Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4](Cl)=[N:5][OH:6].[CH3:12][O:13][C:14](=[O:18])[CH2:15][C:16]#[N:17].C[O-].[Na+]>CO>[CH3:12][O:13][C:14]([C:15]1[C:4]([C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=2[F:1])=[N:5][O:6][C:16]=1[NH2:17])=[O:18]
Reactant: COC(=O)CC#N
Reactant: ON=C(Cl)c1ccccc1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(-c2ccccc2F)noc1N
Yield: 75.5 %

Procedure:
In a similar manner as described in Preparation Example 17, by using methanol (160 mL), 2-fluoro-N-hydroxybenzimidoyl chloride (8.00 g, 46.09 mmol), methylcyanoacetate (5.94 g, 59.92 mmol) and sodium methoxide (4.98 g, 92.18 mmol), a white solid required compound (8.23 g, 34.82 mmol, 76%) was obtained.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.[C:13]1([CH3:25])[CH:18]=[CH:17][CH:16]=[C:15]([C@@H:19]([CH3:24])[C:20](OC)=[O:21])[CH:14]=1>O1CCCC1>[O:21]=[C:20]([C@@H:19]([C:15]1[CH:14]=[C:13]([CH3:25])[CH:18]=[CH:17][CH:16]=1)[CH3:24])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COC(=O)[C@H](C)c1cccc(C)c1
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)[C@H](C)c1cccc(C)c1)OC
Reaction time: 1 h
Yield: 80.2 %

Procedure:
To dimethyl methylphosphonate (1.97 g) was added tetrahydrofuran (THF) (25 mL), and the mixture was cooled to −78° C. n-Butyllithium (1.5 M hexane solution) (10 mL) was added, and the mixture was stirred for 1 hr. Then, a solution of methyl ester {methyl (2R)-2-(m-tolyl)propionate} synthesized in Example 1 (1.34 g) in THF (3.8 mL) was added at −78° C., and the mixture was stirred for 2 hr. The reaction was quenched with 25 mL of saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate 5:1-1:5) to give the title compound (1.63 g). The structural property was as described below.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[N:18]([CH3:19])[C:17](=[O:20])[CH:16]3[CH2:21][CH2:22][CH2:23][N:15]3[CH2:14][C:13]=2[CH:24]=1)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[OH:8][C:9]1[CH:10]=[CH:11][C:12]2[N:18]([CH3:19])[C:17](=[O:20])[CH:16]3[CH2:21][CH2:22][CH2:23][N:15]3[CH2:14][C:13]=2[CH:24]=1
Reactant: CN1C(=O)C2CCCN2Cc2cc(OCc3ccccc3)ccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CN1C(=O)C2CCCN2Cc2cc(O)ccc21

Procedure:
A mixture of 6.44 g. of 7-benzyloxy-1,2,3,5,10,11a- hexahydro-10-methyl-11H-pyrrolo[2,1-c] [1,4]benzodiazepin-11- one, 200 ml. of ethanol and 1.0 g. of 10% palladium-on-carbon catalyst is shaken in a Parr hydrogenator under about 3 atmospheric of hydrogen pressure until the theoretical amount of hydrogen is absorbed. The catalyst is filtered off and the mother liquor is concentrated to remove the solvent. The residue is purified by partition chromatography on a diatomaceous earth column using a heptane/methyl cellosolve solvent system to yield pure 1,2,3,5,10,11a-hexahydro-7-hydroxy- 10-methyl-11H-pyrrolo[2,1-c] [1,4]benzodiazepin-11-one.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=O)=O.[CH:18]1[C:23]([NH:24][NH2:25])=[CH:22][CH:21]=[C:20]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:19]=1.Cl>C(O)C>[F:1][C:2]([F:17])([F:16])[C:3]1[C:5]2[C:6](=[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]3=[CH:13][CH:14]=2)[N:24]([CH:23]2[CH2:22][CH:21]=[C:20]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:19]=[CH:18]2)[N:25]=1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: O=C1c2ccccc2CCC1C(=O)C(F)(F)F
Agent: Cl
Solvent: CCO
Product: NS(=O)(=O)C1=CCC(n2nc(C(F)(F)F)c3ccc4ccccc4c32)C=C1
Yield: 71 %

Procedure:
A 100 mL one necked round bottomed flask equipped with reflux condenser nitrogen inlet and provisions for magnetic stirring was charged with 2-trifluoroacetyl-1-tetralone (1.21 g, 5.0 mmol), 4-sulfonamido phenylhydrazine hydrochloride (1.12 g, 5.0 mmol) and 25 mL of absolute ethanol. The solution was then warmed to reflux for 15 h and then concentrated in vacuo. The residue was dissolved in ethyl acetate and then washed with water, brine, dried over anhyd. MgSO4, filtered and concentrated in vacuo. The residue was recrystallized from a mixture of ethyl acetate and isooctane to give g, 71% of pure product with mp 257°-258° C. 1H NMR (CDCl3 /CD3OD, 4:1) δ2.7 (m, 2H), 2.9 (m, 2H), 6.6 (m, 1H), 6.9 (m, 1H), 7.1 (m, 1H), 7.16 (m, 1H), 7.53 (m, 2H), 7.92 (m, 2H); 19 F NMR CDCl3 δ62.5. FAB-MS M+H=394.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=S)[C:6]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)=[C:5]2[C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21].Cl.[CH3:27][O:28][NH2:29]>C(O)C>[CH3:27][O:28][N:29]=[C:7]1[C:6]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[C:5]([C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[NH:8]1
Reactant: CON
Reactant: CC(C)OC(=O)c1c(-c2ccc(Cl)cc2)c(=S)[nH]c2ccc(Cl)cc12
Agent: Cl
Solvent: CCO
Product: CON=c1[nH]c2ccc(Cl)cc2c(C(=O)OC(C)C)c1-c1ccc(Cl)cc1

Procedure:
0.42 g (1.07 mol) of 6-chloro-3-(p-chlorophenyl)-4-isopropoxycarbonylquinoline-2(1H)-thione (prepared according to methods from Examples 6, 7 and 8 described above, but using 5-chloroisatin and p-chlorophenyl acetic acid as starting materials) is dissolved in 10 ml of abs. ethanol and treated with 0.5 g of O-methylhydroxylamine hydrochloride. The reaction mixture is heated at reflux temperature for 3 hours. It is then concentrated under reduced pressure on a rotary evaporator, the residue is taken up in ethyl acetate, the organic phase is washed twice with water and, after drying by means of sodium sulfate, concentrated under reduced pressure on a rotary evaporator. The crude product obtained is purified by means of chromatography on silica gel (mobile phase: ethyl acetate/n-heptane=1/4). For fine purification, chromatography on ®Sephadex type LH-20 using methanol as the mobile phase is suitable.
Reaction SMILES: [S:1]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:13][CH2:14][C:15](Cl)=[O:16].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[Cl:13][CH2:14][C:15]([C:5]1[CH:6]=[CH:7][C:2]([S:1][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:3][CH:4]=1)=[O:16]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)CSc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)CSc1ccc(C(=O)CCl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of methyl thiophenoxyacetate (60g.) in methylene chloride (100ml.) was added over 20 minutes to a stirred suspension of chloroacetyl chloride (45.2g.) and aluminium chloride (134g.) in methylene chloride (400ml.) at room temperature. The resulting solution was stirred at room temperature overnight and poured onto a mixture of ice (2kg.) and concentrated hydrochloric acid (50ml.). This mixture was then stirred at room temperature for 1 hour. The methylene chloride phase was separated, dried (MgSO4) and evaporated in vacuo. The residue was recrystallised from methanol to give methyl 4-(chloroacetyl)-thiophenoxyacetate (60.1g.), m.p. 61°-63° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([Br:9])[N:3]=1.[C:10](OCC)(OCC)(OCC)[CH3:11].C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C.ClCCl>[Br:9][C:4]1[N:3]=[C:2]2[N:1]=[C:10]([CH3:11])[NH:8][C:7]2=[CH:6][CH:5]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: Nc1ccc(Br)nc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1nc2nc(Br)ccc2[nH]1
Temperature: 25 °C

Procedure:
2,3-Diamino-6-bromopyridine (8.16 g) and triethyl orthoacetate (12.0 ml) were mixed in acetic acid (41 ml), and the mixture was refluxed under heating for 29 hr. The mixture was allowed to cool and the solvent was evaporated to give a crude product (10 g). This was dissolved in a sufficient amount of dichloromethane. Anhydrous potassium carbonate and active carbon were added and the mixture was stirred at room temperature. The insoluble matter was filtered off and the solvent was evaporated to give the objective compound (7.59 g) as a pale-yellow powder.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][CH2:10][N:9]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][N:13]=3)[CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1.[I-].[Na+].I>C(#N)C>[Cl:18][C:17]1[C:12]([N:9]2[CH2:10][CH2:11][C:3]3[C:2]([NH:24][C:23]4[CH:25]=[CH:26][C:20]([F:19])=[CH:21][CH:22]=4)=[N:7][CH:6]=[N:5][C:4]=3[CH2:8]2)=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: Clc1cccnc1N1CCc2c(Cl)ncnc2C1
Reactant: Nc1ccc(F)cc1
Agent: I
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: Fc1ccc(Nc2ncnc3c2CCN(c2ncccc2Cl)C3)cc1
Temperature: 130 °C
Yield: 42.6 %

Procedure:
4-Chloro-7-(3-chloro-pyridin-2-yl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine (100 mg, 0.35 mmol) was dissolved in acetonitrile (2 mL). To the mixture was added 4-flouroaniline (0.067 mL, 0.71 mmol), sodium iodide (80 mg, 0.53 mmol) and HI (47%, 0.2 mL). The mixture was heated in a sealed tube at 130° C. for 10 minutes in a Personal Chemistry Microwave (Smith Creator). The solvent was removed under vacuum and the resulting orange residue dissolved in ethyl acetate and washed with saturated sodium bicarbonate and brine. The organic layer was dried over sodium sulphate, filtered and evaporated. The residue was purified by flash chromatography over silica gel using a 0-100% ethyl acetate-hexane gradient to give the product as an off white solid (53 mg).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([C@@H:11]([NH2:13])[CH3:12])[N:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][NH:25]2.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([C@@H:11]([NH:13][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)[CH3:12])[N:7]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncnc2[nH]cnc12
Reactant: C[C@H](N)c1nc2c(Cl)cccc2n1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2c(Cl)cccc2n1-c1ccccc1
Temperature: 120 °C
Reaction time: 16 h
Yield: 18.4 %

Procedure:
A mixture of (S)-1-(4-chloro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine from Example 9 (250 mg, 0.92 mmol), 6-chloro-9H-purine (200 mg, 1.29 mmol) and DIPEA (0.29 mL, 1.66 mmol) in n-butanol (2 mL) was stirred in a sealed tube for 16 h at 120° C. Additional amounts of 6-chloro-9H-purine (100 mg, 0.64 mmol) and DIPEA (0.14 mL, 0.802 mmol) were added and the stirring was continued at 120° C. for 24 h. After cooling to RT, the crude reaction mixture was partitioned between DCM and water. The aqueous phase was further extracted with DCM (×3) and then the combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-8% 2M NH3/MeOH in DCM) and then by preparative HPLC (Phenomenex Gemini 5 μm C18 on a 60 min gradient 20-98% 0.1% HCO2H in acetonitrile/water) affording 120 (66 mg, 42%). LCMS: RT 3.69 min [M+H]+ 390.0. 1H NMR (CDCl3, 400 MHz): δ 12.90 (1H, bs), 8.28-7.90 (3H, m), 7.71-7.41 (5H, m), 7.32 (1H, d, J=7.75 Hz), 7.19 (1H, t, J=7.90 Hz), 7.03 (1H, d, J=8.10 Hz), 5.46 (1H, br), 1.67-1.53 (3H, m)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](I)=[CH:9][N:10]=2)[CH:7]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21].C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:16]3[CH:17]=[C:18]([O:22][CH3:23])[C:19]([O:20][CH3:21])=[C:14]([O:13][CH3:12])[CH:15]=3)=[CH:9][N:10]=2)[CH:7]=1
Reactant: Brc1ccc2ncc(I)n2c1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1cc(-c2cnc3ccc(Br)cn23)cc(OC)c1OC
Temperature: 90 °C
Yield: 44.4 %

Procedure:
A reaction flask was charged with 6-bromo-3-iodoimidazo[1,2-a]pyridine (2.0 g, 6.2 mmol), (3,4,5-trimethoxyphenyl)boronic acid (1.44 g, 6.8 mmol), 2M. aq. Na2CO3 (8 mL, 16 mmol), 1,4-dioxane (50 mL) and a stir bar. The contents were degassed by vacuum and back filled with argon in three times while stirring. Subsequently, catalyst Pd(PPh3)4 (0.35 g, 0.30 mmol) was added to the reaction contents, repeated degassing cycles and heated at 90° C. for 12 h. Reaction mixture was cooled and filtered the biphasic reaction mixture through Celite® and concentrated the filtrate. The crude solid residue was partitioned between CH2Cl2(150 mL)/water (50 mL). The organic layer was separated, dried over MgSO4, filtered and concentrated. The crude concentrate (2.2 g) was subjected to purification by flash column chromatography (Combiflash® companion System® with RediSep® silica gel column 40 g, 30-60% EtOAC/hexanes as an eluting solvent) to obtain 6-bromo-3-(3,4,5-trimethoxyphenyl)imidazo[1,2-a]pyridine as a white solid (1.0 g).
Reaction SMILES: [C:1]1([C:7]#[C:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]([C:17]([OH:22])([CH2:20][CH3:21])[CH2:18][OH:19])[CH:14]=[N:15][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][C:24]([CH3:26])=O>>[CH2:20]([C:17]1([C:13]2[CH:14]=[N:15][CH:16]=[C:11]([O:10][CH2:9][C:8]#[C:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:12]=2)[CH2:18][O:19][C:24]([CH3:26])([CH3:23])[O:22]1)[CH3:21]
Reactant: CC(C)=O
Reactant: CCC(O)(CO)c1cncc(OCC#Cc2ccccc2)c1
Product: CCC1(c2cncc(OCC#Cc3ccccc3)c2)COC(C)(C)O1
Yield: 59 %

Procedure:
Using the procedure described in Example 1, 2-[5-(3-phenylprop-2-ynyloxy)pyrid-3-yl]butane-1,2-diol was reacted with acetone to give 4-ethyl-2,2-dimethy-4-[5-(3-phenylprop-2-ynyloxy)pyrid-3-yl]-1,3-dioxolane in 59% yield, as an oil.
Reaction SMILES: Cl.[CH:2]1([NH:7][NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.C(O[CH:12]=[C:13]([C:19]#[N:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])C.C([O-])(=O)C.[Na+]>C(O)C>[CH2:17]([O:16][C:14]([C:13]1[CH:12]=[N:8][N:7]([CH:2]2[CH2:6][CH2:5][CH2:4][CH2:3]2)[C:19]=1[NH2:20])=[O:15])[CH3:18]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: NNC1CCCC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnn(C2CCCC2)c1N
Temperature: 70 °C
Yield: 79.3 %

Procedure:
Cyclopentyl-hydrazine hydrochloride (1.000 g; 7.32 mmol), ethyl (ethoxymethylene)-cyanoacetate (1.026 g, 6.61 mmol) and anhydrous sodium acetate (0.644 g, 7.85 mmol) were combined in ethanol (10 mL) and heated at 70° C. for 20 hours. After cooling to room temperature, ethanol was removed in vacuo and the residue was partitioned between methylene chloride and water. The organic phase was washed sequentially with water and brine. Each aqueous phase was back extracted with a single portion of methylene chloride. The two organic phases were combined, dried over sodium sulfate and concentrated. Purification by flash chromatography, eluting with 10-40% EtOAc/hexanes yielded 5-amino-1-cyclopentyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.170 g, 73%). Mass spectrum: m/z: 224.1 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:14][C@H:13]([CH2:15][NH:16][C:17](=[O:19])[CH3:18])[O:12][C:11]2=[O:20])[CH:5]=[C:6]([F:9])[C:7]=1I.FC1C=C(N2C[C@H](CNC(=O)C)OC2=O)C=CC=1[C:28]1[CH:29]=[N:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=1>>[F:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:14][C@H:13]([CH2:15][NH:16][C:17](=[O:19])[CH3:18])[O:12][C:11]2=[O:20])[CH:5]=[C:6]([F:9])[C:7]=1[C:28]1[CH:29]=[N:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=1
Reactant: COc1ccc(-c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)cn1
Reactant: CC(=O)NC[C@H]1CN(c2cc(F)c(I)c(F)c2)C(=O)O1
Product: COc1ccc(-c2c(F)cc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)cn1

Procedure:
N-({(5S)-3-[3,5-difluoro-4-(6-methoxypyridin-3-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide is prepared by the route described in Example 1 substituting N-{[(5S)-3-(3,5-difluoro-4-iodophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide for N-({(5S)-3-[3-fluoro-4-(6-methoxypyridin-3-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide. 1H-NMR (DMSO) δ: 8.25, 7.61, 7.30, 4.73, 4.10, 3.72, 3.49, 3.40, 2.30, 1.90, 1.83
Reaction SMILES: [F:1][CH:2]([F:19])[C:3]#[C:4][C:5]1([OH:18])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1>C1COCC1>[F:19][CH:2]([F:1])/[CH:3]=[CH:4]/[C:5]1([OH:18])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(C#CC(F)F)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(/C=C/C(F)F)CC1
Temperature: -78 °C
Reaction time: 5 h
Yield: 103.3 %

Procedure:
To a solution of tert-butyl 4-(3,3-difluoroprop-1-yn-1-yl)-4-hydroxypiperidine-1-carboxylate (280 mg, 1.016 mmol) in 30 mL of anhydrous THF was added dropwise sodium dihydro-bis-(2-methoxyethoxy)aluminate (587 mg, 2.032 mmol, 70%) at −78° C. under N2. After the addition, the reaction mixture was stirred at −78° C. under N2 for 5 h. The reaction mixture was quenched by sat. NH4Cl aq., and the resulting mixture was extracted with EtOAc (50 mL, 30 mL). The combined organic phase was washed with brine, dried over anhy. Na2SO4 and concentrated in vacuo to afford 291 mg of title compound. MS (ES) M+H expected 278.15, found 178.30. 1H NMR (CHLOROFORM-d) δ: 6.29-6.08 (m, 2H), 6.01-5.84 (m, 1H), 3.98-3.84 (m, 2H), 3.20 (t, J=11.4 Hz, 2H), 1.76-1.62 (m, 4H), 1.48 (s, 9H).
Reaction SMILES: [N+:1]([CH:4]([CH2:18][CH2:19][CH2:20][CH3:21])[C:5](=O)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O-])=O.Cl.[N:23]#[C:24][NH2:25]>[Pd]>[CH2:18]([C:4]1[NH:1][C:24]([NH2:25])=[N:23][C:5]=1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCC(C(=O)CCCCCc1ccccc1)[N+](=O)[O-]
Reactant: N#CN
Agent: [Pd]
Agent: Cl
Product: CCCCc1[nH]c(N)nc1CCCCCc1ccccc1

Procedure:
7-Nitro-1-phenylundecan-6-one (0.049 g, 0.17 mmol) reacted with concentrated HCl (0.85 mmol) and palladium, 5 wt. % on activated carbon (0.072 g, 0.034 mmol) under H2, then reacted with cyanamide (0.035 g, 0.84 mmol) according to the general procedure. Purification by column chromatography gave 0.025 g (52%) over two steps as a yellow oil: 1H NMR (400 MHz, CD3OD) δ 7.22 (m, 2H), 7.15 (m, 3H), 2.60 (t, J=7.2 Hz, 2H), 2.43 (m, 4H), 1.64 (m, 6H), 1.34 (m, 4H), 0.94 (t, J=7.6 Hz, 3H) ppm; 13C NMR (75 MHz, CD3OD) δ 146.4, 142.4, 128.2, 128.1, 125.6, 122.1, 121.9, 35.5, 31.2, 31.1, 28.7, 28.2, 23.0, 22.8, 21.9, 12.9 ppm; IR νmax (cm−1) 3166, 2930, 2857, 1680, 1453, 1030, 748, 699; HRMS (FAB) calcd for C18H27N3 (MH+) 286.2278, found 286.2288.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C(N(CC)CC)C.Cl[Si](C)(C)C.Cl[C:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCCC1>[C:19]1([C:18]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:4][CH2:3][CH2:1][OH:2])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NCCO
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: OCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Ethanolamine (5 g, 82 mmol) and triethylamine (11.4 ml, 8.28 g, 82 mmol) were dissolved in dry tetrahydrofuran (50 ml). Chlorotrimethylsilane (10.4 ml, 8.90 g, 82 mmol) was added over five minutes and the mixture was stirred for 30 minutes. The white solid was removed by filtration and washed with dry tetrahydrofuran. The combined filtrate and washings were stirred and triethylamine (11.4 ml, 8.28 g, 82 mmol) was added followed by chlorotriphenylmethane (22.8 g, 82 mmol). The mixture was stirred at ambient temperature for two hours, when it was filtered and the filtrate cooled to 0° C. for 30 minutes. Following a further filtration the liquors were stirred with methanol (60 ml) for fifteen minutes. The solvent was removed under vacuum and the residue crystallised from hot ethyl acetate. The resulting white solid was dried under vacuum at room temperature for 16 hours before triturating successively with diethyl ether (twice) and acetone (twice). The residue was heated with boiling acetone (700 ml) for ten minutes before the solid was collected by filtration, washed with cold acetone and dried under vacuum for four hours to give N-(triphenylmethyl)ethanolamine.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[C:11]([N:30]1[CH:34]=[C:33]([CH2:35][CH2:36][C:37](OC)=[O:38])[N:32]=[CH:31]1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1.C(Cl)Cl>[C:11]([N:30]1[CH:34]=[C:33]([CH2:35][CH2:36][CH:37]=[O:38])[N:32]=[CH:31]1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Yield: 50.8 %

Procedure:
A solution of 44.4 mmole of diisobutylaluminium hydride in 29 ml of toluene is added to a solution of 8.79 g of methyl 3-(1-tritylimidazol-4-yl)propionate in 175 ml of methylene chloride at -72° under nitrogen. After 5 min the reaction is quenched by adding 14 ml of methanol followed by 90 ml of water. The reaction mixture is allowed to warm to room temperature and is filtered through celite. The organic phase is separated, dried over sodium sulfate and evaporated to a yellow oil which is chromatographed on 280 g of silica with ether to yield 4.13 g of 3-(1-tritylimidazol-4-yl)propionaldehyde as an oil. IR (CDCl3): 2830, 2740, 1730 cm-1.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:41]([CH2:45][CH2:46][CH2:47][CH3:48])[CH:42]=[N:43][CH:44]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:58])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:41]([CH2:45][CH2:46][CH2:47][CH3:48])[CH:42]=[N:43][CH:44]=5)=[O:58])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cncn4CCCC)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cncn4CCCC)cc2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(3-butylimidazol-4-yl)methylthio]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (1.15 g) was dissolved in dichloromethane (40 ml), and the mixture was cooled to −78° C. A solution of 3-chloroperbenzoic acid (0.62 g) in dichloromethane (10 ml) was added dropwise to the solution. The mixture was stirred for 1 hour at −78° C., and then, an aqueous solution of sodium thiosulfate was added to the mixture. The mixture was concentrated, and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: triethylamine/methanol/ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(3-butylimidazol-4-yl)methylsulfinyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 401) (0.72 g) as yellow amorphous.