 8. The resulting crystal was collected by filtration, washed with water and dried under vacuum to give 4.55 g of the desired compound (yield, 82%).
Reaction SMILES: C([O:4][C@@H:5]1[CH2:9][N:8]([CH2:10][C:11]#[C:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:7](=[O:20])[CH2:6]1)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>CO>[OH:4][C@@H:5]1[CH2:9][N:8]([CH2:10][C:11]#[C:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:7](=[O:20])[CH2:6]1
Reactant: CC(=O)O[C@H]1CC(=O)N(CC#CCN2CCCCC2)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1C[C@H](O)CN1CC#CCN1CCCCC1
Reaction time: 8 h
Yield: 97.8 %

Procedure:
A mixture of 1.0 g of (S)-4-(acetyloxy)-1-[4-(1-piperidinyl)-2-butynyl]-2-pyrrolidinone, 0.75 g of sodium carbonate and 40 ml of methanol was stirred overnight, then filtered and concentrated. The residue was concentrated from dichloromethane and purified by chromatography on deactivated alumina, giving 0.83 g of the desired product as a yellow oil [α]D26° =-8° (c, 1.018, dichloromethane).
Reaction SMILES: [CH3:1][CH:2]([C:11]([OH:13])=[O:12])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9]Br)=[CH:5][CH:4]=1.[C-:14]#[N:15].[K+]>CCO.O>[C:14]([CH2:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]([CH3:1])[C:11]([OH:13])=[O:12])=[CH:4][CH:5]=1)#[N:15]
Reactant: CC(C(=O)O)c1ccc(CBr)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C(=O)O)c1ccc(CC#N)cc1
Temperature: 80 °C

Procedure:
A suspension of 2-(4-bromomethyl)phenylpropionic acid (2.0 g, 8.2 mmol) and potassium cyanide (1.6 g, 24.7 mmol) in EtOH (10 mL) and water (2 mL) was heated at 80° C. in a sealed tube for 1 h. The mixture was cooled to room temperature, diluted with water (10 mL) and the EtOH was removed under reduced pressure. The remaining aqueous mixture was extracted once with EtOAc then acidified carefully with 2N HCl until pH˜3 is reached. The aqueous layer was extracted with EtOAc and the combined organic layer was dried over MgSO4, filtered, and concentrated to give 2-[4-(cyanomethyl)phenyl]propionic acid in ˜90% purity. This material was used directly in the next step. A mixture of 2-[4-(cyanomethyl)phenyl]propionic acid (1.4 g, 7.4 mmol) in MeOH (8 mL) and aqueous NaOH (5N, 8 mL, 40 mmol) was heated at 85° C. in a sealed tube for 1.5 h. The mixture was cooled to room temperature, the MeOH was removed under reduced pressure, and the remaining aqueous was extracted with once ether. The aqueous layer was acidified with 2N HCl until pH˜2 to generate a precipitate that was filtered and dried under vacuum to afford 2-[4-(carboxymethyl)phenyl]propionic acid (1.1 g, 71%) as an off-white solid; 1H NMR (400 MHz, DMSO-d6) δ 12.27 (br s, 1H), 7.15-7.22 (m, 4H), 3.61 (q, J=6.8 Hz, 1H), 3.50 (s, 2H), 1.30 (d, J=7.2 Hz, 3H); MS (Electrospray): m/z 163.1 (M−CO2H). To a suspension of (R)-1-[5-(2,2,2-trifluoroethoxy)pyridine-2-yl]ethanamine bis-HCl (0.39 g, 1.3 mmol), 2-[4-(carboxymethyl)phenyl]propionic acid (0.35 g, 1.7 mmol), EDC (0.35 g, 1.8 mmol), and 1-hydroxy-7-azabenzotriazole (0.25 g, 1.8 mmol) in DMF (5 mL) was added diisopropylethylamine (1.2 mL, 6.7 mmol). After stirring for 2 h at room temperature, the mixture was diluted with water (20 mL) and extracted with dichloromethane. The organic layer was dried over MgSO4, filtered, and concentrated to give a crude oil that was purified by preparative reversed-phase HPLC to give 2-{4-[2-oxo-2-(((1R)-1-[5-(2,2,2-trifluoroethoxy)pyridine-2-yl]ethyl)amino)ethyl]phenyl}propionic acid mono-TFA salt as a foam; 1H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J=7.6 Hz, 1H), 8.33 (d, J=2.8 Hz, 1H), 7.49 (dd, J=2.8 and 8.8 Hz, 1H), 7.28 (d, J=8.8 Hz, 1H), 7.19 (s, 4H), 4.88-4.93 (m, 1H), 4.85 (q, J=8.8 Hz, 2H), 3.62 (q, J=7.2 Hz, 1H), 3.44 (s, 2H), 1.35 (d, J=8.0 Hz, 3H), 1.33 (d, J=7.6 Hz, 3H); MS (Electrospray): m/z 411.4 (M+H).