Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:11](=[O:12])[C:10]([OH:13])=[CH:9][C:7](=[O:8])[C:5]=2[CH:6]=1.[CH3:14][C:15]([CH3:20])([CH3:19])[CH2:16][CH:17]=O.N1CCCC1>C1COCC1>[CH3:14][C:15]([CH3:20])([CH3:19])[CH:16]=[CH:17][C:9]1[C:7](=[O:8])[C:5]2[C:4]([C:11](=[O:12])[C:10]=1[OH:13])=[CH:3][CH:2]=[CH:1][CH:6]=2
Reactant: CC(C)(C)CC=O
Reactant: O=C1C=C(O)C(=O)c2ccccc21
Solvent: C1CCOC1
Solvent: C1CCNC1
Product: CC(C)(C)C=CC1=C(O)C(=O)c2ccccc2C1=O

Procedure:
Lawsone (2-hydroxynaphthalene-1,4-dione) (1.4 g) and 3,3-dimethyl-butanal (1.0 g) were dissolved in 20 ml THF at room temperature and 795 μl pyrrolidine added before stirring the reaction for a further 20 minutes. The solvent was removed under vacuum and the residue dissolved in benzene (40 ml) before addition of p-toluenesulphonic acid (2.3 g). The mixture was refluxed for 1 hour, cooled then diluted with ether before the organic phase was washed with sodium bicarbonate solution, followed by one wash with dilute HCl and one wash with water followed by drying under vacuum. The product was purified by chromatograpy using 10% EtOAc/petroleum ether eluant and then crystallised from methanol to yield 260 mg; m.p. 126-128° C.
Reaction SMILES: C1(O[C:8](=[O:23])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:21]=3[CH3:22])[CH:11]=2)C=CC=CC=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][C:34]=1[C:35]([F:38])([F:37])[F:36])[NH:31][CH2:30][CH2:29]2>>[CH3:22][C:21]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[C:12]1[CH:11]=[C:10]([NH:9][C:8]([N:31]2[C:32]3[C:28](=[CH:27][C:26]([O:25][CH3:24])=[C:34]([C:35]([F:37])([F:38])[F:36])[CH:33]=3)[CH2:29][CH2:30]2)=[O:23])[CH:15]=[CH:14][CH:13]=1
Reactant: Cc1ccncc1-c1cccc(NC(=O)Oc2ccccc2)c1
Reactant: COc1cc2c(cc1C(F)(F)F)NCC2
Product: COc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1cccc(-c3cnccc3C)c1)CC2
Yield: 34.2 %

Procedure:
Reaction of phenyl-N-[3-(4-methylpyrid-3-yl)phenyl]carbamate (D28) (0.4 g, 1.3 mmoles) with 5-methoxy-6-trifluoromethylindoline (D11) (0.28 g, 1.3 mmoles) as in the method of Example 28 gave the title compound (E41) (0.19 g, 34%) m.p. 178-180° C.
Reaction SMILES: S(=O)(O)O.[CH:5]1([CH:11]=O)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.CCN(CC)CC.[CH3:20][NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.CCOC(C)=O>[CH2:11]([N:21]([CH2:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[CH3:20])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=CC1CCCCC1
Reactant: CNCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CN(Cc1ccccc1)CC1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of cyclohexanecarboxaldehyde bisulfite adduct (5.0 mmol) and Et3N (5.5 mmol) in dichloroethane (20 mL) was stirred at room temperature for 15 min. The suspension was treated with N-methylbenzylamine (5.5 mmol) and was stirred for 45 min. NaBH(OAc)3 (7.0 mmol) was added portion-wise over approximately 30 min. After 16 h, the reaction mixture was diluted with EtOAc (80 mL), and was washed with 1 N NaOH (25 mL) followed by brine (25 mL). The organic layer was dried (MgSO4) and concentrated to yield benzyl-cyclohexylmethyl-methyl-amine as an oil. The crude material was purified by the General Purification Method as described above.
Reaction SMILES: C1COCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O[C:13]1([CH:23]=[CH:24][CH:25]([OH:27])[CH3:26])[C:17]([CH3:19])([CH3:18])[CH:16]([OH:20])[CH2:15][C:14]1([OH:22])[CH3:21].[OH-].[Na+]>O>[OH:22][C:14]1([CH3:21])[CH2:15][CH:16]([OH:20])[C:17]([CH3:18])([CH3:19])[C:13]1=[C:23]=[CH:24][CH:25]([OH:27])[CH3:26]
Reactant: CC(O)C=CC1(O)C(C)(O)CC(O)C1(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(O)C=C=C1C(C)(O)CC(O)C1(C)C
Reaction time: 10 h
Yield: 55.2 %

Procedure:
To 25 ml of an anhydrous THF suspension containing 583 mg of lithium aluminum hydride was slowly added 20 ml of an anhydrous THF solution containing 1.0 g of 4-(1,2,4-trihydroxy-2,5,5-trimethylcyclopentyl)but-3-en-2-ol under ice-cooling in a nitrogen atmosphere over 10 minutes. After the addition, the mixture was placed under refluxing conditions and stirred for 10 hours. After completion of the reaction, the reaction mixture was cooled, and 0.6 ml of water, 0.6 ml of a 15% sodium hydroxide aqueous solution, and 1.8 ml of water were carefully added thereto in this order, followed by vigorously stirring for 20 minutes. Any insoluble matter was removed by filtration with suction, and the filtrate was concentrated under reduced pressure. The resulting solid was purified by silica gel column chromatography to obtain 509 mg (yield: 55%) of 4-(2,4-dihydroxy-2,5,5-trimethylcyclopentylidene)but-3-en-2-ol.
Reaction SMILES: [CH:1]1([C:7]2([OH:17])[CH2:16][CH2:15][C:10]3(OCC[O:11]3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.CCOC(C)=O.C([O-])(O)=O.[Na+]>C1COCC1>[CH:1]1([C:7]2([OH:17])[CH2:8][CH2:9][C:10](=[O:11])[CH2:15][CH2:16]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1(C2CCCCC2)CCC2(CC1)OCCO2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1CCC(O)(C2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 37 %

Procedure:
To a solution of 1,4-dioxaspiro[4.5]decan-8-one (5.00 g, 24.0 mmol) in THF (100 mL) was dropwise added cyclohexylmagnesium chloride (2.0 M in diethyl ether, 24.0 mL, 48.0 mmol) at −78° C. over 10 min. The mixture was stirred at 0° C. for 1.5 h, and then quenched with aqueous NH4Cl (100 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (Purif, silica gel, hexane to 70:30 hexane/EtOAc) to give crude 8-cyclohexyl-1,4-dioxaspiro[4.5]decan-8-ol as a colorless solid. To a solution of crude 8-cyclohexyl-1,4-dioxaspiro[4.5]decan-8-ol (<24.0 mmol) in THF (45 mL) was added 3 M HCl (15 mL). The mixture was stirred at room temperature for 4 h, and then poured into EtOAc (50 mL) and aqueous NaHCO3 (50 mL). The aqueous layer was extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (15 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (Purif, silica gel hexane to 70:30 hexane/EtOAc) to give the title compound (2.34 g, 37%) as a colorless solid:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13](#[N:15])[CH3:14].[C:16]([C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:28][CH3:29])=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH:19]=1)#[N:17]>C1COCC1>[C:13]([CH:14]1[C:27]2[C:22](=[CH:23][C:24]([O:28][CH3:29])=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH:19]1[CH2:18][C:16]#[N:17])#[N:15]
Reactant: COc1ccc2c(c1)CCC=C2C#N
Reactant: CC#N
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCC(CC#N)C2C#N
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 74.2 %

Procedure:
To a solution of 1.05 mL (7.5 mmol) of diisopropylamine in 10 mL of THF at -78° C., under a nitrogen atmosphere, was added n-butyllithium (2.2 mL of a 2.5 M solution in THF, 5.5 mmol) and the resultant solution was stirred at -78° C. for 40 min. To the stirred solution was added, dropwise over a 25 minute period, a solution of 274 μL (5.25 mmol) of acetonitrile in 5 mL of THF. The solution was stirred for 20 min at -78° C. and then a solution of 926 mg (5 mmol) of 1-cyano-6-methoxy-3,4-dihydronaphthalene (the product of Step 2 of Example 1) in 5 mL of THF was added via syringe pump over a 20 min period. The reaction mixture then allowed to warm to ambient temperature and was was stirred at ambient temperature for 1 h and then the reaction was quenched by pouring the reaction mixture into saturated aqueous ammonium chloride solution. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluted with 25% ethyl acetate in hexane to give 840 mg (74% yield) of the title compound as a 1:1 mixture of the cis and trans isomers; MS DCI-NH3M/Z: 244 (M+H)+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].CN(C)P(N(C)C)(N(C)C)=O.[CH3:32]/[C:33](/[CH2:37][CH2:38]/[CH:39]=[C:40](\[CH3:47])/[CH2:41][CH2:42][CH:43]=[C:44]([CH3:46])[CH3:45])=[CH:34]\[CH2:35]Br>O1CCCC1>[CH3:32]/[C:33](/[CH2:37][CH2:38]/[CH:39]=[C:40](\[CH3:47])/[CH2:41][CH2:42][CH:43]=[C:44]([CH3:46])[CH3:45])=[CH:34]\[CH2:35][CH2:14][C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CC(=O)OC(C)(C)C
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CBr
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 65 %

Procedure:
To a solution of 9.60 mL (68.5 mmol, 1.5 eq.) of diisopropylamine in 100 mL of tetrahydrofuran (THF) at -78° C. under argon was added 28.2 mL (45.0 mmol, 1.0 eq.) of 1.6M n-butyllithium in hexanes over 20 minutes. After warming to 0° C. for 15 minutes, the solution was recooled to -78° C. and 6.05 mL (45 mmol, 1.0 eq.) of t-butyl acetate was added over 20 minutes. After an additional 15 minutes, 16.0 mL (92 mmol, 2.05 eq.) of hexamethylphosphoramide (HMPA) was added, followed by a solution of 12.53 g (45.0 mmol) of Part A(1) farnesyl bromide in 100 mL of THF over 20 minutes. The reaction was stirred at -78° C. for 2.5 hours, quenched with saturated NH4Cl and allowed to warm to room temperature. After diluting with 400 mL of ethyl acetate, the mixture was washed with four 100 mL portions of water, and 200 mL of brine, dried over MgSO4 and evaporated to provide 12.96 g of crude product as a yellow oil. Purification by flash chromatography on 1 kg of silica gel, eluted with 1:9 ethyl acetate:petroleum ether afforded 9.39 g (65%) of title compound as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24][CH3:25])[N:12]2[CH2:15][CH2:16][CH2:17][NH:18][C@@H:19]2[CH2:23][CH2:22][CH2:21]O2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].F[C:28](F)(F)[C:29](O)=[O:30].C(OC1NC(N)=C2C(N=1)=NC(OC)=N2)CCC>>[CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24][CH3:25])[N:12]2[CH2:15][CH2:16][CH2:17][NH:18][CH2:19][CH:23]2[CH2:22][CH2:21][CH2:28][CH2:29][O:30]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCN[C@@H]3CCCO3)c2n1
Reactant: O=C(O)C(F)(F)F
Agent: CCCCOc1nc2nc(OC)nc-2c(N)[nH]1
Product: CCCCOc1nc(N)c2nc(OC)n(CCCNCC3CCCCO3)c2n1

Procedure:
Prepared similarly to Intermediate 14 from 2-(butyloxy)-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and (tetrahydro-2H-pyran)-2-ylmethyl)amine hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:28][C:29]5[CH:34]=[CH:33][C:32]([O:35]C(=O)C)=[CH:31][CH:30]=5)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.C([O-])([O-])=O.[K+].[K+].Cl>CO>[CH3:1][O:2][C:3](=[O:39])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:28][C:29]5[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=5)[C:20]([C:24]([F:25])([F:26])[F:27])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Cc3ccc(OC(C)=O)cc3)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Cc3ccc(O)cc3)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of {(S)-6-[(R)-4-(4-acetoxy-benzyl)-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (0.19 g), K2CO3 (0.08 g), and methanol (5 ml) is stirred at room temperature for 2 h. The solution is neutralized with 1 N aqueous HCl solution and concentrated. Water is added to the residue, and the resulting mixture is extracted with ethyl acetate. The combined extract is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate) to give the title compound. LC (method 8): tR=1.22 min; Mass spectrum (ESI+): m/z=521 [M+Na]+.
Reaction SMILES: C(S[N:5]1[CH2:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[S:6]1(=[O:15])=[O:14])CC.[OH2:16].ClCl>C(O)(=O)C>[CH2:9]([N:5]1[CH2:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:13]([S:6]([NH2:5])(=[O:14])=[O:16])[C:7]=2[S:6]1(=[O:14])=[O:15])[CH2:8][CH2:7][CH2:13][CH3:12]
Reactant: O
Reactant: CCCSN1Cc2ccccc2S1(=O)=O
Agent: ClCl
Solvent: CC(=O)O
Product: CCCCCN1Cc2cccc(S(N)(=O)=O)c2S1(=O)=O
Temperature: 25 °C

Procedure:
A solution of 9.5 g of 2-pentyl-7-(propylthio-2,3-dihydro-1,2-benzisothiazole-1,1-dioxide in 40 ml of acetic acid containing 1.3 ml of water was contacted with 7.0 ml of liquified chlorine at 10° to 15° C. and allowed to warm to 25° C. The excess chlorine was removed via a stream of nitrogen gas and the solution was poured onto ice. The resulting solid was filtered, washed with water and hexane, dried, dissolved in CH2Cl2 and contacted with 2.0 ml of liquified ammonia at -78° to 25° C. The mixture was added to 100 ml of 1N HCl and extracted with CH2Cl2. The extract was washed with water and brine, dried over MgSO4, concentrated and slurried in ether to give 6.35 g of the title compound as a white powder, m.p. 156°-160° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:6][CH2:5][CH2:4][CH:3]1[NH:7][NH:8]C(OC(C)(C)C)=O.[ClH:17]>CO>[ClH:17].[ClH:17].[ClH:17].[CH3:1][C:2]1([CH3:16])[CH2:6][CH2:5][CH2:4][CH:3]1[NH:7][NH2:8]
Reactant: CC(C)(C)OC(=O)NNC1CCCC1(C)C
Agent: Cl
Solvent: CO
Product: CC1(C)CCCC1NN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl 2-(2,2-dimethylcyclopentyl)hydrazinecarboxylate (2.4 g) and hydrogen chloride in saturated methanol solution (30 mL) was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the obtained solid was washed with diethyl ether to give the title compound (2.0 g).
Reaction SMILES: C1COCC1.[CH2:6]([O:8][C:9]1[CH:14]=[C:13]([C:15](OCC)=[O:16])[CH:12]=[C:11]([O:20][CH2:21][CH3:22])[C:10]=1[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[CH3:7].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O>[CH2:6]([O:8][C:9]1[CH:14]=[C:13]([CH:15]=[O:16])[CH:12]=[C:11]([O:20][CH2:21][CH3:22])[C:10]=1[C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)[CH3:7]
Reactant: CCOC(=O)c1cc(OCC)c(-c2ccc(F)cc2)c(OCC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc(C=O)cc(OCC)c1-c1ccc(F)cc1
Reaction time: 0.08 h
Yield: 83.9 %

Procedure:
A THF (200 mL) solution of ethyl 2,6-diethoxy-4′-fluorobiphenyl-4-carboxylate (50.7 g) was added to a THF (200 mL) suspension of lithium aluminum hydride (4.34 g) under ice cooling. After stirring at the same temperature as above for 30 minutes, water (4.5 mL) and a 1 M aqueous sodium hydroxide solution (4.5 mL) were added thereto, and the mixture was stirred for 5 minutes. Water (13.5 mL) was further added thereto. The reaction mixture was stirred for 1 hour and then filtered through celite, and the filtrate was concentrated under reduced pressure. A sulfur trioxide-pyridine complex (48.6 g) was added to a DMSO (250 mL) solution of the obtained residue and triethylamine (63.8 mL), and the mixture was stirred at room temperature for 30 minutes. Water (450 mL) was added to the reaction mixture, and the deposited solid was collected by filtration. The obtained solid was recrystallized (ethanol/water) to obtain the title compound (36.9 g).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].[N+:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17](Cl)(=[O:19])=[O:18])([O-:10])=[O:9].C(N(C(C)C)CC)(C)C.Cl>C(Cl)Cl>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH:5][S:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N+:8]([O-:10])=[O:9])(=[O:18])=[O:19]
Reactant: COC(CN)OC
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(CNS(=O)(=O)c1ccccc1[N+](=O)[O-])OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2,2-dimethoxyethylamine (2.61 g) in methylene chloride (100 ml) were added 2-nitrophenylsulfonylchloride (5.0 g) and diisopropylethylamine (5 ml) dropwise at −78° C. and the mixture was stirred for 10 minutes at room temperature. To the reaction mixture was added 1N hydrochloric acid and was extracted with chloroform. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and was concentrated to give the title compound having the following physical data.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:12]=[C:11]([C:13]([O:15]CC)=[O:14])[NH:10][N:9]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[NH:10][N:9]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cc(CN2CCOCC2)n[nH]1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc(CN2CCOCC2)n[nH]1

Procedure:
The title compound was prepared from ethyl 3-(morpholinomethyl)-1H-pyrazole-5-carboxylate (0.138 g, 0.57 mmol) and sodium hydroxide solution (2 mL) using the method of Example 225(b). Yield 0.119 g. 1H NMR (400 MHz; MeOD): δ 3.22 (m, 2H), 3.46 (m, 2H), 3.78 (m, 2H), 4.05 (m, 2H), 4.43 (s, 2H), 7.05 (s, 1H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[O:12][C:13]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])=[C:14]([C:16](O)=[O:17])[N:15]=2)[C:8]([CH3:26])=[CH:7][N:6]=1)(=[O:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH3:40][O:41][NH:42][CH3:43]>C(Cl)Cl.O>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[O:12][C:13]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])=[C:14]([C:16]([N:42]([O:41][CH3:40])[CH3:43])=[O:17])[N:15]=2)[C:8]([CH3:26])=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: CNOC
Reactant: CC(=O)Nc1cc(-c2nc(C(=O)O)c(-c3ccccc3Cl)o2)c(C)cn1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: O
Product: CON(C)C(=O)c1nc(-c2cc(NC(C)=O)ncc2C)oc1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
To a solution of 2-(2-acetamido-5-methylpyridin-4-yl)-5-(2-chlorophenyl)-1,3-oxazole-4-carboxylic acid (0.303 g, 0.815 mmol) in DCM (2 mL) was added CDI (0.14 g, 0.87 mmol). The reaction mixture was allowed to stir at rt for 30 min, then at reflux for 30 min. The reaction mixture was allowed to cool to rt and TEA (0.125 mL, 0.896 mmol) and N-methoxymethanamine hydrochloride (0.835 g. 0.856 mmol) were added. The reaction mixture was allowed to stir at rt overnight and then diluted with water. The aqueous solution was separated and extracted with DCM. The organic solutions were combined, washed sequentially with 10% citric acid, saturated aq. NaHCO3 (50 mL) and brine, dried over Na2SO4, filtered and concentrated to give 2-(2-acetamido-5-methylpyridin-4-yl)-5-(2-chlorophenyl)-N-methoxy-N-methyl-1,3-oxazole-4-carboxamide (0.187 g, 55%), which was used without purification in the next step. LCMS (FA): m/z=415.4 (M+H).
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[CH3:19][S:20]([O:1][CH2:2][C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5][CH2:4]1)(=[O:22])=[O:21]
Reactant: CCOC(=O)C1(CO)CCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1(COS(C)(=O)=O)CCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 80.6 %

Procedure:
To a solution of ethyl 1-(hydroxymethyl)cyclobutanecarboxylate (1.0 g, 6.3 mmol) and N,N-diethylethanamine (1.5 g, 8.2 mmol) in CH2Cl2 (30 ml) was added methanesulfonyl chloride (869 mg, 7.6 mmol). The mixture was stirred for 6 hours at ambient temperature. After dilution with CHCl3 and H2O, the organic layer was washed with H2O, dried over MgSO4, and concentrated in vacuo to give ethyl 1-{[(methylsulfonyl)oxy]methyl}cyclobutanecarboxylate (1.2 g).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[CH3:12][NH:13][CH2:14][CH2:15][OH:16].C(N(CC)CC)C>CN1CCCC1=O>[CH3:8][C:6]1[CH:7]=[C:2]([N:13]([CH2:14][CH2:15][OH:16])[CH3:12])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: CNCCO
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Cc1cc(N(C)CCO)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A solution of 5-fluoro-2-nitrotoluene (1.5 g, 9.6 mmol), N-methylethanolamine (0.90 mL, 0.012 mol) and triethylamine (1.6 mL, 0.012 mol) in N-methyl-2-pyrrolidone (15 mL) was stirred at 60° C. for 12 h. Cooled to ambient temperature, the reaction mixture was poured into ice water, extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated to afford 2-[(3-methyl-4-nitrophenyl)-N-methylamino]ethanol as solid (2.0 g, y. 98%).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].Cl.[CH2:10]([N:17]1[CH2:22][CH2:21][C:20](=O)[CH:19]([C:24](OCC)=[O:25])[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[OH:2][C:1]1[CH:8]=[CH:7][C:6]2[C:20]3[CH2:21][CH2:22][N:17]([CH2:10][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH2:18][C:19]=3[C:24](=[O:25])[O:5][C:4]=2[CH:3]=1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCC1=O
Reactant: Oc1cccc(O)c1
Agent: Cl
Product: O=c1oc2cc(O)ccc2c2c1CN(Cc1ccccc1)CC2

Procedure:
Prepared by the method described for Example 1 from resorcinol (22 g, 0.2 moles) and 1-benzyl-3-carbethoxy-4-piperidone hydrochloride (59.6 g, 0.2 moles). The product (55 g) is converted to 1,2,3,4-tetrahydro-3-(phenylmethyl)-8-[(1-phenyl-1H-tetrazol-5-yl)oxy]-5H-[1]benzopyrano [3,4-c]pyridin-5-one without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])=[O:18])[C@@H:13]([OH:24])[C@H:12]2[OH:25])=[C:4](Cl)[N:3]=1.[NH2:27][CH2:28][CH:29]([C:37]1[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=1)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1.CCN(C(C)C)C(C)C>C1COCC1.C(OCC)(=O)C>[OH:36][C:33]1[CH:34]=[CH:35][C:30]([CH:29]([C:37]2[CH:38]=[CH:39][C:40]([OH:43])=[CH:41][CH:42]=2)[CH2:28][NH:27][C:4]2[N:3]=[C:2]([Cl:1])[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])=[O:18])[C@@H:13]([OH:24])[C@H:12]2[OH:25])=[CH:31][CH:32]=1
Reactant: CC(=O)OCC(=O)N[C@H]1C[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: NCC(c1ccc(O)cc1)c1ccc(O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)OCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccc(O)cc4)c4ccc(O)cc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Acetic acid [(1S,2R,3S,4R)-4-(2,6-dichloro-purin-9-yl)-2,3-dihydroxy-cyclopentyl-carbamoyl]-methyl ester (Intermediate ZJ; 1 equivalent) and 4,4′-(2-aminoethylidene)bis-phenol (1.1 equivalents; prepared as described by Schelkun, R. M. et al. Bioorg. Med. Chem. Lett. (1999), 9(16), pp 2447-2452) are combined in dry THF and treated with DIPEA (1.2 equivalents) and stirred at 50° C. overnight. The reaction is diluted with ethyl acetate and washed consecutively with water (×2) and brine, before drying over magnesium sulfate, filtering and removal of the volatile components under reduced pressure to afford the title compound.