Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[O:20])[CH2:11]1)=[O:7])(C)(C)C.[NH2:27][C:28]1[C:36]([Cl:37])=[CH:35][C:31](C(O)=O)=[C:30]([O:38][CH3:39])[CH:29]=1>>[NH2:27][C:28]1[C:36]([Cl:37])=[CH:35][C:31]([C:6]([NH:8][CH2:9][CH:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:21]3[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=3)=[O:20])[CH2:11]2)=[O:7])=[C:30]([O:38][CH3:39])[CH:29]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCCNC(=O)c2ccncc2)C1
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCNC(=O)c2ccncc2)C1

Procedure:
N-(3-(3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)propyl)-4-pyridinecarboxamide (0.90 g) as starting compound was reacted and treated in the same manner as in Example 67 using 4-amino-5-chloro-2-methoxybenzoic acid (0.50 g) to give 4-amino-5-chloro-2-methoxy-N-(1-(3-(4-pyridinecarbonylamino)propyl)pyrrolidin-3-ylmethyl)benzamide.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH2:14][N:15]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:16]2[C:25]3[N:26]=[C:27]([CH2:29][O:30][CH2:31][CH2:32][OH:33])[NH:28][C:24]=3[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>C(Cl)Cl>[C:8]1([CH2:14][N:15]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:16]2[C:25]3[N:26]=[C:27]([CH2:29][O:30][CH2:31][CH2:32][O:33][S:42]([CH3:41])(=[O:44])=[O:43])[NH:28][C:24]=3[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCOCc1nc2c(N(Cc3ccccc3)Cc3ccccc3)nc3ccccc3c2[nH]1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCOCc1nc2c(N(Cc3ccccc3)Cc3ccccc3)nc3ccccc3c2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.9 %

Procedure:
Triethylamine (0.17 mL, 1.25 mmole) was added to a solution of N,N-bis(phenylmethyl)-2-(2-hydroxyethoxy)methyl-1H-imidazo[4,5-c]quinolin-4-amine (0.5 g, 1.14 mmole) in methylene chloride (20 mL). Methanesulfonyl chloride (0.09 mL, 1.14 mmole) was added and the reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was diluted with methylene chloride, washed with water, dried over magnesium sulfate and then concentrated under vacuum to provide 0.6 g of N,N-bis(phenylmethyl)-2-(2-methylsulfonyloxyethoxy)methyl-1H-imidazo[4,5-c]quinolin-4-amine.
Reaction SMILES: [I-].[CH2:2]([N+:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:7]=1[CH3:13])[CH2:3][CH2:4][CH3:5].[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([O:24][CH3:25])=[C:19]([CH:23]=1)[C:20](Cl)=[O:21]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:2]([N:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8]/[C:7]/1=[CH:13]\[C:20]([C:19]1[CH:23]=[C:15]([Cl:14])[CH:16]=[CH:17][C:18]=1[O:24][CH3:25])=[O:21])[CH2:3][CH2:4][CH3:5]
Reactant: CCCC[n+]1c(C)sc(C)c1C
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: [I-]
Solvent: ClCCl
Product: CCCCN1C(C)=C(C)S/C1=C\C(=O)c1cc(Cl)ccc1OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of Example 1A (780 mg, 2.5 mmol) and 5-chloro-2-methoxy-benzoyl chloride (515 mg, 2.5 mmol) in CH2Cl2 (25 mL) under N2 atmosphere at 0° C. was added 4-dimethylaminopyridine (DMAP) (1.22 g. 10 mmol) and the mixture was allowed to warm to room temperature. The mixture was stirred for 20 hours, washed sequentially with saturated sodium bicarbonate and brine. The methylene chloride solution was dried (anhydrous MgSO4), filtered and concentrated under reduced pressure. The residue was purified by chromatography over silica gel (hexane-EtOAc 1:1 as eluent) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 0.96 (t, J=7 Hz, 3H), 1.39 (sextet, J=7 Hz, 2H), 1.66 (quintet, J=7 Hz, 2H), 2.15 (s, 3H), 2.20 (s, 3H), 3.85 (s, 3H), 3.90 (t, J=7 Hz, 2H), 6.54 (s, 1H), 7.10 (d, J=9 Hz, 1H), 7.40 (dd, J=9 Hz, 3 Hz, 1H), 7.65 (d, J=3 Hz, 1H); MS (ESI) m/z 352 (M+H)+. Anal calcd for C18H22ClNO2S: C, 61.44; H, 6.30; N, 3.98. Found: C, 61.34; H, 6.17; N, 3.86.
Reaction SMILES: [N:1]1([C:10]2[S:11][C:12]([C:27]([NH2:29])=[O:28])=[C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]([F:26])([F:25])[F:24])[N:14]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.ClC1SC(C(N)=O)=C(OCC2C=CC=CC=2C(F)(F)[F:45])N=1.FC1C=CC2N=CNC=2C=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:45][C:7]1[CH:8]=[CH:9][C:4]2[N:3]=[CH:2][N:1]([C:10]3[S:11][C:12]([C:27]([NH2:29])=[O:28])=[C:13]([O:15][CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[C:23]([F:26])([F:25])[F:24])[N:14]=3)[C:5]=2[CH:6]=1
Reactant: NC(=O)c1sc(-n2cnc3ccccc32)nc1OCc1ccccc1C(F)(F)F
Reactant: NC(=O)c1sc(Cl)nc1OCc1ccccc1C(F)(F)F
Agent: Fc1ccc2nc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1sc(-n2cnc3ccc(F)cc32)nc1OCc1ccccc1C(F)(F)F

Procedure:
Following the procedure described above for the preparation of 2-(1H-benzimidazol-1-yl)-4-({[2-(trifluoromethyl)phenyl]methyl}oxy)-1,3-thiazole-5-carboxamide using the following materials: 2-chloro-4-({[2-(trifluoromethyl)phenyl]methyl}oxy)-1,3-thiazole-5-carboxamide (0.050 g, 0.14 mmol), 5-fluorobenzimidazole (0.011 g, 0.08 mmol), K2CO3 (0.011 g, 0.08 mmol) and DMF (4 mL). Data for 6 regioisomers: 1H NMR (400 MHz, CDCl3) δ 8.46 (s, 1H), 7.82-7.74 (m, 2H), 7.69-7.58 (m, 3H), 7.54-7.50 (m, 1H), 7.16 (td, J=9.1, 2.4 Hz, 1H), 6.80 (bs, 1H), 5.82 (s, 2H), 5.76 (bs, 1H). MS m/z 437 (m+1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[C:16]2[O:15][C:14](=[O:17])[NH:13][C:12]=2[CH:11]=[CH:10][CH:9]=1.[C:18](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[CH3:18][N:13]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([O:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[C:16]=2[O:15][C:14]1=[O:17]
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]c2cccc(OC3CCCCO3)c2o1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)oc2c(OC3CCCCO3)cccc21
Reaction time: 3 h
Yield: 94.1 %

Procedure:
To a suspension of 7-(tetrahydropyran-2-yloxy)-2(3H)-benzoxazolone (300 mg) and potassium carbonate (529 mg) in dimethylformamide (3 ml) was added methyl iodide at ambient temperature, and the mixture was stirred for 3 hours under nitrogen atmosphere. Water was added to the reaction mixture, and the resulting precipitates were collected by filtration to give 3-methyl-7-(tetrahydropyran-2-yloxy)-2(3H)-benzoxazolone (299 mg).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:16]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([CH:32]=O)[CH2:28][CH2:27]1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[CH2:16]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([CH:32]2[O:4][CH2:1][CH2:2][O:3]2)[CH2:28][CH2:27]1)=[O:25])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: OCCO
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)N1CCC(C2OCCO2)CC1
Yield: 78 %

Procedure:
Ethylene glycol (5 ml) and a catalytic amount of p-toluenesulfonic acid were added to 4-formyl-piperidine-1-carboxylic acid benzyl ester from Example E33.2 (5.6 g, 22.6 mmol) in toluene (100 ml) and the mixture was heated at reflux under Dean and Stark conditions for 2.5 h. Solvents were removed in vacuo and the residue was redissolved in EtOAc, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 50% EtOAc:50% pet. ether) to yield the title compound (5.14 g, 78%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C(N(C(C)C)CC)(C)C.ClC(Cl)(O[C:38](=[O:44])OC(Cl)(Cl)Cl)Cl.[NH2:46][C:47]1[S:48][C:49]([CH3:52])=[N:50][N:51]=1>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:38]([NH:46][C:47]2[S:48][C:49]([CH3:52])=[N:50][N:51]=2)=[O:44])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: Cc1nnc(N)s1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4nnc(C)s4)c(C)c3C)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (100 mg) was dissolved in chloroform (5 ml) and diisopropylethylamine (0.5 ml) to prepare a solution. A solution of triphosgene (100 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 15 min. Next, 2-amino-5-methyl-1,3,4-thiadiazole (43 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Distilled water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine and was dried over sodium sulfate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].S(=O)(=O)(O)O.[N+:18]([O-:21])([OH:20])=[O:19]>C(O)(=O)C>[Cl:1][C:2]1[C:3]([C:9]([F:10])([F:11])[F:12])=[CH:4][C:5]([OH:8])=[C:6]([N+:18]([O-:20])=[O:19])[CH:7]=1.[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:18]([O-:21])=[O:19])[C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1c(O)ccc(Cl)c1C(F)(F)F
Product: O=[N+]([O-])c1cc(Cl)c(C(F)(F)F)cc1O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a mixture of 5.0 g of 4-chloro-3-trifluoromethylphenol and 20 ml of acetic acid, 1.5 ml of concentrated sulfuric acid and then 2.6 g of 69% nitric acid were added dropwise while ice-cooling. To the reaction mixture, 3 ml of concentrated sulfuric acid was added dropwise at room temperature, and stirred for three hours. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The combined organic layers were washed with water, a saturated aqueous solution of sodium hydrogencarbonate and a saturated sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 2.3 g of 4-chloro-2-nitro-5-trifluoromethylphenol, 1.57 g of 4-chloro-2-nitro-3-trifluoromethylphenol.
Reaction SMILES: [Cl-].[CH3:2][C:3]1[O:7][C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)=[N:5][C:4]=1[CH2:18][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[H-].[Na+].[CH:40]([C:42]1[CH:51]=[CH:50][C:45]([C:46]([O:48][CH3:49])=[O:47])=[CH:44][CH:43]=1)=O>CN(C=O)C>[CH3:2][C:3]1[O:7][C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)=[N:5][C:4]=1/[CH:18]=[CH:40]/[C:42]1[CH:51]=[CH:50][C:45]([C:46]([O:48][CH3:49])=[O:47])=[CH:44][CH:43]=1
Reactant: Cc1oc(-c2ccc3ccccc3c2)nc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(/C=C/c2nc(-c3ccc4ccccc4c3)oc2C)cc1
Temperature: 25 °C
Yield: 78.9 %

Procedure:
[5-Methyl-2-(2-naphthyl)-4-oxazolylmethyl]triphenylphosphonium chloride (18.4 g) was suspended in DMF (200 ml), and sodium hydride (60% in oil, 1.42 g) was added little by little at 0° C. After mixture stirring at room temperature for1 hour, methyl 4-formylbenzoate (5.80 g) was added, followed by stirring for 3 hours. The reaction mixture was poured over ice-water; the resulting crystal was collected by filtration. The crystal was then purified by silica gel column chromatography to yield methyl (E)-4-[2-[5-methyl-2-(2-naphthyl)-4-oxazolyl]vinyl]benzoate (10.3 g, 79%) from the fraction eluted with ethyl acetate-chloroform (5:95, v/v), which was then recrystallized from dichloromethane-methanol to yield light yellow prisms having a melting point of 216°-217° C.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[CH2:9]([NH:16][C:17](=[O:24])[C@H:18]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH2:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.Br[CH2:33][C:34]([C:36]1[CH:41]=[CH:40][C:39]([Br:42])=[CH:38][CH:37]=1)=[O:35]>C1COCC1>[Br:42][C:39]1[CH:40]=[CH:41][C:36]([C:34](=[O:35])[CH2:33][N:1]2[CH2:8][CH2:7][CH2:6][C@H:2]2[C:3]([N:16]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:17](=[O:24])[C@H:18]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH2:19])=[O:5])=[CH:37][CH:38]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)c1ccc(Br)cc1
Yield: 67 %

Procedure:
Using the procedure described in Example 5, treatment of a solution of L-proline-L-isoleucine benzylamide (57 mg, 0.18 mmol), with triethylamine (130 uL, 0.93 mmol, 5.0 eq), and 2,-4'-dibromoacetophenone (63 mg, 0.22 mmol, 1.2 eq) in THF (7 mL), provided a crude product. A portion of the product was purified by preparative TLC to provide 62 mg (67%) of L-isoleucine, N-[1-(2-(4-bromophenyl)-2-oxoethyl)-L-prolyl] benzylamide.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:27]([F:30])([F:29])[F:28])=[N:4][N:5]([CH2:8][CH:9]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([Cl:25])=[CH:19][C:18]=3[Cl:26])[CH2:13][CH2:12]2)[NH2:10])[C:6]=1[CH3:7].C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:27]([F:30])([F:29])[F:28])=[N:4][N:5]([CH2:8][CH:9]([NH:10][S:39]([CH3:38])(=[O:41])=[O:40])[CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([Cl:25])=[CH:19][C:18]=3[Cl:26])[CH2:13][CH2:12]2)[C:6]=1[CH3:7]
Reactant: COc1cc(N2CCC(C(N)Cn3nc(C(F)(F)F)c(Cl)c3C)CC2)c(Cl)cc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(N2CCC(C(Cn3nc(C(F)(F)F)c(Cl)c3C)NS(C)(=O)=O)CC2)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
A 25-mL round bottom flask was charged with 2-(4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)-1-(1-(2,4-dichloro-5-methoxyphenyl)piperidin-4-yl)ethanamine (23 mg, 0.047 mmol), anhydrous DCM (2 mL), and triethylamine (0.016 mL, 0.118 mmol). The resultant solution was treated with methanesulfonyl chloride (5.50 μL, 0.071 mmol) and stirred at RT for 1 h. After this time, the mixture was concentrated on a rotary evaporator, and the resultant residue was partitioned between EtOAc and saturated sodium bicarbonate. The organic phase was washed with brine, dried (MgSO4) and concentrated to give the crude product. The crude product was purified by flash chromatography (4 g silica gel cartridge, EtOAc/hexanes) to afford Example 4 g (22 mg, 0.039 mmol, 82% yield). LC-MS: 563.0 (M+H); tR=4.18 min (method c). 1H-NMR (400 MHz, CDCl3) δ ppm 7.16 (1 H, s), 6.49 (1 H, s), 4.59 (1 H, d, J=9.23 Hz), 4.20-4.26 (1 H, m), 4.09-4.15 (1 H, m), 3.76-3.81 (3 H, m), 3.59 (1 H, d, J=6.15 Hz), 3.30-3.39 (2 H, m), 2.65 (3 H, s), 2.48-2.54 (2 H, m), 2.23-2.32 (3 H, m), 1.91 (1 H, s), 1.75-1.81 (1 H, m), 1.55-1.62 (2 H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:30])[CH2:21][O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:15][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]1=[O:14])=[O:5].C(OC)(OC)OC.[C:38]1(C)C=CC(S(O)(=O)=O)=C[CH:39]=1.O>CCOCC>[CH2:23]([O:22][CH2:21][C:20]([NH:19][C:16]1[CH:15]=[C:3]2[C:2](=[CH:18][CH:17]=1)[N:1]=[C:38]([CH3:39])[N:6]([CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]1=[O:14])[C:4]2=[O:5])=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1ccc(NC(=O)COCc2ccccc2)cc1C(=O)NC1CCC(=O)NC1=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COC(OC)OC
Solvent: CCOCC
Product: Cc1nc2ccc(NC(=O)COCc3ccccc3)cc2c(=O)n1C1CCC(=O)NC1=O
Yield: 118.9 %

Procedure:
A solution of 2-amino-5-(2-benzyloxy-acetylamino)-N-(2,6-dioxo-piperidin-3-yl)-benzamide (0.26 g, 0.6 mmol) and trimethyl orthoformate (2 mL) and p-toluene sulfonic acid (60 mg) in acetonotrile (10 mL) was heated to reflux for 21 hours. To the mixture, was added water (25 mL) and ether (25 mL). The suspension was filtered and washed with water (50 mL) and ethyl acetate (50 mL) to give 2-benzyloxy-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-yl]-acetamide as a white solid (180 mg, 72% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 2.87 min (99.3%); mp: 248-250° C.; 1H NMR (DMSO-d6) δ 2.14-2.16 (m, 1H, CHH), 2.62-2.87 (m, 3H, CH2, CHH), 4.15 (s, 2H, CH2), 4.64 (s, 2H, CH2), 5.49-5.50 (m, 1H, NCH), 7.31-7.41 (m, 5H, Ar), 7.68 (d, J=9 Hz, 1H, Ar), 8.06-8.10 (m, 1H, NH), 8.28 (s, 1H, CH), 8.55 (br, 1H, Ar), 10.24 (s, 1H, NH), 11.16 (s, 1H, NH; 13C NMR (DMSO-d6) δ 23.05, 31.48, 58 (br), 69.87, 72.92, 115.69, 122.15, 127.30, 128.16, 128.28, 128.34, 128.77, 137.98, 138.14, 144.06, 146.48, 160.10, 168.93, 170.43, 172.90; LCMS: MH=421; Anal Calcd for C22H20N4O5: C, 62.85; H, 4.79; N, 13.33. Found: C, 60.60; H, 4.29; N, 12.54.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH2:2]1.C([Li])CCC.[CH2:12]([SiH:16]([CH2:23]F)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:13][CH:14]=[CH2:15]>C1COCC1>[CH2:12]([SiH:16]([CH2:23][CH:2]1[S:3][CH2:4][CH2:5][CH2:6][S:1]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:13][CH:14]=[CH2:15]
Reactant: C1CSCSC1
Reactant: C=CCC[SiH](CF)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCC[SiH](CC1SCCCS1)c1ccccc1
Reaction time: 2 h

Procedure:
To a solution of 1,3-dithiane (11.1 g, 91.9 mmol) in THF (150 mL) at -78° C. was added dropwise over 10 min n-butyllithium (1.6M in hexane, 76.6 mmol), and the solution was stirred for 2 h under argon. A solution of 42 (11.9 g, 61.3 mmol) in THF (120 mL) was added dropwise over 30 min, and the mixture was stirred for 3 h at -78° C. and overnight at rt. The reaction mixture was quenched with water (100 mL) and extracted thrice with 100-mL portions of EtOAc. The combined organic extracts were washed with saturated aqueous NaCl, dried over Na2SO4, and concentrated. Flash chromatography over silica gel (1/9 EtOAc:hexane) gave 43 contaminated with 1,3-dithiane. The latter was removed by sublimation (54° C., 8.0 mm Hg) to provide pure 43 as a yellow oil (9.0 g, 50% for three steps from dichlorosilane):R.function. =0.55 (1/9 EtOAc:hexane); 1H NMR (300 MHz, CDCl3) δ7.63-7.61 (m, 2H), 7.42-7.38 (m, 3H), 5.97-5.84 (m, 1H), 5.06-4.90 (m, 2H), 3.95 (s, 1H) 2.93-2.83 (m, 2H), 2.72-2.67 (m, 2H) 2.21-1.97 (m, 4H), 1.18-1.09 (m, 2H), 0.49 (s, 3H); 13C NMR (75 MHz, CDCl3) δ141.0, 134.5, 134.1, 129.9, 127.9, 113.2, 32.9, 31.1, 31.0, 27.2, 25.8, 10.8, -7.0; MS (FAB) m/e (rel. intentsity) 293 (MH+, 23), 239 (21), 175 (20), 159 (9), 149 (58), 121 (100), 119 (37), 115 (23), 105 (34), 97 (28), 92 (22); HRMS (FAB) calcd for C15H22S2Si: 293.0854, found: 293.0861. Anal. Calcd for C15H22S2Si: C, 61.16; H, 7.53. Found C, 61.31; H, 7.74.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]=[CH2:16])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH3:17].B1C2CCCC1CCC2.C1C[O:30]CC1>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:30])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH3:17]
Reactant: C=Cc1ccc(Oc2ccc(C)c(Cl)c2)cc1
Reactant: C1CCOC1
Agent: B1C2CCCC1CCC2
Product: Cc1ccc(Oc2ccc(CCO)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
To the solution of 2-chloro-4-[(4-ethenylphenyl)oxy]-1-methylbenzene (2.8 g, 11.44 mmol) in dry THF (20 mL), was added 9-BBN (30 mL, 15.00 mmol) at 0° C. and stirred at room temperature overnight. Then the reaction mixture was quenched by addition of water (3 mL), followed by aq. NaOH (3M, 15 mL), and 30% H2O2 (15 mL). The reaction mixture was heated at 50° C. for 4 h. Then the THF and some water were removed under reduced pressure, and the residue was diluted with EA (30 mL). The organic layer was washed with water and brine, dried over Na2SO4 and concentrated. Purification via flash chromatography afforded the title compound (2 g, 66.5% yield). LCMS: rt=3.51 min, [M+H+]=245
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[NH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]2[N:23]([C:37]3[C:38]4[C@H:45]([CH3:46])[CH2:44][C@@H:43]([OH:47])[C:39]=4[N:40]=[CH:41][N:42]=3)[CH2:24][C@@:25]3([CH2:29][CH2:28][N:27]([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:26]3)[C:18]=12.[CH3:48][C:49]([CH3:51])=O>ClCCCl.C(Cl)Cl>[CH2:30]([N:27]1[CH2:28][CH2:29][C@:25]2([C:18]3[C:19](=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][NH:15][CH:49]([CH3:51])[CH3:48])[N:23]([C:37]3[C:38]4[C@H:45]([CH3:46])[CH2:44][C@@H:43]([OH:47])[C:39]=4[N:40]=[CH:41][N:42]=3)[CH2:24]2)[CH2:26]1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3C[C@@]4(CCN(Cc5ccccc5)C4)c4c(CN)cccc43)c21
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)NCc1cccc2c1[C@]1(CCN(Cc3ccccc3)C1)CN2c1ncnc2c1[C@H](C)C[C@H]2O
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
NaBH(OAc)3 (57.6 mg, 0.272 mmol) was added to a solution of (5R,7R)-4-((S)-4-(aminomethyl)-1′-benzylspiro[indoline-3,3′-pyrrolidine]-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol (40 mg, 0.091 mmol), acetone (52.6 mg, 0.906 mmol) in DCE (1.0 mL), and the resulting solution was stirred at ambient temperature for 8 hours. The reaction mixture was diluted with DCM and washed with 25% NaOH. The aqueous layer was separated and extracted with DCM (3×). The combined organic layers were dried (Na2SO4) and concentrated to give (5R,7R)-4-((S)-1′-benzyl-4-((isopropylamino)methyl)spiro[indoline-3,3′-pyrrolidine]-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol (40.0 mg, 0.083 mmol, 91%). LCMS (APCI+) M+H+ 484 (100%); Rt=2.64 min.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](F)=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH:19]([CH3:21])[CH3:20])[N:3]=1.[CH3:22][S-:23].[Na+].C[S-].O>CS(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([S:23][CH3:22])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH:19]([CH3:21])[CH3:20])[N:3]=1
Reactant: CC(C)c1cc(-c2ccc(F)c3ccccc23)nc(N)n1
Reactant: C[S-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CSc1ccc(-c2cc(C(C)C)nc(N)n2)c2ccccc12
Reaction time: 2 h
Yield: 98 %

Procedure:
2-Amino-4-(4-fluoronaphth-1-yl)-6-isopropyl-pyrimidine (0.281 g) was dissolved in dimethyl sulphoxide (DMSO) (10 mL) and sodium thiomethoxide (0.070 g) was added. The reaction mixture was stirred at room temperature for 2 hours at which time another equivalent of thiomethoxide was added and the reaction stirred for another 2 hours. The mixture was poured into water (100 mL) and the product was extracted into ethyl acetate/hexane (3×50 mL). The combined organic extracts were dried over sodium sulfate and evaporated to dryness. The reaction product was purified by column chromatography on silica gel, eluting with hexane/ethyl acetate to give 2-amino-4-(4-methylthionaphth-1-yl)-6-isopropylpyrimidine (0.303 g), m.p. 139-140° C.
Reaction SMILES: [C-:1]#[N:2].C([Al+]CC)C.[CH3:8][O:9][C:10]1[CH:28]=[CH:27][C:13]2[O:14][CH2:15][C@@H:16]3[C:18]([C:23]([O:25][CH3:26])=[O:24])([C:19]([O:21][CH3:22])=[O:20])[C@@H:17]3[C:12]=2[CH:11]=1.Cl>C1(C)C=CC=CC=1>[CH3:8][O:9][C:10]1[CH:28]=[CH:27][C:13]2[O:14][CH2:15][C@@H:16]([CH:18]([C:23]([O:25][CH3:26])=[O:24])[C:19]([O:21][CH3:22])=[O:20])[C@H:17]([C:1]#[N:2])[C:12]=2[CH:11]=1
Reactant: [C-]#N
Reactant: COC(=O)C1(C(=O)OC)[C@@H]2c3cc(OC)ccc3OC[C@@H]21
Agent: CC[Al+]CC
Agent: Cl
Solvent: Cc1ccccc1
Product: COC(=O)C(C(=O)OC)[C@@H]1COc2ccc(OC)cc2[C@H]1C#N
Reaction time: 2 h

Procedure:
Under nitrogen 425 ml of diethylaluminum cyanide (1.5M in toluene) is added to 93 g cis-dimethyl 1,1a,2,7b-tetrahydro-6-methoxybenzo[b]cyclopropa[d]pyran-1,1-dicarboxylate in 1250 ml toluene. After stirring 2 h at 25°, the reaction mixture is poured into 1250 ml 17.4% HCl. The aqueous phase is separated and extracted with three 100 ml portions of ethyl acetate and three 200 ml portions of CH2Cl2. The combined organic phases are washed with 500 ml 2N HCl, 500 ml brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give trans(±)-dimethyl 2-(3,4-dihydro-6-methoxy-4-cyano-2H-[1]benzopyran-3-yl)-propanedioate.