Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1([C:6]([CH3:16])=[CH:7][C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=O)CCCC1.[NH2:17][C:18]1[C:22]([C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])=[CH:21][NH:20][N:19]=1>C(O)(=O)C>[CH3:16][C:6]1[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[N:19]2[N:20]=[CH:21][C:22]([C:23]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:24])=[C:18]2[N:17]=1
Reactant: CC(=CC(=O)c1ccncc1)N1CCCC1
Reactant: Nc1n[nH]cc1C(=O)c1ccccc1
Solvent: CC(=O)O
Product: Cc1cc(-c2ccncc2)n2ncc(C(=O)c3ccccc3)c2n1

Procedure:
A mixture of 0.05 mole of 3-(1-pyrrolidinyl)-1-(4-pyridinyl)-2-buten-1-one and 0.05 ml of (3-amino-1H-pyrazol-4-yl)phenyl-methanone in 50 ml of glacial acetic acid was refluxed for 8 hours. The solvent was removed and the residue partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The dichloromethane layer was washed with water, dried over magnesium sulfate and passed through a short pad of hydrous magnesium silicate. The eluent was concentrated and the residue crystallized from dichloromethane:hexane, giving the desired product, mp 209°-210° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C>C(O)=O>[CH2:1]([O:8][C:9](=[O:26])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:15][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CCc1ccc(CC(=O)OCc2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O=CO
Product: O=C(O)CCc1ccc(CC(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Yield: 87 %

Procedure:
1,1-dimethylethyl 3-[4-(2-benzyloxy-2-oxoethyl) phenyl]propanoate (3.0 g, 8.5 mmol) was stirred in formic acid (10 mL) for 8 hours. Removal of the solvent in vacuo provided a colorless oil that was shaken vigorously with a mixture of ethyl acetate and hexanes (1:3, 20 mL) until it solidified. The mixture was cooled in ice water and the product, collected by suction filtration to give 3-[4-(2-benzyloxy-2-oxoethyl)phenyl]propanoic acid, as a white solid (2.2 g, 7.4 mmol) in 87% yield, mp. 62°-64.5° C.
Reaction SMILES: O[C:2]1([C:23]([F:26])([F:25])[F:24])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=2)[C:4]([C:15]2[S:19][C:18]([CH:20]([CH3:22])[CH3:21])=[N:17][N:16]=2)=[N:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:14][S:13][C:10]1[CH:11]=[CH:12][C:7]([N:5]2[CH:6]=[C:2]([C:23]([F:26])([F:25])[F:24])[N:3]=[C:4]2[C:15]2[S:19][C:18]([CH:20]([CH3:22])[CH3:21])=[N:17][N:16]=2)=[CH:8][CH:9]=1
Reactant: CSc1ccc(N2CC(O)(C(F)(F)F)N=C2c2nnc(C(C)C)s2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CSc1ccc(-n2cc(C(F)(F)F)nc2-c2nnc(C(C)C)s2)cc1
Yield: 75.1 %

Procedure:
A mixture of 4-hydroxy-1-[4-(methylthio)phenyl]-2-[2-(isopropyl)-1,3,4-thiadiazol-5-yl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazole (0.361 g, 0.90 mmol) and p-toluenesulfonic acid monohydrate (35 mg) in toluene (50 mL) was heated to reflux for 1 hour. After aqueous work up, the product (0.26 g, 75%) was isolated as a white solid; 1H NMR δ (DMSO-d6) 8.37 (1H, s), 7.50 (2H, d, J=8.3 Hz), 7.38 (2H, d, J=8.6 Hz), 3.42 (1H, m), 2.55 (3H, s), 1.35 (6H, d, J=6.7 Hz); 13C NMR δ (DMSO-d6) 177.4, 157.6, 140.3, 138.5, 133.2, 130.9(q), 127.2, 126.4, 125.7, 122.5(q), 29.9, 22.7, 14.4.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[O:18][C:19]4[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=4[N:21]=3)=[CH:13][C:11]=2[NH2:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[C:28](OC)(OC)[CH3:29]>CO>[O:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=[C:17]1[C:14]1[CH:15]=[CH:16][C:10]2[N:9]([CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:28]([CH3:29])=[N:12][C:11]=2[CH:13]=1
Reactant: COC(C)(OC)OC
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NCCc1ccccc1
Solvent: CO
Product: Cc1nc2cc(-c3nc4ccccc4o3)ccc2n1CCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 65.5 %

Procedure:
To a methanol (5 mL) solution of 2-(2-(2-phenylethyl)aminoanilin-5-yl)benzoxazole (see Working Example 52-1) (140 mg, 0.425 mmol) was added 1,1,1-trimethoxyethane (61.3 mg, 0.510 mmol), and this was stirred at room temperature for 6 hours. After the reaction was complete, this was concentrated, and the residue obtained was purified by silica gel column chromatography to yield the title compound (98.4 mg, 66% yield) as white crystals.
Reaction SMILES: [H-].[Na+].[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([OH:36])[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=1)=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:38]1[C:39]2[N:46]=[N:45][N:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[Cl:53])[C:40]=2[N:41]=[CH:42][N:43]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Si:3]([O:20][CH2:21][CH2:22][O:23][CH2:24][C@H:25]([O:36][C:38]1[C:39]2[N:46]=[N:45][N:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[Cl:53])[C:40]=2[N:41]=[CH:42][N:43]=1)[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=1)=[O:27])([C:16]([CH3:17])([CH3:18])[CH3:19])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)[Si](OCCOC[C@H](O)C(=O)Nc1ccc(Cl)cn1)(c1ccccc1)c1ccccc1
Reactant: Clc1ccccc1-n1nnc2c(Cl)ncnc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCCOC[C@H](Oc1ncnc2c1nnn2-c1ccccc1Cl)C(=O)Nc1ccc(Cl)cn1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 99.5 %

Procedure:
Sodium hydride (38.5 mg, 0.96 mmol) was added to (S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-N-(5-chloropyridin-2-yl)-2-hydroxypropanamide (Intermediate AU3) (200 mg, 0.40 mmol) in anhydrous THF (5 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 7-chloro-3-(2-chlorophenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (Intermediate AP2) (107 mg, 0.40 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was neutralised with 1M citric acid and the majority of the THF removed in vacuo. The reaction mixture was diluted with water (20 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (2×50 mL). The combined organics were washed with saturated brine (25 mL), dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 0 to 50% EtOAc in isohexane to give (2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(3-(2-chlorophenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yloxy)-N-(5-chloropyridin-2-yl)propanamide (290 mg, 99%). m/z (ES+), (M+H)+=728.38: HPLC tR=3.91 min Intermediate AP5: 6-chloro-N4-o-tolylpyrimidine-4,5-diamine
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:16]O)[NH:14][C:13](=[O:15])[CH2:12][O:11][CH2:10]2)[C:5]([Cl:8])=[N:6][CH:7]=1.CCN(S(F)(F)[F:24])CC.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:16][F:24])[NH:14][C:13](=[O:15])[CH2:12][O:11][CH2:10]2)[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: O=C1COCC(CO)(c2cc(Br)cnc2Cl)N1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1COCC(CF)(c2cc(Br)cnc2Cl)N1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a suspension of 5-(5-bromo-2-chloro-pyridin-3-yl)-5-hydroxymethyl-morpholin-3-one (547 mg, 1.70 mmol) in THF (13.6 ml) was added at 0° C. within 5 min a solution of DAST (1.01 ml, 7.65 mmol) in THF (7.2 ml), the reaction mixture was stirred at room temperature for 6 h. The mixture was cooled to 0° C., halfsaturated aq. Na2CO3 was added and the mixture was extracted with EtOAc, the combined organic layers were washed with halfsaturated aq. NaCl, dried with Na2SO4 and evaporated. The residue was purified by chromatography on silica gel (cyclohexane to cyclohexane/EtOAc 1:4) to provide the title compound as colorless solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:6])[CH2:4][CH3:5].Cl[CH2:8][CH2:9][C:10](=[O:12])[CH3:11]>O1CCCC1>[CH2:3]([S:6][CH2:8][CH2:9][C:10](=[O:12])[CH3:11])[CH2:4][CH3:5]
Reactant: CCCS
Reactant: CC(=O)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCSCCC(C)=O
Reaction time: 0.25 h
Yield: 93.7 %

Procedure:
Solid sodium hydride (60% dispersion in oil, 2.90 g, 72.3 mmol) was added in portions over 5 minutes to a stirred solution of 1-propanethiol (6.00 g, 78.8 mmol) in tetrahydrofuran (262 mL). After 15 minutes, a thick white suspension had formed. To the suspension was added 1-chloro-3-butanone (7.00 g, 65.7 mmol), which caused the reaction mixture to warm and a cloudy solution to form. After 30 minutes, the cloudy solution was partitioned between ethyl acetate (100 mL) and water (100 mL). The layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate (100 mL) and brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford a pale brown oil. The crude product was purified by flash chromatography (silica gel, elution with 20% ethyl acetate in hexanes) to provide 9.0 g of 4-(propylthio)butan-2-one as a clear liquid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:16][CH2:17][C:18](Cl)=[O:19].O>C1COCC1>[Cl:16][CH2:17][C:18]([NH:8][C:5]1[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:19]
Reactant: Cc1ccc(N)cn1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)CCl)cn1
Temperature: -60 °C
Yield: 41 %

Procedure:
A mixture of 6-methylpyridin-3-amine (1 g) and triethylamine (2.2 mL) in dry THF (20 mL) was stirred and cooled to −60° C. 2-Chloroacetyl chloride (1.567 g) was added via syringe to the stirred mixture forming a yellow suspension. The mixture was stirred at −60° C. until analysis showed complete disappearance of starting material. The reaction slurry was poured into water and the products extracted with ethyl acetate (2×150 ml). The combined organic extracts were dried over magnesium sulphate and concentrated to dryness. The crude brown solid was recrystallised from ether to afford the subtitled compound (700 mg).
Reaction SMILES: [C:1]1([CH:7]([OH:19])[CH2:8][C:9](=[O:18])[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([BH3-])#N.[Na+]>CC(C)[O-].CC(C)[O-].CC(C)[O-].[Cl-].[Ti+4]>[C:1]1([CH:7]([OH:19])[CH2:8][CH:9]([OH:18])[CH2:10][C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)CC(=O)CC(O)c1ccccc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH3-]C#N
Product: CC(C)(C)OC(=O)CC(O)CC(O)c1ccccc1
Yield: 67.4 %

Procedure:
By carrying out the reaction as in Example 9 but starting from 1.06 g of t-butyl 5-phenyl-5-hydroxy-3-oxopentanoate and using 1.05 cm3 of titanium chloride triisopropoxide (4.17 mmol) and 281.4 mg of sodium cyanoborohydride (4.24 mmol), there is obtained, after reacting for 3 hours 30 minutes, with a yield of 68%, 720 mg of t-butyl 5-phenyl-3,5-dihydroxypentanoate for which the syn/anti ratio is equal to 95/5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[OH:12].C([O-])([O-])=O.[K+].[K+].Br[CH2:20][CH:21]([O:24][CH3:25])[O:22][CH3:23]>CN(C=O)C>[CH3:23][O:22][CH:21]([O:24][CH3:25])[CH2:20][O:12][C:4]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1cc([N+](=O)[O-])ccc1O
Reactant: COC(CBr)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])ccc1OCC(OC)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an oven-dried round bottom flask, add 2-methoxy-4-nitro-phenol (2.45 g, 14.5 mmol) and purge with nitrogen. Add DMF (25 mL) by syringe, followed by K2CO3 (3.0 g, 21.7 mmol) and KI (catalytic) neat. Stir 30 min at room temperature and add 2-bromo-1,1-dimethoxy-ethane (1.9 mL, 15.9 mmol) by syringe. Attach a reflux condenser and stir overnight in a 120° C. oil bath. Quench with water, extract with ether (3×), dry over MgSO4, filter and concentrate under vacuum. Add xylenes and concentrate again under vacuum. Purify by flash chromatography on silica gel using a gradient of EtOAc/hexane (20% to 60%) to give the title compound as a white residue (2.55 g, 68%). Exact mass=257.1, MS (ES+) 258.2 (M+1)+. 1H NMR (CDCl3): δ 7.88 (dd, J=9.1, 2.8 Hz, 1H), 7.74 (d, J=2.8 Hz, 1H), 6.94 (d, J=9.1 Hz, 1H), 4.77 (t, J=5.2 Hz, 1H), 4.13 (d, J=4.9 Hz, 2H), 3.93 (s, 3H), 3.48 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10]O)[CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:31]N1C(=O)CCC1=O>C(Cl)Cl>[Br:31][CH2:10][CH2:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCCCc1cccc(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1cccc(CCCBr)c1
Yield: 70.9 %

Procedure:
Compound 25-1 (1.00 g) was dissolved in methylene chloride (100 ml), triphenylphosphine (1.71 g) and N-bromosuccinimide (1.15 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 5 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (50 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (970 mg) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]([C:16]([OH:18])=O)[NH:15][C:11]=3[N:10]=[CH:9]2)=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.CCN(C(C)C)C(C)C.[CH3:40][O:41][CH2:42][CH2:43][NH2:44]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]3[CH:13]=[C:14]([C:16]([NH:44][CH2:43][CH2:42][O:41][CH3:40])=[O:18])[NH:15][C:11]=3[N:10]=[CH:9]2)=[CH:6][CH:7]=1
Reactant: COCCN
Reactant: O=C(O)c1cc2c(ncn2-c2ccc(Br)cc2)[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCCNC(=O)c1cc2c(ncn2-c2ccc(Br)cc2)[nH]1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 1-(4-bromophenyl)-1,4-dihydropyrrolo[2,3-d]imidazole-5-carboxylic acid (70 mg, 0.23 mmol), CDI (75 mg, 0.46 mmol) and DIPEA (0.1 mL) in dry THF (3 mL) was stirred at 60° C. for 1 h and then treated with 2-methoxyethylamine (0.1 mL). After additional 2 h at 60° C., the mixture was concentrated under reduced pressure, the residue suspended in water (5 mL) and the solid collected by filtration and washed with water to give 1-(4-bromophenyl)-N-(2-methoxyethyl)-1,4-dihydropyrrolo[2,3-d]imidazole-5-carboxamide EXAMPLE 3. LC-MS (ES+): m/z 363/365 (1/1) [MH+]. 1H NMR (CDCl3, 400 MHz): δ=3.41 (s, 3H), 3.57 (t, J=4.9 Hz, 2H), 3.67 (app. q, J=4.9 Hz, 2H), 6.34 (br s, 1H, CONH), 6.60 (s, 1H), 7.42 (d, J=8.7 Hz, 2H), 7.64 (d, J=8.7 Hz, 2H), 7.88 (s, 1H), 9.32 (br s, 1H, NH).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:10]=[C:11]([C:15](=[O:29])[CH2:16][CH2:17][C:18]2[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:12]=[CH:13][CH:14]=1.CB1N2CCCC2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.B.B.C1COCC1.N(CCO)CCO>C1COCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:10]=[C:11]([C@@H:15]([OH:29])[CH2:16][CH2:17][C:18]2[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1ccccc1CCC(=O)c1cccc(COC2CCCCO2)c1
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)C2CCCN12
Solvent: C1CCOC1
Solvent: OCCNCCO
Product: CCOC(=O)c1ccccc1CC[C@H](O)c1cccc(COC2CCCCO2)c1
Temperature: -45 °C
Reaction time: 0.33 h
Yield: 90.7 %

Procedure:
The keto ester of Step 13 (24.8 g, 62.5 mmol) was dissolved in THF (230 mL) and cooled to -45° C. A THF (15 mL) solution of tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole-borane adduct (J. Org. Chem., 56, 751 (1991), 4.55 g, 15.6 mmol) was added dropwise and the resulting mixture was stirred 20 minutes at -45° C. To this solution, 1.0M borane-THF (62.5 mL, 62.5 mmol) was added dropwise over 30 minutes. The reaction mixture was stirred 1 hour at -45° C. followed by another 2 hours with slow warming to -20° C. After cooling the solution of -40° C., it was poured onto 25% aq. NH4OAC (425 mL) and 1.0M diethanolamine (40 mL) at 0° C. and stirred vigorously for 20 minutes. The title compound was extracted with EtOAc (3×), dried over MgSO4 and concentrated under reduced pressure. The crude oil was purified by flash chromatography (25% to 50% EtOAc in hexanes) to yield 22.6 g (91%) of the desired product as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][S:14]([OH:17])(=O)=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:19]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][S:14]([Cl:19])(=[O:17])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(NCCS(=O)(=O)O)OCc1ccccc1
Solvent: Cc1ccccc1
Product: O=C(NCCS(=O)(=O)Cl)OCc1ccccc1
Temperature: 25 °C

Procedure:
2-(N-benzyloxycarbonylamino)ethanesulfonic acid (0.6 g; 2.31 mmol) was suspended in dry toluene (6 mL) and PCl5 was added (0.65 g; 3.11 mmol). The mixture was refluxed for 2 h, until complete dissolution of the reagents. After cooling at room temperature, the solvent was evaporated off under vacuum to give the crude 2-(N-benzyloxycarbonylamino)ethanesulfonyl chloride pure enough for the next step.
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1)(OCC)=O)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:30][C:31]1([CH3:49])[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([CH:41]([CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH:42]=O)[CH:39]=2)[S:34][CH2:33][CH2:32]1>C1COCC1.CCCCCC>[CH3:49][C:31]1([CH3:30])[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([CH:41]([CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])/[CH:42]=[CH:9]/[C:10]3[CH:11]=[CH:12][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:18][CH:19]=3)[CH:39]=2)[S:34][CH2:33][CH2:32]1
Reactant: CCCCCC(C=O)c1ccc2c(c1)C(C)(C)CCS2
Reactant: CCOP(=O)(Cc1ccc(C(=O)OC)cc1)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCC(/C=C/c1ccc(C(=O)OC)cc1)c1ccc2c(c1)C(C)(C)CCS2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 39.3 %

Procedure:
0.51 g of methyl 4-(diethoxyphosphorylmethyl)-benzoate were dissolved in 7.5 ml THF and treated, at −20° C., with 1.8 ml of a 1M solution of lithium bis(trimethylsilyl)amide in hexane. After 15 min. at −20° C., a solution of 350 mg of (RS)-2-(4,4-dimethyl-thiochroman-6-yl)-heptanal in 7.5 ml THF was added. The reaction mixture was stirred at room temperature for 1.5 hour. The mixture quenched by the addition of 10 ml of water and the resulting mixture was partitioned in 25 ml ethyl acetate/15 ml sat. aq. sodium chloride solution. The phases were separated and the organic phase was dried over MgSO4. The solvent was removed in vacuo and the crude product was purified by flash chromatography (SiO2, 10% ethyl acetate/hexanes), giving 200 mg of the corresponding ester. 1H NMR (CDCl3): 7.94 (d, J=8.5 Hz, 2H), 7.38 (d, J=8.5 Hz, 2H), 7.19 (d, J=1.8 Hz, 1H), 7.03 (d, J=8.1 Hz, 1H), 6.91 (dd, J=8.1, 1.8 Hz, 1H), 6.45 (d, J=15.9 Hz, 1H), 6.38 (d, J=15.9 Hz, 1H), 3.90 (s, 3H), 3.30 (m, 1H), 3.05-3.00 (m, 2H), 2.00-1.90 (m, 2H), 1.85-1.75 (m, 2H), 1.33 (s, 6H), 1.40-1.30 (m, 6H), 0.86 (t, J=6.5 HZ, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:28](=[O:29])[N:7]2[CH:8]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=3)[C:9]3[NH:10][C:11]4[C:16]([C:17]=3[CH2:18][C:6]2([CH3:30])[C:5]1=[O:31])=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=4.[CH:32]1([CH2:35][NH2:36])[CH2:34][CH2:33]1>>[CH:32]1([CH2:35][NH:36][CH2:2][CH2:3][N:4]2[C:28](=[O:29])[N:7]3[CH:8]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=4)[C:9]4[NH:10][C:11]5[C:16]([C:17]=4[CH2:18][C:6]3([CH3:30])[C:5]2=[O:31])=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=5)[CH2:34][CH2:33]1
Reactant: NCC1CC1
Reactant: COc1ccc2[nH]c3c(c2c1)CC1(C)C(=O)N(CCBr)C(=O)N1C3c1cccc(O)c1
Product: COc1ccc2[nH]c3c(c2c1)CC1(C)C(=O)N(CCNCC2CC2)C(=O)N1C3c1cccc(O)c1

Procedure:
The title compound is prepared similarly as described for example 30 using (3aSR,10RS)-2-(2-Bromoethyl)-10-(3-hydroxy-phenyl)-6-methoxy-3a-methyl-3a,4,9,10-tetrahydro-2,9,10a-triaza-cyclopenta[b]-fluorene-1,3-dione (example 24) and C-cyclopropyl methyl amine as starting materials. MS: m/z (MH+)=475.2
Reaction SMILES: O.O.O.[OH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1.Cl[CH2:16][C:17]([OH:19])=[O:18]>[OH-].[K+]>[N:8]1([CH2:16][C:17]([OH:19])=[O:18])[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5](=[O:4])[CH:6]=[CH:7]1
Reactant: O=C(O)CCl
Reactant: Oc1ccnc2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)Cn1ccc(=O)c2ccccc21
Yield: 17.2 %

Procedure:
4-Hydroxyquinoline trihydrate (20 g., 0.2 mole) is dissolved in a 50% aqueous potassium hydroxide solution and chloroacetic acid (20 g., 0.2 mole) is incrementally added. The resulting solution is heated at its reflux temperature for 18 hours, chilled, acidified and filtered to give 7 g of 4-quinolone-1-acetic acid having a m.p. 278°-279° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([O:36][CH3:37])=[N:10][C:11]2[N:12]([N:21]=[C:22](S(C)(=O)=O)[C:23]=2[C:24](=[O:31])[NH:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1.[CH3:38][O-:39].[Na+].C(Cl)(Cl)Cl.O>CO.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([O:36][CH3:37])=[N:10][C:11]2[N:12]([N:21]=[C:22]([O:39][CH3:38])[C:23]=2[C:24](=[O:31])[NH:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1
Reactant: COc1nc2c(C(=O)NC3CCCC3)c(S(C)(=O)=O)nn2c(-c2ccc(Cl)cc2)c1-c1ccccc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1nc2c(C(=O)NC3CCCC3)c(OC)nn2c(-c2ccc(Cl)cc2)c1-c1ccccc1Cl
Temperature: 100 °C
Reaction time: 2 h
Yield: 81.1 %

Procedure:
To a solution of the compound obtained in Example 36 (24 mg) in methanol/tetrahydrofuran (2 mL/1 mL) was added sodium methoxide (23 mg) and the mixture was stirred at 100° C. for 2 hours in a microwave reactor. After cooling to room temperature, to the reaction mixture was added chloroform and water and the organic layer was separated and concentrated in vacuo and the resultant crude product was purified by a column chromatography on NH-silica gel (Chromatorex NH-silica gel/Fuji Silicia Chem., solvent; hexane/ethyl acetate=65/35 to 30/70) to give 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-(N-cyclopentylcarbamoyl)-2,5-dimethoxypyrazolo[1,5-a]pyrimidine (17.8 mg; yield: 81%) as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:25][C:26]1([C:30]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][N:31]=2)[CH2:29][CH2:28][CH2:27]1)[C:9]1[N:14]=[N:13][C:12]([C:15]2[S:16][C:17]([C:20]([O:22]CC)=O)=[CH:18][N:19]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:37]>CO>[C:20]([C:17]1[S:16][C:15]([C:12]2[N:13]=[N:14][C:9]([N:8]([CH2:25][C:26]3([C:30]4[C:35]([F:36])=[CH:34][CH:33]=[CH:32][N:31]=4)[CH2:27][CH2:28][CH2:29]3)[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:10][CH:11]=2)=[N:19][CH:18]=1)(=[O:22])[NH2:37]
Reactant: N
Reactant: CCOC(=O)c1cnc(-c2ccc(N(CC3(c4ncccc4F)CCC3)C(=O)OC(C)(C)C)nn2)s1
Solvent: CO
Product: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(-c2ncc(C(N)=O)s2)nn1
Temperature: 120 °C

Procedure:
To a solution of ethyl 2-(6-(tert-butoxycarbonyl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)amino)pyridazin-3-yl)thiazole-5-carboxylate (162 mg, 0.32 mmol) in MeOH (8 mL) was purged with NH3 gas for 5 min. The reaction mixture was sealed and heated in a microwave reactor for 30 min at 120° C. The reaction mixture was concentrated and used in next step without purification, LRMS (M+H+) m/z 484.2.