Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH2:14][CH:15]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1)[C:7]2=[O:13].Cl>O1CCOCC1>[ClH:1].[Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH2:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[C:7]2=[O:13]
Reactant: CC(C)(C)OC(=O)N1CCC(Cn2ccc3c(Cl)c(Cl)ccc3c2=O)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1c2ccc(Cl)c(Cl)c2ccn1CC1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 189.3 %

Procedure:
The compound prepared in Example 76 (0.05 g) was suspended in 1,4-dioxane (4 mL), hydrochloric acid (4 mol/L solution in 1,4-dioxane, 0.88 mL) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated to obtain the title compound (0.04 g) having the following physical data.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:10](=O)([O-])[O-].[K+].[K+].CN(C)C=O.C(=O)(OC)OC>O>[CH3:10][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCN2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COC(=O)OC
Solvent: O
Product: CN1CCc2ccccc21
Temperature: 130 °C
Reaction time: 14 h
Yield: 95 %

Procedure:
Indoline (3 g, 0.025 mol), potassium carbonate (1.59), N,N-dimethylformamide (20 mL) and dimethyl carbonate (6.4 mL ,0.076 mol) were mixed together and heated to reflux (around 130 ° C.) for 14 h. The reaction, monitored by HPLC, went to completion within 14 h. The reaction mixture was cooled down to room temperature, then was slowly diluted with water (50 mL) and extracted with tert-butyl methyl ether (60 mL ). The organic extract was washed with water (3×50 mL) and the solution was evaporated to constant weight under reduced pressure to furnish 3.13 g of the product, N-methylindoline as a light yellow oil (95% yield).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][C:12]([CH:15]([O:22][C:23]3[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=3)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:41][O:42][C:43](=[O:47])[CH2:44][CH2:45][NH2:46].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:14]=[CH:13][C:12]([CH:15]([O:22][C:23]3[CH:24]=[CH:25][C:26]([C:27]([NH:46][CH2:45][CH2:44][C:43]([O:42][CH3:41])=[O:47])=[O:28])=[CH:30][CH:31]=3)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: COC(=O)CCN
Reactant: CCCCCCC(Oc1ccc(C(=O)O)cc1)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCC(Oc1ccc(C(=O)NCCC(=O)OC)cc1)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
To a mixture of 4-{1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-heptyloxy}-benzoic acid (230 mg, 0.5 mmol) in methylene chloride (5 mL) are added triethyl amine (0.21 mL, 1.51 mmol), DMAP (5.0 mg), 3-amino-propionic acid methyl ester (210.5 mg, 1.51 mmol) and EDCI (290 mg, 1.51 mmol) at room temperature. The reaction mixture is stirred at room temperature overnight, loaded on silica gel, eluted with eluted with hexanes with a gradient from 0% of ethyl acetate to 100% of ethyl acetate giving methyl 3-(4-{1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-heptyloxy}-benzoylamino)-propionoate (260 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[S:3]([CH2:6][C:7]1([NH:13]S(C(C)(C)C)=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)(=[O:5])=[O:4].Cl>CO.O1CCOCC1>[NH2:13][C:7]1([CH2:6][S:3]([N:2]([CH3:20])[CH3:1])(=[O:5])=[O:4])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CN(C)S(=O)(=O)CC1(NS(=O)C(C)(C)C)CCCCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CN(C)S(=O)(=O)CC1(N)CCCCC1
Reaction time: 0.5 h

Procedure:
The sulfinamide 1200-C (1.3 g) was dissolved in 40 mL of methanol and treated with 10 mL of 4M HCl solution in dioxane. The mixture was stirred for about 30 min until all the starting material had been consumed as determined by TLC (20% acetone in dichloromethane/hexanes, 1:1). The mixture was evaporated to dryness. Dichloromethane was added (15 mL) to make a cloudy solution. Upon addition of 100 mL of ether a white precipitated formed. The product 1200-D (1.02 g; 98%) was recovered by filtration using filter paper whatman #1.
Reaction SMILES: N1CC=CC1.C(NNC1(N=C=S)C=CC=CC1)=O.[CH:19]([NH:21][NH:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([N:32]([CH2:40][C:41]2[CH:46]=[CH:45]C=CC=2)CC2C=CC=CC=2)=[S:31])=[CH:25][CH:24]=1)=[O:20]>>[CH:19]([NH:21][NH:22][C:23]1[CH:24]=[CH:25][C:26]([NH:29][C:30]([N:32]2[CH2:40][CH:41]=[CH:46][CH2:45]2)=[S:31])=[CH:27][CH:28]=1)=[O:20]
Reactant: O=CNNc1ccc(NC(=S)N(Cc2ccccc2)Cc2ccccc2)cc1
Agent: C1=CCNC1
Agent: O=CNNC1(N=C=S)C=CC=CC1
Product: O=CNNc1ccc(NC(=S)N2CC=CC2)cc1

Procedure:
3-Pyrroline (0.069 g, 0.001 mole) and 1-(2-formylhydrazino)phenyl isothiocyanate (0.19 g, 0.001 mole) were reacted according to the procedure described for NA-11 in Example 3. Yield 0.18 g (69 percent), m.p. 218°-220° C.
Reaction SMILES: C(O[C:6](=[O:22])[N:7]([CH2:13][C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=1[F:21])[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)(C)(C)C.[CH2:23]([O:25][C:26](=[O:38])[CH:27](C(OCC)=O)[C:28](OCC)=[O:29])[CH3:24]>>[CH2:23]([O:25][C:26]([C:27]1[C:6](=[O:22])[N:7]([CH2:13][C:14]2[C:15]([F:21])=[CH:16][CH:17]=[CH:18][C:19]=2[F:20])[N:8]2[CH:9]=[CH:10][CH:11]=[C:12]2[C:28]=1[OH:29])=[O:38])[CH3:24]
Reactant: CC(C)(C)OC(=O)N(Cc1c(F)cccc1F)n1cccc1
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)c1c(O)c2cccn2n(Cc2c(F)cccc2F)c1=O

Procedure:
Prepared according to the thermal cyclization condition used in Example 1 step c) from (2,6-difluoro-benzyl)-pyrrol-1-yl-carbamic acid tert-butyl ester (1.0 eq.) and 2-ethoxycarbonyl-malonic acid diethyl ester (3.0 eq.). ESI (m/z): 349 (M+H)+.
Reaction SMILES: C([O:8][C:9](=[O:51])[CH2:10][C@@H:11]([C:38]([NH:40][CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=1)=[O:39])[NH:12]C([C@@H]1CCCN(C(=O)CCC2CCN(C(OC(C)(C)C)=O)CC2)C1)=O)C1C=CC=CC=1>C(O)(=O)C.[Pd]>[CH3:50][O:49][C:46]1[CH:45]=[CH:44][C:43]([CH2:42][CH2:41][NH:40][C:38]([C@H:11]([CH2:10][C:9]([OH:51])=[O:8])[NH2:12])=[O:39])=[CH:48][CH:47]=1
Reactant: COc1ccc(CCNC(=O)[C@H](CC(=O)OCc2ccccc2)NC(=O)[C@@H]2CCCN(C(=O)CCC3CCN(C(=O)OC(C)(C)C)CC3)C2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1ccc(CCNC(=O)[C@@H](N)CC(=O)O)cc1
Reaction time: 3 h
Yield: 233 %

Procedure:
A mixture of N-[(R)-1-{3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl}-3-piperidylcarbonyl]-3(S)-(4-methoxyphenethylamino)carbonyl-β-alanine benzyl ester (0.9 g) and 10% Pd—C (0.2 g, 50% wet) in acetic acid (10 ml) was hydrogenated at atmospheric pressure for 3 hours. After the catalyst was removed by filtration, the filtrate was concentrated in vacuo. The residue was poured into water and extract with ethyl acetate. The extract washed with water, brine and dried over MgSO4, and evaporated in vacuo. To give N-[(R)-1-{3-(1-tert-butoxycarbonyl)-4-piperidyl)propionyl}-3-piperidylcarbonyl]-3(S)-(4-methoxyphenethylamino)carbonyl-β-alanine as an oil (0.79 g).
Reaction SMILES: C1(=O)[N:5]([C@@H:6]([CH2:11][CH2:12][CH:13]([O:16][CH3:17])[O:14][CH3:15])[C:7]([O:9][CH3:10])=[O:8])C(=O)C2=CC=CC=C12.O.NN>CO>[NH2:5][C@@H:6]([CH2:11][CH2:12][CH:13]([O:16][CH3:17])[O:14][CH3:15])[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)[C@H](CCC(OC)OC)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CO
Product: COC(=O)[C@@H](N)CCC(OC)OC
Temperature: 25 °C
Reaction time: 144 h

Procedure:
(S)-2-Phthalimido-5,5-dimethoxypentanoic acid, methyl ester [prepared as described in Example 4(f), 3.35 g., 10.43 mmol.) in methanol (70 ml.) was treated with hydrazine monohydrate (531 μl., 10.95 mmol., 1.05 eq.) and the solution was stirred at room temperature for 6 days. The mixture was filtered and the solid was washed with methanol. The filtrate was concentrated, triturated with methylene chloride, filtered again, concentrated, and dried in vacuo to yield 1.89 g. of title product as a cloudy oil.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][CH2:15][CH2:16][N:17]1[C:29]2[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:22]=[C:21]([NH2:30])[C:20]=2[N:19]=[C:18]1[CH2:31][O:32][N:33]=[C:34]([CH3:36])[CH3:35])(C)(C)C>ClCCl>[NH2:30][C:21]1[C:20]2[N:19]=[C:18]([CH2:31][O:32][N:33]=[C:34]([CH3:36])[CH3:35])[N:17]([CH2:16][CH2:15][NH2:14])[C:29]=2[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N:22]=1
Reactant: CC(C)=NOCc1nc2c(N)nc3ccccc3c2n1CCNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)=NOCc1nc2c(N)nc3ccccc3c2n1CCN
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 274.3 %

Procedure:
Trifluoroacetic acid (10 mL) was added to a suspension of tert-butyl[2-(4-amino-2-isopropylideneaminooxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]carbamate (4.8 g) in dichloromethane (100 mL). The reaction became homogeneous and was stirred at ambient temperature. At 2.5 hours and 3.5 hours more trifluoroacetic acid (10 mL and 5 mL respectively) was added. After a total reaction time of 4 hours the reaction mixture was concentrated under reduced pressure. The residue was azeotroped with toluene (×3) and then placed under high vacuum overnight to provide 9.97 g of propan-2-one O-{[4-amino-1-(2-aminoethyl)-1H-imidazo[4,5-c]quinolin-2-yl]methyl}oxime as a yellow solid. Based on the weight this material was assumed to contain 5 equivalents of trifluoroacetic acid.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][CH2:5][CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=1.O.Cl>CCO>[CH3:3][O:4][CH2:5][CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1
Reactant: COCCOc1ccc(C(=O)OC)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COCCOc1ccc(C(=O)O)cc1
Reaction time: 1 h
Yield: 68.5 %

Procedure:
4.3 g (64.95 mmol) of potassium hydroxide are added to a solution of 6.1 g (29 mmol) of methyl 4-(2-methoxyethoxy)benzoate in 100 mL of EtOH. The solution is heated up to reflux for one hour and poured onto icy water and acidified with a 25% HCl solution. The mixture is filtered off and washed 2 times with 100 mL of water. The solid is suspended in 100 ml of acetonitrile for 1 hour and the precipitate is filtered off and dried under pressure to yield 3.9 g (70%) of pure 4-(2-methoxyethoxy)benzoic acid as a white powder.
Reaction SMILES: C(NC(C)C)(C)C.[C:8]([O:12][C:13](=[O:15])[CH3:14])([CH3:11])([CH3:10])[CH3:9].[O:16]([C:23]1[CH:33]=[CH:32][C:26]([C:27](OCC)=[O:28])=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[NH4+].[Cl-]>O1CCCC1>[O:28]=[C:27]([C:26]1[CH:32]=[CH:33][C:23]([O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:24][CH:25]=1)[CH2:14][C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:15]
Reactant: CCOC(=O)c1ccc(Oc2ccccc2)cc1
Reactant: CC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)CC(=O)c1ccc(Oc2ccccc2)cc1
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 54.8 %

Procedure:
nButyllithium (2.5 M, 7.9 ml, 19.76 mmol) was added at −20° C. to a solution of di-iso-propylamine (3.29 ml, 23.24 mmol) in tetrahydrofuran (40 ml). The reaction mixture was stirred for 15 minutes under nitrogen at −20° C. then the mixture was allowed to cool down to −78° C. tert-Butylacetate (2.64 ml, 19.67 mmol) was added and the mixture was stirred at −78° C. for 20 minutes. A solution of ethyl 4-phenoxybenzoate (2.17 g, 8.94 mmol) in tetrahydrofuran (5 ml) was further added to this and the resulting mixture was stirred at −78° C. for 50 minutes. A saturated solution of NH4Cl was added and the whole was extracted with EtOAc. The organics were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 8% Et2O in petroleum ether to afford the title compound as a colourless oil (1.53 g, 55% yield). MS (ES+) m/e=313. 1H NMR (CDCl3) δH 1.47 (9H, s), 3.88 (2H, s), 7.02 (2H, d), 7.10 (2H, d), 7.24 (1H, t), 7.43 (2H, t), 7.94 (2H, d).
Reaction SMILES: [CH2:1]([O:3][CH2:4][O:5][C:6](=[O:16])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[CH3:2].[C:17]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1)(=[O:20])[CH:18]=[CH2:19]>ClCCl>[C:17]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([O:15][C:12]2[CH:11]=[CH:10][C:9]([CH:8]=[CH:7][C:6]([O:5][CH2:4][O:3][CH2:1][CH3:2])=[O:16])=[CH:14][CH:13]=2)=[O:34])=[CH:31][CH:30]=1)(=[O:20])[CH:18]=[CH2:19]
Reactant: CCOCOC(=O)C=Cc1ccc(O)cc1
Reactant: C=CC(=O)OCCCCCCOc1ccc(C(=O)O)cc1
Solvent: ClCCl
Product: C=CC(=O)OCCCCCCOc1ccc(C(=O)Oc2ccc(C=CC(=O)OCOCC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.7 %

Procedure:
15.7 g (0.076 mole) of N,N-dicyclohexyl carbodiimide were added to a solution of 18.7 g (0.076 mole) of 4-hydroxycinnamic acid ethoxymethyl ester (23) (90% pure), 22.2 g (0.076 mole) of 4-(6-acryloyloxy-hexyloxy)-benzoic acid (5) and 0.93 g (0.0076 mole) of 4-N,N-dimethylaminopyridine in 200 ml of dichloromethane, cooled in an ice-water bath. After two hours the ice-water bath was removed. The mixture was stirred at room temperature overnight. Then it was filtered through a silica pad and the solvent was evaporated. 15 g of the product (40%) were obtained after crystallization from ethanol.
Reaction SMILES: [CH2:1]([C:4]([C:17](=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][CH3:25])(C(OCC)=O)[C:5]([O:7][C:8](C)(C)[CH3:9])=[O:6])[CH:2]=[CH2:3].C(OC(=O)C)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(=O)C>[CH2:1]([CH:4]([C:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][CH3:25])=[O:26])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCC(C(=O)OCC)(C(=O)OC(C)(C)C)C(=O)c1ccccc1CC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: C=CCC(C(=O)OCC)C(=O)c1ccccc1CC
Temperature: 140 °C
Yield: 71.6 %

Procedure:
A mixture of t-butyl ethyl 2-allyl-2-(2-ethylbenzoyl)malonate (14.3 g.), acetic anhydride (4 ml.) and p-toluenesulphonic acid (100 mg.) in acetic acid (200 ml.) was heated at 140° C. under nitrogen for 75 minutes and then evaporated. The residue was shaken with a mixture of saturated sodium bicarbonate solution (100 ml.) and ethyl acetate (100 ml.). The organic phase was dried (MgSO4) and evaporated. The oil obtained (9.3 g.) was purified by flash column chromatography (280 g.) using toluene as eluant to give ethyl 2-allyl-3-(2-ethylphenyl)-3-oxopropionate (7.4 g.) as a pale yellow oil; NMR: 1.19 (6H,m), (2.74 (4H,m), 4.15 (3H,m), 5.05(2H,m), 5.79 (1H,m), 7.30 (3H,m) and 7.61 (1H,m)ppm.
Reaction SMILES: I[C:2]1[C:3]2[N:4]([C:9]([CH2:12][CH:13]3[CH2:15][CH2:14]3)=[N:10][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:16](B(O)O)[CH3:17].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:16]([C:2]1[C:3]2[N:4]([C:9]([CH2:12][CH:13]3[CH2:15][CH2:14]3)=[N:10][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8])[CH3:17]
Reactant: CCB(O)O
Reactant: Clc1ccn2c(CC3CC3)nnc2c1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCc1c(Cl)ccn2c(CC3CC3)nnc12
Temperature: 100 °C

Procedure:
To a mixture of intermediate D70 (0.6 g, 1.8 mmol) in toluene (14 ml) under a nitrogen atmosphere were added ethylboronic acid (0.665 g, 9 mmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine; X-Phos (0.171 g, 0.36 mmol), palladium(II) acetate (0.04 g, 0.18 mmol) and K2CO3 (0.745 g, 5.396 mmol). The reaction mixture was heated at 100° C. overnight. After cooling, the mixture was diluted with EtOAc and washed with water. The organic layer was separated and concentrated in vacuo. The residue was purified by column chromatography (silica gel; DCM/EtOAc from 100/0 to 20/80 as eluent). The desired fractions were collected and concentrated in vacuo to give a residue that was purified by HPLC to yield intermediate D81 (0.053 g, 12.6%).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:33])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:34](=[O:37])[CH2:35][CH3:36])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:31][CH2:32]1
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-methylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f29) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:18][C:19]2[N:27]=[CH:26][N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][NH:23]3)[CH3:17])[CH2:2]1.[CH3:28][C:29]([CH3:31])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)Cl.CC(O)=O>[CH:29]([N:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:18][C:19]2[N:27]=[CH:26][N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][NH:23]3)[CH3:17])[CH2:2]1)([CH3:31])[CH3:28]
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1[C@@H]1CCCNC1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)N1CCC[C@@H](n2c([C@H](C)Nc3ncnc4[nH]cnc34)nc3ccccc32)C1
Reaction time: 0.08 h
Yield: 34.6 %

Procedure:
To a mixture of [(S)-1-((R)-1-piperidin-3-yl-1H-benzoimidazol-2-yl)ethyl]-(9H-purin-6-yl)amine from Example 16 (150 mg, 0.414 mmol) in anhydrous DCM (3 mL) was added acetone (90 μL, 1.24 mmol) followed by AcOH (1 drop). After stirring for 5 min, sodium triacetoxyborohydride (132 mg, 0.621 mmol) was added and stirring was continued for 22 h. The mixture was then treated with NaOH (1N, 2 mL) and then vigorously stirred for 10 min. Volatiles were removed in vacuo and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-15% 2M NH3/MeOH in DCM) affording 132 (58 mg, 35%). LCMS: RT 1.91 min [M+H]+ 405.1. 1H NMR (DMSO, 400 MHz): δ 12.97 (1H, s), 8.33-8.06 (2H, m), 7.96 (1H, br), 7.72 (1H, d, J=7.33 Hz), 7.62 (1H, d, J=7.14 Hz), 7.24-7.07 (2H, m), 5.93 (1H, s), 4.66-4.52 (1H, m), 3.00-2.83 (2H, m), 2.81-2.65 (2H, m), 2.23 (1H, t, J=11.59 Hz), 2.15-2.01 (1H, m), 1.84-1.57 (5H, m), 1.26-1.07 (1H, m), 0.96 (6H, d, J=6.51 Hz)
Reaction SMILES: [N+:1]([CH2:4][CH2:5][O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1)([O-:3])=O.[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C@H:21]1[CH2:25][O:26][C:27]1[CH:28]=[N:29][CH:30]=[C:31]([C:33]#[CH:34])[CH:32]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C1(N=C=O)C=CC=CC=1.C(N(CC)CC)C>C1C=CC=CC=1.O>[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C@H:21]1[CH2:25][O:26][C:27]1[CH:28]=[N:29][CH:30]=[C:31]([C:33]2[O:3][N:1]=[C:4]([CH2:5][O:6][CH:7]3[CH2:12][CH2:11][CH2:10][CH2:9][O:8]3)[CH:34]=2)[CH:32]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: C#Cc1cncc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)c1
Reactant: O=[N+]([O-])CCOC1CCCCO1
Solvent: O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(-c2cc(COC3CCCCO3)no2)c1
Reaction time: 48 h
Yield: 73.8 %

Procedure:
To a solution of 1-nitro-2-(tetrahydro-2H-pyran-2-yloxy)ethane (0.17 mL, 1.12 mmol, 2.0 equiv.) and 3-[[1-(tert-butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]-5-ethynylpyridine (170 mg, 0.56 mmol) in dry benzene (5.6 mL) were added phenyl isocyanate (122 μL, 1.12 mmol, 2.0 equiv.) and triethylamine (80 μL, 0.57 mmol, 1.0 equiv.). The reaction mixture was stired at 60° C. for 48 h, then diluted with water and stirred vigorously for 2 h. The mixture was extracted with CH2Cl2. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by CC on SiO2 with EtOAc/hexane 1:1 to give 3-[[1-(tert-butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]-5-[3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-5-isoxazolyl]pyridine (190 mg, 74%). The 1H NMR spectrum (CDCl3, 400 MHz) exhibits two sets of signals for two of the heteroaromatic protons: δ 8.53 (br s, 1H), 8.28 (br s, 1H), 7.69 (br s, 1H of the major component), 7.49 (br s, 1H of the minor component), 6.69 (br s, 1H of the major component), 6.65 (br s, 1H of the minor component), 4.75, 4.57 (ABq, 2H, J=12.8 Hz), 4.67 (br s, 1H), 4.23-4.01 (m, 2H), 3.99-3.84 (m, 1H), 3.81 (br t, 1H, J=9.6 Hz), 3.53-3.42 (m, 1H), 3.40-3.20 (m, 2H), 2.03-1.4 (series of overlapping m, 10H), 1.38 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]2[CH2:6][CH2:7][C@H:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[O:9][C:4]=2[CH:3]=1.O.P([O-])([O-])([O-])=O.[OH-].[Na+]>O1CCCC1>[CH2:13]([O:12][C:10]([CH:8]1[CH2:7][CH2:6][C:5]2[CH:15]=[CH:16][C:2]([OH:1])=[CH:3][C:4]=2[O:9]1)=[O:11])[CH3:14]
Reactant: CCOC(=O)[C@H]1CCc2ccc(O)cc2O1
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1CCc2ccc(O)cc2O1
Reaction time: 7 h

Procedure:
This ester was then resubmitted to enzymatic hydrolysis with Pseudomonas lipase (P-30, Amano International) to enhance its enantiomeric purity. A 3 L three-necked flask equipped as described above was charged with 775 mL of deionized water, 194 mL of 0.05M phosphate buffer (pH 7.0) and 28.4 g (0.128 mol) of the above ester in 96 mL of tetrahydrofuran. The pH was adjusted to 8 with adequate 1.0N aqueous sodium hydroxide solution and 2.6 g of Pseudomonas lipase enzyme (P-30 Amano) was added to the mixture. The hydrolysis was allowed to proceed to 70% conversion over a 7 hour period while stirring at a fast rate and maintaining the pH at 8. The tetrahydrofuran was removed from the reaction mixture at 40° C. (10 mm Hg) and the aqueous phase was extracted with 3×250 mL=750 mL of ethyl acetate. The combined organic layers were washed successively with 250 mL of saturated aqueous sodium bicarbonate solution and 250 mL of deionized water. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated at 40° C. (10 mm Hg) to give 6.7 g of nearly racemic 3,4-dihydro-7-hydroxy-2H-benzopyran-2-carboxylic acid ethyl ester. The aqueous layers were acidified to pH=1 with 33 mL of concentrated hydrochloric acid and extracted with 3×250 mL=750 mL of ethyl acetate. The combined organic layers were washed with 250 mL of brine and dried over anhydrous sodium sulfate. After filtration, the solvent was removed at 40° C. (10 mm Hg) to give 20.4 g of (S)-3,4-dihydro-7-hydroxy-2H-1-benzopyran-2-carboxylic acid, 95.5% e.e. This material was esterified as described above to give 21.6 g (76% yield) of (S)-3,4-dihydro-7-hydroxy-2H-1-benzopyran-2-carboxylic acid, ethyl ester as a beige solid, m.p. 77°-79° C.; (α)D22 +19.1° C. (c 1.0, CHCl3); 95.5% e.e.