Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([O:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]2[C:20](=[O:21])[CH2:19][O:18][C:17]2=[O:22])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH3:23]>O1CCCC1.CO>[C:1]1([O:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:22])[O:18][CH2:19][C:20]([NH2:23])=[O:21])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: N
Reactant: O=C1COC(=O)N1CCCCOc1cccc2ccccc12
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)COC(=O)NCCCCOc1cccc2ccccc12
Yield: 46.2 %

Procedure:
1.50 g (5.0 mmol) of 3-[4-(1-naphthalenyl-oxy)butyl]-1,3-oxazolidine-2,4-dione, prepared in Step 3.1., are dissolved in a mixture of 10 ml of tetrahydrofuran and 28 ml of a 7N solution of ammonia (200 mmol) in methanol. The solution is left to react overnight at ambient temperature and then evaporated to dryness. The product is purified by chromatography on silica gel, eluting with a 97/3 mixture of dichloromethane and methanol. It is recrystallized from ethyl acetate and then washed with diethyl ether, to give 0.73 g of product in white solid form.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][N:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=O)=O.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CO>[CH2:20]([N:8]1[CH2:9][CH2:10][N:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][C@@H:7]1[CH2:6][NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1ccccc1
Reactant: CS(=O)(=O)OC[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Solvent: CO
Product: c1ccc(CN2CCN(Cc3ccccc3)[C@@H](CNc3ccccc3)C2)cc1
Temperature: 140 °C
Yield: 73.2 %

Procedure:
A 20-mL vial was charged ((2R)-1,4-dibenzyl-2-piperazinyl)methyl methanesulfonate (1.01 g, 2.70 mmol, Example 184, Step 1), aniline (1.30 mL, 14.3 mmol, Alfa Aesar, Ward Hill, Mass.) and MeOH (12 mL). The reaction mixture was sealed and heated at 140° C. for 30 min in an Initiator microwave reactor (Biotage AB, Inc., Uppsala, Sweden). The mixture was allowed to cool to room temperature and then concentrated in vacuo. The crude product was purified by column chromatography (50 g of silica gel, (2 M NH3 in MeOH) in CH2Cl2 0 to 5%) to afford N-(((2S)-1,4-dibenzyl-2-piperazinyl)methyl)aniline (0.734 g) as an orange oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[N:16][N:15]4[C:18]([C:21]5[CH:22]=[C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]([F:35])([F:34])[F:33])=[O:29])[CH:24]=[CH:25][CH:26]=5)=[CH:19][N:20]=[C:14]4[CH:13]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1.[N:36]1([C:41](Cl)=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37]1>>[N:36]1([C:41]([N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[CH:11]=[C:10]([C:12]4[CH:17]=[N:16][N:15]5[C:18]([C:21]6[CH:22]=[C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]([F:33])([F:35])[F:34])=[O:29])[CH:24]=[CH:25][CH:26]=6)=[CH:19][N:20]=[C:14]5[CH:13]=4)[CH:9]=[N:8]3)[CH2:3][CH2:2]2)=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cnn(C5CCNCC5)c4)cnn23)c1
Reactant: O=C(Cl)N1CCCC1
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cnn(C5CCN(C(=O)N6CCCC6)CC5)c4)cnn23)c1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 30 (Step 6) starting from N-{3-[7-(1-piperidin-4-yl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea and 1-pyrrolidinecarbonyl chloride (Aldrich, Cat. No. 206350). LCMS (M+H)+: m/z=582.3.
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](Cl)=[N:17][OH:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([C:22]1[C:23]([NH2:29])=[N:24][C:25]([NH2:28])=[CH:26][CH:27]=1)#[CH:21].C(N(CC)CC)C>O1CCCC1>[O:1]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[CH:21]=[C:20]([C:22]3[C:23]([NH2:29])=[N:24][C:25]([NH2:28])=[CH:26][CH:27]=3)[O:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ON=C(Cl)Cc1ccc(COc2ccccc2)cc1
Reactant: C#Cc1ccc(N)nc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(Cc3ccc(COc4ccccc4)cc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.7 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (4-phenoxymethyl-phenyl)-acetohydroximoyl chloride (150 mg, 0.545 mmol) described in Manufacturing Example 86-1-5 and 3-ethynyl-pyridin-2,6-diamine (46.3 mg, 0.348 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (104 μL, 0.747 mmol), which was stirred for 1 hour at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound (45 mg, 22%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][C:11]([OH:14])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[CH2:15]([O:17][C:18]([C:20]1([CH2:34]I)[CH2:24][CH2:23][N:22]([C:25](=[O:33])[C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[CH2:21]1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1([CH2:34][O:14][C:11]2[CH:10]=[N:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[CH:13][N:12]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:33])[C:26]2[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=2)[CH2:21]1)=[O:19])[CH3:16]
Reactant: Oc1cnc(-c2ccc(Cl)cc2)cn1
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccc(Cl)cc2)C1
Product: CCOC(=O)C1(COc2cnc(-c3ccc(Cl)cc3)cn2)CCN(C(=O)c2ccc(Cl)cc2)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 5-(4-chloro-phenyl)-pyrazin-2-ol (Preparation 25) and 1-(4-chloro-benzoyl)-3-iodomethyl-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 13) to afford the racemate as a pale yellow solid (42 mg, 20%)
Reaction SMILES: [ClH:1].[C:2]([NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][CH:10]([NH:16][CH2:17][CH2:18][CH3:19])[CH2:11]2)(=[O:4])[CH3:3].[CH2:20](I)[CH2:21][CH2:22][CH3:23].C(=O)([O-])O.[Na+]>CN(C)C=O.O1CCCC1>[ClH:1].[C:2]([NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][CH:10]([N:16]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:17][CH2:18][CH3:19])[CH2:11]2)(=[O:4])[CH3:3]
Reactant: CCCCI
Reactant: CCCNC1CCc2c(cccc2NC(C)=O)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCCN(CCC)C1CCc2c(cccc2NC(C)=O)C1
Reaction time: 8 h

Procedure:
2.83 g (0.010 mol) of 5-acetylamino-2-n-propylamino-tetraline-hydrochloride (Example 4.1.1), 2.76 g (0.015 mol) of n-butyliodide and 1.68 g (0.020 mol) of sodium hydrogen carbonate are refluxed in a mixture of 20 ml of absolute dimethylformamide and 30 ml of absolute tetrahydrofuran for 48 hours with stirring (moment of complete reaction determined by thin layer chromatography). The reaction mixture is concentrated by rotary evaporation, finally at 95° C. under a complete water-jet vacuum. The residue is shaken with 50 ml of methylene chloride and 50 ml of water and the aqueous phase separated is extracted twice more with 15 ml of methylene chloride. The combined extracts are washed with 20 ml of water, dried with sodium sulphate and concentrated by rotary evaporation, finally at 90° C. under a complete water-jet vacuum. The residue is dissolved with 10 ml of ethanol and the solution is acidified with 4.0 ml of 2.5 N ethanolic hydrochloric acid (0.0I mol HCl). After the addition of diethylether until turbidity is just starting, the title compound crystallises. After standing overnight it is suction filtered at 5° C., washed with a mixture of ethanol and ether and dried at 80° C. until a constant weight is obtained. Yield 2.56 g (75.5% of theory), melting point 217° C. After recrystallisation from methanol/ether the melting point does not change.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8](=[O:30])[NH:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.Cl[C:32]([F:38])([F:37])C(OC)=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([O:30][CH:32]([F:38])[F:37])=[N:9][N:10]([C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:4]=2[CH:3]=1
Reactant: O=c1[nH]n(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Reactant: COC(=O)C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)Oc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A solution of 6-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridin-3 (2H)-one (Intermediate 3B; 368 mg, 0.893 mmol) and methyl 2-chloro-2,2-difluoroacetate (0.5 mL, 4.74 mmol) in DMF (2 mL) was charged with K2CO3 (2.5 g, 18.09 mmol) at room temperature. The reaction was stirred at 80° C. for 30 min. The reaction mixture was diluted with H2O and filtered to give 6-chloro-3-(difluoro-methoxy)-1-trityl-1H-pyrazolo[4,3-c]pyridine, which was carried onto the next step without further purification. MS ESI calc'd. For C26H18ClF2N3O [M+1]+ 462. found 462.
Reaction SMILES: O[CH2:2][CH:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[S:5][CH:4]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.N1C=CC=CC=1.S(Cl)([Cl:29])=O>C1C=CC=CC=1>[Cl:29][CH2:2][CH:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[S:5][CH:4]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1Nc2ccccc2SC(c2ccccc2)C1CO
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: O=C1Nc2ccccc2SC(c2ccccc2)C1CCl
Yield: 84 %

Procedure:
5.7 g of 2,3-dihydro-3-hydroxymethyl-2-phenyl-1,5-benzothiazepin-4(5H)-one prepared as described in Reference Example 1 and 1.6 g of pyridine were dissolved in 30 ml of benzene, and 3.6 g of thionyl chloride was added to the solution, followed by heating under refluxing for 1 hour. The solvent was then distilled off and water was added to the residue. The precipitated crystals were filtered, washed with methanol and recrystallized from benzene to obtain 5.1 g of 3-chloromethyl-2,3-dihydro-2-phenyl-1,5-benzothiazepin-4(5H)-one as colorless needles having a melting point of 233° C. (with decomposition).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1>C(O)CCC>[N:20]1([C:2]2[C:3]3[CH:10]=[C:9]([C:11]4[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=4)[NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1
Reactant: c1ccc2c(c1)CCN2
Reactant: O=[N+]([O-])c1ccc(-c2cc3c(Cl)ncnc3[nH]2)cc1
Solvent: CCCCO
Product: O=[N+]([O-])c1ccc(-c2cc3c(N4CCc5ccccc54)ncnc3[nH]2)cc1
Reaction time: 0.25 h

Procedure:
Under a nitrogen atmosphere, 0.5 g (1.82 mmol) of 4-chloro-6-(4-nitro-phenyl)-7H-pyrrolo-[2,3-d]pyrimidine and 0.43 ml (2.1 equivalents) of 2,3-dihydroindole in 10 ml of abs. n-butanol are heated at reflux for 1.5 hours until the starting material is no longer present in TLC, the desired product precipitating out and being filtered off. The brown crude product is stirred thoroughly in about 20 ml of 1N NaOH for about 15 minutes, and the suspension is filtered with suction and the residue is washed with water, n-butanol and hexane and dried under a high vacuum. 4-(2,3-Dihydroindol-1-yl)-6-(4-nitro-phenyl)-7H-pyrrolo[2,3-d]pyrimidine is obtained in the form of a rust-brown powder having a melting point of>300° C. FAB-MS: (M+H)+ =358 (corresponds to C20H15N5O2); Rf value (toluene-acetone--4:6)=0.40.
Reaction SMILES: [OH:1][CH:2]([C@@H:4]1[C@@H:7]([S:8][CH3:9])[N:6]([C:10](=[C:15]([CH3:17])[CH3:16])[C:11]([O:13][CH3:14])=[O:12])[C:5]1=[O:18])[CH3:3].Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)=[O:21]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:16][C:15]([CH3:17])=[C:10]([N:6]1[C@H:7]([S:8][CH3:9])[C@@H:4]([C@H:2]([O:1][C:20]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=2)=[O:21])[CH3:3])[C:5]1=[O:18])[C:11]([O:13][CH3:14])=[O:12]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)C(=C(C)C)N1C(=O)[C@H](C(C)O)[C@H]1SC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)C(=C(C)C)N1C(=O)[C@H]([C@@H](C)OC(=O)OCc2ccc([N+](=O)[O-])cc2)[C@H]1SC
Reaction time: 1.5 h
Yield: 77.9 %

Procedure:
To a solution of a mixture (5:1) of methyl 2-[(3S,4R)-3-{(1RS)-1-hydroxyethyl}-4-methylthio-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (755 mg) and 4-dimethylaminopyridine (440 mg) in dichloromethane (6 ml) was added dropwise a solution of p-nitrobenzyl chloroformate (660 mg) in dichloromethane (4 ml) during three minutes period at 0° C. After 1.5 hours, the solution was concentrated, taken up into ethyl acetate (40 ml), and washed with dilute hydrochloric acid, water and brine. The organic layer was dried over magnesium sulfate and evaporated to leave an oil. Chromatography on silica gel (50 g) eluting with 2-10% ethyl acetate in dichloromethane to give methyl 3-methyl-2-[(3S,4R)-4-methylthio-3-{(1R)-1-(p-nitrobenzyloxycarbonyloxy)ethyl}-2-oxoazetidin-1-yl]but-2-enoate (974 mg).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26]C)=O)=[C:21]([O:28][CH:29]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[Cl:40])[C:30]([F:33])([F:32])[F:31])[CH:20]=3)[C:12]=2[CH:11]=1)(C(C)(C)C)(C)C.[NH3:41]>CO>[Cl:40][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[CH:29]([O:28][C:21]1[CH:20]=[C:19]([N:18]2[C:12]3[CH:11]=[C:10]([CH2:9][OH:8])[N:15]=[CH:14][C:13]=3[N:16]=[CH:17]2)[S:23][C:22]=1[C:24]([NH2:41])=[O:26])[C:30]([F:32])([F:31])[F:33]
Reactant: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1OC(c1ccccc1Cl)C(F)(F)F
Reactant: N
Solvent: CO
Product: NC(=O)c1sc(-n2cnc3cnc(CO)cc32)cc1OC(c1ccccc1Cl)C(F)(F)F
Temperature: 125 °C
Reaction time: 4 h

Procedure:
A mixture of 470 mg of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-[1-(2-chlorophenyl)-2,2,2-trifluoroethoxy]thiophene-2-carboxylate and 40 ml of a saturated solution of ammonia in methanol is stirred in a microwave vial at 125° C. for 4 h in the microwave cavity. The reaction mixture is concentrated to dryness and the resulting residue is purified by flash chromatography (ethyl acetate/methanol, 90/10 (v/v)) to yield the title compound.
Reaction SMILES: [CH:1]1([C:6]([OH:8])=O)[CH2:5][CH:4]=[CH:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:21][NH:22][O:23][CH3:24].O>ClCCl>[CH3:21][N:22]([O:23][CH3:24])[C:6]([CH:1]1[CH2:5][CH:4]=[CH:3][CH2:2]1)=[O:8]
Reactant: CNOC
Reactant: O=C(O)C1CC=CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: O
Product: CON(C)C(=O)C1CC=CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 106 %

Procedure:
To a solution of cyclopent-3-ene-1-carboxylic acid (80.0 g, 0.71 mol) in dichloromethane (300 ml) was added 1,1′-carbonyldiimidazole (127.5 g, 0.78 mol) slowly and the reaction mixture was stirred at room temperature for 1 h. N,O-dimethylhydroxylamine (76.7 g, 0.78 mol) was added and stirred for 18 h at room temperature. The reaction mixture was poured into water (300 ml) and extracted with dichloromethane (100 ml). The organic extracts were washed with hydrochloric acid (1N, 2×200 ml) and then with brine before filtering through cotton wool, drying and concentrating. The product was purified by flash chromatography using silica gel eluting with dichloromethane to give the title compound (116.78 g, 95%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=O)[NH:10][CH:11]=[N:12]2)=[C:7]([O:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:6]=1)(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:42]>>[C:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([Cl:42])=[N:10][CH:11]=[N:12]2)=[C:7]([O:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(OC2CCCC2)c2c(=O)[nH]cnc2c1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=O)Oc1cc(OC2CCCC2)c2c(Cl)ncnc2c1

Procedure:
Using an analogous procedure to that described in the last paragraph of Note [9] in Example 15, 7-acetoxy-5-cyclopentyloxy-3,4-dihydroquinazolin-4-one (5 g) was reacted with carbon tetrachloride and triphenylphosphine to give 7-acetoxy-4-chloro-5-cyclopentyloxyquinazoline (5.3 g); NMR Spectrum: (CDCl3) 1.65–1.8 (m, 2H), 1.8–2.05 (m, 4H), 2.1 (m, 2H), 2.4 (s, 3H), 4.95 (m, 1H), 6.78 (d, 1H), 7.35 (d, 1H), 8.9 (s, 1H); Mass Spectrum: M+H+ 307 and 309.
Reaction SMILES: [ClH:1].C([O:9][C@@H:10]1[C@H:14]([O:15]CC2C=CC=CC=2)[CH2:13][N:12]([CH2:23][CH:24]2[CH2:26][CH2:25]2)[C@:11]1([CH3:35])OCC1C=CC=CC=1)C1C=CC=CC=1.Cl.C([OH:39])C>[Pd]>[ClH:1].[CH:24]1([CH2:23][N:12]2[CH2:13][C@@H:14]([OH:15])[C@H:10]([OH:9])[C@H:11]2[CH2:35][OH:39])[CH2:25][CH2:26]1
Reactant: C[C@@]1(OCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)CN1CC1CC1
Reactant: CCO
Agent: [Pd]
Agent: Cl
Product: OC[C@@H]1[C@@H](O)[C@H](O)CN1CC1CC1
Reaction time: 24 h
Yield: 100 %

Procedure:
To a solution of (2R,3R,4R)-3,4-dibenzyloxy-2-benzyloxy-methyl-1-cyclopropylmethylpyrrolidine, hydrochloride (Compound 8) (0.14 g, 0.28 mmol) in 96% ethanol (15 ml) was added 10% Pd/C (50 mg) and 1M hydrochloric acid (0.1ml). The reaction mixture was hydrogenated in Parr apparatus at 40 psi for 24 hours. The mixture was filtered and concentrated in vacuo giving (2R,3R,4R)-1-cyclopropylmethyl-3,4-dihydroxy-2-hydroxymethylpyrrolidine, hydrochloride as a yellow oil (0.063 g, yield: 100%).
Reaction SMILES: [CH3:1][N:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:4]2([CH2:9][CH2:8][NH:7][CH2:6][CH2:5]2)[CH2:3]1.Br[CH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1.C(N(CC)C(C)C)(C)C>C(O)C>[CH3:1][N:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:4]2([CH2:5][CH2:6][N:7]([CH2:17][C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=3)[CH2:8][CH2:9]2)[CH2:3]1
Reactant: O=C(O)c1ccc(CBr)cc1
Reactant: CN1CC2(CCNCC2)c2ccccc21
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CN1CC2(CCN(Cc3ccc(C(=O)O)cc3)CC2)c2ccccc21
Yield: 142.5 %

Procedure:
A mixed solution of 1-methylspiro[indolin-3,4′-piperidine] (1.0 g) synthesized according to a method described in [WO 2011/046851 pamphlet, (preparation 15)], 4-(bromomethyl) benzoic acid (1.08 g), and N,N-diisopropylethylamine (2.61 mL) in ethanol (20 mL) was heated and refluxed for 2 hours. To the resultant reaction mixture, N,N-diisopropylethylamine (1.04 mL) was further added, and the resultant reaction mixture was heated and refluxed for 2 hours. The reaction solution was left to reach room temperature, and from the reaction solution, the solvent was distilled off under reduced pressure to obtain a mixture (2.37 g) containing the subject compound. The resultant mixture was used in the next reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:6]=[CH:5][C:4]=1[NH:18]C(=O)OC(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:6]=[CH:5][C:4]=1[NH2:18]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N
Temperature: 5 °C
Reaction time: 2 h
Yield: 67.5 %

Procedure:
A mixture of tert-butyl N-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (45.0 g, 0.129 mol) was dissolved in dichloromethane (270 mL) then the solution was cooled to 5° C. in and ice bath. A mixture of 20% trifluoroacetic acid in dichloromethane was added dropwise over the course of one hour while maintaining the temperature of the mixture at <5° C. The reaction mixture was warmed to ambient temperature and stirred for 2 hours. The solvents were removed under reduced pressure then the resulting oil was dissolved in dichloromethane (250 mL) and cautiously extracted with 2.5 N aqueous sodium hydroxide (300 mL) then brine (100 mL). The organic solution was dried over magnesium sulfate, filtered and the fitrate concentrated under reduced pressure to give 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (21.7 g, 67.5%) as a light brown solid bismaleate: 1H NMR (DMSO-d6, 400 MHz) δ 7.06 (d, 1H), 6.98 (s, 1H), 8.09 (d, 1H), 6.59 (d, 1H), 5.13 (bs, 2H), 3.76 (s, 3H), 1.26 (s, 12H); RP-HPLC (Hypersil HS C18 Hypersil HS C18, 5 μm, 100A, 250×4.6 mm; 25%-100% acetonitrile-0.05 M ammonium acetate over 10 min, 1 mL/min) tr 10.85 min.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][C@H:8]1[CH2:17][CH2:18][N:19]1[CH:23]=[C:22]([CH2:24][O:25][Si](C(C)(C)C)(C)C)[N:21]=[CH:20]1)=[O:6])[CH:2]=[CH2:3].Cl>C(#N)C>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:14])=[O:15])[CH2:9][C@H:8]1[CH2:17][CH2:18][N:19]1[CH:23]=[C:22]([CH2:24][OH:25])[N:21]=[CH:20]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CCn1cnc(CO[Si](C)(C)C(C)(C)C)c1
Agent: Cl
Solvent: CC#N
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CCn1cnc(CO)c1
Reaction time: 2 h
Yield: 33.2 %

Procedure:
To a solution of (2R,4R)-1-allyloxycarbonyl-2-[2-{4-(t-butyldimethylsilyloxymethyl)imidazol-1-yl}ethyl]-4-methanesulfonyloxypyrrolidine (23.7 g) in acetonitrile (120 ml) was added concentrated hydrochloric acid (12 ml) dropwise under cooling in an ice-bath. After stirring at the same temperature for 2 hours, the mixture was quenched by the addition of a solution of sodium methoxide in methanol (28% W/W, 27.8 g) then ethyl acetate (240 ml) was added. The precipitate was filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in acetonitrile (120 ml) and dried over magnesium sulfate. The solution was filtered and the filtrate was washed with hexane (200 ml×5) then concentrated in vacuo. The residual yellow paste was chromatographed on a 140 g of silica gel eluting with a mixture of chloroform and methanol (100:0 to 99:1 to 95:5) to give (2R,4R)-1-allyloxycarbonyl-2-[2-(4-hydroxymethylimidazol-1-yl) ethyl]-4-methanesulfonyloxypyrrolidine (6.02 g) as a yellow paste.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]1[C:14]([OH:15])=[CH:13][CH:12]=[CH:11][C:9]=1[OH:10].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[CH2:16]([O:10][C:9]1[C:8]([CH3:7])=[C:14]([OH:15])[CH:13]=[CH:12][CH:11]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1c(O)cccc1O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(O)cccc1OCc1ccccc1
Temperature: 80 °C
Yield: 22.8 %

Procedure:
Anhydrous potassium carbonate (30.4 g.) was added to a stirred solution of 2-methylresorcinol (24.8 g) in N,N-dimethylformamide (DMF, 250 ml) and benzyl chloride (25.3 g) was added over 15 minutes. The mixture was heated to 80° C. and maintained at this temperature overnight with continued stirring. On cooling the DMF was removed in vacuo to give an oil which was partitioned between water and ether. The dried ethereal phase was evaporated and chromatographed on silica eluting with chloroform to give 9.78 g (23%) of the title compound of mp 58°-59° C. (Found; C, 78.16; H, 6.63; C14H14O2 requires C, 78.48, H, 6.58%).
Reaction SMILES: C([BH3-])#N.[Na+].[Cl:5][C:6]1[N:11]=[CH:10][C:9]([CH2:12][NH2:13])=[CH:8][CH:7]=1.[C:14]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([CH3:28])[CH:26]=O)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>CO>[C:14]([C:18]1[CH:19]=[CH:20][C:21]([CH2:24][CH:25]([CH3:28])[CH2:26][NH:13][CH2:12][C:9]2[CH:10]=[N:11][C:6]([Cl:5])=[CH:7][CH:8]=2)=[CH:22][CH:23]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: NCc1ccc(Cl)nc1
Reactant: CC(C=O)Cc1ccc(C(C)(C)C)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(CNCc1ccc(Cl)nc1)Cc1ccc(C(C)(C)C)cc1
Reaction time: 4 h

Procedure:
Route A: After suspending 620 mg (9.84 mmol) of sodium cyanoborohydride in 2 ml of absolute methanol, 700 mg (4.91 mmol) of 6-chloro-3-pyridylmethylamine was added thereto. Subsequently, to this was added a solution of 1.0 g (4.90 mmol) 3-(4-t-butylphenyl)-2-methylpropionaldehyde/2 ml absolute methanol by portions and then, stirring was conducted at room temperature for 4 h.