Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[CH2:14][CH2:13]2)[C:7]1=[O:28].[CH3:29]I>C1COCC1.N>[CH3:29][O:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:19])[CH2:14][CH2:13]2)[C:7]1=[O:28]
Reactant: O=C(OCc1ccccc1)N1CCC(N2CCCN(CCO)C2=O)CC1
Reactant: CI
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCN1CCCN(C2CCN(C(=O)OCc3ccccc3)CC2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% in oil; 71 mg) was added under ice-cooling to a solution of benzyl 4-[3-(2-hydroxyethyl)-2-oxotetrahydropyrimidin-1(2H)-yl]piperidin-1-carboxylate (0.59 g) obtained in Example 39a} in THF (30 mL), and the mixture was stirred at room temperature for 30 minutes. Methyl iodide (0.11 mL) was added to the reaction mixture, followed by stirring at room temperature for 15 hours. The reaction solution was diluted with an aqueous saturated ammonia solution to separate the organic layer. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (0.60 g, quantitative) as a white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][CH2:26][C:27](OCC)=[O:28])[CH:20]=1.[Li+].CC([N-]C(C)C)C>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:11]3[C:12](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:26]([CH2:25][C:21]3[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=3)[C:27]2=[O:28])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=Cc1cccnc1Nc1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)CCc1cccnc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=c1c(Cc2cccnc2)cc2cccnc2n1-c1cccc([N+](=O)[O-])c1

Procedure:
The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), ethyl 3-(pyridin-3-yl)propionate (1.2 eq., prepared in Synthetic Example 5) and LDA (1.5 eq.) to obtain 1-(3-nitrophenyl)-3-(pyridin-3-ylmethyl)-1,8-naphthyridin-2(1H)-one, mp 226 to 227° C./DMF.
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.S(=O)(=O)(O)O.[CH3:19][O:20][C:21]([C:23]1[N:24]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:25]=[C:26]([CH:28]=[O:29])[CH:27]=1)=[O:22]>O.CC(C)=O>[CH3:19][O:20][C:21]([C:23]1[N:24]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:25]=[C:26]([C:28]([OH:3])=[O:29])[CH:27]=1)=[O:22]
Reactant: COC(=O)c1cc(C=O)cn1S(C)(=O)=O
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1cc(C(=O)O)cn1S(C)(=O)=O
Reaction time: 0.33 h

Procedure:
The Jones reagent was made up in 1.00-mol batches by dissolving 100 g of CrO3 in a minimum of distilled water. Sulfuric acid (87 mL) was added and more water (200 mL total) was then added to effect solution of precipitated CrO3. The final volume was 350 mL (2.86 M with respect to CrO3). To a solution of 4-formyl-1-methanesulfonyl-1H-pyrrole-2-carboxylic acid methyl ester (700 mg, 3.03 mmol) in acetone (5 mL) was added the Jones reagent at 10° C. dropwise until a persistent orange color was observed. The reaction mixture was stirred for additional 20 minutes, and then the orange color was removed by the addition of isopropyl alcohol. After dilution with water (20 mL) the solution was extracted with CHCl3 (3×30 mL). The combined organic layers were washed once by water and then extracted to aqueous NaHCO3 solution (60 mL). The NaHCO3 solution was acidified by concentrated HCl to pH 2 and the resulting white precipitate was collected by filtration and washed with cold water. The crude product was dried on the oil pump for the next step without further purification (600 mg, 80%). 1H NMR (500 MHz, DMSO-d6) δ12.87 (s, 1H), 7.91 (s, 1H), 7.30 (s, 1H), 3.93 (s, 3H), 3.84 (s, 3H) ppm. MS (ES+): m/e=248.1 (M+H); LC/Method A/2.38 min.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C1COCC1.[Br:18]Br>C(Cl)(Cl)Cl.C(O)(=O)C>[Br:18][CH2:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([B:10]([OH:12])[OH:11])=[CH:8][CH:9]=1)=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1ccc(B(O)O)cc1
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: O=C(CBr)c1ccc(B(O)O)cc1
Temperature: 25 °C

Procedure:
An oven-dried, two liter, three-necked, round-bottomed flask was charged with 4-acetyl-phenylboronic acid (20 grams, 0.152 mole). While stirring, 175 ml of THF were added to the reaction mixture, followed by 700 ml of chloroform. To the resulting solution was added 5 ml of glacial acetic acid. A chloroform solution of bromine (prepared by dissolving 7 ml of bromine in 30 ml of chloroform) was added slowly to the reaction mixture at about 5° C. After the completion of the addition of bromine, the reaction mixture was allowed to warm to room temperature and stirred at room temperature for 16 hours. The solvent was removed by rotary evaporation and the residue was dissolved in 1 liter of ethyl acetate. The resulting solution was extracted with deionized water (3×200 ml) and brine (2×100 ml). The organic layer was dried over anhydrous sodium sulfate for 1 hour. The solution was then filtered and concentrated to about ⅓ of its volume. The resulting solution was kept in a freezer to crystallize the product. The solid was filtered to give an off white solid. Yield=16 grams.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:14][C:15]1[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19][C:16]=1[C:17]#[N:18]>>[F:14][C:15]1[CH:22]=[CH:21][C:20]([CH2:23][N:4]2[CH2:5][CH2:6][N:1]([C:7]3[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=3)[CH2:2][CH2:3]2)=[CH:19][C:16]=1[C:17]#[N:18]
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Product: N#Cc1cc(CN2CCN(c3cc(=O)[nH]cn3)CC2)ccc1F

Procedure:
2-Fluoro-5-[4-(6-oxo-1,6-dihydro-pyrimidin-4-yl) -piperazin-1-ylmethyl]-benzonitrile was prepared using Procedure A from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 2-fluoro-5-formylbenzonitrile. Mass spectrum (ES) MH+=314.
Reaction SMILES: [CH2:1]([C:3]1O[C:5](=[O:13])[C:6]2[CH:12]=[CH:11][CH:10]=[N:9][C:7]=2[N:8]=1)[CH3:2].[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[N:19]([C:18]2[CH:20]=[CH:21][C:15]([F:14])=[CH:16][CH:17]=2)[C:5](=[O:13])[C:6]2[CH:12]=[CH:11][CH:10]=[N:9][C:7]=2[N:8]=1)[CH3:2]
Reactant: Nc1ccc(F)cc1
Reactant: CCc1nc2ncccc2c(=O)o1
Solvent: Cc1ccccc1
Product: CCc1nc2ncccc2c(=O)n1-c1ccc(F)cc1
Temperature: 120 °C
Yield: 31.9 %

Procedure:
A suspension of the pyrido-oxazine (16) (0.5 g, 2.84 mmol) and 4-fluoroaniline (0.32 g, 2.84 mmol) in toluene (21 mL) was heated to reflux overnight. The solution was concentrated to dryness under reduced pressure and ethylene glycol (2 mL) and sodium hydroxide (5 mg) were added. The mixture was heated again to 120° C. for 4 h, and the ethylene glycol was distilled off under reduced pressure. The resulting dark brown solid was subjected to silica-gel column chromatography [eluent: Ethyl acetate:Hexane, 20:80, v/v→100:0, v/v] to give the title pyrido-pyrimidinone (17) (244 mg, 32%) as a beige solid:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[C:10](O)(=[O:14])[CH:11]([CH3:13])[CH3:12].C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl.Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])=[N:6][CH:7]=1
Reactant: NNc1ccc(F)cn1
Reactant: CC(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: ClCCl
Product: CC(C)C(=O)NNc1ccc(F)cn1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 45.8 %

Procedure:
A solution of 5-fluoro-2-hydrazinyl-pyridine (0.59 g, 4.65 mmol), isobutyric acid (528 mg, 6 mmol), and HOBt hydrate (153 mg, 1 mmol) in DCM (10 mL) was treated with EDCl HCl (1.15 g, 6 mmol). The reaction mixture was stirred at RT for 40 min, poured onto sat. aq. sodium bicarbonate (40 mL), extracted with four portions of DCM, dried (Na2SO4), evaporated and purified by FCC (DCM/EtOAc 9/1 to 3/7) to give the title compound (0.42 g, 46%). LCMS (Method 8): Rt 2.46 min, m/z 198 [MH+].
Reaction SMILES: [CH:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10](Cl)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C([C@H]1CC[C@H](C(O)=O)CC1)(C)C.[NH2:25][C@@H:26]([C:34]([OH:36])=[O:35])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O.CC(C)=O>[CH3:2][CH:1]([CH3:3])[C@@H:4]1[CH2:9][CH2:8][C@@H:7]([C:10]([NH:25][C@H:26]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:34]([OH:36])=[O:35])=[O:11])[CH2:6][CH2:5]1
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Reactant: CC(C)[C@H]1CC[C@H](C(=O)Cl)CC1
Agent: CC(C)[C@H]1CC[C@H](C(=O)O)CC1
Solvent: CC(C)=O
Solvent: O
Product: CC(C)[C@H]1CC[C@H](C(=O)N[C@H](Cc2ccccc2)C(=O)O)CC1

Procedure:
U.S. Pat. No. 7,208,622 describes a process in which trans-4-isopropylcyclohexane carbonyl chloride (i.e. a derivative of trans-4-isopropylcyclohexane carboxylic acid) is reacted with D-phenylalanine in the presence of a caustic solution followed by acidification in a mixture of water and acetone and crystallization at 58-72° C. which results in Form H of nateglinide.
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[OH-].[K+].IC[C:16]#[N:17]>O.C(O)(=O)C.C(O)C>[NH2:6][C:5]1[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:4]=1[S:3][CH2:2][C:16]#[N:17]
Reactant: Nc1nc2ccc(F)cc2s1
Reactant: N#CCI
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: N#CCSc1cc(F)ccc1N
Temperature: 10 °C

Procedure:
A suspension of 2-amino-6-fluoro-benzothiazole (5.13 g) was stirred for 6½ h at 165-170 ° C. under nitrogen in a solution of potassium hydroxide (10.3 g) in water (20 ml). The resulting mixture was cooled to 10° C. and adjusted to pH ˜8 by adding acetic acid, keeping the temperature below 25° C. The mixture was cooled to 10° C. and ethanol (30 ml) and iodoacetonitrile (2.20 ml) were added. After stirring for 15 min acetic acid (1.8 ml) was added and approx. half of the solvent was removed in vacuo. The residue was diluted with water (150 ml) and extracted with ethyl acetate (50 ml). The extract was dried over sodium sulfate, filtered and evaporated to give the title compound as a practically pure yellow oil. Yield 4.88 g (88%); 1H-NMR (DMSO-d6), δ (ppm): 7.26-7.14 (m, 1H, Ar—H), 7.09-6.95 (m, 1H, Ar—H), 6.85-6.72 (m, 1H, Ar—H), 5.36 (br, 2H, NH2), 3.99 (s, 2CH2).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9](I)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]([CH3:14])[CH3:13].[S:15]1[CH:19]=[C:18](B(O)O)[C:17]2[CH:23]=[CH:24][CH:25]=[CH:26][C:16]1=2.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(O)C>[S:15]1[CH:19]=[C:18]([C:9]2[N:8]=[C:7]3[C:3]([N:4]=[CH:5][N:6]3[CH:12]([CH3:14])[CH3:13])=[C:2]([Cl:1])[N:10]=2)[C:17]2[CH:23]=[CH:24][CH:25]=[CH:26][C:16]1=2
Reactant: CC(C)n1cnc2c(Cl)nc(I)nc21
Reactant: OB(O)c1csc2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)n1cnc2c(Cl)nc(-c3csc4ccccc34)nc21
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A round-bottom flask was charged with 6-chloro-2-iodo-9-isopropyl-9H-purine (prepared in Example 15c, 3.31 g, 0.0103 mol), benzo[b]thiophen-3-ylboronic acid (2.74 g, 0.0154 mol), and tetrakis(triphenylphosphine)palladium(0) (1.19 g, 0.0103 mol). To this mixture was added toluene (80 ml), ethanol (25 ml) and aqueous sodium carbonate solution (2M, 21 ml). The flask was sealed and the reaction mixture was stirred at 90° C. for 1 h. Water was added to the cooled mixture, which was extracted with ethyl acetate. The organic fractions were combined, dried over sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel, eluting with 20 to 50% EtOAc in hexane to afford the title compound as a solid, which was recrystallized from 1:1 methanol/water. 1H NMR (400 MHz, DMSO-d6): δ=9.15 (d, 1H), 8.85 (s, 2H), 8.17 (d, 1H), 7.62 (t, 1H), 7.53 (t, 1H), 5.06 (m, 1H), 1.71 (d, 6H); MS m/z 329.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[N:11]([CH3:29])[C:12]2[C:21]3[C:20](=[O:22])[NH:19][C:18]([CH3:23])=[C:17]([CH2:24][C:25](O)=[O:26])[C:16]=3[CH:15]=[CH:14][C:13]=2[N:28]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1>CN(C=O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH:9][C:10]1[N:11]([CH3:29])[C:12]2[C:21]3[C:20](=[O:22])[NH:19][C:18]([CH3:23])=[C:17]([CH2:24][C:25]([N:52]4[CH2:57][CH2:56][O:55][CH2:54][CH2:53]4)=[O:26])[C:16]=3[CH:15]=[CH:14][C:13]=2[N:28]=1
Reactant: C1COCCN1
Reactant: Cc1[nH]c(=O)c2c(ccc3nc(Nc4c(Cl)cccc4Cl)n(C)c32)c1CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: Cc1[nH]c(=O)c2c(ccc3nc(Nc4c(Cl)cccc4Cl)n(C)c32)c1CC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-(2,6-dichlorophenylamino)-1,7-dimethyl-9-oxo-1,8-dihydro-imidazo[4,5-h]isoquinolin-6-yl acetic acid (prepared using Methods C and A) (1.0 g, 2.3 mmol) in DMF (7 mL) was added O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) (0.82 g, 2.6 mmol) and morpholine (0.24 mL, 2.8 mmol), and the mixture stirred 18 h at room temperature. Ice water was added, the precipitate collected, washed with water and dried to give the title compound, 0.97 g, 84%, mp>300° C.; MS (ES) 500, 502 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]1C(=O)C2=CC=CC=C2C1=O)=[N:8]3.O>C(O)C>[CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])=[N:8]3
Reactant: Cc1nc2cccc3nc(SCCCCCN4C(=O)c5ccccc5C4=O)c1n23
Solvent: CCO
Solvent: O
Product: Cc1nc2cccc3nc(SCCCCCN)c1n23
Yield: 70.4 %

Procedure:
To a suspension of 2.50 g (6.2 mmol) of 3-methyl-2-[5-(phthalimido)pentan-1-ylthio]-1,4,7b-triazacyclopent[cd]indene in 50 ml of ethanol was added 928 mg (18.5 mmol) of hydrazinemonohydrate. The mixture was heated for two hours under reflux. After cooling, the resulting precipitates were collected by filtration and washed with ethanol. The filtrate and washing were combined and concentrated to give the residue. Water was added, extracted with methylene chloride, dried over anhydrous magnesium sulfate. The solvent was distilled off to afford 1.197 g of the desired compound (70.6%, a greenish brown solid).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:15])=[C:6]([CH:14]=1)[O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].C1C(=O)N([Br:23])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:12]([O:11][C:9](=[O:10])[CH2:8][O:7][C:6]1[CH:14]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[CH2:15][Br:23])[CH3:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)COc1cc(F)ccc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)COc1cc(F)ccc1CBr
Yield: 30.3 %

Procedure:
A solution of ethyl (5-fluoro-2-methylphenoxy)acetate (from Step 1) (0.65 g, 3.06 mmol), NBS (0.65 g, 3.68 mmol), and benzoyl peroxide (0.05 g, 0.21 mmol) in CCl4 (7.0 mL) were refluxed at 90° C. for 2.5 h. Additional NBS (0.16 g, 0.92 mmol) added, and reaction continued overnight. Solid filtered and filtrate concentrated onto silica gel. Purified by flash column chromatography using hexane and 2.5% EtOAc/hexane as eluent. Product obtained as yellow liquid (0.27 g, 30%). 1H NMR (CD3OD/400 MHz) δ7.37 (m, 1H), 6.69 (m, 2H), 4.80 (s, 2H), 4.60 (s, 2H), 4.23 (q, 2H, J=7.2 Hz), 1.27 (t, 3H, J=7.2 Hz).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]([CH2:10][CH3:11])[CH2:8][CH3:9].S=[C:13]1[CH2:17][S:16][C:15](=[O:18])[NH:14]1>C(O)C>[CH2:10]([N:7]([CH2:8][CH3:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:13]1[CH2:17][S:16][C:15](=[O:18])[N:14]=1)[CH3:11]
Reactant: O=C1NC(=S)CS1
Reactant: CCN(CC)CCOCCN
Solvent: CCO
Product: CCN(CC)CCOCCNC1=NC(=O)SC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
To a solution of 2-(2-aminoethoxy)-N,N-diethylethanamine (2.23 g) in ethanol (50 mL) was added 4-thioxo-1,3-thiazolidin-2-one (1.76 g), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate) to give the title compound (1.85 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[CH:14]=[CH:13][CH:12]=3)=O)C.[H-].C([Al+]CC(C)C)C(C)C.CO.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][C:15]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:16]=2[C:17]2[C:18]([CH2:19][O:20][CH3:21])=[C:6]([CH2:4][OH:3])[N:7]=[CH:8][C:9]=2[NH:10]3)=[CH:28][CH:27]=1
Reactant: CCOC(=O)c1ncc2[nH]c3cccc(Cc4ccc(Cl)cc4)c3c2c1COC
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COCc1c(CO)ncc2[nH]c3cccc(Cc4ccc(Cl)cc4)c3c12
Temperature: -75 °C
Reaction time: 0.17 h
Yield: 20.1 %

Procedure:
0.5 g (0.00122 mol) of 5-(4-chlorobenzyl)-4-methoxymethyl-β-carboline-3-carboxylic acid ethyl ester is dissolved in 13 ml of toluene. To the solution cooled to -75° C. 2.3 ml of a 1,2-molar solution of diisobutylaluminiumhydride in toluene is slowly instilled under argon. It is stirred for 10 minutes more at -75° C., then for one hour at room temperature. 0.9 ml of methanol is slowly instilled to the reaction mixture again cooled to -75° C., it is stirred 10 minutes more, then 1.5 ml of a saturated potassium sodium tartrate solution is instilled. It is stirred for 20 minutes more at room temperature, then the mixture is extracted with ethyl acetate. The combined extracts are dried and concentrated by evaporation, the residue is recrystallized from ethanol. Thus 0.09 g (20% of theory) of 5-(4-chlorobenzyl)-4-methoxymethyl-β-carboline-3-methanol is obtained, melting point 220°-222° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[NH2:7][C:8]1[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=1[CH2:10][S:11]([N:14]([CH3:16])[CH3:15])(=[O:13])=[O:12].[CH3:21][N:22]([CH:24]=O)[CH3:23]>>[CH3:21][N:22]([CH:24]=[N:7][C:8]1[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=1[CH2:10][S:11]([N:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])[CH3:23]
Reactant: CN(C)S(=O)(=O)Cc1ccccc1N
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Product: CN(C)C=Nc1ccccc1CS(=O)(=O)N(C)C

Procedure:
Dimethylformamide (20 ml) was cooled under a nitrogen atmosphere to −40° C. in a dry ice-acetonitrile bath. Oxalyl chloride (2 ml) was added dropwise at such a rate as to maintain the temperature below −30° C. Upon completion of the addition, the suspension was allowed to rise to room temperature. After about an hour, 2-aminobenzyl-N,N-dimethylsulfonamide (0.630 g) dissolved in DMF (5 ml) was added with stirring and the reaction mixture was stirred at room temperature for 4 h. The solution was partitioned between 1% sodium hydroxide solution and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and evaporated to dryness to afford C-[2-(dimethylamino-methyleneamino)-phenyl]-N,N-dimethyl-methanesulfonamide as an oil which was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3N=[C:19]([C:21]([O:23]CC)=[O:22])[CH:18]=[N:17]3)[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[CH3:30]N([C@H]1C2C(=CC=CC=2)CCC1)C(C1C=NN(C2CCN(C(=O)CN3C(C)=CC(C(F)(F)F)=N3)CC2)C=1)=O.[OH-].[Na+]>>[CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:11][CH2:12][CH:13]([N:16]3[CH:30]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[N:17]3)[CH2:14][CH2:15]2)=[O:9])[N:5]=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(n2cc(C(=O)N(C)[C@@H]3CCCc4ccccc43)cn2)CC1
Reactant: CCOC(=O)c1cnn(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(n2cc(C(=O)O)cn2)CC1

Procedure:
By a procedure analogous to that of Example 32 Step C, ethyl 2-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-2H-1,2,3-triazole-4-carboxylate (0.24 g, 0.58 mmol) (i.e. the product of Example 33, Step B) was hydrolyzed with 1 N aqueous sodium hydroxide (1.2 mL, 1.2 mmol) to afford 0.125 g of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH:22]([CH2:27][CH2:28][CH3:29])[C:23]([O:25]C)=[O:24].[OH-].[Na+]>CO.C(O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[C:3]=1[CH:22]([CH2:27][CH2:28][CH3:29])[C:23]([OH:25])=[O:24]
Reactant: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: CCCC(C(=O)O)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Temperature: 25 °C
Yield: 56 %

Procedure:
To a solution of methyl [2-methyl-4-p-tolyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate (0.100 g; 0.245 mmol) in methanol (5 mL) and ethanol (2.5 mL) was added a 5% sodium hydroxide solution (6.6 mL; 8.250 mmol). The reaction mixture was heated under reflux for 4 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was suspended in water, acidified with 1N HCl (pH˜2) and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was crystallized from a mixture of ethyl acetate/heptane to afford 0.054 g (56%) of the title compound as a white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][C:10]([N+]([O-])=O)=[CH:11][CH:12]=3)[CH:7]([CH:20]3[O:24][CH2:23][CH2:22][O:21]3)[C:6]=2[CH:5]=1)([O-:3])=[O:2].[O-:25][CH2:26][CH3:27].[K+]>>[CH2:26]([O:25][C:10]1[CH:11]=[CH:12][C:13]2[C:14]3[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:16][CH:15]=3)[CH:7]([CH:20]3[O:21][CH2:22][CH2:23][O:24]3)[C:8]=2[CH:9]=1)[CH3:27]
Reactant: CC[O-]
Reactant: O=[N+]([O-])c1ccc2c(c1)C(C1OCCO1)c1cc([N+](=O)[O-])ccc1-2
Agent: [K+]
Product: CCOc1ccc2c(c1)C(C1OCCO1)c1cc([N+](=O)[O-])ccc1-2

Procedure:
Following the same procedure described in Example 1, from 10 parts of 2-(2,7-dinitro-9-fluorenyl)-1,3-dioxolane and 12.5 parts of potassium ethoxide there was obtained 9 parts of product, its 1H and 13C NMR was consistent with the assigned structure.
Reaction SMILES: [NH2:1][C:2]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[C:13]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:14][C:15]4[N:20](CCC#N)[C:19](=[O:25])[CH2:18][O:17][C:16]=4[N:26]=3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3]1.[C:33]([O:37]C(=O)NC1(C2C=CC(C3C(C4C=CC=CC=4)=CC4N(CCCCC#N)C(=O)COC=4N=3)=CC=2)CCC1)(C)(C)[CH3:34]>>[NH2:1][C:2]1([C:6]2[CH:7]=[CH:8][C:9]([C:12]3[C:13]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)=[CH:14][C:15]4[NH:20][C:19](=[O:25])[CH:18]([CH2:34][CH2:33][OH:37])[O:17][C:16]=4[N:26]=3)=[CH:10][CH:11]=2)[CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CCCCC#N)C(=O)CO4)cc2)CCC1
Reactant: N#CCCN1C(=O)COc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc21
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)C(CCO)O4)cc2)CCC1

Procedure:
Following the procedure for 3-(6-(4-(1-aminocyclobutyl)phenyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)propanenitrile, tert-butyl(1-(4-(1-(4-cyanobutyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (15 mg, 0.029 mmol) was reacted to afford the title compound (8.5 mg). 1H NMR (500 MHz, CD3OD): 7.28-7.42 (m, 8H), 7.18 (m, 2H), 5.08 (dd, 1H), 3.84-3.93 (m, 2H), 2.73-2.79 (m, 2H), 2.55-2.61 (m, 2H), 2.25-2.29 (m, 2H), 2.15-2.24 (m, 1H), 1.95-1.97 (m, 1H). LCMS (Method A): RT=3.49 min, M+H+=416.18.