Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:7]=1[S:15]([OH:18])(=[O:17])=[O:16].[Cl-].[NH4+]>O>[NH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[C:7]([S:15]([OH:18])(=[O:17])=[O:16])[CH:8]=1
Reactant: COCCOc1ccc([N+](=O)[O-])cc1S(=O)(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: COCCOc1ccc(N)cc1S(=O)(=O)O
Reaction time: 2 h

Procedure:
A mixture composed of 30 g of 2-(2-methoxyethoxy)-5-nitrobenzenesulfonic acid, 30 g of reduced iron, 0.6 g of ammonium chloride and 60 ml of water was kept at about 80° to 85° C. and stirred for 2 hours. After conclusion of the reaction, insoluble materials were removed by filtration, and 200 ml of isopropyl alcohol was added to the filtrate, which was cooled with ice. The crystals thus-formed were separated by filtration, washed with 50 ml of isopropyl alcohol and dried in the air. Yield: 23 g. m.p.: more than 250° C.
Reaction SMILES: [NH2:1][C:2]1NCC2C(=CC=C(Cl)C=2Cl)N=1.ClC1C=CC=C(Cl)C=1Cl.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[C:26](Cl)[C:25]=1[Cl:34].C([Cu])#N>>[Cl:34][C:25]1[C:24]([Cl:23])=[CH:29][CH:28]=[C:27]([N+:30]([O-:32])=[O:31])[C:26]=1[C:2]#[N:1]
Reactant: NC1=Nc2ccc(Cl)c(Cl)c2CN1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1Cl
Agent: N#C[Cu]
Agent: Clc1cccc(Cl)c1Cl
Product: N#Cc1c([N+](=O)[O-])ccc(Cl)c1Cl

Procedure:
As shown below in the Examples, a preferred process is set forth for making 2-amino-5,6-dichloro-3,4-dihydroquinazoline from commercially available starting materials. In one process 1,2,3-trichlorobenzene is used as the starting material and is nitrated using, for example, nitric/sulfuric acids to form 1,2,3-trichloro-4-nitrobenzene. This compound is then reacted with a cyanating agent such as CuCN to form 2,3-dichloro-6-nitrobenzonitrile. The nitrile is then reacted under reducing conditions using for example B2H6 to form 2,3-dichloro-6-nitrobenzylamine HCl which is then reduced and reacted with CNX to form the desired compound.
Reaction SMILES: CON=[C:4]([CH2:10][C:11](=O)[CH3:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Cl:14][C:15]1[C:16]([NH:21][NH2:22])=[N:17][CH:18]=[CH:19][CH:20]=1.O1CCCC1>C(O)(=O)C>[Cl:14][C:15]1[C:16]([N:21]2[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:10][C:11]([CH3:12])=[N:22]2)=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)C(CC(C)=O)=NOC
Reactant: NNc1ncccc1Cl
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(C)nn1-c1ncccc1Cl
Yield: 15.8 %

Procedure:
A mixture of 1.34 g of ethyl 2-methoxyimino-4-oxopentanoate, 1.23 g of 3-chloro-2-hydrazinopyridine, 25 ml of tetrahydrofuran and 50 ml of acetic acid was heated to reflux for 8 hours. The reaction mixture was concentrated under reduced pressure. Water was poured into the residue, and the mixture was extracted with methyl t-butyl ether two times. The combined organic layer was washed successively with a 1N aqueous sodium hydroxide solution, water and an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.30 g of ethyl 1-(3-chloro-2-pyridinyl)-3-methyl-1H-pyrazole-5-carboxylate of the formula:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:16]([NH:18][C@H:19]([C:21]2[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][CH:22]=2)[CH3:20])=[O:17])[C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[CH3:30][C:31]1[CH:32]=[C:33]([S:37]([NH2:40])(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=1>>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)=[C:4]([CH:3]=1)[C:16]([NH:18][C@H:19]([C:21]1[CH:22]=[CH:23][C:24]([C:25]([NH:40][S:37]([C:33]2[CH:34]=[CH:35][CH:36]=[C:31]([CH3:30])[CH:32]=2)(=[O:38])=[O:39])=[O:27])=[CH:28][CH:29]=1)[CH3:20])=[O:17]
Reactant: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1ccc(F)cc1)c1ccc(C(=O)O)cc1
Reactant: Cc1cccc(S(N)(=O)=O)c1
Product: Cc1cccc(S(=O)(=O)NC(=O)c2ccc([C@H](C)NC(=O)c3cc(Cl)cnc3Oc3ccc(F)cc3)cc2)c1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 103 from 4-[(1S)-1-({[5-chloro-2-(4-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic acid (step 5 of Example 44) and 3-methylbenzenesulfonamide: 1H-NMR (CDCl3) δ 8.90 (1H, br.s), 8.51 (1H, d, J=2.6 Hz), 8.13 (1H, d, J=2.6 Hz), 8.09 (1H, d, J=7.2 Hz), 7.97–7.89 (2H, m), 7.74 (2H, d, J=8.3 Hz), 7.48–7.38 (4H, m), 7.20–7.05 (4H, m), 5.37–5.24 (1H, m), 2.44 (3H, s), 1.56 (3H, d, J=7.0 Hz); MS (ESI) m/z 568 (M+H)+, 566 (M−H)−.
Reaction SMILES: [F:1][CH2:2][C:3]([C@H:28]1[CH2:33][CH2:32][C@H:31]([C:34]([O:36]CC)=[O:35])[CH2:30][CH2:29]1)([OH:27])[C:4]1[S:5][C:6]([C:9]2[CH:14]=[C:13]([NH:15][C:16]3[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=3)[CH:12]=[C:11]([CH3:26])[CH:10]=2)=[CH:7][N:8]=1.Cl>CS(C)=O>[F:1][CH2:2][C:3]([C@H:28]1[CH2:33][CH2:32][C@H:31]([C:34]([OH:36])=[O:35])[CH2:30][CH2:29]1)([OH:27])[C:4]1[S:5][C:6]([C:9]2[CH:14]=[C:13]([NH:15][C:16]3[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=3)[CH:12]=[C:11]([CH3:26])[CH:10]=2)=[CH:7][N:8]=1
Reactant: CCOC(=O)[C@H]1CC[C@H](C(O)(CF)c2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1
Agent: Cl
Solvent: CS(C)=O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(O)(CF)[C@H]3CC[C@H](C(=O)O)CC3)s2)c1

Procedure:
Ethyl trans-4-{2-fluoro-1-hydroxy-1-[5-(3-methyl-5-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]ethyl}cyclohexanecarboxylate (72 mg, 0.130 mmol) was dissolved in HCl (10 M in water, 2 ml, 20.0 mmol) and heated to reflux for 20 min. The reaction was diluted with DMSO and purified on reverse phase HPLC (acetonitrile/water with a 0.1% TFA modifier) to afford racemic trans-4-{2-fluoro-1-hydroxy-1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]ethyl}cyclohexanecarboxylic acid. MS ESI calc'd. for C24H24F4N4O3S [M+H]+ 525. found 525.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:17][CH2:16][C:15]3[C:18]4[CH2:24][CH2:23][CH2:22][CH2:21][C:19]=4[S:20][C:14]=3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1B1OC(C)(C)C(C)(C)O1)(=[O:3])[CH3:2].I[C:37]1[N:45]=[C:44]2[C:40]([N:41]=[CH:42][N:43]2[CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])=[C:39]([NH:54][C:55]2[CH:60]=[CH:59][C:58]([N:61]3[CH2:66][CH2:65][N:64]([CH:67]4[CH2:70][O:69][CH2:68]4)[CH2:63][CH2:62]3)=[CH:57][CH:56]=2)[N:38]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C.O>[C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[C:13](=[O:25])[C:14]3[S:20][C:19]4[CH2:21][CH2:22][CH2:23][CH2:24][C:18]=4[C:15]=3[CH2:16][CH2:17]2)=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:37]1[N:45]=[C:44]2[C:40]([N:41]=[CH:42][N:43]2[CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:51])([CH3:52])[CH3:53])=[C:39]([NH:54][C:55]2[CH:56]=[CH:57][C:58]([N:61]3[CH2:66][CH2:65][N:64]([CH:67]4[CH2:68][O:69][CH2:70]4)[CH2:63][CH2:62]3)=[CH:59][CH:60]=2)[N:38]=1)(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)CCOCn1cnc2c(Nc3ccc(N4CCN(C5COC5)CC4)cc3)nc(I)nc21
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCc2c(sc3c2CCCC3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2nc(Nc3ccc(N4CCN(C5COC5)CC4)cc3)c3ncn(COCC[Si](C)(C)C)c3n2)cc(F)cc1N1CCc2c(sc3c2CCCC3)C1=O
Temperature: 100 °C
Yield: 60 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with (4-fluoro-2-{6-oxo-8-thia-5-azatricyclo[7.4.0.02,7]trideca-1(9),2(7)-dien-5-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl acetate 103g (288 mg, 0.60 mmol), 2-iodo-N-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purin-6-amine 117f (364 mg, 0.60 mmol), Pd(dppf)Cl2 (49 mg, 0.060 mmol), K3PO4 (254 mg, 1.20 mmol), sodium acetate (98 mg, 1.20 mmol), water (0.5 mL), and acetonitrile (10 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 119a (307 mg, 60%). MS-ESI: [M+H]+ 853.4
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1.[CH3:31][N:32](C=O)C>[C-]#N.[Zn+2].[C-]#N.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[OH:29][C@@H:24]1[CH2:25][CH2:26][CH2:27][CH2:28][C@H:23]1[N:13]1[C:12](=[O:30])[C:11]2[C:16](=[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[C:9]([CH2:8][C:5]3[CH:4]=[CH:3][C:2]([C:31]#[N:32])=[N:7][CH:6]=3)[CH:10]=2)[N:15]=[CH:14]1
Reactant: CN(C)C=O
Reactant: O=c1c2cc(Cc3ccc(Cl)nc3)c3ccccc3c2ncn1[C@@H]1CCCC[C@H]1O
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc(Cc2cc3c(=O)n([C@@H]4CCCC[C@H]4O)cnc3c3ccccc23)cn1
Temperature: 25 °C

Procedure:
To a solution of rac-6-[(6-chloropyridin-3-yl)methyl]-3-[trans-2-hydroxycyclohexyl]benzo[h]quinazolin-4(3H)-one (0.050 g, 0.12 mmol) and zinc cyanide (0.042 g, 0.36 mmol) in 2 mL of DMF under an atmosphere of nitrogen was added bis(tri-tert-butylphosphine)palladium(0) (10 mol %). The mixture was irradiated in a microwave reactor at 160° C. for 1 h, cooled to rt, filtered, and purified via preparative reverse phase HPLC to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 411.0 for [M+H]+: 1H NMR (400 MHz, CDCl3) δ 9.04-9.02 (m, 1H), 8.70 (s, 1H), 8.46 (s, 1H), 8.06 (s, 1H), 7.84-7.80 (m, 1H), 7.76-7.64 (m, 2H), 7.57-7.52 (m, 2H), 4.67 (br s, 1H), 4.55 (s, 2H), 4.02 (br s, 1H), 2.30-2.22 (m, 1H), 2.10-2.03 (m, 1H), 2.00-1.83 (m, 3H), 1.59-1.21 (m, 3H).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:37])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:30]=[N:31][CH:32]=[CH:33][C:34]=5[O:35][CH3:36])=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO>[CH3:36][O:35][C:34]1[CH:33]=[CH:32][N:31]=[CH:30][C:29]=1[C:26]1[CH:25]=[CH:24][C:23]([C:20]2([C:17]3[N:13]4[CH2:14][CH2:15][S:16][C:10]([CH2:9][OH:8])([CH3:37])[CH2:11][C:12]4=[N:19][N:18]=3)[CH2:22][CH2:21]2)=[CH:28][CH:27]=1
Reactant: COc1ccncc1-c1ccc(C2(c3nnc4n3CCSC(C)(CO[Si](C)(C)C(C)(C)C)C4)CC2)cc1
Agent: Cl
Solvent: CO
Product: COc1ccncc1-c1ccc(C2(c3nnc4n3CCSC(C)(CO)C4)CC2)cc1
Yield: 75.5 %

Procedure:
A solution of the compound (337 mg, 0.63 mmol) obtained in Example 57-1) and 4 M hydrochloric acid (1,4-dioxane solution, 1 mL) in methanol (4 mL) was stirred at room temperature for 15 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 40:60, gradient) to obtain the title compound (201 mg, 76%) as a colorless solid.
Reaction SMILES: C([O-])(O)=O.[Na+].[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7]1.[C:15](Cl)(=[O:17])[CH3:16]>C(Cl)Cl>[N:6]1([C:15](=[O:17])[CH3:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7]1
Reactant: CC(=O)Cl
Reactant: c1ccc2c(c1)CCN2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.7 %

Procedure:
To a suspension of NaHCO3 (504 g, 6.0 mol) and 2,3-dihydro-1H-indole (60 g, 0.5 mol) in CH2Cl2 (600 mL) cooled in an ice-water bath, was added dropwise acetyl chloride (78.5 g, 1.0 mol). The mixture was stirred at room temperature for 2 h. The solid was filtered off and the filtrate was concentrated to give 1-(2,3-dihydro-indol-1-yl)-ethanone (82 g, 100%).
Reaction SMILES: [O:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:20]2[CH:25]=[CH:24][C:23]([C:26]#[C:27][CH:28]([OH:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[C:22]([CH3:34])[CH:21]=2)([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:11][C:10]=1[CH3:35])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[H][H]>[Pd].CO>[O:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]\[CH:28]([OH:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[C:22]([CH3:34])[CH:21]=2)([CH2:16][CH3:17])[CH2:18][CH3:19])=[CH:11][C:10]=1[CH3:35])[Si:2]([C:5]([CH3:6])([CH3:7])[CH3:8])([CH3:3])[CH3:4]
Reactant: CCC(CC)(c1ccc(C#CC(O)C(C)(C)C)c(C)c1)c1ccc(O[Si](C)(C)C(C)(C)C)c(C)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCC(CC)(c1ccc(/C=C\C(O)C(C)(C)C)c(C)c1)c1ccc(O[Si](C)(C)C(C)(C)C)c(C)c1
Reaction time: 3 h
Yield: 70.7 %

Procedure:
A solution of 1-(4-{1-[4-(tert-butyl-dimethylsiloxy)-3-methylphenyl]-1-ethylpropyl}-2-methylphenyl)-4,4-dimethylpent-1-yn-3-ol (0.4 g, 0.8 mmol) in anhyd MeOH (10 mL) was sparged with a stream of nitrogen (5 min) and then charged with 5% Pd/C (17 mg). Next an atmosphere of hydrogen (ambient pressure) was introduced into the reaction flask via a hydrogen-filled balloon with an inlet needle. After sparging briefly with hydrogen (5 min), the reaction mixture was stirred 3 h at ambient pressure. The reaction mixture was diluted with EtOAc (30 mL) and filtered through Celite. The filter agent was rinsed with EtOAc, and the combined filtrates were concentrated to yield (Z)-1-(4{-1-[4-(tert-butyl-dimethylsiloxy)-3-methylphenyl]-1-ethylpropyl}-2-methylphenyl)-4,4-dimethylpent-1-en-3-ol (0.28 g, 71%), which was used without purification in the next step.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[C:5]([O:9][C:10](=[O:32])[NH:11][C:12]([CH3:31])([CH3:30])[CH2:13][CH2:14][NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([OH:29])([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C.N>C1COCC1.CCOC(C)=O>[C:5]([O:9][C:10](=[O:32])[NH:11][C:12]([CH3:30])([CH3:31])[CH2:13][CH2:14][N:15]1[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([CH2:23][CH2:24][CH3:25])([CH2:26][CH2:27][CH3:28])[O:29][C:1]1=[O:2])([CH3:6])([CH3:7])[CH3:8]
Reactant: CCCC(O)(CCC)c1ccccc1NCCC(C)(C)NC(=O)OC(C)(C)C
Reactant: O=C(Cl)Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC1(CCC)OC(=O)N(CCC(C)(C)NC(=O)OC(C)(C)C)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
8.85 mL (16.81 mmol) of phosgene solution (20 wt. % in toluene) is slowly added dropwise at 0° C. to a solution of 6.00 g (15.28 mmol) of tert-butyl{3-[2-(1-hydroxy-1-propylbutyl)phenylamino]-1,1-dimethylpropyl}carbamate and 5.32 mL (38.21 mmol) of triethylamine in absolute THF (80 mL). The mixture is stirred for 2 hours at RT, diluted with EtOAc, combined with ice, and made basic with saturated aqueous ammonia solution. The aqueous phase is exhaustively extracted with EtOAc and the combined organic phases are washed with saturated aqueous NaCl, dried with sodium sulfate, and evaporated down in vacuo. After column chromatography (silica gel, cyclohexane/EtOAc 6:1) the product is obtained as a yellow oil. Yield: 4.57 g (71%).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23]C(OC2C=CC=CC=2)=O)[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[CH2:42][C:43]#[C:44][C:45]([CH3:48])([OH:47])[CH3:46].O1CCCC1.[OH-].[K+]>CO>[Si:1]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][CH2:42][C:43]#[C:44][C:45]([OH:47])([CH3:48])[CH3:46])[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(O)C#CCBr
Reactant: C[C@H](SC(=O)Oc1ccccc1)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](SCC#CC(C)(C)O)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 73.2 %

Procedure:
Under the same conditions as in Example 3, 1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-phenoxycarbonylthiopregna-5,7,16-triene (59.4 mg, 0.102 mmol), 5-bromo-2-methyl-3-pentyn-2-ol (90.5 mg, 0.511 mmol), tetrahydrofuran (1 ml) and 1M KOH solution in methanol (1 ml) were reacted and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, dichloromethane:ethyl acetate=5:1, developed twice) to give the title compound as a colorless oil (41.6 mg, 73%).
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][CH2:5][C:6]1[C:11]([OH:12])=[C:10]([C:13]([CH3:15])=[O:14])[CH:9]=[CH:8][C:7]=1[OH:16].[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29]Cl)=[CH:22][CH:21]=1)([O-:19])=[O:18].[I-].[Na+]>CN(C)C=O>[OH:12][C:11]1[C:6]([CH2:5][CH2:4][CH3:3])=[C:7]([O:16][CH2:29][CH2:28][CH2:27][O:26][C:23]2[CH:24]=[CH:25][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=2)[CH:8]=[CH:9][C:10]=1[C:13](=[O:14])[CH3:15]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: O=[N+]([O-])c1ccc(OCCCCl)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1c(OCCCOc2ccc([N+](=O)[O-])cc2)ccc(C(C)=O)c1O
Temperature: 100 °C

Procedure:
To sodium hydride (6.1 g, 50% dispersion) in dry dimethylformamide (200 ml) was added 2,4-dihydroxy-3-propylacetophenone (24.6 g) in dimethylformamide (20 ml), dropwise with stirring under nitrogen. The resulting solution was heated to 100° C. and 4-nitro-1-(3-chloropropoxy)benzene (27.3 g) and sodium iodide (19.0 g) were added rapidly. The reaction mixture was left to stir over night at 100° C., cooled and evaporated under reduced pressure to a brown oil. The oil was taken up in water, extracted with dichloromethane (×2), washed with aqueous sodium hydroxide (2N), then aqueous sodium thiosulphate, dried over magnesium sulphate, filtered and evaporated under reduced pressure to a dark brown solid. The solid was recrystallised from methanol, with charcoaling, to give pale yellow needles of product, m.p. 98° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]=[C:5]([OH:24])[C:6]2[CH2:12][CH:11]([CH2:13][CH2:14][C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=3)[CH2:10][NH:9][C:7]=2[N:8]=1.CN1CCOCC1.ClC1N=C(OC)N=C(OC)N=1.[NH2:43][C:44]1([C:51]([OH:53])=[O:52])[CH2:49][CH:48]2[CH2:50][CH:45]1[CH2:46][CH2:47]2.[NH4+].CC(C([O-])=O)CCCCC.[K+].[Br-].[OH-].[Na+]>CN(C)C=O>[NH4+:2].[NH2:2][C:3]1[N:4]=[C:5]([OH:24])[C:6]2[CH2:12][CH:11]([CH2:13][CH2:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:43][C:44]4([C:51]([O-:53])=[O:52])[CH2:49][CH:48]5[CH2:50][CH:45]4[CH2:46][CH2:47]5)=[O:20])=[CH:17][CH:16]=3)[CH2:10][NH:9][C:7]=2[N:8]=1
Reactant: NC1(C(=O)O)CC2CCC1C2
Reactant: Nc1nc(O)c2c(n1)NCC(CCc1ccc(C(=O)O)cc1)C2
Agent: CCCCCC(C)C(=O)[O-]
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Nc1nc(O)c2c(n1)NCC(CCc1ccc(C(=O)NC3(C(=O)[O-])CC4CCC3C4)cc1)C2

Procedure:
After flame drying a 15-mL two-neck round bottom flask under argon, 0.20 g (0.57 mmol) of 4-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)ethyl]-benzoic acid hydrochloride was suspended in 2 mL of anhydrous N,N-dimethylformamide, followed by the addition of 0.19 mL (1.7 mmol) of 4-methylmorpholine. After stirring the reaction at room temperature for 15 minutes, 0.15 g (0.86 mmol) of 2-chloro-4,6-dimethoxy-1,3,5-triazine was added. The reaction was stirred at room temperature for 30 minutes and 0.134 g (0.86 mmol) of 2-aminonorbornane-2-carboxylic acid was added. The reaction mixture was stirred at room temperature for 3 hours. The volatiles were concentrated in vacuo, and the residue was treated with 50 mL of H20, and the white solid was filtered and dried in a vacuum oven at 60° C. The crude solid was purified using rotor chromatography on a 2 mm Chromatotron® silica gel plate, and eluted with a gradient of 20% CH3OH/CHCl3 to 75:25:1 CHCl3 /CH3OH/NH4OH. The correct fractions were combined and removed in vacuo to give 0.025 g (9%) of 2-{4-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)ethyl]benzoylamino}bicyclo[2.2.]heptane-2-carboxylic acid ammonium salt as a white solid. Rf=0.30 (6/3.2/0.8) (CHCl3 /CH3OH/NH4OH); m.p. 241° C. (foam); IR (KBr, cm-1)=615, 647, 772, 1019, 1121, 1218, 1307, 1370, 1477, 1538, 1641, 2952, 3344; UV (0.1N NaOH) λmax =273, 241, 218 (ε=9839, 14408, 21458); Exact mass: Calcd=452.2298; Found=452.2338 5; 1H NMR (300 MHz, DMSOd6) δ1.26-1.37 (m, 2H), 1.48-1.81 (m, 7H), 1.84-1.88 (m, 4H), 2.63-2.83 (m, 4H), 3.19-3.27 (m, 2H), 5.97 (s, 2H), 6.27 (S, 1H), 7.31 (d, J=8.1 Hz, 2H), 7.78 (d, J=7.9 Hz, 2H), 8.53 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([C:29]([O:31]C)=[O:30])=[O:28])=[CH:17][CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].O.[OH-].[Li+]>>[CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([C:29]([OH:31])=[O:30])=[O:28])=[CH:17][CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(-c2ccccc2C(=O)C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(-c2ccccc2C(=O)C(=O)O)cc1
Yield: 69.5 %

Procedure:
684 mg of 2-ethyl-3-(2'-methoxalylbiphenyl-4-yl)methyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine [prepared as described in step (a) above] were subjected to hydrolysis using 201 mg of lithium hydroxide monohydrate in the same manner as described in Example 1(b), to give 460 mg of the title compound as a powder, melting at 209°-210° C.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([O:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:11][C:10]=1[N:22]=[C:23]=[O:24].[OH:25][CH:26]([C:31]([CH3:33])=[CH2:32])[C:27]([O:29]C)=O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[F:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([O:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:11][C:10]=1[N:22]1[C:27](=[O:29])[C:26](=[C:31]([CH3:33])[CH3:32])[O:25][C:23]1=[O:24]
Reactant: C=C(C)C(O)C(=O)OC
Reactant: O=C=Nc1cc(OC2CCCC2)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)=C1OC(=O)N(c2cc(OC3CCCC3)c(Cl)cc2F)C1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 75.6 %

Procedure:
Triethylamine (40 ml) was gradually dropwise added to a toluene solution (10 liters) containing 2-fluoro-4-chloro-5-cyclopentyloxyphenylisocyanate (4.0 kg, 15.6 mol) and methyl 2-hydroxy-3-methyl-3-butenoate (2.4 kg, purity about 90%, 18.4 mol), as put in a 20-liter stainless steel vessel, with cooling in an ice-water bath, in such a way that the temperature of the reaction solution did not rise. The whole was stirred for 2 hours at the determined temperature until the starting materials disappeared by TLC. Next, after addition of potassium carbonate (200 g, 1.45 mol), the reaction mixture was heated in a water bath (100° C.) for 4 hours with stirring with removing the methanol formed therefrom through a distillation device equipped to the reactor. After reaction, the reaction mixture was washed with 1N hydrochloric acid (10 liters) and 1N sodium hydroxide (10 liters) and further with 1N hydrochloric acid (10 liters). The toluene layer was dried over anhydrous magnesium sulfate, the solvent was removed by distillation under reduced pressure, and hexane of about a half of the oily product formed was added to the oily product formed. This was then allowed to stand at room temperature for a while. A whitish yellow solid precipitated out, which was taken out by filtration and well dried to obtain 3N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-5-isopropylidene-1,3-oxazolidine-2,4-dione (4.19 kg, 11.8 mol). Yield: 75.7%. Spectral data and other data of the product are those as shown in Example 27.