Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1([C:36](OCC)=[O:37])[CH2:10][CH2:9][CH2:8][N:7]1[C:11]1[CH:12]=[N:13][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[O:25][CH:26]=[C:27]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[N:28]=3)=[CH:20][CH:19]=2)=[CH:15][CH:16]=1)=O)C.[NH2:41][C:42]([NH2:44])=[O:43].[H-].[Na+]>CS(C)=O>[F:35][C:32]1[CH:31]=[CH:30][C:29]([C:27]2[N:28]=[C:24]([C:21]3[CH:20]=[CH:19][C:18]([O:17][C:14]4[N:13]=[CH:12][C:11]([N:7]5[C:6]6([C:4](=[O:3])[NH:44][C:42](=[O:43])[NH:41][C:36]6=[O:37])[CH2:10][CH2:9][CH2:8]5)=[CH:16][CH:15]=4)=[CH:23][CH:22]=3)[O:25][CH:26]=2)=[CH:34][CH:33]=1
Reactant: CCOC(=O)C1(C(=O)OCC)CCCN1c1ccc(Oc2ccc(-c3nc(-c4ccc(F)cc4)co3)cc2)nc1
Reactant: NC(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C1NC(=O)C2(CCCN2c2ccc(Oc3ccc(-c4nc(-c5ccc(F)cc5)co4)cc3)nc2)C(=O)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
1-(6-{4-[4-(4-Fluoro-phenyl)-oxazol-2-yl]-phenoxy}-pyridin-3-yl)-pyrrolidine-2,2-dicarboxylic acid diethyl ester (5.0 grams, 9.16 mmol) and recrystallized urea (2.75 grams, 45.82 mmol) were dissolved in anhydrous dimethylsulfoxide (110 mL), and the solution was placed in a cold water bath. Sodium hydride (770 mg of a 60% dispersion in mineral oil, 19.23 mmol) was added in two portions. The cold water bath was removed after an addition of the second portion, and the resulting solution was stirred for 1 hour at room temperature. The reaction was then poured into 550 mL water and stirred for 20 minutes until cool. The aqueous layer was extracted three times with diethyl ether, and the combined organic layers were set aside. The pH of the aqueous layer was adjusted to 5 with 1 M hydrochloric acid, and the aqueous layer was extracted three times with ethyl acetate. The combined ethyl acetate layers were washed with water and a solution of saturated sodium chloride, dried over sodium sulfate, and concentrated to give 4.8 grams of crude product as a white foam. This material was chromatographed on silica gel (ISCO MPLC purification, 50 minutes, 0-100% ethyl acetate gradient, Biotage flash 40 m column) to provide 3.44 grams (73%) of the title compound as a white solid. MS m/z: ESI+ 514.0 (M+H)+; ESI− 512.1 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[NH:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][NH:10][C:4]=2[CH:3]=1>C(Cl)Cl.O=[Mn]=O>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[NH:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=[N:10][C:4]=2[CH:3]=1
Reactant: Clc1ccc2c(c1)NCc1ccccc1N2
Agent: O=[Mn]=O
Solvent: ClCCl
Product: Clc1ccc2c(c1)N=Cc1ccccc1N2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 102.6 %

Procedure:
To a solution of 8-chloro-10,11-dihydro-5H-dibenzo[b,f][1,4]diazepine (8.75 g, 37.9 mmol) in CH2Cl2 (375 mL) was added MnO2 (14.5 g, 166 mmol). The reaction mixture was stirred at room temperature for 1.5 h. After filtration through dicalite, washing with CH2Cl2, the volatiles were removed in vacuo. The crude product was dissolved in ethanol (250 mL) wherafter 2N (aq) NaOH (20 mL) was added. This mixture was stirred at room temperature for 2.5 h. The reaction mixture was filtrated through dicalite and washed with CH2Cl2. After removal of the solvent under reduced pressure, the residu was dissolved in ethanol (350 mL). NaOH (2N, 20 mL) was added and the mixture was stirred for 3 h. Water was added and the mixture was extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried and evaporated to afford the title compound (8.9 g, 38.9 mmol).
Reaction SMILES: [C:1]([CH2:4][C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].C(N(CC)CC)C.[C:15]1([N:21]=[C:22]=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>C1C=CC=CC=1>[C:1]([CH:4]([C:5](=[O:7])[CH3:6])[C:22]([NH:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:23])(=[O:3])[CH3:2]
Reactant: CC(=O)CC(C)=O
Reactant: O=C=Nc1ccccc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)C(C(C)=O)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.9 %

Procedure:
A mixture of acetylacetone (5 g) and triethylamine (5.2 g) in dry benzene (50 ml) was treated with phenyl isocyanate (6 g) in dry benzene (25 ml). The mixture was stirred for 3 hr at room temperature. Water (50 ml) was then added, the mixture shaken and the water layer separated. The benzene solution was extracted with two further portions (25 ml) of water and the combined aqueous extracts acidified with dilute hydrochloric acid. The product precipitated and was collected by filtration, washed with water and dried. Diacetyl acetanilide (7.0 g, 73%) was obtained as a colourless solid, m.p. 119-121° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:27][CH:26]([C:28]([OH:30])=[O:29])[CH2:25]3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:33][OH:34].C(=O)([O-])O.[Na+]>>[OH:34]/[N:33]=[C:8](/[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1)\[CH2:9][C@H:10]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:27][CH:26]([C:28]([OH:30])=[O:29])[CH2:25]2)=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: NO
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(N3CC(C(=O)O)C3)cc2)c2ccccc2C)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@H](c2ccc(N3CC(C(=O)O)C3)cc2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 1, step 2, from 1-{4-[(R)-3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-phenyl}-azetidine-3-carboxylic acid and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a light yellow foam, MS (ESI+): m/z=430.3 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]([O:6][CH3:7])([CH3:5])[CH3:4].C[CH:9](CO)[CH2:10][OH:11]>C1COCC1>[CH3:4][C:3]1([CH3:5])[O:6][CH2:7][CH:9]([CH2:10][OH:11])[CH2:1][O:2]1
Reactant: CC(CO)CO
Reactant: COC(C)(C)OC
Solvent: C1CCOC1
Product: CC1(C)OCC(CO)CO1

Procedure:
A solution of 2,2-dimethoxypropane (5.88 g, 56.5 mmol), 2-methyl-propane-1,3-diol (5.0 g, 47 mmol), and PTSA monohydrate (0.48 g, 2.3 mmol) in THF (100 mL) was stirred O/N at rt. The mixture was concentrated in vacuo to give the title compound as a colorless liquid: yield 6.87 g (99%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([N:7]([CH2:18][CH3:19])[C:8](=[O:17])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:6].[Cl:20][CH2:21][C:22](Cl)=[O:23]>C(Cl)Cl>[CH2:18]([N:7]([CH2:5][CH3:6])[C:8](=[O:17])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:22](=[O:23])[CH2:21][Cl:20])=[CH:13][CH:12]=1)[CH3:19]
Reactant: CCN(CC)C(=O)COc1ccccc1
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCN(CC)C(=O)COc1ccc(C(=O)CCl)cc1
Reaction time: 16 h

Procedure:
Aluminium chloride (83.3g.) was added in portions over 30 minutes to a rapidly stirred solution of N,N-diethylphenoxyacetamide (51.6g.) and chloroacetyl chloride (31.0g.) in methylene dichloride (200ml.) at 0° C. The mixture was stirred and allowed to reach room temperature over 16 hours. The solvent was evaporated and the residue poured into a mixture of ice (300g.) and concentrated hydrochloric acid (15ml.). The mixture was extracted with methylene dichloride (5 × 100ml.), and the extracts washed with water (2 × 50ml.) dried and evaporated. The residue was chromatographed on alumina to give N,N-diethyl-4-(chloroacetyl)phenoxyacetamide, m.p. 89°-91° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15](=[O:38])[NH:16][CH:17]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]3[CH:32]=[N:33][C:34]([NH2:37])=[CH:35][CH:36]=3)[CH:26]=2)[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][CH2:10]1)(C)(C)C.CC1(C)C(C)(C)OB(C2C=CC(N)=NC=2)O1>>[NH2:37][C:34]1[N:33]=[CH:32][C:31]([C:27]2[CH:26]=[C:25]([CH:17]([NH:16][C:15]([CH:12]3[CH2:13][CH2:14][CH:9]([CH2:8][NH2:7])[CH2:10][CH2:11]3)=[O:38])[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:30]=[CH:29][CH:28]=2)=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)NCC1CCC(C(=O)NC(Cc2ccccc2)c2cccc(-c3ccc(N)nc3)c2)CC1
Agent: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: NCC1CCC(C(=O)NC(Cc2ccccc2)c2cccc(-c3ccc(N)nc3)c2)CC1

Procedure:
(4-{1-[3-(6-Amino-pyridin-3-yl)-phenyl]-2-phenyl-ethylcarbamoyl}-cyclohexylmethyl)-carbamic acid tert-butyl ester: Compound 2B was converted to compound 66A according to the procedure described in Example 24, by replacing 4-(methoxy-carbonylamino) phenyl boronic acid with 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine. LC/MS m/z (M+H)+=529.4.
Reaction SMILES: [OH:1][CH2:2][C:3]#[C:4][C:5]1[CH:6]=[C:7]([CH:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH2:12][C:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=2)=O)[CH:8]=[CH:9][CH:10]=1.Cl.[NH2:30][OH:31].C([O-])(O)=O.[Na+]>>[OH:1][CH2:2][C:3]#[C:4][C:5]1[CH:6]=[C:7]([CH:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH2:12][C:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=2)=[N:30][OH:31])[CH:8]=[CH:9][CH:10]=1
Reactant: Cc1cc(C(=O)CC(c2cccc(C#CCO)c2)c2ccccc2C)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(C(CC(c2cccc(C#CCO)c2)c2ccccc2C)=NO)ccn1

Procedure:
In analogy to example 74, step 7, from 3-[3-(3-hydroxy-prop-1-ynyl)-phenyl]-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (3:1) as a white foam, MS (ESI+): m/z=385.1 ([M+H]+).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][NH:3]1.Cl[CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][C:20]([C:24]([N:26]([CH2:30][CH:31]3[CH2:33][CH2:32]3)[CH2:27][CH2:28][CH3:29])=[O:25])=[C:21]([CH3:23])[N:22]=2)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(#N)C>[CH:31]1([CH2:30][N:26]([CH2:27][CH2:28][CH3:29])[C:24]([C:20]2[O:19][C:18]([C:15]3[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][CH2:8][N:3]4[CH2:4][CH2:5][CH2:6][CH:2]4[CH3:1])=[CH:17][CH:16]=3)=[N:22][C:21]=2[CH3:23])=[O:25])[CH2:33][CH2:32]1
Reactant: CC1CCCN1
Reactant: CCCN(CC1CC1)C(=O)c1oc(-c2ccc(OCCCCl)cc2)nc1C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCCN(CC1CC1)C(=O)c1oc(-c2ccc(OCCCN3CCCC3C)cc2)nc1C
Reaction time: 20 h
Yield: 35 %

Procedure:
2-methylpyrrolidine (0.24 ml, 2.46 mmol, 1.2 eq) is added to a solution of 2-[4-(3-chloropropoxy)phenyl]-N-(cyclopropylmethyl)-4-methyl-N-propyl-1,3-oxazole-5-carboxamide i44 (0.8 g, 2 mmol, 1 eq), potassium carbonate (0.55 g, 4 mmol, 2 eq) and a catalytic quantity of sodium iodide in refluxing acetonitrile (25 ml). After stirring for 20 h at reflux, the solvent is evaporated and the residue is taken up in ethyl acetate and washed two times with an aqueous solution of sodium hydrogenocarbonate. The organic layer is dried over magnesium sulfate, filtered and concentrated under vacuum. Purification by chromatography over silicagel (eluent: dichloromethane/methanol/ammonia 96:3.6:0.4) affords 0.31 g of N-(cyclopropylmethyl)-4-methyl-2-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}-N-propyl-1,3-oxazole-5-carboxamide 97.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:7]2[CH:15]=[CH:16][CH:17]=[CH:18][C:6]=2[S:5]1(=[O:20])=[O:19].[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[C:25]2[CH2:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(=O)(O)[O-].[Na+]>CN(C)C=O.O1CCCC1>[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[C:25]2[CH2:31][CH:32]1[CH2:37][CH2:36][N:35]([CH2:2][CH2:3][N:4]2[CH:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:7]3[CH:15]=[CH:16][CH:17]=[CH:18][C:6]=3[S:5]2(=[O:20])=[O:19])[CH2:34][CH2:33]1
Reactant: Fc1ccc2[nH]cc(CC3CCNCC3)c2c1
Reactant: O=S1(=O)c2ccccc2C(c2ccccc2)N1CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=S1(=O)c2ccccc2C(c2ccccc2)N1CCN1CCC(Cc2c[nH]c3ccc(F)cc23)CC1
Temperature: 20 °C
Reaction time: 48 h
Yield: 55.8 %

Procedure:
The procedure is as in Example 1, starting with 2-(2-chloroethyl)-3-phenyl-1,2-benzisothiazole 1,1-dioxide (2.85 g), 4-[(5-fluoro-3-indolyl)methyl]-piperidine (2.15 g) and sodium bicarbonate (2.3 g) in a mixture of dimethylformamide (30 cc) and tetrahydrofuran (20 cc). The mixture is heated to boiling for 48 hours and then cooled to a temperature in the region of 20° C. After purification by flash chromatography on a silica column under a stream of nitrogen at moderate pressure (0.5-1.5 bar) with a mixture of ethyl acetate and cyclohexane (80:20 by volume) as eluent, 2-{2-[4-((5-fluoro-3-indolyl)methyl)piperidino]ethyl}-3-phenyl-1,2-benzisothiazole 1,1-dioxide (2.6 g) is obtained, and is converted to a hydrochloride, m.p. 175° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=2)[CH:3]=1.[BH4-].[Na+].S(Cl)(Cl)=O.[CH3:23][N:24]1[CH:28]=[C:27]([CH2:29][C:30]2[C:31](=[O:37])[NH:32][C:33](=[S:36])[NH:34][CH:35]=2)[CH:26]=[N:25]1>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH2:13][S:36][C:33]3[NH:34][CH:35]=[C:30]([CH2:29][C:27]4[CH:26]=[N:25][N:24]([CH3:23])[CH:28]=4)[C:31](=[O:37])[N:32]=3)=[CH:11][CH:10]=2)[CH:3]=1
Reactant: Cn1cc(Cc2c[nH]c(=S)[nH]c2=O)cn1
Reactant: O=Cc1ccc(Oc2cc(Cl)ccn2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: Cn1cc(Cc2c[nH]c(SCc3ccc(Oc4cc(Cl)ccn4)cc3)nc2=O)cn1
Temperature: 60 °C
Reaction time: 8 h
Yield: 58.4 %

Procedure:
To a solution of 4-[(4-chloro-2-pyridinyl)oxy]benzaldehyde (120 mg, 0.514 mmol), (which may be prepared according to procedures described in the International Patent Application Publication No. WO 199847869) in methanol (2.0 mL) was added NaBH4 (23.32 mg, 0.616 mmol). After the suspended solution turned clear, it was quenched with water. The mixture was extracted with EA and concentrated. After removing the solvent, thionyl chloride (0.187 mL, 2.57 mmol) and DCM (2 mL) was added, and stirring continued overnight. Then 5-[(1-methyl-1H-pyrazol-4-yl)methyl]-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone (114 mg, 0.514 mmol) was added. The reaction mixture was heated at 60° C. for 0.5 h. Purification via MDAP then afforded the title compound (132 mg, 58.4% yield). LCMS: rt=2.84 min, [M+H+]=440
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:17]=[CH:16][C:7]([CH:8]([OH:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.Cl[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH:28]=[CH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:23][CH2:22]1.O>C1(C)C(C)=CC=CC=1>[CH3:3][C:4]1[CH:17]=[CH:16][C:7]([CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:15][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH:28]=[CH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:23][CH2:22]2)=[CH:6][CH:5]=1
Reactant: ClCCN1CCN(CC=Cc2ccccc2)CC1
Reactant: Cc1ccc(C(O)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1C
Product: Cc1ccc(C(OCCN2CCN(CC=Cc3ccccc3)CC2)c2ccccc2)cc1

Procedure:
2 g of 60% sodium hydride in paraffin oil were added to a solution of 10 g (0.05 mol) of 4-methylbenzhydrol in 100 ml of anhydrous xylene. The reaction mixture was refluxed for half an hour and then 12.7 g (0.05 mol) of 1-(2-chloroethyl)-4-(3-phenyl-2-propenyl)piperazine (German Pat. appl. 2.431.178) in 50 ml of xylene were added dropwise. The reaction mixture was refluxed for another three hours and then cooled and poured into water. The organic layer was separated off, washed with water and concentrated. The residue was purified by column chromatography (Silicagel) with chloroform/ethylacetate/methanol/ammonia (25:25:1:0.5) as the eluent which yielded 1-[2-[(4-Methylphenyl)phenylmethoxy]ethyl]-4-(3-phenyl-2-propenyl)piperazine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:4][C:3]=1[CH3:18]>CO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:4][C:3]=1[CH3:18]
Reactant: Cc1cc(C=CCCCCCC(=O)O)ccc1F
Agent: [Pd]
Solvent: CO
Product: Cc1cc(CCCCCCCC(=O)O)ccc1F
Temperature: 25 °C
Reaction time: 63 h
Yield: 95 %

Procedure:
To a solution of 8-(4-fluoro-3-methylphenyl)oct-7-enoic acid (0.976 g, 3.899 mmol) in 30 mL of MeOH, was added 10% Pd on C (0.195 g). After stirring at room temperature under H2 for 63 h, the reaction mixture was filtered through a pad of Celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was used directly in the next step without further purification (0.938 g, 95% yield). LC-MS: tR=10.1 min, m/z 253 (M+H)+.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[CH2:5]([NH:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1(C)C=CC=CC=1>[CH2:5]([N:12]([CH2:13][CH2:14][CH2:15][CH3:16])[C:1]([Cl:4])=[O:2])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: CCCCNCc1ccccc1
Solvent: Cc1ccccc1
Product: CCCCN(Cc1ccccc1)C(=O)Cl

Procedure:
A solution of 20.0 g of phosgene in 100 ml. of toluene is stirred at 0° C. while a solution of 32.6 g. of N-benzyl-n-butylamine in 50 ml. of toluene is added during 15 minutes. The mixture is filtered and the filtrate is evpaorated. The residue is evaporatively distilled at 105° C. under reduced pressure (250-350 microns) to yield N-benzyl-N-(n-butyl)carbamyl chloride as a colorless liquid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])[C:5]([Cl:22])=[CH:4][N:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=2)[CH2:26][CH2:25]1>C(Cl)Cl.CO>[Cl:22][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])=[N:7][C:2]([NH:35][C:34]2[CH:33]=[CH:32][C:31]([CH2:30][N:27]3[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]3)=[CH:37][CH:36]=2)=[N:3][CH:4]=1
Reactant: O=C(c1ccccc1Nc1nc(Cl)ncc1Cl)N1CCCC1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)N4CCCC4)n3)cc2)CC1
Yield: 73 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from (2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)(pyrrolidin-1-yl)methanone and 4-((4-methylpiperazin-1-yl)methyl)aniline in 73% yield (yellow solid) after flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ 9.68 (s, 1H), 8.40 (d, 1H, J=8.2 Hz), 8.04 (s, 1H), 7.46 (d, 2H, J=8.2 Hz), 7.39-7.34 (m, 2H), 7.21 (d, 2H, J=8.2 Hz), 7.06 (t, 1H, J=7.5 Hz), 3.65 (t, 2H, J=7.0 Hz), 3.48 (t, 2H, J=6.3 Hz), 3.44 (s, 2H), 2.44 (bs, 8H), 2.26 (s, 3H), 1.95 (m, 2H), 1.83 (m, 2H); MS (ESI): 506.1 [M+H]+.
Reaction SMILES: C([C@@H:4]([C@@H:20]([OH:29])/[CH:21]=[CH:22]/[C:23]1C=CC=CC=1)[C:5]([N:7]1[C@H:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10]O[C:8]1=[O:19])=[O:6])C=C.[C:30]1(C)C=CC=CC=1>Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1>[CH2:12]([C@H:11]1[N:7]([C:5]([C@H:4]2[CH2:23][CH:22]=[CH:21][C@@H:20]2[OH:29])=[O:6])[C:8](=[O:19])[CH2:30][CH2:10]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C=CC[C@H](C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)[C@@H](O)/C=C/c1ccccc1
Reactant: Cc1ccccc1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Product: O=C1CC[C@@H](Cc2ccccc2)N1C(=O)[C@H]1CC=C[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
A solution of (R)-3-((2S,3S,E)-2-allyl-3-hydroxy-5-phenylpent-4-enoyl)-4-benzyloxazolidin-2-one (50 g, 128 mmol) and Grubbs 2nd generation catalyst (5.4 g, 6.4 mmol) in toluene (300 mL) was degassed with nitrogen three times, and stirred at room temperature overnight. The reaction mixture was then concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:4) to afford the title compound (32 g, 87%) as a dark brown oil, which solidified upon standing. MS (ES+) C17H19NO3 requires: 285, found: 270 [M+H−H2O]+.
Reaction SMILES: C(O[CH:4]=[N:5][C:6]1[S:17][C:9]2[CH2:10][N:11]([C:14](=[O:16])[CH3:15])[CH2:12][CH2:13][C:8]=2[C:7]=1[C:18]([O:20]CC)=O)C.[NH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[O:38][CH3:39])[CH2:28][CH2:27]1>C(O)C>[C:14]([N:11]1[CH2:12][CH2:13][C:8]2[C:7]3[C:18](=[O:20])[N:23]([CH2:24][CH2:25][N:26]4[CH2:27][CH2:28][N:29]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[O:38][CH3:39])[CH2:30][CH2:31]4)[CH:4]=[N:5][C:6]=3[S:17][C:9]=2[CH2:10]1)(=[O:16])[CH3:15]
Reactant: COc1ccccc1N1CCN(CCN)CC1
Reactant: CCOC=Nc1sc2c(c1C(=O)OCC)CCN(C(C)=O)C2
Solvent: CCO
Product: COc1ccccc1N1CCN(CCn2cnc3sc4c(c3c2=O)CCN(C(C)=O)C4)CC1
Yield: 79.5 %

Procedure:
5.8 g (23.4 mmol) of 2-ethoxymethyleneamino-3-carboethoxy-6-acetyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine in 50 ml of ethanol were mixed with 5.5 g (23.4 mmol) of 1-(2-aminoethyl)-4-(2-methoxyphenyl)piperazine and refluxed for 2 h. The mixture was then concentrated in a rotary evaporator, and the residue was taken up in 30 ml of ethyl acetate, heated to boiling and left to cool with stirring. The solid which crystallized out was filtered off with suction after cooling in an ice bath and was washed with ethyl acetate. 8.7 g (80%) of product with melting point 170-172° C. were isolated.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:31][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([NH:31][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1)=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccncc1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(CNC(=O)OCc1ccccc1)Nc1ccncc1
Reaction time: 0.25 h
Yield: 71.7 %

Procedure:
36 g of N-benzyloxycarbonyl glycine was dissolved in 400 ml of dimethylformamide and the solution was cooled to -8° C., to which 56.8 g of dicylohexylcarbodiimide dissolved in 50 ml of dimethylformamide was added while maintaining the temperature at -8° to -6° C. After stirring at -6° to -3° C. for 15 minutes, 17 g of 4-aminopyridine was added at -3° to -1° C. The reaction liquid was allowed to stand so as to rise its temperature to room temperature over 2 hours and stirred at room temperature overnight. Then, dicyclohexylurea was filtered off and dimethylformamide was distilled off under reduced pressure. The residue was purified through the chromatography on silica gel (silica gel 1 kg; chloroform-methanol (3%→6%) as the eluent) and recrystallized from methanol-ethyl acetate to obtain 35.2 g of 4-[(N-benzyloxycarbonyl glycyl)amino]pyridine having the melting point of 154° to 156° C. This was dissolved in 1 l of methanol and 2.3 g of palladium black was added thereto followed by subjecting to the catalytic hydrogenation at room temperature and under atmospheric pressure. After 5 hours, the catalyst was filtered off and the filtrate was concentrated to about 50 ml. 200 ml of ethyl acetate was added and again the resultant solution was concentrated to about 60 ml so as to obtain the precipitate, which was allowed to stand overnight and filtered to obtain the titled compound.