Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(P(N(C)C)N(C)C)C.C(OP([C:19]([Cl:22])([Cl:21])Cl)(=O)OCC)C.[CH2:23]([O:25][C:26]([CH:28]1[CH:30]([CH:31]=O)[C:29]1([CH3:34])[CH3:33])=[O:27])[CH3:24]>O>[CH2:23]([O:25][C:26]([CH:28]1[CH:30]([CH:31]=[C:19]([Cl:21])[Cl:22])[C:29]1([CH3:33])[CH3:34])=[O:27])[CH3:24]
Reactant: CCOP(=O)(OCC)C(Cl)(Cl)Cl
Reactant: CCOC(=O)C1C(C=O)C1(C)C
Agent: CN(C)P(N(C)C)N(C)C
Solvent: O
Product: CCOC(=O)C1C(C=C(Cl)Cl)C1(C)C
Temperature: 90 °C
Yield: 88 %

Procedure:
16.3 g (0.1 mole) of tris-dimethylaminophosphine were added dropwise to a mixture of 25.5 g (0.1 mole) of trichloromethanephosphonic acid diethyl ester and 17.2 g (0.1 mole) of 3-formyl-2,2-dimethyl-cyclopropane-1-carboxylic acid ethyl ester at a temperature of 40° C. The reaction mixture was then warmed to 90° C. for 3 to 4 hours. It was subsequently cooled and poured into 200 ml of water. This suspension was extracted twice with 100 ml of methylene chloride each time. The combined extracts were dried over sodium sulphate and then concentrated. 3-(2,2-Dichloro-vinyl)-2,2-dimethyl-cyclopropane-1-carboxylic acid ethyl ester was obtained in a yield of 88% of theory.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.[Cl:14][C:15]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17]Br>>[Cl:14][C:15]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][N:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1
Reactant: N#Cc1ccnc(-c2c[nH]cn2)c1
Reactant: Clc1cccc(CBr)c1Cl
Product: N#Cc1ccnc(-c2cn(Cc3cccc(Cl)c3Cl)cn2)c1

Procedure:
The title compound was prepared from 2-(1H-imidazol-4-yl)pyridine-4-carbonitrile (PREPARATION 4) and 2,3-dichlorobenzylbromide according to the procedure for the preparation of Example 43, part A using room temp. [M+H] Calc'd for C16H10Cl2N4, 330. Found, 330.
Reaction SMILES: C[Si](C)(C)CCOC[N:7](COCC[Si](C)(C)C)[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([O:27][CH2:28][CH:29]2[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]2)[C:9]=1[Br:42].Cl>CO.O1CCOCC1>[Br:42][C:9]1[C:10]([O:27][CH2:28][CH:29]2[CH2:30][CH2:31][NH:32][CH2:33][CH2:34]2)=[N:11][C:12]2[N:13]([N:14]=[CH:15][C:16]=2[C:17]2[CH:18]=[N:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:8]=1[NH2:7]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2nc3c(-c4cnc5ccccc5c4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Nc1c(Br)c(OCC2CCNCC2)nc2c(-c3cnc4ccccc4c3)cnn12

Procedure:
tert-Butyl 4-((7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yloxy)methyl)piperidine-1-carboxylate (0.56 g, 68.9 mmol) was dissolved in methanol (6 ml) and treated with 4N hydrochloride solution in dioxane (4 ml) at 65° C. for 30 min. The reaction solution was concentrated and the crude product (0.48 g) was used in the next step without further purification. LC-MS: 453 [M+H].
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][C:21]=1[Cl:22]>>[Cl:15][C:16]1[CH:17]=[C:18]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Product: Nc1nnc(-c2ccc(Cl)c(Cl)c2)c(-c2ccccc2)n1
Yield: 54.8 %

Procedure:
6-(3,4-Dichlorophenyl)-5-phenyl-1,2,4-triazin-3-amine (52 mg, 54%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (75 mg, 0.299 mmol) and 3,4-dichlorophenylboronic acid (65.5 mg, 0.344 mmol) according to the general procedure of Example 1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH3:13])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[C:14](OC(=O)C)(=[O:16])[CH3:15]>N1C=CC=CC=1>[C:14]([O:12][C:11]1[C:10]([CH3:13])=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[CH3:1])(=[O:16])[CH3:15]
Reactant: COC(=O)c1cc(C)c(O)c(C)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COC(=O)c1cc(C)c(OC(C)=O)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of methyl 3,5-dimethyl-4-hydroxybenzoate (2.146 g) in pyridine (20 mL) was cooled in an ice-bath under a nitrogen atmosphere. Acetic anhydride (5 mL) was added drop wise and after 30 minutes at 0° C., the reaction was warmed to room temperature and stirred for 2-3 hours. The solvent was then removed under reduced pressure and the crude product was dissolved in ethyl acetate (50 mL). This solution was washed with 1 N HCl, water and brine. It was then dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. Yield=2.4 g, white powder.
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14][C:13]=2[O:24][CH3:25])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:27])[N:6]2[CH3:26].[Cl:28][C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=1[S:36](Cl)(=[O:38])=[O:37]>N1C=CC=CC=1>[Cl:28][C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=1[S:36]([NH:1][C:2]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14][C:13]=2[O:24][CH3:25])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:27])[N:6]2[CH3:26])(=[O:38])=[O:37]
Reactant: CCOC(=O)Cc1ccc(Oc2ccc3c(cc(C)n3C)c2N)c(OC)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Solvent: c1ccncc1
Product: CCOC(=O)Cc1ccc(Oc2ccc3c(cc(C)n3C)c2NS(=O)(=O)c2ccc(Cl)cc2Cl)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a room temperature solution of 3.3 (29 mg, 0.079 mmol) dissolved in pyridine (2 mL) was added 2,4-dichlorobenzenesulfonyl chloride (21 mg, 0.087 mmol). The resulting red solution was stirred at room temperature for 2 h, after which time HPLC indicated no 3.3 remained. The reaction solution was concentrated in vacuo on a rotary evaporator and the concentrate partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic separation was washed with water then brine. The organic extract was stirred over magnesium sulfate, filtered and the filtrate concentrated in vacuo on a rotary evaporator to afford an orange oil. The product was isolated by chromatography on silica gel, eluting with an ethyl acetate/hexane gradient, to afford a faint yellow oil. 1H NMR (500 MHz) (CDCl3) δ 7.71 (d, J=8.4 Hz, 1H); 7.48 (s, 1H); 7.04 (d, J=8.8 Hz, 1H); 6.88 (d, J=1.8 Hz, 1H); 6.70 (s, 1H); 6.59 (d, J=8.7 Hz, 1H); 6.53 (d, J=6.4 Hz, 1H); 6.52 (d, J=1.8 Hz, 1H); 6.16 (d, J=8.2 Hz, 1H); 4.19 (q, J=7.1 Hz, 2H); 3.86 (s, 3H); 3.64 (s, 3H); 3.59 (s, 2H); 2.48 (s, 3H) ppm.
Reaction SMILES: [OH-].[K+].C[O:4][C:5]([C:7]1[C:16]2[C:10]([CH:11]=[CH:12][CH:13]=[C:14]([CH:17]([CH3:19])[CH3:18])[CH:15]=2)=[CH:9][CH:8]=1)=[O:6].Cl>C(O)C.O>[C:5]([C:7]1[C:16]2[C:10]([CH:11]=[CH:12][CH:13]=[C:14]([CH:17]([CH3:19])[CH3:18])[CH:15]=2)=[CH:9][CH:8]=1)([OH:6])=[O:4]
Reactant: COC(=O)c1ccc2cccc(C(C)C)cc1-2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)c1cccc2ccc(C(=O)O)c-2c1
Temperature: 25 °C

Procedure:
Potassium hydroxide (10.5 g) was dissolved in a mixture of ethanol (80 ml) and water (15 ml). The compound (17) (12.43 g) was added thereto and the mixture was heated under reflux for 50 minutes in an oil bath. The reaction solution was cooled to room temperature, and then poured into water (400 ml). The solution was made acidic (pH 3) with conc. HCl. The precipitate was filtered, washed with water and dried to obtain 1-carboxy-7-isopropylazulene (18), at a yield of 2.1 g (92.3%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[N:15]1[CH:23]=[C:22]2[C:18]([N:19]=[CH:20][NH:21]2)=[N:17][CH:16]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@H:12]([N:19]2[CH:20]=[N:21][C:22]3[C:18]2=[N:17][CH:16]=[N:15][CH:23]=3)[CH3:13])[CH2:11][O:10]1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: c1ncc2[nH]cnc2n1
Product: C[C@@H](n1cnc2cncnc21)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 47.7 %

Procedure:
Using (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol (1.03 g) and purine (500 mg), (2S)-2-(2,4-difluorophenyl)-2-[(1R)-1-(9H-9-purinyl)ethyl]oxirane (600 mg) was obtained by the same way as in Reference Example 2.
Reaction SMILES: Br[CH2:2][C@H:3]1[CH2:8][CH2:7][Si@H:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:5][CH2:4]1.[Mg].I[CH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)[CH2:19][CH2:18]1>[Cu]I.P(OCC)(OCC)(OCC)=O.C1COCC1>[CH2:9]([Si@H:6]1[CH2:7][CH2:8][C@H:3]([CH2:2][CH2:16][C@H:17]2[CH2:18][CH2:19][C@H:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:30]=[CH:31][C:32]([C:35]([F:36])([F:37])[F:38])=[CH:33][CH:34]=4)=[CH:25][CH:24]=3)[CH2:21][CH2:22]2)[CH2:4][CH2:5]1)[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: FC(F)(F)c1ccc(-c2ccc([C@H]3CC[C@H](CI)CC3)cc2)cc1
Reactant: CCCCC[Si@H]1CC[C@H](CBr)CC1
Agent: [Cu]I
Agent: [Mg]
Solvent: CCOP(=O)(OCC)OCC
Solvent: C1CCOC1
Product: CCCCC[Si@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccc(-c4ccc(C(F)(F)F)cc4)cc3)CC2)CC1

Procedure:
26.3 g (0.1 mol) of trans-1-bromomethyl-4-n-pentyl-4-silacyclohexane was dripped into a mixture of 2.5 g (0.11 mol) of magnesium and 300 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 500 ml THF solution of 0.5 g of triethyl phosphate, 0.1 g of copper (I) iodide and 44.4 g (0.1 mol) of 4-(trans-4-iodomethylcyclohexyl)-4'-trifluoromethylbiphenyl. After a conventional after treatment, purification was conducted by means of chromatography to obtain 38.5 g (yield 76.9%) of 4-(trans-4-(2-(trans-4-n-pentyl-4-silacyclohexyl)ethyl)cyclohexyl)-4'-trifluoromethylbiphenyl was obtained.
Reaction SMILES: C([BH3-])#[N:2].[Na+].[C:5]([C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=1)(=O)[CH2:6][CH2:7][CH3:8].C([O-])(=O)C.[NH4+]>CO>[NH2:2][CH:5]([C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=1)[CH2:6][CH2:7][CH3:8]
Reactant: CCCC(=O)c1ccc(C(=O)OCC)cc1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCCC(N)c1ccc(C(=O)OCC)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Sodium cyanoborohydride (29.8 g, 0.450 mol) was added to a solution of Intermediate 1 (66.1 g, 0.300 mol) and ammonium acetate (236 g, 3.00 mol) in methanol (1000 mL). The solution was fitted with a reflux condenser and heated to 60° C. for 16 h. The solution was allowed to cool to room temperature. The reaction was quenched by dropwise addition of 1N HCl (300 mL) and allowed to stir at room temperature for 1 h. The reaction mixture was concentrated to remove methanol. This mixture was diluted by careful addition of 1N NaOH (500 mL) followed by extraction with dichloromethane (3×500 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. Purification by silica gel flash chromatography (methanol/dichloromethane) gave ethyl(+/−)-4-(1-aminobutyl)benzoate (Intermediate 2). 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J=8.2 Hz, 2H), 7.40 (d, J=8.2 Hz, 2H), 4.38 (q, J=7.2 Hz, 2H), 3.98 (t, J=6.9 Hz, 1H), 1.95 (br. s., 2H), 1.74-1.56 (m, 2H), 1.40 (t, J=7.1 Hz, 3H), 1.16-1.37 (m, 2H), 0.91 (t, J=7.4 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Br[CH2:14][CH2:15][F:16].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C.O>[F:16][CH2:15][CH2:14][O:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([OH:1])[CH:11]=1
Reactant: COC(=O)c1ccc(O)cc1O
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCF)cc1O
Temperature: 57.5 °C

Procedure:
A mixture of methyl 2,4-dihydroxybenzoate (5.04 g, 30 mmol), 1-bromo-2-fluoroethane (4.18 g, 2.46 mL, 33 mmol), potassium carbonate (4.55 g, 33 mmol) and potassium iodide (1 g) in DMF (20 mL) was heated overnight at 55-60° C. before it was poured into water (150 mL). The resulting white precipitate was filtered, redissolved in dichloromethane, dried (MgSO4), concentrated and diluted with hexane to afford the ether in two crops (1.30 g and 2.19 g). The first crop was characterized:
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[N:12]1[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]1.[CH:19]([Si:22](OS(C(F)(F)F)(=O)=O)([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])([CH3:21])[CH3:20].CCN(CC)CC>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[N:12]1[CH2:17][CH2:16][CH:15]([O:18][Si:22]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:19]([CH3:21])[CH3:20])[CH2:14][CH2:13]1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: COc1cc([N+](=O)[O-])ccc1N1CCC(O)CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc([N+](=O)[O-])ccc1N1CCC(O[Si](C(C)C)(C(C)C)C(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.4 %

Procedure:
Dissolve 1-(2-methoxy-4-nitro-phenyl)-piperidin-4-ol (1.19 g, 4.72 mmol) in DMF (25 mL), followed by addition of triisopropylsilyl-trifluoromethanesulfonate (1.50 mL, 5.56 mmol) and Et3N (0.80 mL, 5.87 mmol). Stir the solution at room temperature for 2 h, then add water (50 mL) and extract with EtOAc (2×50 mL). Combine the organic solutions and wash with water (2×30 mL) and brine (30 mL), then dry, filter, and concentrate. Purify the crude material by flash chromatography, using a linear gradient of 100% hexanes to 20% EtOAc/hexanes, to give the title compound as a yellow solid (1.55 g, 80%). MS (ES+) 409.3 (M+1)+. 1H NMR (400 MHz, CDCl3) δ: 7.84 (dd, 1H, J=8.8, 2.6 Hz), 7.68 (d, 1H, J=2.6 Hz), 6.89 (d, 1H, J=8.8 Hz), 4.07-4.01 (m, 1H), 3.93 (s, 3H), 3.45-3.38 (m, 2H), 3.13-3.06 (m, 2H), 1.99-1.91 (m, 2H), 1.81-1.73 (m, 2H), 1.07-1.06 (m, 21H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:17]1(=[O:22])[CH2:21][CH2:20][CH:19]=[CH:18]1.O>CCCCCCC.C1CC=CCCC=C1.C1CC=CCCC=C1.[Cl-].[Cl-].[Rh].[Rh].C(Cl)Cl.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:19]2[CH2:20][CH2:21][C:17](=[O:22])[CH2:18]2)[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: O=C1C=CCC1
Agent: [Rh]
Agent: C1=C\CC/C=C\CC/1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1=CCCC=CCC1
Solvent: ClCCl
Product: O=C1CCC(c2cccc(F)c2)C1
Temperature: 90 °C
Reaction time: 2 h
Yield: 61.6 %

Procedure:
A 40 mL vial was charged with (3-fluorophenyl)boronic acid (1.278 g, 9.14 mmol) and purged with nitrogen for 10 min. The reaction vessel was then sequentially charged with dioxane (15.2 mL), an aqueous solution of sodium carbonate (5.1 mL, 1.9 M), and 2-cyclopenten-1-one (0.510 ml, 6.09 mmol) via syringe. Chloro(1,5-cyclooctadiene)rhodium (I) dimer (0.090 g, 0.183 mmol) was introduced in a single portion. The vial was sealed with a PTFE line cap and the resultant reaction mixture was heated to 90° C. After 2 h, the reaction mixture was allowed to cool to RT and poured into a mixture of water (30 mL) and EtOAc (30 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×30 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (50-g Biotage column, eluent: gradient, 0 to 100% EtOAc in heptane with 10% CH2Cl2 as an additive) to afford 3-(3-fluorophenyl)cyclopentanone (668 mg, 3.75 mmol, 61.6% yield) as a clear oil. 1H NMR (400 MHz, CHLOROFORM-d) δ=7.37-7.23 (m, 1H), 7.08-6.99 (m, 1H), 6.99-6.89 (m, 1H), 3.50-3.33 (m, 1H), 2.68 (dd, J=7.7, 18.3 Hz, 1H), 2.53-2.40 (m, 2H), 2.39-2.25 (m, 2H), 2.05-1.90 (m, 1H). m/z (ESI) 179.2 (+H)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8]([NH:10][C@H:11]([C:17]([OH:19])=[O:18])[CH2:12][CH2:13][C:14]([OH:16])=O)=[O:9]>C(OC(=O)C)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8]([NH:10][C@@H:11]1[C:17](=[O:18])[O:19][C:14](=[O:16])[CH2:13][CH2:12]1)=[O:9]
Reactant: O=C(O)CC[C@H](NC(=O)C=Cc1ccco1)C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C(C=Cc1ccco1)N[C@H]1CCC(=O)OC1=O
Temperature: 100 °C

Procedure:
In 20 ml of acetic anhydride was dissolved 5 g of DL-N-[β-(2-furyl)acryloyl]glutamic acid, and the resulting solution was heated at 100° C. for 15 minutes, after which the excessive acetic anhydride was removed by distillation under reduced pressure to obtain DL-N-[β-(2-furyl)acryloyl]glutamic acid anhydride. This product was added to a mixed solution of 5 ml of di(n-propyl)-amine and 5 ml of water with ice-cooling, and the resulting mixture was subjected to reaction for 2 hours. After completion of the reaction, the reaction mixture was adjusted to pH 4 with diluted hydrochloric acid and extracted with two 20-ml portions of ethyl acetate, and the organic layers were combined and then dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by distillation under reduced pressure to obtain 4 g (yield 62%) of DL-N2 -[β-(2-furyl)acryloyl]-N1,N1 -di-n-propyl-α-glutamylamide having a melting point of 130°-131° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.Cl[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=1.[OH-].[K+].O>CS(C)=O>[CH3:9][O:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=2)=[CH:7][N:6]=1
Reactant: COc1ccc(O)cn1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(Oc2ccc(C(F)(F)F)cn2)cn1
Temperature: 25 °C
Yield: 94.7 %

Procedure:
A solution of 5-hydroxy-2-methoxypyridine (1.25 g, 10.0 mmol), 2-chloro-5-trifluoromethylpyridine (1.82 g, 10.0 mmol) and potassium hydroxide (85% pure, 1.08 g, 10.0 mmol) in dimethyl sulfoxide (25 mL) was heated at 90° C. for 2.5 hours. The solution was cooled to room temperature and poured slowly into water (200 mL). After cooling with an external ice-bath, the precipitate was collected by suction, washed thoroughly with water and dried in a vacuum oven at 45° C., yielding the title compound (2.56 g, 95% yield).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[NH2:8][C:9]([NH:11][C:12]1[NH:13][C:14]2[C:19]([C:20]=1[C:21]([NH2:23])=[O:22])=[CH:18][CH:17]=[C:16]([C:24]1[CH:29]=C[CH:27]=[C:26](CO)[CH:25]=1)[CH:15]=2)=[O:10]>N1C=CC=CC=1>[C:5]([O:4][CH2:1][C:2]1[CH:29]=[C:24]([C:16]2[CH:15]=[C:14]3[C:19]([C:20]([C:21]([NH2:23])=[O:22])=[C:12]([NH:11][C:9]([NH2:8])=[O:10])[NH:13]3)=[CH:18][CH:17]=2)[CH:25]=[CH:26][CH:27]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)Nc1[nH]c2cc(-c3cccc(CO)c3)ccc2c1C(N)=O
Solvent: c1ccncc1
Product: CC(=O)OCc1cccc(-c2ccc3c(C(N)=O)c(NC(N)=O)[nH]c3c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
Pyridine (4 mL) and acetic anhydride (61 μL, 0.65 mmol) were added to 2-aminocarbonylamino-6-(3-hydroxymethylphenyl)indole-3-carboxamide (Compound 12-1, 0.18 g, 0.55 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and water (10 mL) was added to the residue. The precipitated solid was separated by filtration. The resultant solid was washed with water (10 mL) and dried under reduced pressure to give the title compound (0.17 g) as a slightly brown solid (yield 87%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH:10]([OH:14])[CH2:11][CH2:12][CH3:13])(=[O:9])[O:6]CC.Cl>O>[NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH:10]([OH:14])[CH2:11][CH2:12][CH3:13])(=[O:6])[OH:9]
Reactant: CCCC(O)P(=O)(CCCN)OCC
Agent: Cl
Solvent: O
Product: CCCC(O)P(=O)(O)CCCN
Yield: 85.8 %

Procedure:
A mixture of 2.0 g ethyl 3-aminopropyl(1-hydroxybutyl)-phosphinate and 20.0ml 2M aqueous hydrochloric acid is refluxed for 2 hours and then evaporatedto dryness. The residual oil is dissolved in 10 ml of water, and re-evaporated. The residue is dissolved in 20 ml of ethanol and treated with propylene oxide and to give 1.5 g of 3-aminopropyl(1hydroxybutyl)phosphinic acid, m.p. 188°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].[C:10](OC(=O)C)(=[O:12])[CH3:11]>O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(F)c(Cl)c1
Solvent: O
Product: CC(=O)Nc1ccc(F)c(Cl)c1
Reaction time: 0.5 h

Procedure:
To 3-chloro-4-fluoroaniline (100 g) was slowly added acetic anhydride (200 ml). After allowed to stand for 30 minutes, the reaction mixture was poured into water (1 litter). The resulting precipitate was collected by filtration and recrystallized from aqueous ethanol to give the title compound (119.4 g), mp 118°-119° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]([C:18]2[N:26]=[C:25]3[C:21]([N:22]=[CH:23][N:24]3[C@@H:27]3[CH2:31][C@H:30]([N:32]4[CH:36]=[C:35]([CH2:37][OH:38])[CH:34]=[N:33]4)[C@@H:29]([OH:39])[C@H:28]3[OH:40])=[C:20]([NH:41][CH2:42][CH:43]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[N:19]=2)=[O:17])[CH2:11][CH2:10]1.FC(F)(F)C(O)=O.C(NC(=O)NCCCNC(C1N=[C:81]2C(N=[CH:79][N:80]2[C@@H:83]2C[C@H](N3C=C(CO)C=N3)[C@@H](O)[C@H:84]2[OH:96])=C(NCC(C2C=CC=CC=2)C2C=CC=CC=2)N=1)=O)C.Cl.CC(C)(N)C(Cl)=O>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:79][N:80]([CH3:81])[CH2:83][C:84]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]([C:18]2[N:26]=[C:25]3[C:21]([N:22]=[CH:23][N:24]3[C@@H:27]3[CH2:31][C@H:30]([N:32]4[CH:36]=[C:35]([CH2:37][OH:38])[CH:34]=[N:33]4)[CH:29]([OH:39])[CH:28]3[OH:40])=[C:20]([NH:41][CH2:42][CH:43]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[N:19]=2)=[O:17])[CH2:11][CH2:10]1)=[O:96]
Reactant: CCNC(=O)NCCCNC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3C[C@H](n4cc(CO)cn4)[C@@H](O)[C@H]3O)c2n1
Reactant: NC1CCC(NC(=O)c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](n5cc(CO)cn5)[C@@H](O)[C@H]4O)c3n2)CC1
Agent: CC(C)(N)C(=O)Cl
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CC(=O)NC1CCC(NC(=O)c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](n5cc(CO)cn5)C(O)C4O)c3n2)CC1

Procedure:
This compound is prepared from 9-[(1R,2S,3R,4S)-2,3-dihydroxy-4-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid (4-amino-cyclohexyl)-amide trifluoroacetate (Example 83, first step a) using a procedure analogous to that of 9-[(1R,2S,3R,4S)-2,3-dihydroxy-4-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid [3-(3-ethyl-ureido)-propyl]-amide trifluoroacetate (Example 87) replacing ethyl isocyanate with dimethyl-amino-acetyl chloride hydrochloride.