Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH2:9][C:10]([C:26]([O:28]CC)=[O:27])=[CH:11][C:12]2[CH:18]=[CH:17][C:16]([C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])=[CH:15][C:13]=2[N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O>C1COCC1.O>[C:1]([O:5][C:6]([C:8]1[CH2:9][C:10]([C:26]([OH:28])=[O:27])=[CH:11][C:12]2[CH:18]=[CH:17][C:16]([C:19]([F:25])([F:24])[C:20]([F:21])([F:23])[F:22])=[CH:15][C:13]=2[N:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1=Cc2ccc(C(F)(F)C(F)(F)F)cc2N=C(C(=O)OC(C)(C)C)C1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1=Nc2cc(C(F)(F)C(F)(F)F)ccc2C=C(C(=O)O)C1
Reaction time: 4 h

Procedure:
To a solution of (1E,4E)-ethyl 2-(tert-butoxycarbonyl)-8-(perfluoroethyl)-3H-benzo[b]azepine-4-carboxylate in THF/H2O (4:1, 10 mL) was added LiOH.H2O (42 mg, 1.00 mmol). After 4 hours the mixture was made acidic (pH 4) with 10% citric acid and extracted with CH2Cl2 (2×100 mL). The combined organics were dried and concentrated. The material was used without further purification.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]#[N:22])[CH:19]=2)[NH:14][C:13]=1[C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1.[C:29]([C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34](Cl)=[O:35])#[N:30].[Cl-].[NH4+]>C1COCC1>[C:29]([C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34]([N:14]1[C:15]2[C:20](=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)[C:12]([CH3:11])=[C:13]1[C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)=[O:35])#[N:30]
Reactant: N#Cc1cccc(C(=O)Cl)c1
Reactant: Cc1c(-c2cccnc2)[nH]c2ccc(C#N)cc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1c(-c2cccnc2)n(C(=O)c2cccc(C#N)c2)c2ccc(C#N)cc12
Reaction time: 0.08 h

Procedure:
KHMDS (0.5 M in toluene, 1.46 mL, 0.73 mmol) is added to a solution of 3-methyl-2-pyridin-3-yl-1H-indole-5-carbonitrile (Example 6, 122 mg, 0.480 mmol) in THF (10 mL) at room temperature. After 5 min, 3-cyanobenzoyl chloride (178 mg, 1.08 mmol) is added. The mixture is stirred under N2 for 1 h, whereupon aqueous ammonium chloride (0.5 mL) is added. The solvents are removed in vacuo and the residue is purified by Xbridge RP18 with a 0.1% aqueous ammonium hydroxide in acetonitrile gradient to give 1-(3-cyano-benzoyl)-3-methyl-2-pyridin-3-yl-1H-indole-5-carbonitrile. 1H NMR (400 MHz, CDCl3) δ ppm 2.35 (s, 3H), 7.37-7.44 (m, 1H), 7.47-7.52 (m, 1H), 7.60-7.64 (m, 1H), 7.68-7.83 (m, 5H), 8.01 (d, J=1.5 Hz, 1H), 8.51 (d, J=4.5 Hz, 1H), 8.53 (s, 1H). HRMS (ESI) m/z 363.1247 [(M+H)+ Calcd for C23H15N4O: 363.1246].
Reaction SMILES: [CH:1]([C:4]1[C:13]([C:14]2[NH:18][C:17]([CH2:19][CH2:20][O:21][CH3:22])=[N:16][N:15]=2)=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[C:6]([CH3:23])[CH:5]=1)([CH3:3])[CH3:2].O.[OH-].[Li+].CO>O>[CH:1]([C:4]1[C:13]([C:14]2[NH:18][C:17]([CH2:19][CH2:20][O:21][CH3:22])=[N:16][N:15]=2)=[CH:12][C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH3:23])[CH:5]=1)([CH3:3])[CH3:2]
Reactant: COCCc1nnc(-c2cc(C(=O)OC)c(C)cc2C(C)C)[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COCCc1nnc(-c2cc(C(=O)O)c(C)cc2C(C)C)[nH]1
Reaction time: 3 h

Procedure:
To crude methyl 4-isopropyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoate (compound 198.5, 0.12 mmol, 1.0 equiv) from the previous step in a 4-mL vial was added lithium hydroxide monohydrate (10.1 mg, 0.24 mmol, 2.0 equiv), methanol (0.9 mL) and water (0.3 mL). The resulting mixture was stiffed at room temperature for 3 hours followed by 50° C. for 3 hours and 40° C. for 17 hours. The solvents were removed in vacuo and the residue was diluted with water (7 mL) plus saturated NaHCO3 (1 mL) and the aqueous was washed with diethyl ether (2 mL). The organic was back extracted with a mix of water (2 mL) plus saturated NaHCO3 (0.5 mL). The combined aqueous was acidified to pH=3 with 1 M H3PO4 and extracted with dichlormethane (3×5 mL). The organics were dried (Na2SO4), filtered and removed in vacuo to obtain the title compound as a white waxy solid (31.5 mg, 88% over 2 steps). m/z (ES+) 304 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:6]([NH2:7])=[C:5]([N+:14]([O-])=O)[CH:4]=1.Cl[Sn]Cl>C(O)C>[F:1][C:2]([F:17])([F:18])[C:3]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:6]([NH2:7])=[C:5]([NH2:14])[CH:4]=1
Reactant: Nc1cc(C(F)(F)F)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1cc(C(F)(F)F)c(C(F)(F)F)cc1N
Yield: 93.9 %

Procedure:
A solution of 122 mg (0.445 mmol) of 4,5-bis(trifluoromethyl)-2-nitroaniline and 498 mg (2.62 mmol) of SnCl2 in 6 mL of ethanol was heated at 70° C. for 2 h. The solution was evaporated to remove the ethanol. The residue was treated with 2N NaOH to pH=13. White precipitate was observed. The mixture was extracted by CHCl3 (3×10 mL). The extract was dried (MgSO4) and evaporated to leave 102 mg (94%) of oil. 1H NMR (CDCl3), 3.70 (mb, 4), 7.069 (s, 2) and some impurity. 19F NMR (CDCl3), 56.659 (s).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:29]([CH3:33])([C:30](=[S:32])[NH2:31])[C:28](=[O:34])[NH:27][C:4]=2[N:5]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=3)[N:10]([CH2:18][CH2:19][C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[N:9]=2)[N:7]=1.Br[CH:36]([CH3:40])[C:37](=O)[CH3:38]>C(O)C>[NH2:1][C:2]1[C:3]2[C:29]([C:30]3[S:32][C:36]([CH3:40])=[C:37]([CH3:38])[N:31]=3)([CH3:33])[C:28](=[O:34])[NH:27][C:4]=2[N:5]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=3)[N:10]([CH2:18][CH2:19][C:20]([F:26])([F:25])[C:21]([F:24])([F:22])[F:23])[N:9]=2)[N:7]=1
Reactant: CC1(C(N)=S)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4cc(Cl)ccc34)nc(N)c21
Reactant: CC(=O)C(C)Br
Solvent: CCO
Product: Cc1nc(C2(C)C(=O)Nc3nc(-c4nn(CCC(F)(F)C(F)(F)F)c5cc(Cl)ccc45)nc(N)c32)sc1C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of the intermediate from Step A above (11 mg, 0.021 mmol) in ethanol (423 μl), was added 3-bromo-2-butanone (32.0 mg, 0.212 mmol). The mixture was stirred at 80° C. overnight. The solvent was then removed in vacuo. The residue was purified by preparative TLC using hexanes/EtOAc (1/1) as the eluent to give the indicated compound. Chiral separation using SFC on a Chiralpak AD column provided both enantiomers of the title compound. 1H NMR (500 MHz, CH3OH-d4): δ 8.59 (d, J=8.7 Hz, 1H); 7.86 (s, 1H); 7.36 (d, J=8.7 Hz, 1H); 4.92-4.82 (m, 2H); 3.08-2.88 (m, 2H); 2.38 (s, 3H); 2.34 (s, 3H); 1.94 (s, 3H). m/z=572.0 (M+H).
Reaction SMILES: C1(C)C=CC(S[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:13]=2)([CH3:11])[C:9]#[N:10])=CC=1.C[S-].[Na+].[Cl-].[NH4+]>CO>[C:18]([C:14]1[CH:13]=[C:12]([CH:8]([CH3:11])[C:9]#[N:10])[CH:17]=[CH:16][CH:15]=1)(=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1ccc(SC(C)(C#N)c2cccc(C(=O)c3ccccc3)c2)cc1
Agent: C[S-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CC(C#N)c1cccc(C(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
314 mg of alpha-(p-tolylthio)-alpha-(m-benzoylphenyl)propionitrile was dissolved in 1 ml of methanol, and 1.0 ml of a 2.3 M methanol solution of sodium methanethiolate was added dropwise. The mixture was stirred at room temperature for 1 hour. An aqueous solution of ammonium chloride (1 g/5 ml) was added, and the mixture was extracted with 10 ml of ether three times. The extract was washed with 15 ml of water three times, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel; benzene and methylene chloride) to afford 133 mg (yield 64%) of alpha-(m-benzoylphenyl)-propionitrile as colorless crystals.
Reaction SMILES: C[O:2][C:3](=[O:33])[C@H:4]([CH2:27][CH2:28][C:29]([O:31]C)=[O:30])[NH:5][C:6](=[O:26])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]2[C:23]3[C:22](=[O:24])[NH:21][C:20]([NH2:25])=[N:19][C:18]=3[NH:17][CH:16]=2)=[CH:9][CH:8]=1.[OH-].[Na+].Cl>>[NH2:25][C:20]1[NH:21][C:22](=[O:24])[C:23]2[C:15]([CH2:14][CH2:13][C:10]3[CH:9]=[CH:8][C:7]([C:6]([NH:5][C@H:4]([C:3]([OH:33])=[O:2])[CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:26])=[CH:12][CH:11]=3)=[CH:16][NH:17][C:18]=2[N:19]=1
Reactant: COC(=O)CC[C@H](NC(=O)c1ccc(CCc2c[nH]c3nc(N)[nH]c(=O)c23)cc1)C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc2[nH]cc(CCc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 58.9 %

Procedure:
A mixture of 0.50 g (1.1 mmol) of N-[4-[2-[2-amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl]ethyl]benzoyl]glutamic acid dimethyl ester, prepared in Preparation 5, and 3.3 ml of 2N aqueous sodium hydroxide was stirred at room temperature for 48 hours and neutralized to a pH of 5 with 6M aqueous hydrochloric acid. The precipitate was filtered, washed with water and dried, to give 0.277 g of the above product in a yield of 59 percent.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH:20](C(O)=O)[C:19]3[C:14](=[CH:15][C:16]([CH:24]([CH3:26])[CH3:25])=[CH:17][CH:18]=3)[C:13](=[O:27])[N:12]2[CH3:28])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[CH2:20][C:19]3[C:14](=[CH:15][C:16]([CH:24]([CH3:25])[CH3:26])=[CH:17][CH:18]=3)[C:13](=[O:27])[N:12]2[CH3:28])=[CH:9][CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)c1ccc2c(c1)C(=O)N(C)C(c1ccc(C(C)(C)C)cc1)C2C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)c1ccc2c(c1)C(=O)N(C)C(c1ccc(C(C)(C)C)cc1)C2
Temperature: 150 °C
Yield: 88 %

Procedure:
To 20 ml of a solution containing 2.70 g of 3-(4-tert-butylphenyl)-7-isopropyl-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline- 4-carboxylic acid (mixture of diastereomers) in dimethylsulfoxide, 1.10 g of sodium carbonate was added and the resulting mixture was heated at 150° C. for 12 hours. After the reaction, the solvent was evaporated under reduced pressure and 200 ml of water was added thereto. The resultant was extracted with ethyl acetate (50 ml×3) The organiclayers were combined and washed with saturated aqueous sodium chloride solution and the resultant was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by column chromatography on silica gel (hexane/ethyl acetate=5/1 v/v) to obtain 2.10 g of 3-(4-tertbutylphenyl)-7-isopropyl-2-methyl-l,2,3,4-tetrahydroisoquinoline-1-one.
Reaction SMILES: [NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:2]([C:4]([N:6]1[CH2:20][CH2:19][CH2:18][C@H:7]1[C:8]([O:10]CC1C=CC=CC=1)=[O:9])=[O:5])[CH3:3].[OH-].[Na+].Cl>C(O)C>[NH:1]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[C@H:2]([C:4]([N:6]1[CH2:20][CH2:19][CH2:18][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
The substance [24] was dissolved in ethanol (200 ml). 1 N NaOH (240 ml, 1.2 molar excess) was added dropwise at 0° C. and the mixture was stirred at room temperature. After two hours, 1 N NaOH (20 ml) was added and the mixture was further stirred for 30 minutes. The reaction mixture was neutralized with 1 N HCl (60 ml) at 0° C., and the ethanol was distilled off in vacuo. After twice washing the aqueous layer with ether (100 ml), 1 N HCl (200 ml) was added thereto at 0° C. The precipitate thus formed was filtered, washed completely and dried in vacuo. Recrystallization was effected from ethyl acetate (450 ml)-hexane to crystallize the substance [25] (47.92 g, yield: 83.8%).
Reaction SMILES: C(O[C:4]1[CH2:9][CH2:8][CH2:7][C:6](=[O:10])[CH:5]=1)C.[CH2:11]([Mg]Br)[CH3:12]>C(OCC)C.C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C>[CH2:11]1[C:4]2([CH2:9][CH2:8][CH2:7][C:6](=[O:10])[CH2:5]2)[CH2:12]1
Reactant: CC[Mg]Br
Reactant: CCOC1=CC(=O)CCC1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Solvent: CCOCC
Product: O=C1CCCC2(CC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Ethoxycyclohex-2-enone (25 g) was dissolved in diethyl ether (500 mL), and tetraisopropoxytitanium (55 mL) was added, followed by the addition of ethyl magnesium bromide (3.0 Min diethyl ether, 180 mL) over 30 minutes. The reaction was stirred at room temperature for another two hours, and quenched by the careful addition of water (250 mL). The mixture was filtered through diatomaceous earth, and rinsed with diethyl ether. The filtrate was transferred to a separatory funnel, the aqueous layer was drawn off, and p-toluenesulfonic acid monohydrate (2 g) was added to the organic layer, which was stirred at room temperature for two days. The reaction mixture was washed with saturated aqueous NaHCO3 and brine, then dried over Na2SO4. The mixture was filtered, and concentrated and chromatography on silica gel using 93/7 hexanes/ethyl acetate provided the title compound.
Reaction SMILES: [C:1]1([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[CH2:24][CH2:23]1>CN(C)C=O.O.C(OCC)(=O)C>[F:34][C:31]1[CH:30]=[CH:29][C:28]([N:25]2[CH2:24][CH2:23][N:22]([CH2:21][CH2:20][CH2:19][N:11]([C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)[S:12]([CH3:15])(=[O:14])=[O:13])[CH2:27][CH2:26]2)=[CH:33][CH:32]=1
Reactant: CS(=O)(=O)Nc1cccc2ccccc12
Reactant: Fc1ccc(N2CCN(CCCCl)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N(CCCN1CCN(c2ccc(F)cc2)CC1)c1cccc2ccccc12
Temperature: 110 °C
Reaction time: 0.25 h
Yield: 39.1 %

Procedure:
A solution of N-(1-naphthyl)methanesulphonamide (6.6 g) in dry N,N-dimethylformamide (20 cc) is added dropwise to a suspension of sodium hydride (0.9 g, 80% suspension in oil) in N,N-dimethylformamide (50 cc). After stirring for 15 minutes, a solution of 1-(3-chloropropyl)-4-(4-fluorophenyl)piperazine (7.2 g) in N,N-dimethylformamide (20 cc) is added. The reaction mixture is heated to 110° C. for 2 hours and 30 minutes and is then cooled and poured in a mixture of water (300 cc) and ethyl acetate (500 cc). The organic phase is washed with water, is diluted with dichloromethane (50 cc), is dried over magnesium sulphate and is concentrated to dryness under reduced pressure (2.7 kPa) down to 50 cc. The crystals are filtered off and washed with ethyl acetate (3×50 cc) and then with isopropyl ether (2×30 cc) and are dried. After recrystallization, from ethyl acetate (300 cc), N[3-(4-(4-fluorophenyl)- 1-piperazinyl)propyl]-N-(1-naphthyl)methanesulphonamide (4.84 g) is obtained, melting at 170° C.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[Cl:4][C:5]1[CH:18]=[C:17]([Cl:19])[C:16]([CH3:20])=[CH:15][C:6]=1[C:7]([CH2:9][C:10](OCC)=[O:11])=O>CCOCC>[Cl:4][C:5]1[CH:18]=[C:17]([Cl:19])[C:16]([CH3:20])=[CH:15][C:6]=1[C:7]1[CH2:9][C:10](=[O:11])[N:2]([CH3:1])[N:3]=1
Reactant: CCOC(=O)CC(=O)c1cc(C)c(Cl)cc1Cl
Reactant: CNN
Solvent: CCOCC
Product: Cc1cc(C2=NN(C)C(=O)C2)c(Cl)cc1Cl
Temperature: 100 °C

Procedure:
13.5 g (292 mol) of methylhydrazine were added slowly to 80.4 g (292 mmol) of ethyl 2,4-dichloro-5-methylbenzoylacetate in 300 m of diethylene glycoldimethyl ether. The reaction solution was heated at 100° C. for 4 hours and then stirred into 11 of ice-water. The precipitate formed was filtered off, washed with a little-methylene chloride and dried. Yield: 38.8 g; m.p. 196°-198° C.;
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][NH2:20]>C(O)(C)C>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:20][CH2:19][C:18]3[CH:21]=[CH:22][CH:23]=[C:16]([O:15][CH3:14])[CH:17]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: COc1cccc(CN)c1
Reactant: CSc1ncnc2cc(N)ncc12
Solvent: CC(C)O
Product: COc1cccc(CNc2ncnc3cc(N)ncc23)c1
Yield: 76.6 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (136 mg, 0.71 mmol) (described in a previous experimental) and 3-methoxybenzylamine (1.37 g, 10.0 mmol) in isopropanol (3 mL) is stirred under N2 at reflux for 3 h. Evaporation of the solvent and chromatography on silica gel (5-10% EtOH/EtOAc) gives 7-amino-4-(3-methoxybenzylamino)pyrido[4,3-d]pyrimidine (153 mg, 77%) as a white solid. 1H NMR (DMSO) δ 9.11 (1H, s), 8.83 (1H, t, J=5.7 Hz), 8.26 (1H, s), 7.24 (1H, dt, Jd=0.8 Hz, Jt=8.1 Hz), 6.92 (2H, m), 6.81 (1H, dt, Jd=8.2 Hz, Jt=1.2 Hz), 6.46 (2H, brs), 6.37 (1H, s), 4.71 (2H, d, J=5.8 Hz), 3.73 (3H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:12]2[C:16](=O)[CH2:15][C:14]([CH3:19])([CH3:18])[C:13]2=O)[CH:5]=[C:6]([O:8][CH2:9][O:10][CH3:11])[CH:7]=1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:16][CH2:15][C:14]([CH3:19])([CH3:18])[CH2:13]2)[CH:5]=[C:6]([O:8][CH2:9][O:10][CH3:11])[CH:7]=1
Reactant: COCOc1cc(Br)cc(N2C(=O)CC(C)(C)C2=O)c1
Solvent: C1CCOC1
Product: COCOc1cc(Br)cc(N2CCC(C)(C)C2)c1
Reaction time: 12 h
Yield: 87.5 %

Procedure:
To a solution of 1-(3-bromo-5-methoxymethoxy-phenyl)-3,3-dimethyl-pyrrolidine-2,5-dione (643 mg, 1.88 mmol) in dry THF (8 ml) (under nitrogen) was added a solution of borane-dimethylsulfide complex (1.7 ml, 16.9 mmol, 10.1M) via slow drop-wise addition. The material was stirred for 12 hours. The mixture was cooled (ice bath) and carefully quenched via the slow drop-wise addition of water (10 ml). Methylene chloride (60 ml), and water (50 ml) were added and the material shaken. The organic phase was collected and washed with brine (60 ml). The aqueous phases were back extracted with methylene chloride (2×50 ml). The organics were combined, dried (MgSO4), filtered and stripped to provide a crude oil. The material was adsorbed onto silica (12 g) and purified by silica gel chromatography, eluting with 5% to 9% ethyl acetate in hexanes to afford 517 mg of 1-(3-bromo-5-methoxymethoxy-phenyl)-3,3-dimethyl-pyrrolidine as a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15]=1[N+:16]([O-])=O)[CH2:6][CH2:7][PH:8](=[O:12])[O:9][CH2:10][CH3:11]>C(O)C.[Pd]>[NH2:16][C:15]1[CH:14]=[CH:13][C:5]([CH2:6][CH2:7][PH:8](=[O:12])[O:9][CH2:10][CH3:11])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: CCO[PH](=O)CCc1ccc([N+](=O)[O-])c(OC)c1
Agent: [Pd]
Solvent: CCO
Product: CCO[PH](=O)CCc1ccc(N)c(OC)c1
Reaction time: 16 h
Yield: 94.9 %

Procedure:
A solution of ethyl (3-methoxy-4-nitrobenzyl)methylphosphinate (0.64 g, 2.34 mmol) in ethanol (5.0 mL) was charged with palladium 10% wt on activated carbon (0.25 g). The reaction mixture was evacuated and purged with hydrogen gas (3×) and allowed to stir under hydrogen for 16 h. The reaction mixture was filtered through a pad of celite and the filtrate concentrated in vacuo to afford 0.54 g of ethyl (4-amino-3-methoxybenzyl)methylphosphinate (yield: 95% yield). This material was used in successive reactions without further purification. MS (ES+): m/z 244.01 [MH+] (ZQ3, polar 5 min).
Reaction SMILES: [CH:1]([C@@:3]([C:10]([OH:12])=[O:11])([CH2:5][CH2:6][C:7]([OH:9])=[O:8])[NH2:4])=[CH2:2].[C:13](Cl)(=[O:15])[CH3:14].Cl>[OH-].[Na+].O1CCOCC1>[C:13]([NH:4][C@:3]([CH:1]=[CH2:2])([C:10]([OH:12])=[O:11])[CH2:5][CH2:6][C:7]([OH:9])=[O:8])(=[O:15])[CH3:14]
Reactant: C=C[C@](N)(CCC(=O)O)C(=O)O
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C=C[C@@](CCC(=O)O)(NC(C)=O)C(=O)O

Procedure:
To a solution of 2-vinylglutamic acid (350 mg, 2 mM) in 5 ml of 1 N sodium hydroxide at 0° C. are added simultaneously from 2 syringes acetyl chloride (160 mg) diluted in dioxane (1 ml) and 2 ml of 1 N sodium hydroxide. After 30 minutes at 0° the solution is acidified by the addition of 3 N hydrochloric acid, then extracted well with dichloromethane. The organic phase is dried and concentrated to afford N-acetyl-2-vinylglutamic acid.
Reaction SMILES: [OH:1][C:2]([CH3:7])([CH3:6])[C:3](O)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:41][N:42]1[C:51]2[C:46](=[CH:47][N:48]=[C:49]([CH3:52])[CH:50]=2)[CH:45]=[C:44]([C:53]2[CH:54]=[C:55]([NH:60]/[C:61](/[NH2:64])=[N:62]/O)[CH:56]=[CH:57][C:58]=2[CH3:59])[C:43]1=[O:65]>CN(C=O)C>[OH:1][C:2]([C:3]1[O:4][N:62]=[C:61]([NH:60][C:55]2[CH:56]=[CH:57][C:58]([CH3:59])=[C:53]([C:44]3[C:43](=[O:65])[N:42]([CH3:41])[C:51]4[C:46]([CH:45]=3)=[CH:47][N:48]=[C:49]([CH3:52])[CH:50]=4)[CH:54]=2)[N:64]=1)([CH3:7])[CH3:6]
Reactant: CC(C)(O)C(=O)O
Reactant: Cc1cc2c(cn1)cc(-c1cc(N/C(N)=N/O)ccc1C)c(=O)n2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2c(cn1)cc(-c1cc(Nc3noc(C(C)(C)O)n3)ccc1C)c(=O)n2C
Temperature: 100 °C
Reaction time: 1 h

Procedure:
2-Hydroxy-2-methylpropanoic acid (16.1 mg, 0.15 mmol), HATU (59 mg, 0.15 mmol), and DIPEA (0.027 mL, 0.15 mmol) were stirred in dry DMF (3 mL) for 1 h before 17 (50 mg, 0.14 mmol) was added at rt. The stirring was continued for 1 h before it was heated at 100° C. for 5 h. After cooling and filtration, the mixture was purified by preparative LC/MS to give 3-(5-(5-(2-hydroxypropan-2-yl)-1,2,4-oxadiazol-3-ylamino)-2-methylphenyl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (A32) as a solid. 1H NMR (400 MHz, d4-MeOH) δ 8.90 (s, 1H), 7.94 (s, 1H), 7.81 (s, 1H), 7.62 (dd, J=8, 4 Hz, 1H), 7.52 (d, J=8, 4 Hz, 1H), 7.35 (d, J=4 Hz, 1H), 7.26 (dd, J=8, 4 Hz, 1H), 7.14 (d, J=8 Hz, 1H), 3.79 (s, 3H), 2.75 (s, 3H), 2.06 (s, 3H), 1.35 (m, 6H). MS m/z 406.2 (M+1).
Reaction SMILES: O.[OH-].[Li+].[CH:4]1([CH:9]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][N:31]3[C:36](=[O:37])[CH2:35][O:34][C:33]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[N:32]3)=[CH:26][CH:25]=2)[C:10]([NH:12][CH2:13][CH2:14][CH2:15][C:16]2([CH2:19][C:20]([O:22]C)=[O:21])[CH2:18][CH2:17]2)=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5]1>C1COCC1.O>[CH:4]1([CH:9]([C:24]2[CH:25]=[CH:26][C:27]([CH2:30][N:31]3[C:36](=[O:37])[CH2:35][O:34][C:33]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[N:32]3)=[CH:28][CH:29]=2)[C:10]([NH:12][CH2:13][CH2:14][CH2:15][C:16]2([CH2:19][C:20]([OH:22])=[O:21])[CH2:18][CH2:17]2)=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: COC(=O)CC1(CCCNC(=O)C(c2ccc(CN3N=C(c4ccccc4)OCC3=O)cc2)C2CCCC2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CC1(CCCNC(=O)C(c2ccc(CN3N=C(c4ccccc4)OCC3=O)cc2)C2CCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
71 mg (1.69 mmol) of lithium hydroxide monohydrate were added to a solution of 230 mg (0.42 mmol) of methyl (1-{3-[(cyclopentyl{4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl)methyl]phenyl}acetyl)amino]propyl}cyclopropyl)acetate in 2.8 ml of THF and 1.4 ml of water, and the mixture was stirred at RT overnight. After the reaction had gone to completion, the THF was removed under reduced pressure and the reaction solution was diluted with water and then adjusted to pH 2 with 1 M hydrochloric acid. The precipitated solid was filtered off, washed with water and dried under reduced pressure at 45° C. overnight. This gave 217 mg (0.41 mmol, 97% of theory) of the title compound as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:29]=[CH:28][C:6]([C:7]([NH:9][C:10]2[S:11][C:12]3[C:18]([CH:19]4[CH2:25][O:24][CH2:23][CH2:22][O:21][CH2:20]4)=[CH:17][CH:16]=[C:15]([O:26][CH3:27])[C:13]=3[N:14]=2)=[O:8])=[CH:5][CH:4]=1.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.COC1C2N=C(NC(=O)C3C=CC(CN4CCCC4)=CC=3)SC=2C(C2C=CC=CC=2)=CC=1>>[O:24]1[CH2:25][CH:19]([C:18]2[C:12]3[S:11][C:10]([NH:9][C:7](=[O:8])[C:6]4[CH:5]=[CH:4][C:3]([CH2:2][N:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)=[CH:29][CH:28]=4)=[N:14][C:13]=3[C:15]([O:26][CH3:27])=[CH:16][CH:17]=2)[CH2:20][O:21][CH2:22][CH2:23]1
Reactant: COc1ccc(C2COCCOC2)c2sc(NC(=O)c3ccc(CCl)cc3)nc12
Reactant: C1CCNC1
Agent: COc1ccc(-c2ccccc2)c2sc(NC(=O)c3ccc(CN4CCCC4)cc3)nc12
Product: COc1ccc(C2COCCOC2)c2sc(NC(=O)c3ccc(CN4CCCC4)cc3)nc12

Procedure:
4-Chloromethyl-N-(7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-yl)-benzamide and pyrrolidine were reacted as described for N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-4-pyrrolidin-1-ylmethyl-benzamide in WO01/9786. Usual workup, preparative reversed-phase HPLC and final dry-freezing afforded the title compound as light brown powder. MS: m/e=468(M+H+).