Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([N:23]3C(=O)C4C(=CC=CC=4)C3=O)[CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][N:4]=[C:3]1[CH3:34].O.NN>O1CCCC1>[CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([NH2:23])[CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:5][N:4]=[C:3]1[CH3:34]
Reactant: Cc1ncc(C(=NOCc2cccc(N3C(=O)c4ccccc4C3=O)n2)c2ccccc2)n1C
Agent: NN
Solvent: O
Solvent: C1CCOC1
Product: Cc1ncc(C(=NOCc2cccc(N)n2)c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 28 h
Yield: 50.9 %

Procedure:
To a solution of 2-{6-[({[(1,2-dimethyl-1H-imidazol-5-yl)(phenyl)methylene]amino}-oxy)methyl]pyridin-2-yl}-1H-isoindole-1,3(2H)-dione (1.02 g, 2.26 mmol) in tetrahydrofuran (30 mL) was added dropwise hydrazine hydrate (0.55 mL, 11.3 mmol). After stirring at room temperature for 28 h, the reaction mixture was filtered, the insolubles washed with ethyl acetate, and the filtrate concentrated in vacuo. Purification on silica gel afforded 6-[({[(1,2-dimethyl-1H-imidazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-amine [370 mg, yield 43%; HPLC/MS: m/z=322 (M+H); log P(HCOOH)=0.39].
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7](OC)=[O:8])=[CH:5][C:4]=1[O:13][CH3:14])#[N:2].[BH4-].[Li+].CCOC(C)=O>C1COCC1.Cl>[C:1]([C:3]1[CH:12]=[CH:11][C:6]([CH2:7][OH:8])=[CH:5][C:4]=1[O:13][CH3:14])#[N:2]
Reactant: COC(=O)c1ccc(C#N)c(OC)c1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(CO)ccc1C#N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.2 %

Procedure:
To a solution of the ester from Step D (48.8 g, 255 mmol) in 400 mL of dry THF under argon at room temperature was added lithium borohydride (255 mL, 510 mmol, 2M THF) over 5 minutes. After 1.5 hours, the reaction was warmed to reflux for 0.5 hours, then cooled to room temperature. The solution was poured into EtOAc/IN HCl soln. [CAUTION], and the layers were separated. The organic layer was washed with water, sat Na2CO3 soln. and brine (4x), dried (Na2SO4), and concentrated in vacuo to provide the titled product (36.3 g, 87% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:10]([N:13]([CH2:29][C:30]([OH:32])=[O:31])[C:14]2[CH:15]=[CH:16][C:17]3[N:18]([CH2:27][CH3:28])[C:19]4[C:24]([C:25]=3[CH:26]=2)=[CH:23][CH:22]=[CH:21][CH:20]=4)(=[O:12])=[O:11])[CH:5]=[C:6]([C:8]#[CH:9])[CH:7]=1.[H][H]>C(OCC)(=O)C.[Pt](=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([S:10]([N:13]([CH2:29][C:30]([OH:32])=[O:31])[C:14]2[CH:15]=[CH:16][C:17]3[N:18]([CH2:27][CH3:28])[C:19]4[C:24]([C:25]=3[CH:26]=2)=[CH:23][CH:22]=[CH:21][CH:20]=4)(=[O:12])=[O:11])[CH:5]=[C:6]([CH2:8][CH3:9])[CH:7]=1
Reactant: [H][H]
Reactant: C#Cc1cc(Cl)cc(S(=O)(=O)N(CC(=O)O)c2ccc3c(c2)c2ccccc2n3CC)c1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: CCc1cc(Cl)cc(S(=O)(=O)N(CC(=O)O)c2ccc3c(c2)c2ccccc2n3CC)c1

Procedure:
104 mg [(3-chloro-5-ethynyl-phenylsulphonyl)-(9-ethyl-9H-carbazol-3-yl)-amino]-acetic acid are dissolved in 5 ml of ethyl acetate. 30 mg of platinum dioxide are added and the mixture is hydrogenated for 5.5 hours at 3 bar hydrogen pressure. Then the catalyst is removed by suction filtering, the solvent is eliminated in vacuo and the residue is purified by preparative HPLC.
Reaction SMILES: [NH2:1][C:2]1[C:17]([N+:18]([O-])=O)=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[C:4]([F:21])[CH:3]=1>[Pt].C1COCC1.CO>[NH2:1][C:2]1[C:17]([NH2:18])=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[C:4]([F:21])[CH:3]=1
Reactant: Nc1cc(F)c(C(=O)OCc2ccccc2)cc1[N+](=O)[O-]
Agent: [Pt]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cc(F)c(C(=O)OCc2ccccc2)cc1N

Procedure:
Prepared analogously to example 659c from benzyl 4-amino-2-fluoro-5-nitro-benzoate by hydrogenation using platinum on charcoal in THF and methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH:7]2[CH2:10][NH:9][CH2:8]2)=[C:4]([F:13])[CH:3]=1.CCN(CC)CC.[Cl:21][C:22]1[N:27]=[C:26](Cl)[N:25]=[CH:24][N:23]=1>CC#N>[Cl:21][C:22]1[N:27]=[C:26]([N:9]2[CH2:10][CH:7]([O:6][C:5]3[CH:11]=[CH:12][C:2]([Cl:1])=[CH:3][C:4]=3[F:13])[CH2:8]2)[N:25]=[CH:24][N:23]=1
Reactant: Fc1cc(Cl)ccc1OC1CNC1
Reactant: Clc1ncnc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Fc1cc(Cl)ccc1OC1CN(c2ncnc(Cl)n2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.1 %

Procedure:
To a solution of 3-(4-chloro-2-fluorophenoxy) azetidine (3.6 g, 18.0 mmol) in CH3CN (60 mL, 3 mL/mmol) was added Et3N (7.2 mL, 50.0 mmol) and 2, 4-dichloro-1, 3, 5-triazine (3.0 g, 20.0 mmol) and the reaction mixture was stirred at RT for 1 h. Then the reaction mixture was concentrated under reduced pressure and extracted with EtOAc (2×50 mL). The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography to obtain 2-chloro-4-(3-(4-chloro-2-fluorophenoxy)azetidin-1-yl)-1,3,5-triazine (0.800 g, 20%) as a solid. Observed mass (M+1): 315.0
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:27].CCOC(C)=O>>[ClH:27].[ClH:27].[CH:21]1([CH:14]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(C2CCCCC2)C2CCCCC2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: C1CCC(C(C2CCCCC2)N2CCNCC2)CC1

Procedure:
A solution of the product from Step I (200 mg, 0.55 mmol) in 1N HCl/EtOAc (5.5 mL) was stirred at room temperature overnight. Solvent was removed under reduced pressure and solid washed twice with Et2O to afford the title compound as a white solid. MS m/z 264.9 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][C:9]=1[Cl:18]>C1COCC1.CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[Cl:18]
Reactant: COC(=O)c1ccc(OCc2ccc(OC)c(OC)c2)c(Cl)c1
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(COc2ccc(C(=O)O)cc2Cl)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.4 %

Procedure:
A solution of 1A (600 mg, 1.78 mmol) in THF (30 mL) and MeOH (10 mL) was treated with a solution of LiOH monohydrate (375 mg, 8.93 mmol) in water (10 mL) at room temperature. The resulting suspension was stirred at room temperature for 18 hours. The reaction was concentrated to 30 mL, diluted with water (50 mL) and cooled to 0° C. The solution was brought to pH 5 with 1 N HCl and the resulting solid was collected by vacuum filtration. Residual water was removed from the solid material using azeotrope with toluene to afford 1B as a white solid (370 mg, 65%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]#[N:28])=[CH:22][CH:21]=1.[CH:29](OCC)=[O:30]>C(O)(=O)C.O1CCCC1>[C:27]([CH:26]([C:23]1[CH:24]=[CH:25][C:20]([O:19][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][O:13]2)=[CH:21][CH:22]=1)[CH:29]=[O:30])#[N:28]
Reactant: N#CCc1ccc(OC2CCCCO2)cc1
Reactant: CCOC=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: N#CC(C=O)c1ccc(OC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a cold (0° C) solution of 20.2 g. of diisopropylamine in 70 ml. of anhydrous tetrahydrofuran, is added 12.8 g. of n-butyllithium, and 10 g. of 4-tetrahydropyran-2-yloxyphenylacetonitrile, under nitrogen atmosphere, the resulting mixture is stirred at 0° C for 30 minutes and then 7.4 g. of ethyl formate is added. The reaction mixture is stirred for 18 hours at room temperature, under nitrogen atmosphere, poured into ice water and acidified to pH 5 with 10% acetic acid. It is then extracted three times with methylene chloride, the organic extracts are washed with water to neutrality, dried over sodium sulfate and evaporated to dryness under vacuo. The crude residue is treated with dihydropyran in benzene solution, in accordance with the method of Preparation 3, part B, to afford 2-cyano-2-(4-tetrahydropyran-2-yloxyphenyl)acetaldehyde which can be purified by crystallization from acetone-hexane.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].[H-].[Na+].I[CH2:15][CH3:16]>CN(C=O)C>[CH2:15]([O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][N:10]=[C:2]([Cl:1])[C:3]=1[Cl:11])[CH3:16]
Reactant: CCI
Reactant: O=C(O)c1ccnc(Cl)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccnc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,3-dichloroisonicotinic acid (5.62 mmol) in 15 mL DMF were added NaH (7.31 mmol) followed by iodoethane (6.75 mmol) at 0° C. The cooling bath was removed and the mixture was stirred at RT overnight. The reaction was quenched with sat. aq. NaHCO3 solution and extracted with EtOAc. The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification by CC (KP-SIL™ from Biotage) using Hept/EtOAc (6/4) gives the desired product as yellow oil;
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[N:10]1[C:14]([CH3:15])=[N:13][C:12]([NH:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[N:11]1.Cl[C:24]1[S:28][N:27]=[C:26]([CH3:29])[N:25]=1>>[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[N:10]1[C:14]([CH3:15])=[N:13][C:12]([NH:16][CH:17]2[CH2:18][CH2:19][N:20]([C:24]3[S:28][N:27]=[C:26]([CH3:29])[N:25]=3)[CH2:21][CH2:22]2)=[N:11]1
Reactant: Cc1nc(NC2CCNCC2)nn1-c1ccc(Cl)cc1Cl
Reactant: Cc1nsc(Cl)n1
Agent: Cl
Product: Cc1nsc(N2CCC(Nc3nc(C)n(-c4ccc(Cl)cc4Cl)n3)CC2)n1

Procedure:
Prepared in analogy to example 1 step b) starting from [1-(2,4-dichloro-phenyl)-5-methyl-1H-[1,2,4]triazol-3-yl]-piperidin-4-yl-amine hydrochloride and 5-chloro-3-methyl-[1,2,4]thiadiazole (example 1 step a)). The title compound was obtained as slightly yellow solid (yield=10%).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH3:15].Cl>[Cu]Cl.C(OCC)(=O)C>[NH2:15][C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: N
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1Cl
Agent: Cl[Cu]
Agent: Cl
Solvent: CCOC(C)=O
Product: Nc1nc(C(F)(F)F)ccc1C(=O)O
Temperature: 100 °C
Reaction time: 15 h
Yield: 58 %

Procedure:
2-Chloro-6-trifluoromethylnicotinic acid (3000 mg, 13.30 mmol) was added under argon to 24% aqueous ammonia solution (5 ml), and copper(I) chloride (1580 mg, 15.96 mmol) was added. The resulting reaction mixture was stirred at a temperature of 100° C. and at an elevated pressure of approx. 5 bar in a pressure vessel for 15 h. After cooling to room temperature and lowering the pressure to standard pressure, ethyl acetate and dilute hydrochloric acid (2N) were added to the reaction mixture. The aqueous phase was extracted repeatedly with ethyl acetate, and the combined organic phases were then dried over magnesium sulfate, filtered and concentrated under reduced pressure. Column chromatography purification (ethyl acetatein-heptane gradient) of the crude product gave 2-amino-6-trifluoromethylnicotinic acid (1640 mg, 58% of theory) as a colorless solid. 2-Amino-6-trifluoromethylnicotinic acid (500 mg, 2.43 mmol) was dissolved in abs. tetrahydrofuran (8 ml), and triethylamine (369 mg, 3.64 mmol) was added. Thereafter, the reaction solution was cooled under argon to 0° C., and cyclobutanecarbonyl chloride (316 mg, 2.69 mmol) was slowly added dropwise. The resulting reaction mixture was stirred at room temperature for a further 7 h, then dist. water and dichloromethane were added. The aqueous phase was extracted repeatedly with dichloromethane, and the combined organic phases were then dried over magnesium sulfate, filtered and concentrated under reduced pressure. Preparative HPLC purification (acetonitrile/water/trifluoroacetic acid gradient) of the crude product gave 2-[(cyclobutylcarbonyl)amino]-6-(trifluoro-methyl)nicotinamide (197 mg, 28% of theory) as a colorless solid. 2-[(Cyclobutyl-carbonyl)amino]-6-(trifluoromethyl)nicatinamide (197 mg, 0.68 mmol) was dissolved in acetic anhydride (5 ml) and stirred under reflux conditions under argon for 5 h. After cooling to room temperature, concentrated ammonia solution was added (10 ml) and the reaction mixture was stirred at room temperature for a further 6 h. The precipitated solid was filtered off with suction and dried. Preparative HPLC purification of the crude product gave 2-cyclobutyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-4(3H)-one (55 mg, 30% of theory) as a yellowish solid. 1H NMR (400 MHz, CDCl3 δ, ppm) 8.79 (d, 1H), 7.78 (d, 1H), 7.28 (br. s, 1H, NH), 3.62 (quint, 1H), 2.64 (m, 2H), 2.48 (m, 2H), 2.18 (m, 1H), 2.02 (m, 1H).
Reaction SMILES: C(C1C=C(OC)C=C(C(C)(C)C)C=1[C:17]1[CH:25]=[C:24]([N:26]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH:28]2[CH3:34])[CH:23]=[CH:22][C:18]=1[C:19]([O-])=[O:20])(C)(C)C.C[O-].[Na+].[CH2:44]([NH:46][CH2:47][CH3:48])[CH3:45].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C1(C)C=CC=CC=1.CN1CCCC1=O.C1COCC1.CCOCC.C(N(CC)CC)C>[CH3:33][N:30]1[CH2:31][CH2:32][CH:27]([N:26]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:24]2[CH:23]=[CH:22][C:18]([C:19]([N:46]([CH2:47][CH3:48])[CH2:44][CH3:45])=[O:20])=[CH:17][CH:25]=2)[CH:28]([CH3:34])[CH2:29]1
Reactant: CCNCC
Reactant: COc1cc(C(C)(C)C)c(-c2cc(N(c3ccccc3)C3CCN(C)CC3C)ccc2C(=O)[O-])c(C(C)(C)C)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: C[O-]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc(N(c2ccccc2)C2CCN(C)CC2C)cc1
Yield: 90 %

Procedure:
(±)-2,6-Di-tert-butyl-4-methoxyphenyl-4-[N-{(3RS,4SR)-N,3-dimethyl-4-piperidinyl}phenylamino]benzoate (6a) (6.5 g, 11.99 mmol) in toluene (150 mL) and N-methylpyrrolidinone (NMP, 40 mL) was added to freshly prepared sodium methoxide (120 mmol) and heated at reflux for 4 h. After evaporation of the toluene under reduced pressure, the residue was dissolved in a mixture of MeOH and H2O (12:1, 150 mL) and heated at reflux for 1 h. After evaporation of the alcohol, the residue was taken up in water (400 mL) and extracted with hexanes (2×100 mL). The aqueous layer was made acidic (pH=1) with 10% HCl, saturated with NaCl, and extracted with a mixture of CH2Cl2 and THF (3:1, 5′ 200 mL). After drying over Na2SO4, the solvents were evaporated under reduced pressure. This was then treated with diethylamine (1.2 mL), benzotriazol-1-yl-oxy-tris-(dimethylamino)phosphonium hexafluorophosphate (BOP a.k.a. Castro's reagent) (5.0 g, 11.31 mmol) ), and triethylamine (4.2 mL) in THF (100 mL) for 30 min. The reaction mixture was next diluted with ether (300 mL), washed with water (2×75 mL), saturated NaHCO3 (75 mL), and dried over Na2SO4 providing a black oil following evaporation of the solvents under reduced pressure. Chromatography on silica gel using hexanes/ethyl acetate/ethanol/triethylamine (60:40:2:2) afforded 7a (4.10 g, 90%) as a yellow liquid. This was converted to the hydrochloride salt using 1N HCl in ether. 1H NMR (CD3OD) δ1.07-1.38 (m, 12H), 1.42D1.61 (m, 1H), 1.68-1.92 (m, 1H), 2.86 (s, 3H), 3.03D3.21 (m, 1H), 3.27D3.60 (m, 6H), 4.30D4.48 (m, 1H), 6.80 (d, 2H, J=8.3 Hz), 7.14 (d, 2H, J=7.7 Hz), 7.26 (t, 3H, J=7.5 Hz), 7.40 (t, 2H, J=7.4 Hz); 13C NMR (CD3OD) δ12.2, 25.6 30.4, 44.5, 55.7, 56.0, 60.2, 119.4, 127.4, 128.8, 130.7, 130.8, 146.1, 150.8, 173.8. Anal. (C24H34ClN3O.H2O): C, H, N.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:8]([O:10]CC1C=CC=CC=1)=[O:9])[CH2:3][CH2:4][C:5](=O)[OH:6].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:40]1[C:45]([S:46]([OH:49])(=[O:48])=[O:47])=[C:44]([OH:50])[C:43]([NH2:51])=[CH:42][C:41]=1Cl.C1COCC1>C(Cl)Cl>[OH:50][C:44]1[C:45]([S:46]([OH:49])(=[O:48])=[O:47])=[CH:40][CH:41]=[CH:42][C:43]=1[NH:51][C:5](=[O:6])[CH2:4][CH2:3][C@@H:2]([C:8]([OH:10])=[O:9])[NH2:1]
Reactant: O=C(O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: Nc1cc(Cl)cc(S(=O)(=O)O)c1O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: N[C@@H](CCC(=O)Nc1cccc(S(=O)(=O)O)c1O)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
Z-Glu-OBn (371 mg, 1 mmol) was dissolved in methylene chloride (1 mL), and CDI (180 mg, 1.1 mmol) was added thereto and stirred at room temperature for 30 minutes. Then, 2-amino-4-chlorophenol-6-sulfonic acid (223 mg, 1 mmol) and THF (1 mL) were added thereto and stirred overnight at room temperature. After removing a solvent, purification was conducted in accordance with the purification process A. The obtained intermediate was dissolved in a mixed solvent of methanol and water. Pd/C in catalyst quantity was added thereto and stirred under hydrogen atmosphere overnight at room temperature. After filtering out the catalyst and removing a solvent, purification was conducted in accordance with the purification process A to obtain a title compound.
Reaction SMILES: C(C1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[OH:14])(=O)C.C12C(=[O:24])C(CCC1)CCC2.N1CCOCC1>C1(C)C=CC=CC=1>[O:24]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][CH:5]1[OH:14]
Reactant: CC(=O)c1c(O)ccc2ccccc12
Reactant: O=C1C2CCCC1CCC2
Solvent: Cc1ccccc1
Solvent: C1COCCN1
Product: OC1CCc2ccccc2O1
Reaction time: 5 h

Procedure:
A solution was prepared by dissolving 10 g (0.054 mole) of 1-acetyl-2-naphthol, 8.29 g (0.06 mole) of bicyclo[3,3,1]nonan-9-one and 8.7 g (0.10 mole) of morpholine in 300 cc of toluene, and the solution was boiled for 5 hours and water was separated. After termination of the reaction, toluene was removed under reduced pressure and the remaining chromanone compound was recrystallized from acetone. Then, the chromanone compound was dissolved in 200 cc of methanol and lithium aluminum hydride was added to the solution to form a chromanol compound. Then, 6.49 g of this chromanol compound was heated at 170° C. to 180° C. together with anhydrous copper sulfate in a carbon dioxide current for 10 minutes, and the obtained brown viscous liquid was purified by the chromatography on silica gel to obtain 5.8 g of a chromene compound represented by the following formula: ##STR162##
Reaction SMILES: Br[C:2]1[C:3](=[O:21])[CH2:4][CH2:5][C:6]2([CH2:17][CH2:18][CH2:19][CH3:20])[C:14]=1[C:13]1[C:8](=[CH:9][C:10]([O:15][CH3:16])=[CH:11][CH:12]=1)[CH2:7]2.[Cu][C:23]#[N:24]>CN1CCCC1=O>[CH2:17]([C:6]12[CH2:5][CH2:4][C:3](=[O:21])[C:2]([C:23]#[N:24])=[C:14]1[C:13]1[C:8](=[CH:9][C:10]([O:15][CH3:16])=[CH:11][CH:12]=1)[CH2:7]2)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCC12CCC(=O)C(Br)=C1c1ccc(OC)cc1C2
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: CCCCC12CCC(=O)C(C#N)=C1c1ccc(OC)cc1C2
Temperature: 160 °C
Yield: 81 %

Procedure:
A solution of 4-bromo-9a-butyl-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one (50 mg, 0.138 mmol) in anhydrous 1-methyl-2-pyrrolidinone (0.276 mL) was treated with copper(I) cyanide (25 mg, 0.275 mmol). The resulting mixture was stirred under a nitrogen atmosphere and heated in an oil bath at 160° C. for 40 minutes. The mixture was partitioned between EtOAc (20 mL) and water (20 ml). The organic phase was washed with water (2×20 mL) and brine (10 mL), dried over MgSO4, filtered, and evaporated under vacuum. The residue was purified by preparative layer chromatography on a 0.1×20×20 cm silica gel GF plate, developing with 5% EtOAc in CH2Cl2, to afford 9a-butyl-4-cyano-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one (33 mg) as an oil.
Reaction SMILES: N[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:23][C@H:22]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[C@@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]2[O:13][C:14](=[O:16])[CH3:15])=[C:4]([Cl:29])[N:3]=1.O.N(OC(C)(C)C)=[O:32]>C(O)(C)(C)C>[Cl:29][C:4]1[N:3]=[C:2]([OH:32])[N:10]=[C:9]2[C:5]=1[N:6]=[CH:7][N:8]2[C@@H:11]1[O:23][C@H:22]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[C@@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]1[O:13][C:14](=[O:16])[CH3:15]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(C)(C)ON=O
Solvent: O
Solvent: CC(C)(C)O
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(O)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Amino-6-chloro-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine (42.7 g, 100 mmoles) is dissolved in 2 liters of a tert-butyl alcohol:water mixture (1:1, v/v) with heating. After cooling the solution with an ice bath, tert-butyl nitrite (50 mL, 422 mmoles) is added in one portion. The ice bath is removed and the mixture is stirred at room temperature until gas evolution ceases (approximately 3 hours). The mixture is then frozen (dry ice/2-propanol) and lyophilized to afford the desired intermediate as a yellow solid that is used immediately or stored frozen at −20° C. without purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[Cl:16])[N:3]=1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>O1CCOCC1>[NH2:1][C:2]1[N:7]=[C:6]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[N:5]=[C:4]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[Cl:16])[N:3]=1
Reactant: C1CNCCN1
Reactant: Nc1nc(Cl)nc(-c2cc(Cl)ccc2Cl)n1
Solvent: C1COCCO1
Product: Nc1nc(-c2cc(Cl)ccc2Cl)nc(N2CCNCC2)n1
Yield: 95.8 %

Procedure:
2-Amino-4-chloro-6-(2,5-dichlorophenyl)-s-triazine (1.3 grams) and 2.0 grams of piperazine were stirred with refluxing for two hours in 20 milliliters of dioxane. The reaction solution was evaporated to dryness in vacuo, water was added to the residue, crystals thereby separated out were collected by filtration, and washed with methanol to give 1.47 grams of 2-amino-4-piperazino-6-(2,5-dichlorophenyl)-s-triazine, melting at 194° to 195° C.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:8]=[C:9]([CH:17]=[CH:18][CH:19]=2)[CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[O:6]CCO1.[C:20]1([C:26]2[O:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:2]([C:7]1[CH:8]=[C:9]([CH:17]=[CH:18][CH:19]=1)[CH2:10][N:11]1[N:15]=[C:14]([NH:16][C:31]([C:27]2[N:28]=[CH:29][O:30][C:26]=2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:32])[CH:13]=[N:12]1)(=[O:6])[CH3:1]
Reactant: CC1(c2cccc(Cn3ncc(N)n3)c2)OCCO1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Product: CC(=O)c1cccc(Cn2ncc(NC(=O)c3ncoc3-c3ccccc3)n2)c1

Procedure:
Following general procedure A followed by B, starting from 2-[3-(2-methyl-[1,3]dioxolan-2-yl)-benzyl]-2H-[1,2,3]triazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].[K].[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12>CN(C=O)C>[C:13]1(=[O:23])[N:17]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12
Reactant: OCCCCCCCCCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCCCCCCO
Temperature: 100 °C

Procedure:
A stirred mixture of 9-bromononanol (Aldrich)(1.0 g, 4.5 mmol), phthalimide potassium derivative (1.85 g, 10 mmol) and DMF (10 ml) was heated at 100° C. for 1 hour. The mixture was allowed to cool to room temperature and was partitioned between ethyl acetate and water. The organic layer was washed with water, brine, dried over magnesium sulfate and evaporated under reduced pressure to afford the title compound as a white solid, 1.53 g, quantitative yield. m/z (LCMS ES+, 70 v) 290.1 (MH+), 312.1 (MNa+). δH (CHCl3-d) 7.81 (2H, m), 7.73 (2H, m), 3.64 (4H, m), 1.68 (2H, m), 1.59 (2H, m), 1.32 (10H, m). Intermediate 27