Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC(C(N=C=O)N=[C:9]=[O:10])=CC=1.[C:14]1([CH3:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:14]([CH:19]([CH2:18][CH2:17][CH2:16][CH3:15])[CH2:9][OH:10])[CH3:20]
Reactant: O=C=NC(N=C=O)c1ccccc1
Reactant: Cc1ccccc1
Product: CCCCC(CC)CO

Procedure:
The batch is then diluted with 185.0 parts of toluene and a mixture of 180.0 parts of the semi-blocked toluylene diisocyanate referred to in Example 1 and 150.0 parts of a semi-blocked toluylene diisocyanate obtained from 2-ethylhexanol and an 80/20 toluylene diisocyanate isomer mixture is added in the course of 2 hours 15 minutes at 90° C. After completion of this addition, stirring is continued for 1 hour at 90° C., and the mixture is then heated to 120° C., kept at this temperature for 3.5 hours, and diluted after cooling with 81 parts of toluene. The solids content of the resulting polyether-polyol derivative containing blocked isocyanate groups, ie. of component A, is 71%.
Reaction SMILES: [O:1]=[C:2]1[CH2:9][C:6]([CH3:8])([CH3:7])[CH2:5][C:4]([CH3:10])=[CH:3]1.[O-]CC.[Na+].[CH2:15]([N:19]([CH2:30][CH2:31][CH2:32][CH3:33])[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[C:22]([O:28][CH3:29])[CH:21]=1)[CH2:16][CH2:17][CH3:18].C(OCC)(=O)C>O1CCCC1>[CH2:15]([N:19]([CH2:30][CH2:31][CH2:32][CH3:33])[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[CH:10][C:4]2[CH2:5][C:6]([CH3:8])([CH3:7])[CH2:9][C:2](=[O:1])[CH:3]=2)=[C:22]([O:28][CH3:29])[CH:21]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CC1=CC(=O)CC(C)(C)C1
Reactant: CCCCN(CCCC)c1ccc(C=O)c(OC)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCN(CCCC)c1ccc(C=CC2=CC(=O)CC(C)(C)C2)c(OC)c1
Temperature: 50 °C
Reaction time: 4.5 h
Yield: 45 %

Procedure:
In 15 ml of tetrahydrofuran, 1.5 g (10.85 mmol) of isophorone was dissolved, and 3.4 g of sodium ethoxide (20% solution in ethanol) (10.0 mmol) was added thereto. To this mixture, 2.6 g (9.87 mmol) of 4-dibutylamino-2-methoxybenzaldehyde in tetrahydrofuran was added dropwise with heating at 50° C., and the mixture was stirred for 4.5 hours. To the mixture, 100 ml of ethyl acetate was added. Washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. The residue was purified by silica gel column chromatography to give 1.7 g of a reddish orange oily matter (yield: 45.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:8][CH2:7]1.[S:22](N)([NH2:25])(=[O:24])=[O:23]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[O:5][CH:6]1[CH2:7][CH2:8][N:9]([CH:12]2[CH2:13][CH2:14][N:15]([S:22]([NH2:25])(=[O:24])=[O:23])[CH2:16][CH2:17]2)[CH2:10][CH2:11]1
Reactant: Clc1ccc(OC2CCN(C3CCNCC3)CC2)cc1Cl
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Product: NS(=O)(=O)N1CCC(N2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)CC1
Temperature: 25 °C
Yield: 80.6 %

Procedure:
4-(3,4-Dichlorophenoxy)-1,4′-bipiperidine (5 g, 0.0152 mol) and sulfamide (1.45 g, 0.0152 mol) were stirred together in dioxan (150 ml) at reflux for 24 hours. The resulting mixture was cooled to ambient temperature, evaporated to dryness and the residue was triturated with ether to give the title compound as a tan solid (5 g; MS APCI 409/411 (M+H)).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6]1[C:11](=[O:12])[CH2:10][CH:9]([CH3:13])[CH2:8][CH2:7]1)=[O:5].C(N(CC)C(C)C)(C)C.[F:23][C:24]([F:30])([F:29])[S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH3:13][CH:9]1[CH2:8][CH2:7][C:6]([C:4]([O:3][CH2:2][CH3:1])=[O:5])=[C:11]([O:12][S:25]([C:24]([F:30])([F:29])[F:23])(=[O:27])=[O:26])[CH2:10]1
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: CCOC(=O)C1CCC(C)CC1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CC(C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.5 %

Procedure:
To a solution of ethyl 4-methyl-2-cyclohexanone-1-carboxylate (50 g, 0.27 mol) in dichloromethane (500 ml) at −10° C. was added N,N-diisopropylethylamine (52 ml, 0.3 mol) followed by dropwise addition of trifluoromethanesulphonyl chloride (57 ml, 0.3 mol) keeping the temperature between −5 and −100° C. The reaction mixture was allowed to warm to room temperature and stirred for 3 hours. TLC showed 80% reaction, it was cooled to −5° C. and more N,N-diisopropylethylamine (14 ml, 0.1 mol) was added followed by trifluoromethanesulphonyl chloride (15.5 ml, 0.1 mol) and the reaction mixture was stirred for 15 hours at room temperature. The mixture was washed with cold water (2×200 ml), cold saturated sodium bicarbonate (2×200 ml) and brine (1×200 ml). The organic layer was dried (MgSO4), filtered and evaporated to give the required product (85 g) as a colourless oil. 1H NMR (250 MHz, CDCl3) δ 1.04 (3H, d, J=6.5 Hz), 1.43 (3H, m), 1.73-2.09 (4H, m), 2.39-2.63 (3H, m), 4.25 (2H, m).
Reaction SMILES: [C:1]1([C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:8][NH:9][C:10](=O)[C@H:11]([CH2:20][OH:21])[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:1]1([C:7](=[N:8][N:9]2[CH2:10][C@H:11]([NH:12][C:13](=[O:14])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:20]2=[O:21])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)NN=C(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CN(N=C(c2ccccc2)c2ccccc2)C1=O
Temperature: 55 °C
Yield: 65.7 %

Procedure:
A solution of 7.9 ml (0.05 mol) of diethyl azidodicarboxylate in 50 ml of tetrahydrofuran was added to a stirred solution of 9.6 g, (0.05 mol) of N-(t-butyloxycarbonyl)-L-serine-2-(diphenylmethylene)hydrazide and 9.6 g, (0.05 mol) of triphenylphosphine in 250 ml of tetrahydrofuran. The mixture was stirred and heated at 55° C. for 6 hours. The resulting solution was evaporated to dryness in vacuo. The residue was dissolved in 50 ml of ethyl acetate and chilled. The crystalline precipitate was removed by filtration and the filtrate was evaporated to dryness. The residue was chromatographed on silica gel using ethyl acetate-hexane (1:1) as the eluent to afford 12.0 g (66%) of the desired product; mp 167°-170° C.; IR (KBr) 1775 cm-1 (C=O); NMR (CDCL3) δ1.38 (s, 9H, (CH3)3C), 2.85 (dd, 1H, J=3 and 6 Hz, 4βH), 3.25 (t, 1H, J=6 and 6 Hz, 4αH), 4.70 (m, 1H, 3αH), 5.25 (d, 1H, NH), 7.40 (m, 10H, aromatic protons).
Reaction SMILES: [Li]CCCC.I[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:9][CH:8]=1.C(O[B:25]1[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]1)(C)C>C1COCC1>[CH3:32][C:27]1([CH3:33])[C:28]([CH3:31])([CH3:30])[O:29][B:25]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:9][CH:8]=2)[O:26]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: CCCCCCCCc1ccc(I)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
n-BuLi (16.6 mL, 1.6 M in hexanes) was added over 10 minutes to a solution of 1-iodo-4-octylbenzene from Part A (6.9 g, 21.8 mmol) in dry THF (100 mL) at −78° C. under a nitrogen atmosphere. The mixture was stirred for another 10 minutes at −78° C. 2-Isopropoxy-4,4,5,5-tetramethyl[1,3,2]dioxaborolane (6.21 mL, 30.4 mmol) was subsequently added dropwise to the mixture and stirring was continued at room temperature overnight. The reaction was then quenched with distilled water, and THF was removed under vacuum. The product was then extracted into diethyl ether and the organic layer was washed with brine, dried over MgSO4, filtered and evaporated in vacuo to give 6.38 g of 4,4,5,5-tetramethyl-2-(4-octylphenyl)-1,3,2-dioxaborolane as a colorless oil. The product was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:18][CH:17]([C:19](O)=[O:20])[N:8]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]([F:16])[C:14]=4[CH:15]=[C:7]3[C:6]=2[N:22]=1.CCN(CC)CC.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>O=S(Cl)Cl.ClCCl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:18][CH:17]([C:19]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[O:20])[N:8]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]([F:16])[C:14]=4[CH:15]=[C:7]3[C:6]=2[N:22]=1
Reactant: O=C(O)C1Oc2ccc(Cl)nc2-c2cc3c(F)cccc3n21
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: O=C(C1Oc2ccc(Cl)nc2-c2cc3c(F)cccc3n21)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.9 %

Procedure:
A solution of 2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole-6-carboxylic acid (300 mg, 0.94 mmol) in SOCl2 (5 mL) was reflux for 2.0 hours, then concentrated the solution and afforded to the residue. A mixture of the residue, Et3N (0.2 mL) and morpholine (250 mg, 2.87 mmol) in dichloromethane (5 mL) was stirred at room temperature for overnight. Then the mixture was diluted with water (30 mL) and extracted with EtOAc (10 mL*3). The combined organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using prep-TLC (petroleum ether:EtOAc=1:1) to provide (2-chloro-11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-6-yl)(morpholino)methanone (120 mg, yield: 32.9%). 1H-NMR (CDCl3, 400 MHz) δ7.37˜7.47 (s, 1H), 7.24 (d, J=4.4, 1H), 7.11˜7.20 (m, 2H), 6.94 (d, J=8.4 Hz, 1H), 6.79˜6.86 (m, 1H), 6.70˜6.75 (m, 1H), 3.79˜3.90 (m, 2H), 3.62˜3.73 (m, 3.51˜3.59 (m, 1H), 3.36˜3.45 (m, 1H). MS (M+H)+: 388.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:4]=2[O:3]1.[H-].[Na+].[CH3:19]I>C1COCC1>[CH3:1][C:2]1([CH3:16])[C:7](=[O:8])[N:6]([CH3:19])[C:5]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:4]=2[O:3]1
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2NC1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1C(=O)C(C)(C)Oc2ccc([N+](=O)[O-])cc21
Reaction time: 0.17 h
Yield: 90.9 %

Procedure:
A solution of 2,2-dimethyl-6-nitro-2H-1,4-benzoxazin-3(4H)-one (300 mg, 1.35 mmol, 1 equiv) in 5 mL of THF was added dropwise to mixture of NaH (81 mg, 2.03 mmol, 1.5 equiv., 60%) in 3 mL of THF at 0° C. The mixture was stirred at this temperature for 10 min. Then MeI (0.25 mL, 4.05 mmol, 3 equiv.) was added and the reaction was left at room temperature overnight. The reaction mixture was partitioned between EtOAc and water. The organic layer was separated and concentrated. The residue was purified by column chromatography using a mixture of EtOAC/hexane (1:4) as eluent to give 290 mg (Yield=91%) of product as a pale yellow solid.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([C:9]2[CH:25]=[CH:24][C:12]([O:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:11][CH:10]=2)[N:6]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[N:5]=1)([CH3:3])=[CH2:2]>O1CCCC1.CO.[Pd]>[CH:1]([C:4]1[CH:8]=[C:7]([C:9]2[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[CH:24][CH:25]=2)[N:6]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[N:5]=1)([CH3:3])[CH3:2]
Reactant: C=C(C)c1cc(-c2ccc(OCCNC(=O)OC(C)(C)C)cc2)n(-c2ccc(OC)cc2)n1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(C(C)C)cc2-c2ccc(OCCNC(=O)OC(C)(C)C)cc2)cc1

Procedure:
A mixture of 10% Pd-C 50% wet (65 mg) and tert-butyl 2-{4-[3-isopropenyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethylcarbamate obtained by Example 7 (645 mg) in tetrahydrofuran (2 ml) and methanol (4 ml) was hydrogenated under H2 1 atm at room temperature for 3 hrs.
Reaction SMILES: Br[CH2:2][C:3]([CH3:6])([CH3:5])[CH3:4].[Mg].Br[C:9]1[C:10]([O:15][CH3:16])=[N:11][CH:12]=[CH:13][CH:14]=1.[Cl-].[NH4+]>C(OCC)C.C1COCC1.CC(C1C=CC=C(C(C)C)C=1N1[C-]=[N+](C2C(C(C)C)=CC=CC=2C(C)C)CC1)C>[CH3:16][O:15][C:10]1[C:9]([CH2:2][C:3]([CH3:6])([CH3:5])[CH3:4])=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CC(C)(C)CBr
Reactant: COc1ncccc1Br
Agent: CC(C)c1cccc(C(C)C)c1N1[C-]=[N+](c2c(C(C)C)cccc2C(C)C)CC1
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ncccc1CC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under an argon atmosphere, a solution of 1-bromo-2,2-dimethylpropane (14.8 mL) in diethyl ether (120 mL) was added dropwise to magnesium (3.15 g) at a slow refluxing rate. The reaction mixture was heated under reflux for 30 min, and the obtained solution was added dropwise to a solution of 3-bromo-2-methoxypyridine (4.43 g) and PEPPSI™-SIPr (trade name) (805 mg) in THF (80 mL) at room temperature. The reaction mixture was stirred at room temperature for 30 min, and saturated aqueous ammonium chloride solution was added at room temperature. The reaction mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a crude product of the title compound (4.24 g) as a pale-yellow oil. This compound was used for the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:25])=[C:5]([C:16]([O:23][CH3:24])=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:15])=[C:11]([CH:14]=1)[CH:12]=[O:13].C(=O)([O-])[O-].[K+].[K+].[CH:32](Br)([CH3:34])[CH3:33]>CN(C=O)C>[CH3:1][O:2][C:3]1[C:4]([CH3:25])=[C:5]([C:16]([O:23][CH3:24])=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:15][CH:32]([CH3:34])[CH3:33])=[C:11]([CH:14]=1)[CH:12]=[O:13]
Reactant: COc1c(C)c(Cc2ccc(O)c(C=O)c2)c(OC)c(OC)c1OC
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1c(C)c(Cc2ccc(OC(C)C)c(C=O)c2)c(OC)c(OC)c1OC
Yield: 94.5 %

Procedure:
5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-hydroxybenzaldehyde (0.500 g, 1.45 mmol) was dissolved in DMF (15 ml) and after adding thereto in sequence anhydrous potassium carbonate (0.359 g, 2.60 mmol) and isopropyl bromide (0.320 g, 2.60 mmol), the solution was refluxed under heating for 3 hours. The reaction mixture was filtered, the filtrate was concentrated and the obtained residue was purified by silica gel column chromatography (hexand:ethyl acetate=4:1) to obtain the titled compound (0.530 g, 1.37 mmol, 94%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:10][N+:11]([O-:13])=[O:12])=[O:9])=[C:4]([Cl:14])[CH:3]=1.N1C=CC=CC=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.Cl>O.C1COCC1>[Cl:14][C:4]1[CH:3]=[C:2]([NH:1][S:28]([C:25]2[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=2)(=[O:30])=[O:29])[CH:7]=[CH:6][C:5]=1[C:8]([CH2:10][N+:11]([O-:13])=[O:12])=[O:9]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Nc1ccc(C(=O)C[N+](=O)[O-])c(Cl)c1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(C[N+](=O)[O-])c1ccc(NS(=O)(=O)c2ccc(Cl)cc2)cc1Cl
Temperature: 40 °C

Procedure:
A mixture composed of 2 g (9.3 mmol) of the amine obtained in Example 13, 1.5 ml (18.5 mmol) of pyridine, 2.95 g (13.9 mmol) of 4-chlorobenzenesulfonic acid chloride and 80 ml of THF is heated for 16 h at 40° C. After cooling, 100 ml of water and 5 ml of concentrated hydrochloric acid are added before extracting with ethyl acetate. The organic phase is washed with a dilute sodium hydroxide solution. This aqueous phase is then acidified with HCl and extracted with ethyl acetate, which is then washed with water until neutral, dried over Na2SO4 and concentrated under vacuum. The residue is purified by chromatography on a silica column in a dichloromethane/methanol (98:2) mixture.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[C:7]([CH:8]=O)[C:6]([OH:11])=[CH:5][CH:4]=1)=O.C1(P(=[CH:31][C:32]([O:34][CH3:35])=[O:33])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:35][O:34][C:32](=[O:33])/[CH:31]=[CH:1]/[C:3]1[CH:4]=[CH:5][C:6]([OH:11])=[C:7](/[CH:8]=[CH:31]/[C:32]([O:34][CH3:35])=[O:33])[CH:10]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(O)c(C=O)c1
Solvent: Cc1ccccc1
Product: COC(=O)/C=C/c1ccc(O)c(/C=C/C(=O)OC)c1
Reaction time: 8 h
Yield: 92.4 %

Procedure:
A mixture of 5.0 g (33.3 mmol) of 5-formylsalicylaldehyde and 24.5 g (73.3 mmol) of methyl (triphenyl phosphoranylidene)acetate, in 150 mL of toluene was stirred and refluxed for 2.5 hr and then kept at room temperature overnight. The solvent was removed in vacuo and the solid residue was flash-chromatographed on silica gel. There was obtained 8.07 g (92.5%) of the title compound as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH2:12][CH:13]=[CH2:14])=[C:10]([OH:15])[CH:9]=[CH:8][C:3]=1[C:4](OC)=[O:5].[CH3:16][NH2:17].[Cl-].[NH4+].Cl>>[OH:1][C:2]1[C:11]([CH2:12][CH:13]=[CH2:14])=[C:10]([OH:15])[CH:9]=[CH:8][C:3]=1[C:4]([NH:17][CH3:16])=[O:5]
Reactant: C=CCc1c(O)ccc(C(=O)OC)c1O
Reactant: CN
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Product: C=CCc1c(O)ccc(C(=O)NC)c1O
Yield: 75 %

Procedure:
The compound of Example 5 (3.5 g) and excess methyl amine (40% aqueous solution) were stirred overnight at 50° C. in the presence of a few crystals of ammonium chloride. The reaction mixture was cooled and neutralized with 10% hydrochloric acid then extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under vacuum. The crude crystals were dissolved in chloroform and then hexane was added until the product precipitated out of solution. The precipitate was filtered and dried to give the product (2.5 g, 75% yield).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:21])[N:4]=[C:5]([CH2:8][O:9][N:10]2C(=O)C3=CC=CC=C3C2=O)[NH:6][CH:7]=1.CNN>CN(C)C=O>[NH2:10][O:9][CH2:8][C:5]1[NH:6][CH:7]=[C:2]([OH:1])[C:3](=[O:21])[N:4]=1
Reactant: O=C1c2ccccc2C(=O)N1OCc1nc(=O)c(O)c[nH]1
Agent: CNN
Solvent: CN(C)C=O
Product: NOCc1nc(=O)c(O)c[nH]1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
5-Hydroxy-2-[(phthalimidooxy)methyl]-4(1H)-pyrimidinone (0.875 g) (3 mmol) is suspended in 7 ml of dimethylformamide. 136 mg (3 mmol) of methylhydrazine are added thereto at 10° C. and the mixture is stirred at room temperature for 1 hour. The solution is washed four times with 50 ml of n-pentane, the solid residue is taken up in ether, the product is filtered off and crystallized from ethanol. There is obtained 2-(aminooxy)methyl-5-hydroxy-4(1H)-pyrimidinone of m.p. 163° C. (dec.) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([SH:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[CH:19]1[CH2:24][CH2:23][O:22][C:20]1=[O:21].Cl>O.C(OC(=O)C)(=O)C.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:19]3([C:7](=[O:9])[C:6]=2[CH:10]=1)[CH2:24][CH2:23][O:22][C:20]3=[O:21]
Reactant: O=C1OCCC1Br
Reactant: O=C(O)c1cc(Cl)ccc1S
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1OCCC12Sc1ccc(Cl)cc1C2=O
Temperature: 25 °C
Reaction time: 21 h
Yield: 28.1 %

Procedure:
In 250 ml of water were dissolved 18.9 g of 5-chlorothiosalicyclic acid and 26.5 g of sodium carbonate, and 25 g of α-bromo-γ-butyrolactone was added dropwise to the solution under ice-cooling, followed by stirring at room temperature for 21 hours. 100 ml of 3 N-HCl was added to the reaction solution at room temperature to acidify the solution, and the solution was subjected to extraction with ethyl acetate. The extract was washed with aqueous saturated solution of sodium chloride and dried, and then, the solvent was distilled off. The residue was dissolved in 300 ml of toluene and heated under reflux for 2 hours while distilling off the produced water. After cooling the solution, insolubles were filtered off, and the filtrate was evaporated to dryness under reduced pressure, resulting in crude α-[(2-carboxy-4-chlorophenyl)thio]-γ-butyrolactone. The crude product was dissolved in 200 ml of acetic anhydride and 40 ml of triethylamine, and heated under a stream of nitrogen at 130° C. for 10 minutes. The reaction solution was evaporated to dryness under reduced pressure and chromatographed on a column by use of 50 g of activated carbon, 50 g of silica gel and chloroform. Recrystallization from ethanol of the resulting crude crystals yielded 7.17 g of 5-chloro-4',5'-dihydrospiro[benzo[b]thiophene-2(3H),3'(2'H)-furan]-3,2'-dione as pale yellow needles. Melting point: 143°-143.5° C.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)[C:10]2[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=3)[C:10]3[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CCc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(Cl)nc2s1
Reactant: c1nc[nH]n1
Product: CCc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(-n3cncn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-ethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-ethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[N:5]=[C:4]([NH:17][C@H:18]([CH3:21])[CH2:19][OH:20])[CH:3]=1.[N:22]([O-])=[O:23].[Na+]>C(O)(=O)C.O>[NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[N:5]=[C:4]([NH:17][C@H:18]([CH3:21])[CH2:19][OH:20])[C:3]=1[N:22]=[O:23]
Reactant: O=N[O-]
Reactant: C[C@H](CO)Nc1cc(N)nc(SCc2ccccc2F)n1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: C[C@H](CO)Nc1nc(SCc2ccccc2F)nc(N)c1N=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 43.9 %

Procedure:
To a stirred solution of the product from example 4, step (c) (10 g) in acetic acid (300 ml) at room temperature was added a solution of sodium nitrite (2.24 g) in water (30 ml). The reaction was stirred at 0° C. for 30 min, and the resultant purple precipitate isolated by filtration, washing with water, to give the subtitled compound as a dark blue solid (4.8 g).
Reaction SMILES: [CH3:1][C:2]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:16])[CH2:3][CH:4]1[C:11]2[CH:10]=[C:9]([C:12]([O:14]C)=[O:13])[NH:8][C:7]=2[CH2:6][CH2:5]1.O.[OH-].[Li+]>>[CH3:16][C:2]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([CH3:1])[CH2:3][CH:4]1[C:11]2[CH:10]=[C:9]([C:12]([OH:14])=[O:13])[NH:8][C:7]=2[CH2:6][CH2:5]1
Reactant: COC(=O)c1cc2c([nH]1)CCC2CC(C)(C)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CC(C)(CC1CCc2[nH]c(C(=O)O)cc21)c1ccccc1
Yield: 2.6 %

Procedure:
The title compound was synthesized from methyl 4-(2-methyl-2-phenylpropyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.10 g, 0.33 mmol) and lithium hydroxide monohydrate (142 mg, 3.3 mmol) according to General Procedure 7. Silica gel was added, the solvent stripped off and the silica gel-imbedded material was purified by flash chromatography (0-100% EtOAc/Heptane) to give 4-(2-methyl-2-phenylpropyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylic acid (35) as a reddish brown solid (2.4 mg).