Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH2:8]O)[CH:3]=1.[C:10]1(=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[NH:11]1.P(CCCC)(CCCC)CCCC.N(C(OC(C)C)=O)=NC(OC(C)C)=O>CN(C=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH2:8][N:11]2[C:12](=[O:19])[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10]2=[O:20])[CH:3]=1
Reactant: Nc1cc(CO)ncn1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: CN(C)C=O
Product: Nc1cc(CN2C(=O)c3ccccc3C2=O)ncn1
Temperature: 80 °C
Reaction time: 48 h
Yield: 29.5 %

Procedure:
To a stirred solution of (6-aminopyrimidin-4-yl)methanol (1.0 g, 8.0 mmol), isoindoline-1,3-dione (1.4 g, 9.6 mmol), n-Bu3P (2.42 g, 12.0 mmol) in dry DMF (20 mL) at room temperature was added diisopropyl azodicarboxylate (2.42 g, 12.0 mmol) dropwise. After addition, the resulting mixture was allowed to stir at 80° C. for 48 hours. Solvents were removed under reduced pressure and the residue was purified via chromatography column on silica gel eluting with a 2% gradient of methanol in dichloromethane to give the desired target as a gray solid (0.60 g, 30% yield). 1H-NMR (500 MHz, DMSO-d6): δ 8.22 (s, 1H), 7.95-7.88 (m, 4H), 6.85 (s, 2H), 6.28 (s, 1H), 4.63 (s, 2H). LCMS (ESI) Method B: RT=3.23 min, m/z 233.1 [M+H+].
Reaction SMILES: [C:1](C1C=C2C(=CC=1)N(C1CCCCO1)N=C2)#C.[C:18]([C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[N:27]([CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1)[N:26]=[CH:25]2)#[C:19][CH2:20][CH3:21]>>[C:18]([C:22]1[C:23]([CH3:1])=[C:24]2[C:28](=[CH:29][CH:30]=1)[N:27]([CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1)[N:26]=[CH:25]2)#[C:19][CH2:20][CH3:21]
Reactant: C#Cc1ccc2c(cnn2C2CCCCO2)c1
Reactant: CCC#Cc1ccc2c(cnn2C2CCCCO2)c1
Product: CCC#Cc1ccc2c(cnn2C2CCCCO2)c1C

Procedure:
The title compound was prepared from 4-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-((trimethylsilypethynyl)-1H-indazole following the procedures outlined for Intermediate 2 (step 2) and Intermediate 3. 1H NMR (300 MHz, DMSO-d6): δ 7.97 (s, 1H), 7.27 (d, 1H), 7.11 (d, 1H), 5.59 (dd, 1H), 3.58 (m, 1H), 3.50 (m, 1H), 2.38 (s, 3H), 2.17 (q, 2H), 2.13 (m, 1H), 1.77 (m, 2H), 1.50 (m, 1H), 1.36 (m, 2H), 0.98 (t, 3H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=1)[C@@H:3]([C@H:5]1[CH2:10][O:9][C@@H:8]([O:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C@H:7]([CH3:17])[NH:6]1)[OH:4].[C:27](OC(=O)C)(=[O:29])[CH3:28].[ClH:34]>C(OCC)C.C1C=CC=CC=1>[ClH:34].[F:26][C:21]1[CH:20]=[C:19]([CH:24]=[C:23]([F:25])[CH:22]=1)[CH2:18][C@H:2]([NH:1][C:27](=[O:29])[CH3:28])[C@@H:3]([C@H:5]1[CH2:10][O:9][C@@H:8]([O:11][CH2:12][C:13]([CH3:15])([CH3:16])[CH3:14])[C@H:7]([CH3:17])[NH:6]1)[OH:4]
Reactant: C[C@@H]1N[C@@H]([C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)CO[C@H]1OCC(C)(C)C
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccccc1
Solvent: CCOCC
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1CO[C@@H](OCC(C)(C)C)[C@H](C)N1
Reaction time: 1 h
Yield: 45 %

Procedure:
Dissolve (1S,2S)-2-amino-3-(3,5-difluorophenyl)-1-[(3R,5S,6R)-6-(2,2-dimethylpropoxy)-5-methylmorpholin-3-yl]-propan-1-ol (70 mg, 0.188 mmol) in dry dichloromnethane (1.8 mL) under nitrogen. Add dropwise acetic anhydride (22 μL, 0.233 mmol) and stir for 1 hour. Add 1 M hydrogen chloride in diethyl ether (1 mL) and dilute with benzene. Concentrate and purify (HPLC, eluting with 30% to 70% acetonitrile with 0.1% hydrochloric acid in water) to give the title compound as a white solid (38 mg, 45%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2([C:15]([OH:17])=O)[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCOC(OC(OCC)=O)=O.[N:29]1([C:34]2[CH:39]=[C:38]([CH2:40][NH2:41])[CH:37]=[C:36]([C:42]3[CH:47]=[CH:46][C:45]([C:48]([F:51])([F:50])[F:49])=[CH:44][CH:43]=3)[N:35]=2)[CH2:33][CH2:32][CH2:31][CH2:30]1>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2([C:15]([NH:41][CH2:40][C:38]3[CH:37]=[C:36]([C:42]4[CH:43]=[CH:44][C:45]([C:48]([F:51])([F:49])[F:50])=[CH:46][CH:47]=4)[N:35]=[C:34]([N:29]4[CH2:30][CH2:31][CH2:32][CH2:33]4)[CH:39]=3)=[O:17])[CH2:13][CH2:14]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: NCc1cc(-c2ccc(C(F)(F)F)cc2)nc(N2CCCC2)c1
Reactant: O=C(O)C1(NS(=O)(=O)c2ccc(F)cc2)CC1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: O=C(NCc1cc(-c2ccc(C(F)(F)F)cc2)nc(N2CCCC2)c1)C1(NS(=O)(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Yield: 21.3 %

Procedure:
A solution of acid 15C (0.50 g, 1.75 mmol) in THF (25 mL) was added with DEPC (0.34 mL, 1.3 mol eq) and the mixture was stirred at room temperature for 5′. Then [2-pyrrolidin-1-yl-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 27A (0.61 g, 1.1 mol eq) and a catalytic amount of TEA were added, then the reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, water (40 mL) was added to the residue that is extracted with EtOAc (3×25 mL) and washed with brine (1×40 mL). The separated organic phase was dried over Na2SO4, evaporated to dryness and the residue was purified by flash chromatography (1:1 EtOAc:Petroleum ether) to afford a pale orange solid (0.21 g) after crystallization from a mixture of ethyl ether/petroleum ether. Yield=22%, 1HNMR (DMSO, 200 MHz) δ 0.71 (m, 2H), 1.09 (m, 2H9, 1.96 (m, 4H), 3.38 (m, 4H), 4.18 (d, 2H, J=6.1), 6.33 (s, 1H), 6.46 (s, 1H), 7.47-7.38 (m, 4H), 7.88-7.80 (m, 4H), 8.37 (t, 1H), 8.71 (bs, 1H); [M+1] 562.58 (C27H26F4N4O3S requires 562.16).
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C([Li])CCC.[Cl:12][CH2:13][CH2:14][CH2:15][CH2:16]I.O>O1CCCC1>[Cl:12][CH2:13][CH2:14][CH2:15][CH2:16][C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1]
Reactant: C#C[Si](C)(C)C
Reactant: ClCCCCI
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)C#CCCCCCl
Reaction time: 0.5 h

Procedure:
A solution of trimethylsilylacetylene (4.9 g., Aldrich) in dry tetrahydrofuran (40 ml.) was stirred at 0° under a current of nitrogen and n-butyllithium (31.25 ml. of 1.6M solution in hexane) was added dropwise. The solution was stirred for 30 minutes and a solution of 1-chloro-4-iodobutane (10.9 g.) in dry tetrahydrofuran (30 ml.) was added. The reaction mixture was allowed to warm to 20° and stirred for 18 hours. The mixture was poured into water and the aqueous mixture was extracted with diethyl ether. The ethereal extracts were washed with water and dried over anhydrous magnesium sulphate. The solvent was removed in vacuo. 6-Chloro-1-trimethylsilylhex-1-yne was obtained as a yellow liquid and was used without further purification.
Reaction SMILES: [CH2:1]([S:8]([C:11]1[CH:12]=[C:13]([O:21]COC)[C:14](=[O:20])[N:15](COC)[CH:16]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O1CCOCC1.CO>[CH2:1]([S:8]([C:11]1[CH:12]=[C:13]([OH:21])[C:14](=[O:20])[NH:15][CH:16]=1)(=[O:9])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCOc1cc(S(=O)(=O)Cc2ccccc2)cn(COC)c1=O
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=c1[nH]cc(S(=O)(=O)Cc2ccccc2)cc1O
Temperature: 120 °C
Yield: 44.5 %

Procedure:
To a solution of 5-(benzylsulfonyl)-3-(methoxymethoxy)-1-(methoxymethyl)pyridin-2(1H)-one (Intermediate 40; 75 mg, 0.212 mmol) in dioxane (0.7 ml) and methanol (0.8 ml) was added hydrogen chloride (4.0 M in dioxane, 1.597 ml, 6.39 mmol) and the reaction irradiated in the microwave with heating to 120° C. for 10 minutes. The resulting white precipitate that had formed was filtered and washed with ethanol to yield 5-(benzylsulfonyl)-3-hydroxypyridin-2(1H)-one (25 mg, 44%).
Reaction SMILES: [Cl:1][C:2]1[CH:41]=[CH:40][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[C:9]([C:28]([CH3:31])([CH3:30])[CH3:29])=[C:8]2[CH2:32][C:33]([CH3:39])([CH3:38])[C:34]([O:36]C)=[O:35])=[CH:4][CH:3]=1.ClC1C=CC(CN2C3C(=CC(OCC4C=CC5C(=CC=CC=5)N=4)=CC=3)C(SC(C)(C)C)=C2CC(C)(C)C(O)=O)=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[C:9]([C:28]([CH3:31])([CH3:29])[CH3:30])=[C:8]2[CH2:32][C:33]([CH3:39])([CH3:38])[C:34]([OH:36])=[O:35])=[CH:40][CH:41]=1
Reactant: COC(=O)C(C)(C)Cc1c(C(C)(C)C)c2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1
Agent: CC(C)(C)Sc1c(CC(C)(C)C(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(OCc3ccc4ccccc4n3)cc12
Product: CC(C)(Cc1c(C(C)(C)C)c2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1)C(=O)O

Procedure:
The title compound was prepared according to the conditions described in Step B of Example 1, but substituting the ester from Step B for the ester of Example 1. The title compound was recrystallized from EtOAc-EtOH; m.p. 201°-202° C.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].Cl.[NH2:26][CH2:27][CH2:28][CH2:29][C:30]([CH3:35])([CH3:34])[C:31]([OH:33])=[O:32].C[O-].[Na+].CO.Cl>O>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:26][CH2:27][CH2:28][CH2:29][C:30]([CH3:35])([CH3:34])[C:31]([OH:33])=[O:32])=[O:4])[N:6]=1)#[N:24]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: CC(C)(CCCN)C(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(CCCNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)C(=O)O
Yield: 16 %

Procedure:
A mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (80 mg, 0.25 mmol) and 5-Amino-2,2-dimethyl-pentanoic acid HCl salt (136 mg, 0.75 mmol) in 0.5 M NaOMe/MeOH (2.5 mL, 5 mmol) was microwaved at 120° C. for 2.5 h. Reaction mixture was diluted with water (100 mL) and acidified by 1 N HCl to pH=3-4. It was extracted with EtOAc. Organic layer was washed with brine, dried over MgSO4, filtered and concentrated. Crude product was purified by silica gel chromatography, eluting with 10-100% EtOAc/hexanes to provide the title compound 17 mg (0.04 mmol) in 16% yield. LC-MS ESI−: 431.94 (M−1)−.
Reaction SMILES: [ClH:1].[CH3:2][O:3][N:4]1[C:8](=[O:9])[CH2:7][C:6]2([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[C:5]1=[O:15].C(OC([NH:23][CH2:24][CH2:25][CH2:26][C:27](O)=[O:28])=O)(C)(C)C.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.C(N(CC)CC)C>[ClH:1].[NH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:12]1[CH2:13][CH2:14][C:6]2([C:5](=[O:15])[N:4]([O:3][CH3:2])[C:8](=[O:9])[CH2:7]2)[CH2:10][CH2:11]1)=[O:28]
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Reactant: CON1C(=O)CC2(CCNCC2)C1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON1C(=O)CC2(CCN(C(=O)CCCN)CC2)C1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 58.7 %

Procedure:
To a solution of 2-methoxy-2,8-diazaspiro[4,5]decane-1,3-dione hydrochloride (1.5 g) in dimethylformamide (100 ml) were added triethylamine (1 ml), 4-(tert-butyloxycarbonylamino)butyric acid (2.03 g), N-hydroxybenztriazole (1.35 g) and dicylohexylcarbodiimide (2.06 g) in sequential additions, and this was followed by stirring at room temperature for 5 hours. The resulting precipitates were then removed. The solvent was evaporated under reduced pressure, and the resulting residual oily substance was dissolved in dichloromethane (50 ml), after which it was washed with a 10% aqueous solution of citric acid and then with water. The organic layer was then dried with anhydrous magnesium sulfate, and this was followed by the evaporation of the solvent under reduced pressure. The resulting residual oil was separated by silica gel column chromatography (eluent; chloroform-acetone-methanol=10:3:2 (v/v)). To the resulting oily substance containing the desired product was added a solution of 6N hydrogen chloride in ethanol (20 ml), and it was kept standing at room temperature for 10 minutes. The solvent was then evaporated under reduced pressure. The resulting oily substance was separated by silica gel column chromatography (eluent; chloroform-methanol-water=14:6:1) to obtain 1.2 g of a noncrystalline solid.
Reaction SMILES: [CH3:1][CH:2]1[CH:11]=[C:10]2[CH:5]([CH:6]([CH2:13][CH2:14][CH:15]([OH:22])[CH2:16][CH:17]([OH:21])[CH2:18][CH2:19]O)[CH:7]([CH3:12])[CH:8]=[CH:9]2)[CH:4]([O:23][C:24](=[O:29])[CH:25]([CH3:28])[CH2:26][CH3:27])[CH2:3]1.CCN(C(C)C)C(C)C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O>C(Cl)Cl>[OH:21][CH:17]1[CH2:18][CH2:19][O:22][CH:15]([CH2:14][CH2:13][CH:6]2[CH:5]3[C:10](=[CH:11][CH:2]([CH3:1])[CH2:3][CH:4]3[O:23][C:24](=[O:29])[CH:25]([CH3:28])[CH2:26][CH3:27])[CH:9]=[CH:8][CH:7]2[CH3:12])[CH2:16]1
Reactant: CCC(C)C(=O)OC1CC(C)C=C2C=CC(C)C(CCC(O)CC(O)CCO)C21
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(C)C(=O)OC1CC(C)C=C2C=CC(C)C(CCC3CC(O)CCO3)C21

Procedure:
To a cooled (−77° C.) solution of 73 mg (0.18 mmol) of 2-methyl-butyric acid 3,7-dimethyl-8-(3,5,7-trihydroxy-heptyl)-1,2,3,7,8,8a-hexahydro-naphthalen-1-yl ester in 5 ml of methylene chloride is added 0.9 g (7 mmol) Hunig's base and 0.08 ml (0.5 mmol) triflic anhydride. After 30 minutes the reaction is quenched with saturated aqueous sodium bicarbonate. The phases are separated and the water phase is extracted twice with ethyl acetate. The organic phases are combined, washed with brine and dried over sodium sulfate. The solvent is evaporated and the crude product is purified by silica gel chromatography (diethyl ether/hexane 1/4) to afford the desired product as a colorless oil.
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].[C:5]([O:9][C:10](=[O:26])[NH:11][C@H:12]([C:17](=[O:25])[C:18]1[CH:23]=[CH:22][C:21](F)=[CH:20][CH:19]=1)[C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:8])([CH3:7])[CH3:6]>CN(C=O)C>[C:5]([O:9][C:10](=[O:26])[NH:11][C@H:12]([C:17](=[O:25])[C:18]1[CH:23]=[CH:22][C:21]([NH2:1])=[CH:20][CH:19]=1)[C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:8])([CH3:7])[CH3:6]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)c1ccc(F)cc1)C(C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](C(=O)c1ccc(N)cc1)C(C)(C)C
Temperature: 120 °C
Yield: 31.2 %

Procedure:
Sodium azide (1.26 g, 19.4 mmol) was added to a solution of [1(S)-(4-fluorobenzoyl)-2,2-dimethylpropyl]-carbamic acid tert-butyl ester (0.20 g, 0.7 mmol) in DMF (15 mL), and the mixture heated at 120° C. for 40 hours. The solvent was removed in vacuo before addition of 10% NaHCO3 (aq.) (30 mL) to the residual solid. The aqueous phase was extracted with ethyl acetate (2×30 mL) and the organic phases washed with brine (1×30 mL), dried over MgSO4, filtered and the solvent removed in vacuo to give a yellow solid. Purification by column chromatography (SiO2, 4:1 iso-hexane:ethyl acetate) afforded the title compound as a yellow solid (67 mg, 36%).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH3:16][S:17][CH2:18][C:19]([N:21]([CH3:23])[CH3:22])=[O:20].C(OCl)(C)(C)C.C(N(CC)CC)C>C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:4](=[O:5])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:12][CH:13]=[CH:14][C:15]=1[CH:18]([S:17][CH3:16])[C:19]([N:21]([CH3:23])[CH3:22])=[O:20]
Reactant: CSCC(=O)N(C)C
Reactant: Nc1ccccc1C(=O)c1ccccc1
Agent: CC(C)(C)OCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSC(C(=O)N(C)C)c1cccc(C(=O)c2ccccc2)c1N
Temperature: 25 °C
Yield: 80.8 %

Procedure:
A solution of 29.6 g (0.15 mole) of 2-aminobenzophenone in 350 ml of methylene chloride was cooled to -70° C. and 20.0 g (0.15 mole) of 2-methylthio-N,N-dimethylacetamide was added. To the mixture (-70° C.) was added dropwise a solution of 17.2 g (0.15 mole) of 95% t-butylhypochlorite in 30 ml of methylene chloride. The temperature was maintained at or below -65° C. for 1.5 hr, then 15.1 g (0.15 mole) of triethylamine was added rapidly. The solution was allowed to warm to room temperature and was washed with water. The organic solution was concentrated and the residue crystallized when mixed with isopropyl ether. The solid was recrystallized from isoproyl alcohol to give 39.8 g (81%) bright yellow crystals, m.p. 153°-155° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:11])=[CH:8][C:9]=1[OH:10])=[O:3].CN(C)C=O.[H-].[Na+].[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(OCC)(=O)C>[CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([O:11][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:8][C:9]=1[OH:10])=[O:3]
Reactant: ClCc1ccccc1
Reactant: CC(=O)c1ccc(O)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(OCc2ccccc2)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Fifty grams of 2,4-dihydroxyacetophenone were dissolved in 250 ml. of dimethylformamide and the solution was cooled to 0° C. by means of an external ice-bath. After the addition of 15 grams of a 50% oil dispersion of sodium hydride, 40 ml. of benzyl chloride were added in a dropwise fashion and the reaction was allowed to warm to room temperature. After stirring overnight, the reaction mixture was added to 700 ml. of ethyl acetate. The organic phase was washed with 1000 ml. of 1N hydrochloric acid and twice each with 1000 ml. of a saturated sodium chloride solution. The organic layer was dried, and the solvent removed in vacuo. The oily residue was treated with 100 ml. of methanol and 50 ml. of hexane. The desired 2-hydroxy-4-benzyloxyacetophenone (36.7 grams) was recovered by filtration.
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[C:7](=[N:8][C:9]([N:15]3[CH:19]=[CH:18]N=C3)=[N:10][CH:11]=2)[N:6]([CH:20]([CH3:22])[CH3:21])[C:5]1=[O:23])[CH:2]=[CH2:3].[CH2:24]([N:26]([CH2:37][CH3:38])[CH2:27][CH2:28][O:29][C:30]1[CH:36]=CC(N)=[CH:32][CH:31]=1)[CH3:25]>C(Cl)(Cl)Cl>[CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[C:7](=[N:8][C:9]([NH:15][C:19]3[CH:18]=[CH:36][C:30]([O:29][CH2:28][CH2:27][N:26]([CH2:37][CH3:38])[CH2:24][CH3:25])=[CH:31][CH:32]=3)=[N:10][CH:11]=2)[N:6]([CH:20]([CH3:22])[CH3:21])[C:5]1=[O:23])[CH:2]=[CH2:3]
Reactant: CCN(CC)CCOc1ccc(N)cc1
Reactant: C=CCn1c(=O)c2cnc(-n3ccnc3)nc2n(C(C)C)c1=O
Solvent: ClC(Cl)Cl
Product: C=CCn1c(=O)c2cnc(Nc3ccc(OCCN(CC)CC)cc3)nc2n(C(C)C)c1=O
Temperature: 180 °C
Yield: 36.6 %

Procedure:
A mixture of 200 mg (0.64 mmol) of 3-allyl-7-(imidazol-1-yl)-1-isopropyl-1H-pyrimido[4,5-d]pyrimidine-2,4-dione and 400 mg (1.92 mmol) of 4-(2-diethylaminoethoxy)aniline is heated at 180° C. for 3 hours. The reaction mixture is cooled, dissolved into chloroform, and chromatographed on silica eluting with 4:96 methanol/chloroform. The resulting oily material partially crystallizes on standing, and the mixture is triturated with diethyl ether/hexane and filtered to give 106 mg (36%) of the title compound: mp 90-96° C.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=2)=[O:28])([CH2:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[O:17])[C:7]1=[O:38])C.O.Cl>CC(C)=O>[CH:4]([CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=2)=[O:28])([CH2:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[O:17])[C:7]1=[O:38])=[O:3]
Reactant: CCOC(CN1C(=O)C(CC(=O)Nc2ccc(C)cc2)(NC(=O)Nc2cccc(OC)c2)c2ccccc21)OCC
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: COc1cccc(NC(=O)NC2(CC(=O)Nc3ccc(C)cc3)C(=O)N(CC=O)c3ccccc32)c1
Yield: 79.4 %

Procedure:
To a solution of 1.61 g of (RS)-1-(2,2-diethoxyethyl)-3-(N′-(3-methoxyphenyl)ureido)-3-((4-methylphenyl)aminocarbonylmethyl)indolin-2-one in 40 ml of acetone were added 10 ml of water and 1 ml of concentrated hydrochloric acid, and the mixture was heated under reflux for 2 hours. The reaction mixture was poured into water, and the thus formed precipitate was collected by filtration and washed with ethyl ether to obtain 1.11 g (79%) of the title compound.
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:6][O:7][C:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:4][OH:5].C(N(CC)CC)C.[C:34]1([CH3:44])[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1.Cl>C(Cl)Cl>[CH3:1][O:2][CH:3]([CH2:4][O:5][S:40]([C:37]1[CH:38]=[CH:39][C:34]([CH3:44])=[CH:35][CH:36]=1)(=[O:42])=[O:41])[CH2:6][O:7][C:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(CO)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)COS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 89.4 %

Procedure:
In 40 ml of methylene chloride were dissolved 3.484 g (10 mmole) of the alcohol derivative as synthesized in (i) and 3.036 g (30 mmole) of triethylamine, and 2.478 g (13 mmole) of p-toluenesulfonyl chloride was added to the solution under ice-cooling. The reaction solution was stirred at room temperature for 17 hours, treated with 1N hydrochloric acid and extracted with chloroform. The organic layer was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The resulting crude product was purified by column chromatography [silica gel: 170 g; eluent: n-hexane/ethyl acetate=5/1 to 3/1] to give 4.491 g (89.4%) of the objective compound as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.[CH:18]1([C:21](=[O:26])[CH2:22][C:23](=O)[CH3:24])[CH2:20][CH2:19]1>C(O)(=O)C.S(=O)(=O)(O)O>[CH:18]1([C:21]([C:22]2[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:3]3[C:4]4[CH2:9][CH2:8][CH2:7][C:5]=4[S:6][C:2]3=[N:1][C:23]=2[CH3:24])=[O:26])[CH2:20][CH2:19]1
Reactant: CC(=O)CC(=O)C1CC1
Reactant: Nc1sc2c(c1C(=O)c1ccccc1)CCC2
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1nc2sc3c(c2c(-c2ccccc2)c1C(=O)C1CC1)CCC3
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 33.7 %

Procedure:
To a stirred solution of 60 mg (0.24 mmol) (2-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-phenyl-methanone (the preparation of which is described in example 3) in 2 ml acetic acid was added 41 mg (0.32 mmol) of 1-cyclopropyl-butane-1,3-dione (prep. described in the patent DE 94-4404059) and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Preparative HPLC (30% CH3CN/H20) afforded 27 mg (33%) cyclopropyl-(2-methyl-4-phenyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl)-methanone as a light brown oil. ES-MS m/e (%): 334 (M+H+, 100).
Reaction SMILES: CCN(CC)CC.C(O[C:16](=[O:32])[CH2:17][C:18](=O)[CH2:19][O:20][C:21]12[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2)C1C=CC=CC=1.Cl.[CH:34]1([NH:40][NH2:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>CCO>[C:21]12([O:20][CH2:19][C:18]3[CH:17]=[C:16]([OH:32])[N:40]([CH:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)[N:41]=3)[CH2:28][CH:27]3[CH2:29][CH:23]([CH2:24][CH:25]([CH2:26]3)[CH2:30]1)[CH2:22]2
Reactant: NNC1CCCCC1
Reactant: O=C(COC12CC3CC(CC(C3)C1)C2)CC(=O)OCc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Oc1cc(COC23CC4CC(CC(C4)C2)C3)nn1C1CCCCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
NEt3 (800 μl, 5.7 mmol) was added to a solution of 4-(adamantan-1-yloxy)-3-oxo-butyric acid benzyl ester (1.91 g, 5.6 mmol), and cyclohexyl hydrazine hydrochloride (877 mg, 5.82 mmol) in EtOH (30 mL) at 0° C. The mixture was allowed to warm to room temperature and stirred for 4 h. The precipitated white solid was filtered and dried to afford the product as a white solid, (1.23 g, 66%.).