Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[N:6][CH:7]=1.[Cl:20][C:21]1[C:22](F)=[N:23][CH:24]=[C:25]([O:27]CCC2OCCO2)[CH:26]=1>>[Cl:20][C:21]1[CH:26]=[C:25]([OH:27])[CH:24]=[N:23][C:22]=1[O:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][N:10]=[C:9]2[NH:8][C:5]1[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][N:6]=1
Reactant: Fc1ncc(OCCC2OCCO2)cc1Cl
Reactant: Cc1cnc(Nc2ncnc3ccc(O)cc23)cn1
Product: Cc1cnc(Nc2ncnc3ccc(Oc4ncc(O)cc4Cl)cc23)cn1

Procedure:
Using 4-[(5-methylpyrazin-2-yl)amino]quinazolin-6-ol and 3-chloro-5-[2-(1,3-dioxolan-2-yl)ethoxy]-2-fluoropyridine, 5-chloro-6-({4-[(5-methylpyrazin-2-yl)amino]quinazolin-6-yl}oxy)pyridin-3-ol (194 mg) was obtained as a brown solid by the methods as in Example 6-2) and Example 6-3), methods equivalent thereto or combinations of these with usual methods.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH:13]=O)[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1.[NH:21]1[CH2:26][CH2:25][CH:24]([C:27]([OH:30])([CH3:29])[CH3:28])[CH2:23][CH2:22]1.C(OC)(OC)OC.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:21]3[CH2:26][CH2:25][CH:24]([C:27]([OH:30])([CH3:29])[CH3:28])[CH2:23][CH2:22]3)[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1
Reactant: Cn1c(CC=O)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CC(C)(O)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cn1c(CCN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)acetaldehyde (150 mg, 0.51 mmol) in DCE (10 mL) was added 2-piperidin-4-ylpropan-2-ol (110 mg, 0.77 mmol), trimethyl orthoformate (0.55 mL, 5.02 mmol) and acetic acid (0.03 mL, 0.52 mmol). The reaction mixture was stirred at room temperature for 5 h, sodium triacetoxyborohydride (154 mg, 0.73 mmol) was added and the resulting mixture stirred for a further 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, the cartridge was washed with MeOH then the desired product eluted with 2 M NH3 in MeOH. The resulting residue was purified by column chromatography (Si—PCC, 0-10% MeOH in DCM) to give the title compound as an off white solid (109 mg, 51%). LCMS (Method H): RT=2.54 min, [M+H]+ 423.5
Reaction SMILES: I.F[C:3]1[CH:8]=[CH:7][C:6]([C:9](=[NH:11])[NH2:10])=[CH:5][CH:4]=1.[Cl:12][C:13]([SH:16])(Cl)Cl.[OH-].[Na+].[Cl:19]CCl>O>[Cl:19][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:11]=[C:13]([Cl:12])[S:16][N:10]=2)=[CH:5][CH:4]=1
Reactant: N=C(N)c1ccc(F)cc1
Reactant: ClCCl
Reactant: SC(Cl)(Cl)Cl
Agent: I
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Clc1ccc(-c2nsc(Cl)n2)cc1
Temperature: 25 °C
Yield: 31.2 %

Procedure:
To a solution of 4-fluorobenzenecarboximidamide hydroiodide (5.00 g, 17.7 mmol) and perchloromethyl mercaptan (1.90 ml, 17.7 mmol) in dichloromethane (100 ml) was added dropwise a solution of sodium hydroxide (3.55 g, 88.8 mmol) in water (7 ml) under ice-cooling. Then, the reaction mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. The organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 1.78 g (31.2%) of the desired product as a solid.
Reaction SMILES: C(OC(=O)COC1C=CC(SC2C=C(OCC3CCCC3)C=C(Br)C=2)=CC=1C)C.[CH2:30]([N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)[C:31]#[CH:32].[CH2:39]([O:41][C:42](=[O:79])[CH2:43][O:44][C:45]1[CH:50]=[CH:49][C:48]([S:51][C:52]2[CH:57]=[C:56](C#CC3C=CC(CO)=CC=3)[CH:55]=[C:54]([O:68][CH2:69][CH2:70][C:71]3[CH:76]=[CH:75][C:74](Cl)=[CH:73][CH:72]=3)[CH:53]=2)=[CH:47][C:46]=1[CH3:78])[CH3:40]>>[CH2:39]([O:41][C:42](=[O:79])[CH2:43][O:44][C:45]1[CH:50]=[CH:49][C:48]([S:51][C:52]2[CH:57]=[C:56]([C:32]#[C:31][CH2:30][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH:55]=[C:54]([O:68][CH2:69][CH2:70][CH:71]3[CH2:72][CH2:73][CH2:74][CH2:75][CH2:76]3)[CH:53]=2)=[CH:47][C:46]=1[CH3:78])[CH3:40]
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(CO)cc3)cc(OCCc3ccc(Cl)cc3)c2)cc1C
Reactant: C#CCN1CCOCC1
Agent: CCOC(=O)COc1ccc(Sc2cc(Br)cc(OCC3CCCC3)c2)cc1C
Product: CCOC(=O)COc1ccc(Sc2cc(C#CCN3CCOCC3)cc(OCCC3CCCCC3)c2)cc1C

Procedure:
The title product was prepared from {4-[3-Bromo-5-cyclopentylmethoxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (260 mg; 0.54 mmol) and 4-prop-2-ynyl-morpholine (203.6 mg; 1.63 mmol) applying the procedure described for {4-[3-[2-(4-Chlorophenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 80 mg (28%). HPLC-MS: m/z: 523.9 (M)+; Rt: 2.19 min
Reaction SMILES: CS(C1C=CC(N2CCCC2)=C(C=1)C(O)=O)(=O)=O.Cl[C:20]1[CH:28]=[CH:27][C:26]([S:29](=[O:35])(=[O:34])[NH:30][CH:31]([CH3:33])[CH3:32])=[CH:25][C:21]=1[C:22]([OH:24])=[O:23].[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>>[CH:31]([NH:30][S:29]([C:26]1[CH:27]=[CH:28][C:20]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[C:21]([CH:25]=1)[C:22]([OH:24])=[O:23])(=[O:35])=[O:34])([CH3:33])[CH3:32]
Reactant: C1COCCN1
Reactant: CC(C)NS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Agent: CS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Product: CC(C)NS(=O)(=O)c1ccc(N2CCOCC2)c(C(=O)O)c1
Yield: 38 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 5-Methanesulfonyl-2-pyrrolidin-1-yl-benzoic acid from 2-Chloro-5-isopropylsulfamoyl-benzoic acid and morpholine and obtained in 38% yield. MS (m/e): 327.2 (MH−, 100%).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([N:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]3[CH:21]=2)=[CH:9][CH:8]=1)C)=[O:4].C(=O)([O-])[O-:25].[K+].[K+].O>CO>[F:1][C:2]([F:23])([F:22])[C:3]([OH:25])=[O:4].[N:14]1[C:13]([C:10]2[CH:11]=[CH:12][C:7]([NH:5][CH3:3])=[CH:8][CH:9]=2)=[CH:21][N:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=12
Reactant: O=C([O-])[O-]
Reactant: CN(C(=O)C(F)(F)F)c1ccc(-c2cn3ccccc3n2)cc1
Agent: [K+]
Solvent: O
Solvent: CO
Product: CNc1ccc(-c2cn3ccccc3n2)cc1
Product: O=C(O)C(F)(F)F

Procedure:
0.75 g (2.35 mmol) 2,2,2-Trifluoro-N-(4-imidazo[1,2-a]pyridin-2-yl-phenyl)-N-methyl-acetamide (educt IV.2.d) and 0.65 g (4.70 mmol) potassium carbonate are suspended in 20 mL methanol and 20 mL water and stirred at 50° C. over night. The mixture is extracted with ethyl acetate. The organic phase is dried and evaporated.
Reaction SMILES: N1C=CC=CC=1S[C:8](=[O:25])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1.[CH:26]1([Mg]Br)[CH2:30][CH2:29][CH2:28][CH2:27]1.CCOCC>C1COCC1>[CH2:18]([O:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][C:8]([CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:25])=[CH:16][CH:15]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(CCc1ccc(OCc2ccccc2)cc1)Sc1ccccn1
Reactant: Br[Mg]C1CCCC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(CCc1ccc(OCc2ccccc2)cc1)C1CCCC1
Temperature: -78 °C
Reaction time: 0.58 h
Yield: 84 %

Procedure:
3-(4-Benzyloxyphenyl)thiopropionic acid S-pyridin-2-yl ester (3.00 g, 8.58 mmol) from Step 4 above was dissolved in dry THF (45 mL) and cooled to −78° C. A solution of cyclopentylmagnesium bromide in Et2O (2.0 M, 4.51 mL, 9.02 mmol) was added dropwise along the sides of the reaction vessel. After stirring 35 min, the cooling bath was removed. The reaction mixture was quenched with saturated aq. NH4Cl upon reaching ambient temperature and extracted with Et2O (500 mL). The organic phase was washed with brine (50 mL), dried over MgSO4 and evaporated. The residue was purified by flash column chromatography (10% EtOAc in hexanes) to give the product (2.22 g, 84%) as a white semi-crystalline material. 1H NMR (CDCl3) δ 1.48-1.83 (m, 8H), 2.69-2.77 (m, 2H), 2.79-2.88 (m, 3H), 5.03 (s, 2H), 6.86-6.92 (m, 2H), 7.07-7.12 (m, 2H), 7.28-7.45 (m, 5H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[C:9]([Br:28])[CH:8]=1)[C:3]([OH:5])=[O:4].[C:29]1([CH3:42])[CH:34]=[CH:33][C:32]([N:35]([CH2:39][CH2:40]O)[CH2:36][CH2:37]O)=[CH:31][CH:30]=1>>[Br:28][C:9]1[CH:8]=[C:7]([CH2:6][C@H:2]([N:1]2[CH2:40][CH2:39][N:35]([C:32]3[CH:31]=[CH:30][C:29]([CH3:42])=[CH:34][CH:33]=3)[CH2:36][CH2:37]2)[C:3]([OH:5])=[O:4])[CH:12]=[CH:11][C:10]=1[O:13][CH2:14][CH2:15][C:16]1[N:17]=[C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:19][C:20]=1[CH3:21]
Reactant: Cc1ccc(N(CCO)CCO)cc1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1Br
Product: Cc1ccc(N2CCN([C@@H](Cc3ccc(OCCc4nc(-c5ccccc5)oc4C)c(Br)c3)C(=O)O)CC2)cc1
Yield: 24 %

Procedure:
Following the procedures described in Example 1, Intermediate 3B was used in place of Intermediate 3A, and 2,2′-(p-tolylazanediyl)diethanol was used in place of 2,2′-(m-tolylazanediyl)diethanol to give (2S)-3-{3-bromo-4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-p-tolyl-piperazin-1-yl)-propionic acid as a white solid with the yield of 24% and mp of 203-205° C.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][O:14][CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH:21]([N:24]2[C:29](=[O:30])[C:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]4[C:39]([C:44]#[N:45])=[CH:40][CH:41]=[CH:42][CH:43]=4)=[CH:34][CH:33]=3)=[C:27]([CH2:46][CH2:47][CH3:48])[N:26]3[N:49]=[CH:50][N:51]=[C:25]23)[CH2:20][CH2:19]1>C(OCC)(=O)C>[CH3:13][O:14][CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH:21]([N:24]2[C:29](=[O:30])[C:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[C:44]4[NH:3][C:4](=[O:7])[O:5][N:45]=4)=[CH:34][CH:33]=3)=[C:27]([CH2:46][CH2:47][CH3:48])[N:26]3[N:49]=[CH:50][N:51]=[C:25]23)[CH2:20][CH2:19]1
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(OCCOC)CC2)c2ncnn12
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC(OCCOC)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 46.1 %

Procedure:
A mixture of hydroxylammonium chloride (0.15 g), sodium hydrogen carbonate (0.25 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-({4-[4-(2-methoxyethoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.078 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.029 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.024 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.04 g, 46%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si:5]([CH3:12])([O:9][CH2:10]C)[O:6][CH2:7]C.C(N)C=C.C[Si](C)(C)N(CC=C)[Si](C)(C)C.C[SiH](OC)OC>[Pt].CO>[NH2:1][CH2:2][CH2:3][CH2:4][Si:5]([CH3:12])([O:9][CH3:10])[O:6][CH3:7]
Reactant: CCO[Si](C)(CCCN)OCC
Agent: [Pt]
Agent: C=CCN([Si](C)(C)C)[Si](C)(C)C
Agent: CO[SiH](C)OC
Solvent: CO
Solvent: C=CCN
Product: CO[Si](C)(CCCN)OC

Procedure:
There is considerable prior art relating to the synthesis of poly(aminoalkylmethylsiloxanes). Generally, poly(aminoalkylmethylsiloxanes) have been produced by first preparing aminoalkylmethyldialkoxysilanes, followed by hydrolysis with or without an endblocking agent, such as a trimethylsilyl derivative, to form cyclic and linear poly(3-aminoalkylmethylsiloxanes). The isomeric purity of the poly(aminoalkylmethylsiloxane) fluids, prepared in the manner of the prior art, is dependent upon the isomeric purity of the aminoalkylmethyldialkoxysilane prepared in the first step of the synthesis. German Patent No. 2408480 describes the reaction of a silazane derivative from allylamine and an organohydrochlorosilane, in the presence of a proton acceptor to form an intermediate silazane which then undergoes a hydrosilylation reaction catalyzed by a platinum catalyst. Upon alcoholysis, the intermediate hydrosilylation product forms 3-aminopropylmethyldiethoxysilane in 70% overall yield. A molar excess of at least 50% of allylamine is used in this process. Identification of the beta-isomer in the product was not made. Japanese Patent No. 10017578 describes another method of synthesis by hydrosilylation of N,N-bis(trimethylsilyl)allylamine by methyldimethoxysilane. The product of that reaction is then heated with methanol to form 3-aminopropylmethyldimethoxysilane in at least 85% overall yield. The presence of the beta-isomer in the product was not made. Japanese Patent No. 11209384 describes the use of a rhodium:cyclooctadiene complex as a hydrosilylation catalyst for the addition of methyldiethoxysilane to allylamine to form 3-aminopropylmethyldiethoxysilane in 78% yield. 2-Aminopropylmethyldiethoxysilane is formed at very low levels in this process not exceeding 0.5%. U.S. Pat. No. 5,391,675 describes the formation of an aminopropylmethylsiloxy-containing polydimethylsiloxane by barium or strontium hydroxide catalyzed condensation of a silanol terminated polydimethylsiloxane with a 3-aminopropylalkoxysilane with elimination of an alcohol.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([N:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[C:21]([OH:26])[CH:22]=4)[CH:17]3[C:27]([O:29][CH3:30])=[O:28])(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[NH:33]1[CH2:38][CH2:37][CH:36](CCO)[CH2:35][CH2:34]1.F[C:43]1C=CC(OC2C=CC(S(N3CCC4C(=CC=C(OCCCN5CCN(C)CC5)C=4)C3C(OC)=O)(=O)=O)=CC=2)=C[CH:44]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([S:13]([N:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[C:21]([O:26][CH2:43][CH2:44][N:33]5[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]5)[CH:22]=4)[CH:17]3[C:27]([O:29][CH3:30])=[O:28])(=[O:14])=[O:15])=[CH:11][CH:12]=2)=[CH:31][CH:32]=1
Reactant: COC(=O)C1c2ccc(O)cc2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reactant: COC(=O)C1c2ccc(OCCCN3CCN(C)CC3)cc2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reactant: OCCC1CCNCC1
Product: COC(=O)C1c2ccc(OCCN3CCCCC3)cc2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1

Procedure:
Methyl 2-[4-(4-fluorophenoxy)benzenesulfonyl]-6-hydroxy-1,2,3,4-tetrahydro-isoquinoline-1-carboxylate (3B) is reacted with 2-piperidin-4-ylethanol by the method described under 3C.
Reaction SMILES: CS[C:3]([NH:8][CH2:9][CH2:10][S:11][CH2:12][C:13]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][N:14]=1)=[CH:4][N+:5]([O-:7])=[O:6].[CH3:21][NH2:22]>C(O)C>[CH3:21][NH:22][C:3]([NH:8][CH2:9][CH2:10][S:11][CH2:12][C:13]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][N:14]=1)=[CH:4][N+:5]([O-:7])=[O:6]
Reactant: CN
Reactant: COc1cccnc1CSCCNC(=C[N+](=O)[O-])SC
Solvent: CCO
Product: CNC(=C[N+](=O)[O-])NCCSCc1ncccc1OC

Procedure:
1-Methylthio-1-[2-((3-methoxy-2-pyridyl)methylthio)ethylamino]-2-nitroethylene (1.4 g) was stirred with a solution of methylamine in ethanol (25 ml, 33% solution) and dissolved within a minute. After a further 3 minutes a crystalline product separated and recrystallisation from ethanol/ether yielded the title product (1.1 g), m.p. 145.5° - 147°.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=O.[CH2:11]([NH:13][CH2:14][CH3:15])[CH3:12].[B-]C#N.[Na+].C(O)(=O)C>CO>[CH2:11]([N:13]([CH2:14][CH3:15])[CH:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1)[CH3:12]
Reactant: CCNCC
Reactant: O=C1Cc2ccccc2C1
Agent: [B-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCN(CC)C1Cc2ccccc2C1
Reaction time: 8 h

Procedure:
To a solution of 1H-inden-2(3H)-one (6.00 g, 45.4 mmol) in methanol (100 ml) was added diethylamine (6.64 g, 91 mmol), sodium cyanotrihydroborate (5.71 g, 91 mmol) and acetic acid (5.45 g, 91 mmol). The reaction mixture was stirred overnight and concentrated. The residue was diluted with methylene chloride, washed with saturated aqueous NaHCO3 (2×50 mL), dried over Na2SO4, filtered, and concentrated. The resulting residue was dissolved in 1M aqueous HCl (100 ml), and extracted with methylene chloride (2×50 mL). The aqueous layer was treated with 6N aqueous NaOH solution until the pH=14 and was extracted with methylene chloride (4×100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to provide the title compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH:3]1[CH2:15][NH:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].C(O)(C)C>C(=O)=O>[OH:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[CH2:15][NH:16][C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18].[OH:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@@H:3]1[CH2:15][NH:16][C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18]
Reactant: CC(C)(C)OC(=O)N1CCC(O)C(CNC(=O)OCc2ccccc2)C1
Agent: O=C=O
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CC[C@@H](O)[C@@H](CNC(=O)OCc2ccccc2)C1
Product: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H](CNC(=O)OCc2ccccc2)C1

Procedure:
1,1-Dimethylethyl 4-hydroxy-3-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1-piperidinecarboxylate was resolved via supercritical fluid chromatography (SFC) using a Chiralpak AD-H 30×250 mm column (20% Isopropanol in CO2; 70 ml/min; 30 deg C.; uv 220 nm) to obtain the E1 (first eluting isomer: 98% ee) and E2 (second eluting isomer; 94% ee) enantiomers presumed 1,1-dimethylethyl (3S,4R)-4-hydroxy-3-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1-piperidinecarboxylate (E2) and presumed 1,1-dimethylethyl (3R,4S)-4-hydroxy-3-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1-piperidinecarboxylate (E1) as white solids.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]#[N:9].[C:10]1([CH3:19])[C:11]([C:16](Cl)=[O:17])=[CH:12][CH:13]=[CH:14][CH:15]=1>C(Cl)Cl>[CH3:1][N:2]1[C:6]([C:16]([C:11]2[C:10]([CH3:19])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:17])=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]#[N:9]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: Cn1cccc1CC#N
Solvent: ClCCl
Product: Cc1ccccc1C(=O)c1ccc(CC#N)n1C

Procedure:
To a solution of 24 g. (0.20 mole) of 1-methylpyrrole-2-acetonitrile and 30.92 g. (0.20 mole) o-toluoyl chloride in 200 ml. methylene chloride (cooled externally to -20° C.) is added dropwise 23.4 ml. (0.20 mole) of stannic chloride. After the addition is complete, the yellow mixture is permitted to come to room temperature. The mixture is then poured into ice-dilute hydrochloric acid. The two phases are separated. The organic phase is washed consecutively with N,N-dimethyl-1,3-propanediamine, 3N hydrochloric acid, and saturated sodium chloride solution; dried over magnesium sulfate; and the product, 1-methyl-5-(o-toluoyl)-pyrrole-2-acetonitrile, is separated from the residual oil by chromatography. The column is packed with acid washed alumina in hexane. The eluant is benzene. The product is found in the first compound bearing fraction as determined by ultraviolet absorption at 260 mμ. The benzene is evaporated and the resultant solid is purified by recrystallization twice from methanol, m.p. 90-92.5° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])[CH2:14][CH3:15])[CH2:9]1)=O)(C)(C)C.Cl.CCO>>[Cl:24][C:18]1[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=1[O:16][C@H:13]([C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[CH2:14][CH3:15]
Reactant: CC[C@H](Oc1ccc(Cl)cc1Cl)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCO
Product: CC[C@H](Oc1ccc(Cl)cc1Cl)[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
60% NaH in mineral oil (60:40, NaH:mineral oil, 10 mg, 260 μmmol) was slowly added to a mixture of (S)-3-(S)-1-hydroxypropyl)pyrrolidine-1-carboxylic acid t-butyl ester (50 mg, 0.2 mmol, 1 eq.) in DMF (680 μL, 8.7 mmol). The resulting mixture was stirred for 15 minutes, at room temperature. 2,4-Dichloro-1-fluorobenzene (76 μL, 3 eq.) was added and the mixture was heated at 90° C. for 3 hours. The reaction was quenched with MeOH (1 mL). DMF and MeOH was removed under reduced pressure, leaving the BOC-protected intermediate, (S)-3-[(S)-1-(2,4-dichlorophenoxy)propyl]pyrrolidine-1-carboxylic acid t-butyl ester. Deprotection was carried out using 1.25 M HCl in EtOH (1.7 mL, 2.2 mmol). The mixture was stirred overnight at room temperature. The product was then purified by preparative HPLC to yield the title compound as a mono-TFA salt (41.5 mg). MS m/z: [M+H]+ calcd for C13H17Cl2NO, 274.07; found 274.0.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18](=[O:32])[N:19]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH:20]=[N:21]2)=[CH:16][C:15]=1[O:33][CH3:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:54][N:55]([CH2:62][CH2:63]O)[C:56]([C:58]([CH3:61])([CH3:60])[CH3:59])=[O:57]>C(Cl)Cl>[CH3:34][O:33][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:14]=1[O:13][CH2:63][CH2:62][N:55]([CH3:54])[C:56]([C:58]([CH3:61])([CH3:60])[CH3:59])=[O:57])[N:21]=[CH:20][N:19]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:28])([CH3:29])[CH3:30])[C:18]2=[O:32]
Reactant: CN(CCO)C(=O)C(C)(C)C
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCN(C)C(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
Diethyl azodicarboxylate (679 mg, 3.9 mmol) was added dropwise to a suspension of 7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (918 mg, 3 mmol), triphenylphosphine (1 g, 3.9 mmol) and 2-(N-methyl-N-(t-butylcarbonyl)amino)ethanol (682 mg, 3.9 mmol), prepared as described below, in methylene chloride (20 ml) and the mixture stirred for 1 hour at ambient temperature. Further 2-(N-methyl-N-(t-butylcarbonyl)amino)ethanol (105 mg, 0.6 mmol), triphenylphosphine (786 mg, 3 mmol) and diethyl azodicarboxylate (522 mg, 3 mmol) were added and the mixture stirred for 30 minutes at ambient temperature. The mixture was concentrated to half volume by evaporation and purified by column chromatography eluting with methylene chloride/ether (7/3 increasing to 1/1) to give 6-methoxy-7-(2-(N-methyl-N-(t-butylcarbonyl)amino)ethoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (1.3 g, 98%). 1H NMR Spectrum: (CDCl3) 1.2(s, 9H); 1.45(s, 9H); 3.05(br s, 3H); 3.72(br s, 2H); 3.98(s, 3H); 4.25(br s, 2H); 5.95(s, 2H); 7.1(br s, 1H); 7.6(s, 1H); 8.2(s, 1H)