Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C[O:3][C:4](=[O:29])[C@H:5]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:6][C:7](=[O:18])[C@@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:9][CH3:10].[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([O:41][CH3:42])[CH:40]=1)[C:35](O)=[O:36]>>[CH3:42][O:41][C:39]1[CH:38]=[C:34]([CH:33]=[C:32]([O:31][CH3:30])[CH:40]=1)[C:35]([N:9]([CH3:10])[C@@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:3])=[O:29])[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)=[O:18])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:36]
Reactant: CN[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Reactant: COc1cc(OC)cc(C(=O)O)c1
Agent: Cl
Product: COc1cc(OC)cc(C(=O)N(C)[C@H](Cc2ccccc2)C(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)O)c1

Procedure:
Coupling of N-methyl-(D)-phenylalanyl-(L)-tryptophan methyl ester hydrochloride (see example 1) with 3,5-dimethoxybenzoic acid according to example 12 followed by hydrolysis of the methyl ester moiety according to example 1 gives N-(3,5-dimethoxybenzoyl)-N-methyl-(D)-phenylalanyl-(L)-tryptophan; FAB-MS m/e 530 (M+H)+.
Reaction SMILES: [OH-].[Na+].[NH2:3][C@@H:4]([CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])[C:5]([OH:7])=[O:6].[CH2:13]([O:20][C:21](Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(#N)C>[CH2:13]([O:20][C:21]([NH:3][C@@H:4]([CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])[C:5]([OH:7])=[O:6])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)C[C@H](N)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CC(C)(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a 1M solution of NaOH (135 ml, 135 mmol) was added 2(S)-amino-4,4-dimethylpentanoic acid (commercially available) (9.8 g, 67.5 mmol), followed by benzyloxycarbonyl chloride (11.6 ml, 80.99 mmol) in acetonitrile (20 ml) and the reaction mixture was stirred for 12 h at room temperature. The solvent was evaporated using rotavap and the slurry was washed with hexane and then adjusted the pH to 6 using 6N HCl. The resulting solution was extracted with ethyl acetate. The organic layer was washed with brine and dried over MgSO4. The solvent was evaporated to get 2(S)-benzyloxycarbonylamino-4,4-dimethylpentanoic acid (18.6 g) as a sticky gum which was used in the next step without further purification.
Reaction SMILES: [C:1]1([C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:29]([Mg]Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(OCC)C>[C:23]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][C:13]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([OH:16])[CH2:12][CH2:11]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Br[Mg]Cc1ccccc1
Reactant: O=C1CCN(CCC(c2ccccc2)(c2ccccc2)c2ccccn2)CC1
Solvent: CCOCC
Product: OC1(Cc2ccccc2)CCN(CCC(c2ccccc2)(c2ccccc2)c2ccccn2)CC1

Procedure:
A solution of 1 part of this ketal in 5 parts of glacial acetic acid is added 0.1 part of sulfuric acid and the mixture is heated on a steam bath for 1 hour. The reaction mixture is poured into 50 parts of cold water to provide 1-[3,3-diphenyl-3-(2-pyridyl)propyl]-4-oxopiperidine. 3 Parts of this ketone in 20 parts by volume of ethyl ether and 5 parts by volume of 3 molar solution of benzylmagnesium bromide in ethyl ether are reacted under reflux for 4 hours. The mixture is cooled, quenched with water, and the ethereal layer is dried over anhydrous sodium sulfate. Removal of the ether provides 1-[3,3-diphenyl-3-(2-pyridyl)propyl]-4-benzyl-4-hydroxypiperidine, having the following structural formula ##STR22##
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]([OH:18])=[O:17])[C:10]1=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(#N)C.CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]([O:18][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:17])[C:10]1=[O:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(CC(=O)O)C1=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(CC(=O)OCc2ccccc2)C1=O
Yield: 95.7 %

Procedure:
To a suspension of 21 (20.0 g, 0.0735 mol; see Example 46) in 700 mL of anhydrous acetonitrile and 30 mL of anhydrous N,N-dimethylformamide was added anhydrous, powdered K2CO3 (12.68 g, 0.0918 mol) followed by benzyl bromide (13.81 g, 0.0808 mol, 9.61 mL). The mixture was stirred and vigorously refluxed for 6 hrs, cooled, filtered, and evaporated. The residue was purified by flash chromatography on silica gel eluting with a gradient system of 40 to 50% ethyl acetate/hexane to afford 25.50 g (96% yield) of product 40 as a pale yellow oil; TLC (silica gel; ethyl acetate/hexane: 1,1): Rf=0.35.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([CH2:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)[CH2:3]1.[CH3:18]N1CCNCC1=O>>[CH3:18][N:7]1[CH2:6][CH2:5][N:4]([CH2:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)[CH2:3][C:2]1=[O:1]
Reactant: O=C1CN(Cc2ccc(C(=O)O)cc2)CCN1
Reactant: CN1CCNCC1=O
Product: CN1CCN(Cc2ccc(C(=O)O)cc2)CC1=O

Procedure:
Utilising the procedure described for 4-[(3-oxo-1-piperazinyl)methyl]benzoic acid, but employing 1-methylpiperazin-2-one in place of piperazin-2-one afforded the title compound as cream crystalline solid.
Reaction SMILES: [CH2:1]([C:3]([C:22]1[CH:35]=[CH:34][C:25]([O:26][CH2:27][CH:28]([OH:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[C:24]([CH3:36])[CH:23]=1)([C:6]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[C:8]([CH3:21])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].[CH3:37][O:38][C:39](=[O:48])[CH2:40][C:41]1[CH:42]=[N:43][CH:44]=[C:45](Br)[CH:46]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O>[CH3:37][O:38][C:39](=[O:48])[CH2:40][C:41]1[CH:42]=[N:43][CH:44]=[C:45]([C:9]2[CH:10]=[CH:11][C:6]([C:3]([CH2:1][CH3:2])([C:22]3[CH:35]=[CH:34][C:25]([O:26][CH2:27][CH:28]([OH:33])[C:29]([CH3:31])([CH3:32])[CH3:30])=[C:24]([CH3:36])[CH:23]=3)[CH2:4][CH3:5])=[CH:7][C:8]=2[CH3:21])[CH:46]=1
Reactant: COC(=O)Cc1cncc(Br)c1
Reactant: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Temperature: 140 °C
Yield: 63.6 %

Procedure:
A solution of 1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenoxy)-3,3-dimethyl-butan-2-ol (Example 31; 0.06 g, 0.12 mmol), (5-bromo-pyridin-3-yl)acetic acid methyl ester (Example 24-(2); 41.8 mg, 0.18 mmol), tetrakistriphenylphosphine palladium (19.5 mg, 0.0169 mmol) and potassium phosphate (38.6 mg, 0.18 mmol) in N,N-dimethylformamide (0.3 mL) was stirred with microwave heating at 140° C. for 10 minutes. The reaction mixture was filtered through cotton plug, and the residue was purified by silica gel chromatography (50% ethyl acetate/hexane) to give the title compound (39.5 mg, 62%).
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[CH:2]=1.[CH3:20][N:21]([CH:33]1[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]1)[C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][C:23]=1[C:29]([F:32])([F:31])[F:30]>C(Cl)Cl.CO>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][C:17]([NH:28][C:25]3[CH:26]=[CH:27][C:22]([N:21]([CH3:20])[CH:33]4[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH2:38]4)=[C:23]([C:29]([F:32])([F:30])[F:31])[CH:24]=3)=[O:19])=[CH:14][CH:15]=2)[CH:2]=1
Reactant: CN1CCC(N(C)c2ccc(N)cc2C(F)(F)F)CC1
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1
Solvent: CO
Solvent: ClCCl
Product: CN1CCC(N(C)c2ccc(NC(=O)Cc3ccc(-n4cnc5cccnc54)cc3)cc2C(F)(F)F)CC1

Procedure:
The title compound is prepared as described in Example 1 but using (4-imidazo[4,5-b]pyridin-3-yl-phenyl)-acetic acid (Step 7.1) and 4-[methyl-(1-methyl-piperidin-4-yl)-amino]-3-trifluoromethyl-phenylamine. Title compound: ES-MS: 523.0 [M+H]+; single peak at tR=3.33 min (System 1); Rf=0.18 (CH2Cl2/MeOH+1% NH3aq, 9:1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5](=[O:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[CH3:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH:26]=[N:25][CH:24]=[CH:23]2)=[CH:18][CH:17]=1)=[O:15]>C(O)C>[CH2:9]([O:8][C:6](=[O:7])[C:5]([OH:11])([CH2:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]([N:22]2[CH:23]=[CH:24][N:25]=[CH:26]2)=[CH:20][CH:21]=1)=[O:15])[C:4]([O:3][CH2:1][CH3:2])=[O:12])[CH3:10]
Reactant: CC(=O)c1ccc(-n2ccnc2)cc1
Reactant: CCOC(=O)C(=O)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C(O)(CC(=O)c1ccc(-n2ccnc2)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.2 %

Procedure:
A mixture of diethylketomalonate (87.08 g, 0.50 mole) and 4-(imidazol-1-yl)acetophenone (93.1 g, 0.50 mole) is warmed to 95°-100° C. with stirring for three hours. During this time, the original tan slurry is transformed into a black syrup. At the end of three hours, anhydrous ethanol (130 ml) is added with stirring, resulting in a black solution. This solution is cooled to room temperature, an aliquot is removed and scratched to induce crystallization, and the crystals thus obtained returned to the cool solution. Upon standing overnight at 8° C., the solution forms a solid mass, which is suspended in absolute ethanol (100 ml) and filtered to obtain a brownish solid, which is dried at 43° in a vacuum oven for four hours to yield 67 g hydroxy [2-[4-(1H-imidazol-1-yl)-phenyl]-2-oxoethyl]propanedioic acid diethyl ester. Material thus obtained is suitable for use without additional purification, however, it can be recrystallized from methanol to give pure product, mp 155°-156° C.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].C[O-].[Na+].[F:13][C:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=1>CO.C1COCC1>[F:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[CH:18][CH:19]=1
Reactant: COC(=O)/C=C/c1ccc(F)cc1
Reactant: COC(=O)CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)CC(c1ccc(F)cc1)C(C(=O)OC)C(=O)OC
Reaction time: 0.25 h
Yield: 73.3 %

Procedure:
Dimethyl malonate (14.7 g, 111 mmol) was added dropwise to the mixture of sodium methoxide in methanol (methanol solution 28%, 19.3 g, 100 mmol) and methanol (30 ml) under ice cooling and stirred for 15 minutes. To the mixture was added a solution of methyl (2E)-3-(4-fluorophenyl)-2-propenoate (10.0 g, 55.5 mmol) obtained in Reference Example 1 in THF (50 ml) under ice cooling and the mixture was refluxed for 12 hours. The resulting mixture was concentrated under reduced pressure, and the residue was diluted with water. The aqueous layer was acidified with dilute hydrochloric acid, extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified using silica gel column chromatography (hexane/ethyl-acetate=8/1) to obtain 12.7 g (yield 73%) of 2-(4-fluorophenyl)-1,1,3-trimethoxy carbonyl propane via recrystallization (ethyl acetate-hexane). mp. 75–76° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:4][OH:5])[CH3:3].[C:6]1(=O)[O:11][C:9](=[O:10])[C:8]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:7]12>C(Cl)Cl>[OH:5][CH2:4][C@H:2]([N:1]1[C:9](=[O:10])[C:8]2[C:7](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]1=[O:11])[CH3:3]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: C[C@@H](N)CO
Solvent: ClCCl
Product: C[C@H](CO)N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Yield: 85.3 %

Procedure:
D-Alaninol (3.90 ml, 50 mmol) and phthalic anhydride (7.41 g, 50 mmol) were heated at 160° C. for 30 min. To cooled reaction mixture was added ice water and DCM. Organic phase was collected and the water phase was extracted with DCM. Combined organic phases were dried over Na2SO4 and evaporated to obtain 8.75 g (85%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.32 (d, 3H), 3.54 (m, 1H), 3.84 (m, 1H), 4.26 (m, 1H), 4.91 (m, 1H), 7.84 (m, 4H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[CH:17].[Li]CCCC.Cl[C:24]([O:26][CH3:27])=[O:25]>C1COCC1>[CH3:27][O:26][C:24](=[O:25])[C:17]#[C:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1
Reactant: C#CCCCCCCCCOC1CCCCO1
Reactant: COC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)C#CCCCCCCCCOC1CCCCO1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
A flame-dried round-bottomed flask was charged with 9-decyn-1-ol tetrahydropyranyl ether (1 equiv, 31.7 mmol, 7.55 g) and THF (40 mL), and cooled to −78° C. n-BuLi (1.1 equiv, 34.9 mmol, 21.8 mL of a nominally 1.6 M solution in hexanes) were added dropwise over 5 min. The reaction was stirred for 30 min at −78° C. and then added to a solution of methyl chloroformate (1.5 eq, 47.6 mmol, 4.50 g, 3.7 mL) in THF (20 mL) dropwise via cannula. The reaction was stirred for 30 min at −78° C., then warmed to rt over 1 h and quenched dropwise with H2O (40 mL). The layers were separated and the aqueous layer was extracted with Et2O (2×25 mL). The combined organic layers were dried with Na2SO4, evaporated in vacuo, and purified by flash column chromatography (step gradient, 5% EtOAc/Hex to 10% EtOAc/Hex) to afford Methyl-11-[(tetrahydro-2H-pyran-2-yl)oxy]-undecynoate (8.50 g, 28.7 mmol, 90%). TLC Rf=0.33 (10% EtOAc/Hex) 1HNMR (600 MHz): δ 4.55-4.61 (1H), 3.84-3.91 (m, 1H), 3.70-3.78 (m plus ovlp. s, 4H), 3.47-3.54 (m, 1H), 3.39 (dt, 1H, J1=9.6 Hz, J2=6.7 Hz), 2.33 (t, 2H, J=7.1 Hz), 1.80-1.89 (1H), 1.68-1.76 (1H), 1.50-1.63 (8H), 1.28-1.44 (8H); 13CNMR (150 MHz): δ 154.3, 98.9, 89.9, 72.9, 67.6, 62.3, 52.5, 30.8, 29.7, 29.2, 28.9, 28.7, 27.5, 26.2, 25.5, 19.7, 18.6; FTIR: 2932, 2856, 2236, 1714, 1434, 1249, 1075, 1023, 752 cm−1; HRMS-ESI: calc. for C17H28NaO4 (M+Na)+: 319.1885. found: 319.1887.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16](=[O:30])[N:17]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:18][CH2:19][CH2:20][CH2:21][OH:22])([CH3:14])([CH3:13])[CH3:12]>ClCCl>[CH2:23]([N:17]([C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:30])[CH2:18][CH2:19][CH2:20][CH:21]=[O:22])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N(CCCCO)Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CCCC=O)Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 63.6 %

Procedure:
A commercially available 2 M solution of oxalyl chloride in DCM solution (13.8 mL of 27.6 mmol), obtained from Aldrich Chemical Co., was diluted with anhydrous dichloromethane (50 mL). The solution was cooled to −78° C., and a solution of dimethyl sulfoxide “DMSO” (4.45 ml 62 mmol) in DCM (10 ml) was added over a 45 min period. After the addition was completed a solution of benzyl-(4-hydroxy-butyl)-carbamic acid tert butyl ester (6.9 g, 25 mmol) in DCM (20 mL) was added was added over a 30 min period resulting in a thick white suspension. The reaction mixture was stirred for an additional 15 min followed by the addition of triethylamine TEA (24 mL) over a 30 min period. The cooling bath was removed and stirring was continued for 1 h. The reaction mixture was quenched with water (200 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (3×100 mL). The organic layer was washed with water, brine, and dried over Na2SO4. The crude yellow oil was purified by chromatography using a 8:2 ethyl acetate-hexane mixture as eluent to afford N-benzyl-N-(t-butoxycarbonyl)-4-amino-1-butanal (4.41 g, 63%) as a colorless, viscous oil. 1H NMR δ 9.74 (s, 1H); 7.24-7.36 (m, 5H); 4.41 (bs, 2H); 3.18 (bs, 2H); 2.42 (bs, 2H); 1.66 (bs, 2H); 1.50 (bs, 9H). ELSD/MS: m/z 278 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][NH:12][CH3:13].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][N:12]([CH3:13])[CH3:11]
Reactant: CNC
Reactant: O=Cc1ccc(F)cc1Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN(C)Cc1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
Combine 2-bromo-4-fluorobenzaldehyde (5 g, 24.63 mmol), dimethylamine (2 M, 49.26 mL, 98.52 mmol) and acetic acid (8.47 mL, 147.78 mmol) in DCM (50 mL), and stir for 30 min. To this mixture, add sodium triacetoxyborohydride (49.26 mmol, 10.44 g) and stir overnight at RT. Wash with saturated NaHCO3 solution (100 mL), dry with aqueous saturated sodium chloride, and then dry over sodium sulfate. Filter the organics and remove the solvent under reduced pressure to give the title compound as a brownish oil (4.56 g). GCMS m/z 232 [M]+.
Reaction SMILES: [CH:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])OCC.[P:11]([O:18]Cl)([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14]>>[CH2:13]([O:12][P:11]([CH:1]([O:5][CH2:6][CH3:7])[O:8][CH2:9][CH3:10])(=[O:18])[O:15][CH2:16][CH3:17])[CH3:14]
Reactant: CCOP(OCl)OCC
Reactant: CCOC(OCC)OCC
Product: CCOC(OCC)P(=O)(OCC)OCC
Temperature: 135 °C
Yield: 83.3 %

Procedure:
To a flask containing triethyl orthoformate (23.6 gm; 0.16 mole) equipped with a magnetic stirrer, condensor, and nitrogen atmosphere, is added diethyl chloro phosphite (25 gm; 0.16 mole) over 15-30 minutes and an extremely exothermic reaction occurs. The reaction solution is then heated at 135° C. for 3 hours. The resulting solution is distilled using a Kugelrohr distillation apparatus at 80° C. (0.01 mm Hg) to yield 32 gm of diethoxymethylphosphonic acid diethyl ester (31P NMR 13.2 ppm).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.CCOCC.[CH2:14]([NH:16][C:17](=[O:26])[C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[Cl:25])[CH3:15].[CH3:27][Si:28](Cl)([CH3:30])[CH3:29]>C1COCC1>[Cl:24][C:22]1[C:23]([Si:28]([CH3:30])([CH3:29])[CH3:27])=[C:18]([C:19]([Cl:25])=[CH:20][CH:21]=1)[C:17]([NH:16][CH2:14][CH3:15])=[O:26]
Reactant: C[Si](C)(C)Cl
Reactant: CCNC(=O)c1cc(Cl)ccc1Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCNC(=O)c1c(Cl)ccc(Cl)c1[Si](C)(C)C
Temperature: -100 °C
Reaction time: 0.5 h
Yield: 43.1 %

Procedure:
A solution of 1.5M LDA in THF (13 mL, 19.5 mmol) was added dropwise to an ether/liquid N2 cooled solution of N-ethyl 2,5-dichlorobenzamide (2.0 g, 9.2 mmol) and TMSCl (1.5 mL, 11.5 mmol) in THF (50 mL), maintaining the internal reaction temperature ≤-80° C. The resulting reaction mixture was stirred at -100° C. for 30 min, then was partitioned between ether and sat aq NaHCO3. The ether solution was dried (MgSO4), concentrated, and crystallized from EtOAc/hexanes to afford 1.15 g of the title compound as a white solid. m.p. 150°-153° C.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:9][CH2:10][OH:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl[C:13]1[C:14]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][S:19][C:15]=2[N:16]=[CH:17][N:18]=1>C1COCC1.O>[C:22]1([C:21]2[C:14]3[C:13]([O:11][CH2:10][CH2:9][N:3]4[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]4)=[N:18][CH:17]=[N:16][C:15]=3[S:19][CH:20]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: OCCN1CCCCC1
Reactant: Clc1ncnc2scc(-c3ccccc3)c12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(-c2csc3ncnc(OCCN4CCCCC4)c23)cc1
Reaction time: 0.17 h
Yield: 71.4 %

Procedure:
Sodium hydride (8 mg, 0.16 mmol) was suspended in dry THF (0.5 mL). To this was added 2-(1-piperidyl)ethanol (16 μL, 0.12 mmol) and the reaction stirred for 10 min until effervescence had ceased. Then 4-chloro-5-phenyl-thieno[2,3-d]pyrimidine (20 mg, 0.08 mmol) in dry THF (0.5 mL) was added and the reaction left to stir at room temperature for 72 hrs. The reaction mixture was diluted with water and extracted with DCM. The organic layers were concentrated and the residue purified by preparative TLC (eluent 10% MeOH in DCM) to give 5-phenyl-4-[2-(1-piperidyl)ethoxy]thieno[2,3-d]pyrimidine as a yellow oil (19.4 mg, 72%). LCMS RT=3.03 min. M+1=340.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([NH:12][S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:22][NH:23][CH3:24]>>[CH3:22][N:23]([CH3:24])[C:2]1[C:11]2[C:6](=[C:7]([NH:12][S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Nc1cccc2c(Cl)ccnc12)c1ccccc1
Reactant: CNC
Product: CN(C)c1ccnc2c(NS(=O)(=O)c3ccccc3)cccc12
Yield: 23.2 %

Procedure:
In a similar fashion using route 48 general procedure 114, N-(4-chloro-quinolin-8-yl)-benzenesulfonamide 224 (80 mg, 0.250 mmol) and dimethyl amine (2M in THF; 1.25 ml, 2.50 mmol) gave the title compound (19 mg, 23%) after purification by column chromatography with chloroform/MeOH (1 drop NH3) (98:2) as the eluent followed by recrystallisation from MeOH/DCM.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(OCC)(=O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH2:32][N:34]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: O=Cc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(CN4CCOCC4)cn3)[nH]2)cc1)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a solution of 6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine-3-carbaldehyde (200 mg) in 1,2-dichloroethane (5 mL) was added morpholine (240 μL), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added sodium triacetoxyborohydride (280 mg), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (192 mg, yield 83%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). MS: 536 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:26]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]([CH3:37])[CH3:36])[C:30]=1[N:38]=[C:39]=[O:40])([CH3:28])[CH3:27]>>[CH:26]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]([CH3:36])[CH3:37])[C:30]=1[NH:38][C:39](=[O:40])[N:11]([CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[C:12]1[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:16][CH:17]=1)([CH3:27])[CH3:28]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CCCCCCCCc1ccc(NCc2ccc([N+](=O)[O-])cc2)cc1
Product: CCCCCCCCc1ccc(N(Cc2ccc([N+](=O)[O-])cc2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Yield: 6.5 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using [(4-nitrophenyl)methyl](4-octylphenyl)amine (2.6 g) and 2,6-diisopropylphenyl isocyanate (1.55 g) as starting materials, N′-(2,6-diisopropylphenyl)-N-[(4-nitrophenyl)methyl]-N-(4-octylphenyl)urea (0.27 g) was obtained.