Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=[O:15])[CH2:12][CH2:13][CH3:14])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[CH2:16]([O:18][C:19]1[CH:20]=[CH:21][C:22]([NH2:26])=[N:23][C:24]=1[CH3:25])[CH3:17]>>[CH2:16]([O:18][C:19]1[CH:20]=[CH:21][C:22]([NH:26][CH:4]=[C:5]([C:11](=[O:15])[CH2:12][CH2:13][CH3:14])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[N:23][C:24]=1[CH3:25])[CH3:17]
Reactant: CCOc1ccc(N)nc1C
Reactant: CCCC(=O)C(=COCC)C(=O)OCC
Product: CCCC(=O)C(=CNc1ccc(OCC)c(C)n1)C(=O)OCC

Procedure:
Ethyl 2-(ethoxymethylene)-3-oxohexanoate (22.4 g) was added to a suspension of 5-ethoxy-6-methylpyridin-2-amine (14.9 g) in IMS (50 ml). After the initial exotherm had subsided IMS (100 ml) was added and the mixture boiled under reflux until a solution was obtained. This solution was cooled and filtered to give ethyl 2-(5-ethoxy-6-methylpyrid-2-ylaminomethylene)-3-oxohexanoate, m.p. 117°-120° C.
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]=[CH: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.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[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[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:37](=[O:38])[CH2:36][O:35][CH3:34])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:33])[NH:14][C:15]=23)[CH2:31][CH2:32]1
Reactant: COCC(=O)Cl
Reactant: Cc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c1
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C)ccc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-methylphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f20) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:4]([NH:6][C@H:7]([C:17]([NH:19][C@H:20]([C:29]([NH:31][C@H:32]([C:42]([NH:44][C@H:45]([C:48]([NH:50][C@H:51]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH3:52])=[O:49])[CH2:46][OH:47])=[O:43])[CH2:33][CH2:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:30])[CH2:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:18])[CH2:8][CH2:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:5])[CH3:3]>[Pd].CO>[NH2:1][C@H:2]([C:4]([NH:6][C@H:7]([C:17]([NH:19][C@H:20]([C:29]([NH:31][C@H:32]([C:42]([NH:44][C@H:45]([C:48]([NH:50][C@H:51]([C:53]([O:55][C:56]([CH3:57])([CH3:58])[CH3:59])=[O:54])[CH3:52])=[O:49])[CH2:46][OH:47])=[O:43])[CH2:33][CH2:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:30])[CH2:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:18])[CH2:8][CH2:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:5])[CH3:3]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: C[C@H](N)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)OC(C)(C)C
Yield: 83 %

Procedure:
A solution of 6.1 g. (6.2 mmoles) of Z-27-32-OtBu in 120 ml. of methanol is hydrogenated in the presence of 1 g. of palladium-on-carbon. When the reaction terminates, the catalyst is filtered off, and the filtrate is evaporated to dryness. The residue is crystallized from a mixture of ethanol and ether. 4.35 g. (83 %) of H-27-32-OtBu are obtained. M.p.: 192°-194°C; Rf12 = 0.25; Rf3 = 0.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>CC(C)=O>[CH2:21]([O:20][C:18](=[O:19])[CH:17]([S:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH3:23])[CH3:22]
Reactant: CCOC(=O)C(C)Br
Reactant: COc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C)Sc1ccc(OC)cc1

Procedure:
To a stirred solution of 4-methoxybenzenethiol (2.5 gm, 14 mmol) and anhydrous K2CO3 (4.0 gm, excess) in dry acetone (100 ml), ethyl 2-bromo-propionate (3.0 gm, 16 mmol) was added in a round bottom flask and the reaction mixture was heated at reflux for 8 hours with good stirring. At the end, reaction was allowed to cool, filtered and the reaction mixture was concentrated to a residue. The residue was extracted with chloroform and washed with H2O and the organic layer dried over MgSO4, filtered and concentrated to afford 2-(4-methoxy-phenylsulfanyl)-propionic acid ethyl ester as a light yellow oil. Yield 3.6 gms (94%).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[O:9][CH2:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:12]N1C(=O)CCC1=O>CN(C)C=O>[NH2:1][C:2]1[C:10]2[O:9][CH2:8][C:7](=[O:11])[C:6]=2[C:5]([Cl:12])=[CH:4][CH:3]=1
Reactant: Nc1cccc2c1OCC2=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: Nc1ccc(Cl)c2c1OCC2=O

Procedure:
By the method of Example 3, Step C, 1.94 g (0.013 mole) of 7-amino-2,3-dihydro-3-benzofuranone and 1.74 g (0.013 mole) of N-chlorosuccinimide are reacted in 40 mL of N,N-dimethylformamide, yielding 7-amino-4-chloro-2,3-dihydro-3-benzofuranone.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]([CH2:14][OH:15])[CH:12]2[CH:16]([CH2:17][O:18][CH3:19])[CH:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH:13]([CH:14]=[O:15])[CH:12]2[CH:16]([CH2:17][O:18][CH3:19])[CH:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCC1C2CCC1N(C(=O)OC(C)(C)C)C2CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COCC1C2CCC1N(C(=O)OC(C)(C)C)C2C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.9 %

Procedure:
Chill a solution of 3-hydroxymethyl-7-methoxymethyl-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (0.780 g, 2.87 mmol) in dichloromethane (20 mL) in an ice bath and add Dess-Martin periodinate (1.46 g, 3.44 mmol). Stir the mixture at room temperature for 2 h and quench with 10% aqueous sodium sulfite. Extract the mixture with dichloromethane (3×20 mL). Wash the organic extracts with saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 25:75 ethyl acetate:hexanes) to give the title compound (0.780 g, 100%).
Reaction SMILES: CS(NCCCCCCC(OCC)=O)(=O)=O.C(S(NCCCCCCC(OCC)=O)(=O)=O)CC.C([O:38][CH:39]([CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[CH2:40][CH2:41][CH2:42][N:43]([CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][C:56]([O:58]CC)=[O:57])[S:44]([CH2:47]CC)(=[O:46])=[O:45])(=O)C>>[OH:38][C@H:39]([CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[C:40]#[C:41][CH2:42][N:43]([CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][C:56]([OH:58])=[O:57])[S:44]([CH3:47])(=[O:45])=[O:46]
Reactant: CCCCCC(CCCN(CCCCCCC(=O)OCC)S(=O)(=O)CCC)OC(C)=O
Agent: CCCS(=O)(=O)NCCCCCCC(=O)OCC
Agent: CCOC(=O)CCCCCCNS(C)(=O)=O
Product: CCCCC[C@@H](O)C#CCN(CCCCCCC(=O)O)S(C)(=O)=O

Procedure:
The synthesis of this compound is carried out as described in Example 1 except that, in Step A, the ethyl 7-(methanesulfonamido)heptanoate is replaced by an equimolar amount of ethyl 7-(propanesulfonamido)heptanoate (Example Q). The product of Step A is thus ethyl 7-[N-(4-acetoxynonyl)propanesulfonamido]heptanoate. The subsequent hydrolysis step yields 7-[N-(4-hydroxynonyl)propanesulfonamido]heptanoic acid (B).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:16](Br)[CH:17]=[CH:18][CH3:19].CC(C1C=C(C=CC=1O)C(C1C=CC=CC=1)=O)C=C>>[CH2:16]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:14][CH:15]=1)[CH:17]=[CH:18][CH3:19]
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: CC=CCBr
Agent: C=CC(C)c1cc(C(=O)c2ccccc2)ccc1O
Product: CC=CCOc1ccc(C(=O)c2ccccc2)cc1

Procedure:
4-crotyloxybenzophenone was prepared from 4-hydroxybenzophenone and crotyl bromide using the procedure of Example 23. Through Claisen rearrangement it was converted into 3-(α-methyl-allyl)-4-hydroxybenzophenone. The crude product (10.1 g) was acylated (procedure of Example 1) and purified by chromatography (40:60 hexane-methylene chloride on silica gel) to produce 12.25 g (91%) of oil.
Reaction SMILES: [CH2:1](OC1C=CC=CC=1)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:17]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:25]([N:24]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:1]/[CH:2]=[CH:3]/[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: C(=Cc1ccccc1)COc1ccccc1
Product: C(=C/c1ccccc1)\CN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.5 %

Procedure:
Following the general procedure using cinnamyloxybenzene (105 mg, 0.50 mmol) and dibenzylamine (148 mg, 0.75 mmol), the reaction was stirred for 0.5 h at rt. Column chromatography on silica gel (eluting with 8% EtOAc/hexanes) afforded the product as a pale yellow liquid (145 mg, 93%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.Br[CH2:12][CH2:13][CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+].O>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:12][CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[NH2:10])=[CH:5][CH:4]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: BrCCC1CCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Cl-]
Solvent: O
Product: NN(CCC1CCCC1)c1ccc(Cl)cc1
Temperature: 60 °C
Yield: 54.4 %

Procedure:
4-Chlorophenylhydrazine hydrochloride (1.65 g, 9 mmol) was added to a vigorously stirred mixture of tetra-n-butylammonium chloride (0.126 g, 0.45 mmol) in 50% aqueous sodium hydroxide (9 mL) followed by (2-bromo-ethyl)-cyclopentane (1.74 g, 9.9 mmol). The reaction was heated to 60° C. (oil bath temperature) for 8 h. The reaction was cooled, diluted with water (75 mL) and extracted with chloroform (3×30 mL). The combined organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure to an orange oil (0.69 g). The oil was subjected to column chromatography (silica gel, eluent: 50% dichloromethane in hexane followed by 70% dichloromethane in hexane) to give a yellow oil (1.17 g, 55%).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:9]1)=O)(C)(C)C.[C:19]([OH:25])([C:21]([F:24])([F:23])[F:22])=[O:20]>C(Cl)Cl>[F:22][C:21]([F:24])([F:23])[C:19]([OH:25])=[O:20].[NH:8]1[CH2:11][CH:10]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:9]1.[C:19]([OH:25])([C:21]([F:24])([F:23])[F:22])=[O:20]
Reactant: CC(C)(C)OC(=O)N1CC(Cc2ccccn2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(CC2CNC2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 257 mg (1.04 mmol) 3-pyridin-2-ylmethyl-azetidine-1-carboxylic acid tert-butyl ester was added 2 mL DCM and 2 mL TFA. The mixture was stirred at room temperature for 30 minutes. The solvent was evaporated to give the desired product as a TFA salt, which was used in the next step without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:11][CH3:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C([O-])([O-])=O.[K+].[K+].[C:19]1([CH:26]=[CH:25][CH:24]=[C:22]([OH:23])[CH:21]=1)[OH:20]>CN(C=O)C>[CH2:11]([N:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][CH2:2][O:20][C:19]1[CH:21]=[C:22]([OH:23])[CH:24]=[CH:25][CH:26]=1)[CH3:12]
Reactant: Oc1cccc(O)c1
Reactant: CCN(CCCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CCOc1cccc(O)c1)c1ccccc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 54.8 %

Procedure:
A mixture of compound 3a (500 mg, 2.7 mmol), K2CO3 (750 mg, 5.4 mmol), KI (90 mg, 0.54 mmol) in DMF (50 mL) was bubbled with argon for 10 min Resorcinol (600 mg, 5.4 mmol) was added to the mixture under argon. The reaction mixture was heated and stirred at 80° C. for 6 hr. After cooling to room temperature, the solvent was evaporated and the residue was quenched with 100 mL water. The mixture was adjusted pH to ˜7 with diluted hydrochloric acid. The mixture was then extracted with EtOAc and the combined organic layer was washed with water and then brine and dried over Na2SO4. The solvent was evaporated and the residue was purified by silica gel column chromatography with CH2Cl2 to provide the compound 18 (380 mg, 1.48 mmol, 55%) as a light-yellow oil. 1H NMR (DMSO-d6, 400 MHz) δ 9.38 (s, 1H), 7.15 (t, J=8 Hz, 2H), 7.04 (t, J=8 Hz, 1H), 6.70 (d, J=8 Hz, 2H), 6.57 (t, J=7.2 Hz, 1H), 6.32 (m, 3H), 4.02 (t, J=5.8 Hz, 2H), 3.64 (t, J=5.8 Hz, 2H), 3.44 (q, J=7 Hz, 2H), 1.10 (t, J=7 Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ 155.14, 151.95, 142.80, 125.44, 124.66, 111.56, 107.52, 103.46, 102.10, 97.43, 60.60, 44.77, 40.83, 7.34; HRMS (ESI, positive) m/z calcd. for C16H20NO2 [M+H]+: 258.1494, found: 258.1534.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:20]([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH3:20])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cccc(NS(=O)(=O)c2ccc(Br)cc2)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(N(C)S(=O)(=O)c2ccc(Br)cc2)c1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-bromo-N-(3-methoxyphenyl)benzenesulphonamide (0.5 g 1.46 mmol) and K2CO3 (0.5 g) in anhydrous DMF (7 ml) MeI (1 ml) was added and this was stirred at 50° C. for 0.5 h. The mixture was diluted to 50 ml with H2O and extracted in EtOAc (50 ml). The organic layer was washed with H2O, dried over MgSO4, filtered and the filtrate was passed through silica gel bead. The filtrate was evaporated to dryness to give the product (0.5 g; 96%), as a pale solid. 1H-NMR (CDCl3) 3.14 (5, 3H); 3.75 (s, 3H); 6.58 (broad d, 1H), 6.69 (t, 1H, J=2.20 Hz); 6.80 (dd, 1H, J=2.5, 8.34, Hz); 7.18 (tr, 1H, J=8.15 Hz); 7.40 (d, 2H, J=8.67 Hz); 7.58 (d, 2H, J=8.64 Hz).
Reaction SMILES: [NH2:1][C@H:2]([CH2:18][CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[C:20]([C:23]1[CH:27]=[C:26]([C:28](O)=[O:29])[NH:25][N:24]=1)(=[O:22])[CH3:21].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[C:20]([C:23]1[CH:27]=[C:26]([C:28]([NH:1][C@H:2]([CH2:18][CH3:19])[CH2:3][N:4]2[CH:8]=[CH:7][C:6]([C:9]3[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=3)=[N:5]2)=[O:29])[NH:25][N:24]=1)(=[O:22])[CH3:21]
Reactant: CC[C@@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(C(C)=O)n[nH]1

Procedure:
The compound was prepared using the method of Example 34(d). The reaction was conducted in 4 ml of DCM at RT overnight using (R)-4-(1-(2-aminobutyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.249 g; 0.91 mmol), 3-acetyl-1H-pyrazole-5-carboxylic acid (0.140 g; 0.91 mmol), 0.24 ml of DIPEA, HOBt (0.184 g; 1.36 mmol) and EDCI (0.261 g; 1.36 mmol) as starting materials. Purification was done by EtOH trituration. 1H-NMR (400 MHz; d6-DMSO): δ 0.90 (t, 3H), 1.42-1.67 (m, 2H), 2.51 (s, 3H), 4.19-4.42 (m, 3H), 6.91 (d, 1H), 7.32 (s, 1H), 7.79 (d, 1H), 7.85-8.07 (m, 3H), 8.38 (d, 1H), 14.14 (s, 1H).
Reaction SMILES: Br[C:2]1[C:6]2=[N:7][C:8]([C:11]3[O:12][C:13]([CH3:16])=[N:14][N:15]=3)=[CH:9][CH:10]=[C:5]2[O:4][CH:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1B(O)O>>[F:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[C:2]1[C:6]2=[N:7][C:8]([C:11]3[O:12][C:13]([CH3:16])=[N:14][N:15]=3)=[CH:9][CH:10]=[C:5]2[O:4][CH:3]=1
Reactant: OB(O)c1cc(F)ccc1F
Reactant: Cc1nnc(-c2ccc3occ(Br)c3n2)o1
Product: Cc1nnc(-c2ccc3occ(-c4cc(F)ccc4F)c3n2)o1
Yield: 43 %

Procedure:
In the same manner as in Example 132 and using 3-bromo-5-(5-methyl-1,3,4-oxadiazol-2-yl)furo[3,2-b]pyridine instead of 2-(3-bromo-1-benzofuran-5-yl)-5-methyl-1,3,4-oxadiazole, using (2,5-difluorophenyl)boronic acid instead of (4-fluorophenyl)boronic acid, and using [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex instead of tetrakis(triphenylphosphine)palladium(0), the title compound (yield 43%) was obtained as colorless crystals.
Reaction SMILES: OC1CN[C@H](C(O)=O)C1.[C:10]([C:12]1[CH:39]=[CH:38][C:15]([CH2:16][C:17]2([C:34]([O:36][CH3:37])=[O:35])[CH2:21][C@@H:20]([OH:22])[CH2:19][N:18]2[C:23](=[O:33])[CH2:24][C:25]2[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=2)=[CH:14][CH:13]=1)#[N:11].N1C=CN=C1.[Si:45](Cl)([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46]>CN(C=O)C.O>[Si:45]([O:22][C@H:20]1[CH2:19][N:18]([C:23](=[O:33])[CH2:24][C:25]2[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=2)[C:17]([CH2:16][C:15]2[CH:14]=[CH:13][C:12]([C:10]#[N:11])=[CH:39][CH:38]=2)([C:34]([O:36][CH3:37])=[O:35])[CH2:21]1)([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46]
Reactant: COC(=O)C1(Cc2ccc(C#N)cc2)C[C@@H](O)CN1C(=O)Cc1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C(O)[C@@H]1CC(O)CN1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1(Cc2ccc(C#N)cc2)C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)Cc1cc(Cl)cc(Cl)c1
Reaction time: 20 h
Yield: 89 %

Procedure:
A 4-Hydroxy-L-proline derivative, methyl (4R)-2-(4-cyanobenzyl)-1-[(3,5-dichlorophenyl)acetyl]-4-hydroxypyrrolidine-2-carboxylate 21 (10 mmol) and imidazole (1.5 g, 22.5 mmol) were suspended in DMF (25 mL) and treated with tert-butyl(dimethyl)silyl chloride (1.6 g, 10.5 mmol). The reaction was stirred for 20 h, poured into water (100 mL) and extracted with diethyl ether (Et2O) (4×30 mL). The organic extracts were combined and washed with 1N HCl aq. (2×30 mL), water (1×50 mL), sat. aqueous NaHCO3 solution (1×30 mL) and sat. aq. NaCl solution (1×30 mL). The organic layer was dried (MgSO4) and solvent removed in vacuo to give methyl (4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-cyanobenzyl)-1-[(3,5-dichlorophenyl)acetyl]pyrrolidine-2-carboxylate (23) (˜5 g, 90%), which was used as such in subsequent reaction without further purification, LCMS, (m/z) 561 (M++H).
Reaction SMILES: [CH:1]([C:4]1[N:8]([C:9]2[N:17]=[C:16]3[C:12]([N:13]=[C:14]([CH:19]=O)[N:15]3[CH3:18])=[C:11]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:10]=2)[C:7]2[CH:27]=[CH:28][CH:29]=[CH:30][C:6]=2[N:5]=1)([CH3:3])[CH3:2].[CH:31]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][C:35]1=[O:40])([CH3:33])[CH3:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:31]([N:34]1[CH2:39][CH2:38][N:37]([CH2:19][C:14]2[N:15]([CH3:18])[C:16]3[C:12]([N:13]=2)=[C:11]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[N:10]=[C:9]([N:8]2[C:7]4[CH:27]=[CH:28][CH:29]=[CH:30][C:6]=4[N:5]=[C:4]2[CH:1]([CH3:2])[CH3:3])[N:17]=3)[CH2:36][C:35]1=[O:40])([CH3:33])[CH3:32]
Reactant: CC(C)N1CCNCC1=O
Reactant: CC(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(C)C)C(=O)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.4 %

Procedure:
A mixture of 2-(2-isopropylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (0.15 g, 0.37 mmol), 1-isopropylpiperazin-2-one (0.078 g, 0.44 mmol) and 4 Å molecular sieves (0.372 g) in DCE (3 mL) was stirred for 3 h at room temperature. Sodium triacetoxyborohydride (0.157 g, 0.74 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, MeOH:EtOAc, gradient 0:100 to 10:90) to give 555 as an off-white solid (0.168 g, 84%). LCMS (Method I): RT=3.43 min, [M+H]+ 532.3. 1H NMR (400 MHz, DMSO-d): δ 7.93-7.89 (m, 1 H); 7.68-7.63 (m, 1 H); 7.28-7.23 (m, 2 H); 4.64-4.58 (m, 1 H); 4.29-4.21 (m, 4 H); 3.97-3.90 (m, 1 H); 3.90 (d, J=4.6 Hz, 2 H); 3.80 (s, 3 H); 3.78 (t, J=4.6 Hz, 4 H); 3.21-3.15 (m, 4 H); 2.78-2.75 (m, 2 H); 1.36 (d, J=6.8 Hz, 6 H); 1.05 (d, J=6.8 Hz, 6 H)
Reaction SMILES: [Br:1][C:2]1[C:3]([O:29][CH3:30])=[C:4]([C:15]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:28])(=[O:21])=[O:20])=[CH:16][CH:17]=1)[C:5]([O:7]CC1C=CC=CC=1)=[O:6].[OH-].[Li+].O1CCOCC1.Cl>O>[Br:1][C:2]1[C:3]([O:29][CH3:30])=[C:4]([C:15]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:28])(=[O:21])=[O:20])=[CH:16][CH:17]=1)[C:5]([OH:7])=[O:6]
Reactant: COc1c(Br)ccc(NS(=O)(=O)c2ccccc2F)c1C(=O)OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1c(Br)ccc(NS(=O)(=O)c2ccccc2F)c1C(=O)O

Procedure:
A mixture of Example 318C (150 mg, 0.3 mmol), lithium hydroxide (127 mg, 3.0 mmol), dioxane (3 mL), and water (1.5 mL) was sealed in a vial and microwaved at 160° C. for 15 minutes. The mixture was acidified to pH 1 with 1M HCl and extracted with ethyl acetate. The ethyl acetate was washed with brine, dried (Na2SO4), filtered, and concentrated to an oil which was triturated with 1:1 hexanes/diethyl ether to provide the desired product. MS (ESI(+)) m/e 404, 406 (M+H)+, 421, 423 (M+NH4)+, 426, 428 (M+Na)+; (ESI(−)) m/e 402, 404 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 13.48 (br s, 1H), 10.34 (br s, 1H), 7.72 (m, 2H), 7.63 (d, 1H), 7.41 (m, 1H), 7.34 (m, 1H), 6.89 (d, 1H), 3.75 (s, 3H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].CCN(CC)CC.Cl[C:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[OH:8][CH2:7][C@H:5]([NH:6][C:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:4]([O:3][CH3:2])=[O:9]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 93.2 %

Procedure:
(U. Larsson and R. Carlson, Acta Chem. Scand. 1994, 48, 511-516; M. Meyer et al., J. Am. Chem. Soc. 1997, 119, 10093-10103). Using the preceding procedure and using L-serine methyl ester hydrochloride (20.00 g, 0.13 mol), Et3N (35.82 mL, 0.26 mol) and TrCl (36.53 g, 0.13 mol) gave 43.80 g (94%) of crude desired product as a pale yellow crystalline solid: Rf=0.50 (1/1 EtOAc/hexanes); 1H NMR (CDCl3) δ 2.31 (br s, 1H), 2.84-3.02 (br m, 1H), 3.29 (s, OCH3), 3.50-3.59 (m, CHH′OH, CH), 3.63-3.74 (m, CHH′OH), 7.18-7.29 (m, 9 PhH), 7.48-7.50 (m, 6 PhH).