Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16]Cl)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.[OH:18][C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=1)[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][O:18][C:19]3[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=3)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cccc(O)c1
Reactant: ClCCCC1CCN(c2ccc(Cl)nn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(OCCCC2CCN(c3ccc(Cl)nn3)CC2)c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
A mixture of 4.1 parts of 3-choro-6-[4-(3-chloropropyl)-1-piperidinyl]pyridazine, 2.5 parts of ethyl 3-hydroxybenzoate, 14 parts of potassium carbonate and 94 parts of N,N-dimethylformamide was stirred overnight at 110° C. The reaction mixture was evaporated and the residue was taken up in water and dichloromethane. The separated organic layer was dried, filtered and evaporated. The residue was crystallized from 2-propanol. The product was filtered off, washed with 2-propanol and 2,2'-oxybispropane and dried at 50° C., yielding 4.6 parts (75.9%) of ethyl 3-[3-[1-(6-chloro-3-pyridazinyl)-4-piperidinyl]propoxy]benzoate; mp. 105.3° C. (comp. 99).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[NH2:15])=[N:4][N:3]=[N:2]1.Cl[C:21]([C:23]1[CH:37]=[CH:36][C:26]([O:27][CH2:28][C:29]([O:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:30])=[CH:25][CH:24]=1)=[O:22]>N1C=CC=CC=1.C(Cl)Cl>[NH:4]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[NH:15][C:21]([C:23]2[CH:37]=[CH:36][C:26]([O:27][CH2:28][C:29]([O:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:30])=[CH:25][CH:24]=2)=[O:22])=[N:1][N:2]=[N:3]1
Reactant: CCCCOC(=O)COc1ccc(C(=O)Cl)cc1
Reactant: Nc1ccccc1Sc1ccccc1-c1nnn[nH]1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCOC(=O)COc1ccc(C(=O)Nc2ccccc2Sc2ccccc2-c2nnn[nH]2)cc1
Reaction time: 8 h
Yield: 81.7 %

Procedure:
In a mixture of 6 ml of pyridine and 80 ml of methylene chloride was dissolved 5.3 g of 2-[2-(1H-tetrazol-5-yl)phenylthio]aniline followed by dropwise addition of 5.4 g of butyl 4-chloroformylphenoxyacetate, and the mixture was stirred overnight. The solvent was then distilled off and the residue was crystallized from aqueous ethanol and then recrystallized ethyl acetate to give 8.1 g of the title compound as white crystals, m.p. 133-135.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:8][C:7]([CH2:15][CH2:16][CH:17]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[C:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:8][C:7]([CH2:15][CH2:16][CH2:17][N:28]2[CH2:29][CH2:30][N:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:26][CH2:27]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1cccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)n1nc(CCCN2CCN(c3ccccc3)CC2)cc1-c1cccs1

Procedure:
81 mg (95%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propanal (50 mg, 0.191 mmol), 1-phenylpiperazine (0.029 mL, 0.191 mmol), DIPEA (0.050 mL, 0.287 mmol) and NaBH(OAc)3 (121 mg, 0.573 mmol).
Reaction SMILES: [Li+].[CH3:2][CH:3]([N-]C(C)C)C.[F:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.C(I)C>C1COCC1>[CH2:2]([C:15]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[F:9])[CH3:3]
Reactant: CC(C)[N-]C(C)C
Reactant: Fc1cccnc1
Agent: [Li+]
Solvent: CCI
Solvent: C1CCOC1
Product: CCc1ccncc1F
Reaction time: 0.5 h
Yield: 51.9 %

Procedure:
To a stirred solution of LDA (200 mmol) in dry THF (400 ml) (prepared by a similar method to that used in Example 1) at -70° C. and under a nitrogen atmosphere was added dropwise 3-fluoropyridine (20 g, 200 mmol). After 30 minutes at this temperature ethyl iodide (60 g, 370 mmol) was added dropwise to the reaction and the mixture was allowed to warm slowly to between -10° and -5° C. whereupon an exotherm occurred and the temperature rose to 15° to 20° C. The mixture was stirred for a further 30 minutes after which time the reaction was quenched by the addition of water (50 ml) and the organic phase separated. The aqueous phase was extracted with ether (3×50 ml) and the combined organic layers were dried over magnesium sulphate and concentrated under reduced pressure. The resulting liquid was distilled at atmospheric pressure to yield the title compound (13 g), b.p. 154°-158° C., which was characterised by 1H-NMR spectroscopy.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.O.[F:13][C:14]([F:27])([F:26])[C:15]([C:22]([F:25])([F:24])[F:23])([C:18]([F:21])([F:20])[F:19])[CH:16]=[CH2:17].C(=O)(O)[O-].[Na+]>C(OCC)C>[F:13][C:14]([F:26])([F:27])[C:15]([C:18]([F:21])([F:20])[F:19])([C:22]([F:23])([F:24])[F:25])[CH:16]1[O:9][CH2:17]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CC(C(F)(F)F)(C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: FC(F)(F)C(C1CO1)(C(F)(F)F)C(F)(F)F

Procedure:
32.9 g (105 mmol) of 3-chloroperbenzoic acid with a peracid content of 55% is added in portions with stirring and cooling with water to a solution of 24.6 g (100 mmol) of 4,4,4-trifluoro-3,3-bis(trifluoromethyl)-but-1-ene in 150 ml of absolute diethyl ether. After addition is completed, it is refluxed for 3 hours. It is allowed to cool, and the solution is stirred in cold, saturated sodium bicarbonate solution. The ethereal solution is separated, washed with sodium chloride solution, dried on sodium sulfate and concentrated by evaporation on a column. The residue is purified by bulb tube distillation (vacuum 30 mbar, 130° C. bath).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10](=[O:13])[CH2:11][Cl:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:14](O)[CH2:15][OH:16].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][N:3]=[C:4]([C:10]1([O:16][CH2:15][CH2:14][O:13]1)[CH2:11][Cl:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: OCCO
Reactant: CCOC(=O)C(=NOC)C(=O)CCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=NOC)C1(CCl)OCCO1
Temperature: 25 °C
Yield: 49.1 %

Procedure:
A mixture of ethyl 2-methoxyimino-3-oxo-4-chlorobutyrate (syn isomer, 41 g), ethylene glycol (24.6 g), p-toluenesulfonic acid (2.0 g) and toluene (250 ml) was heated for 20 hours under reflux while removing water. The reaction mixture was cooled to ambient temperature, washed with a saturated aqueous solution of sodium bicarbonate, a saturated aqueous solution of sodium chloride in turn, dried over magnesium sulfate and then the solvents were removed. The residue was distilled under reduced pressure to give ethyl 2-methoxyimino-3,3-ethylenedioxy-4-chlorobutyrate (syn isomer, 24.4 g), bp 103°-110° C./2 mmHg.
Reaction SMILES: [CH2:1]([C:7]1[CH:40]=[CH:39][C:10]([C:11]([C:13]2[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[C:19]([C:25](=O)[C:26]3[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:28][CH:27]=3)=[CH:18][C:14]=2[C:15]([OH:17])=[O:16])=O)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H][H]>[Pd].O1CCCC1>[CH2:1]([C:7]1[CH:40]=[CH:39][C:10]([CH2:11][C:13]2[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[C:19]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:28][CH:27]=3)=[CH:18][C:14]=2[C:15]([OH:17])=[O:16])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1ccc(C(=O)c2cc(C(=O)O)c(C(=O)c3ccc(CCCCCC)cc3)cc2C(=O)O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCc1ccc(Cc2cc(C(=O)O)c(Cc3ccc(CCCCCC)cc3)cc2C(=O)O)cc1

Procedure:
A mixture of 5.26 grams of 2,5-bis(4-hexylbenzoyl)terephthalic acid, 100 mL of tetrahydrofuran, and 0.53 grams of 5% palladium on carbon (as a catalyst) was heated at 65° C. for 17 hours in an atmosphere of hydrogen at 270 kPa. The resulting mixture was filtered through Celite™ diatomaceous earth filter agent to remove the catalyst. The filtrate was concentrated in vacuo to give 2,5-bis(4-hexylbenzyl)terephthalic acid.
Reaction SMILES: N1C=CC=CC=1.[OH:7][CH2:8][C:9]#[C:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.Cl>ClCCl>[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26]([O:7][CH2:8][C:9]#[C:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=[N+]([O-])c1ccc(C#CCO)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC#Cc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 0 °C

Procedure:
4.4 ml (54 mmol) of pyridine are added dropwise to a solution of 5.8 g (33 mmol) of 4-(3-hydroxyprop-1-ynyl)-nitrobenzene and 5.2 g (27 mmol) of p-toluenesulphonic acid chloride in 50 ml of dichloromethane at 0° C. After 2 hours at 0° C. about 25 g of ice and 8 ml of conc. hydrochloric acid are added. The organic phase is separated off and washed with water. After removal of the solvent in vacuo and chromatography of the residue on silica gel (dichloromethane/methanol=1:1) the product is obtained as an oil.
Reaction SMILES: Br.[N:2]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13][C:14]([OH:16])=O)[CH2:6][CH2:5][CH2:4][CH2:3]1.Cl.[C:18]1([C:24]2([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:32]3[CH:28]([CH2:29][NH:30][CH2:31]3)[S:27][CH2:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[N:2]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13][C:14]([N:30]2[CH2:31][CH:32]3[C:24]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:25][CH2:26][S:27][CH:28]3[CH2:29]2)=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: c1ccc(C2(c3ccccc3)CCSC3CNCC32)cc1
Reactant: O=C(O)Cc1ccccc1N1CCCC1
Agent: Br
Agent: Cl
Product: O=C(Cc1ccccc1N1CCCC1)N1CC2SCCC(c3ccccc3)(c3ccccc3)C2C1
Yield: 30.9 %

Procedure:
By carrying out the procedure as in Example of Use 1, using 1.85 g of [2-(1-pyrrolidinyl)phenyl]acetic acid hydrobromide and 2.0 g of (4aRS,7aRS)4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole hydrochloride, 0.90 g of (4aRS,7aRS)6-{[2-(1-pyrrolidinyl)phenyl]acetyl}4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole is obtained in the form of white crystals; melting point 166° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]3[S:23][C:24]([C:33]4[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=4)=[CH:25][C:26]=3[C:27]#[C:28][Si](C)(C)C)=[O:21])=[CH:15][C:14]=2[O:40][CH3:41])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:28]=[CH:27][C:26]4[CH:25]=[C:24]([C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=5)[S:23][C:22]=4[C:20]3=[O:21])=[CH:15][C:14]=2[O:40][CH3:41])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(NC(=O)c2sc(-c3ccc(Cl)cc3)cc2C#C[Si](C)(C)C)ccc1OC1CN(C(=O)OC(C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(-n2ccc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OC1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.3 %

Procedure:
Dissolve 3-(4-{[5-(4-chloro-phenyl)-3-trimethylsilanylethynyl-thiophene-2-carbonyl]-amino}-2-methoxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (420 mg, 0.69 mmol) in THF (11 mL) and add 1 M tetrabutylammonium fluoride (1.50 mL, 1.50 mmol, solution in THF). Stir the solution at RT overnight. Dilute the solution with EtOAc (100 mL) and wash with water (3×50 mL) and brine (50 mL). Dry the organic solution, filter, and concentrate the filtrate. Purify the crude material by flash chromatography, using a linear gradiant of 30-70% EtOAc/hexanes, to give 280 mg (75%) of the title compound. LC-MS/ES m/z (35Cl) 483.0 [M−t-butyl+H]+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13]([CH:15]1[CH2:19][CH2:18][CH2:17][C:16]1=O)=[O:14])[CH3:11].C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:10]([O:12][C:13]([C:15]1[CH2:19][CH2:18][CH2:17][C:16]=1[NH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1)=[O:14])[CH3:11]
Reactant: NCc1ccc(F)cc1
Reactant: CCOC(=O)C1CCCC1=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=C(NCc2ccc(F)cc2)CCC1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
4-Fluorobenzylamine (12.1 g, 97.5 mmol) was added to a solution of 2-oxo-cyclopentanecarboxylic acid ethyl ester (15.25 g, 97.6 mmol) in toluene (225 mL) at 23° C. Glacial acetic acid (6.15 mL, 107 mmol) was then added, producing a large amount of white solid. The reaction mixture was heated to 70° C. in an oil bath, whereupon most of the solids dissolved. After stirring for 2 h at 70° C., a Dean-Stark apparatus and reflux condenser were fitted to the reaction flask and approximately 40 mL of liquid (predominantly toluene) was removed by distillation over 45 min (oil bath temperature=145° C.). The mixture was allowed to cool to 23° C. and was used in the next step. A small aliquot of the crude reaction mixture was concentrated in vacuo to afford the desired product, 2-(4-fluoro-benzylamino)-cyclopent-1-enecarboxylic acid ethyl ester as an orange oil: 1H NMR (CDCl3) δ: 1.28 (3H, t, J=7.5), 1.79-1.86 (2H, m), 2.51-2.56 (4H, m), 4.15 (2H, q, J=6.9), 4.34-4.36 (2H, m), 6.98-7.03 (2H, m), 7.19-7.23 (2H, m), 7.73 (1H, bs).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([CH:16]1[O:18][CH2:17]1)Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:14]([O:13][C:10]1[CH:9]=[CH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:12][CH:11]=1)[CH:16]1[O:18][CH2:17]1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: c1ccc(-c2ccc(OCC3CO3)cc2)cc1
Temperature: 30 °C
Reaction time: 16 h

Procedure:
4.7 g of p-phenylphenol, 15.1 g of epibromohydrin, 13.6 g of potassium carbonate and 33.3 g of 2-butanone were introduced into a three-necked flask with reflux condenser and stirrer at 30° C. The mixture was heated to 70° C. and stirred for 16 hours. After filtration, the filtrate was freed from low-boiling components in a rotary evaporator. After addition of 2×30 ml of 2-butanone and redistillation, p-phenylphenol glycidyl ether was obtained as a crystalline solid having a melting range of 96-98° C. 1H-NMR (CDCl3, 400 MHz): 2.78 (dd, 1H), 2.90 (t, 1H), 3.36 (m, 1H), 4.02 (dd, 1H), 4.24 (dd, 1H), 7.00 (AA′BB′ system, 2H), 7.30 (t, 1H), 7.40 (t, 1H), 7.55 (m, 4H).
Reaction SMILES: Cl[C:2]1[C:11]2[CH:10]=[C:9]([CH2:12][C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])[CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[CH:21]=[N:22][N:23]([CH3:24])[C:3]=12.C(O)(=[O:27])C>O>[CH3:24][N:23]1[C:3]2[C:2](=[O:27])[C:11]3[CH:10]=[C:9]([CH2:12][C:13]4[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=4)[C:16]#[N:17])[CH:8]=[CH:7][C:6]=3[NH:5][C:4]=2[CH:21]=[N:22]1
Reactant: CC(=O)O
Reactant: Cn1ncc2nc3ccc(Cc4cccc(C#N)c4)cc3c(Cl)c21
Solvent: O
Product: Cn1ncc2[nH]c3ccc(Cc4cccc(C#N)c4)cc3c(=O)c21
Temperature: 25 °C
Yield: 86 %

Procedure:
A suspension of 3-[(9-chloro-1-methyl-1H-pyrazolo[4,3-b]quinolin-7-yl)methyl]benzonitrile (EXAMPLE 28, step 1, 729 mg, 2.19 mmol) in acetic acid (8 ml) and water (8 ml) was refluxed for 5 h. After cooling to room temperature, water (20 ml) was added and the precipitate was collected by filtration. This yellow solid was washed with water, ethanol and hexane to give 594 mg (86%) of the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([C:3]1(CCC)[C:7]2[C:8]([CH3:23])=[CH:9][C:10]([CH3:22])=[C:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[C:6]=2[O:5][CH2:4]1)[CH3:2].C([SiH](CC)CC)C.O>FC(F)(F)C(O)=O>[CH2:1]([CH:3]1[C:7]2[C:8]([CH3:23])=[CH:9][C:10]([CH3:22])=[C:11]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([CH:19]([CH3:20])[CH3:21])=[CH:17][CH:18]=3)[C:6]=2[O:5][CH2:4]1)[CH3:2]
Reactant: CCCC1(CC)COc2c(Cc3ccc(C(C)C)cc3)c(C)cc(C)c21
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCC1COc2c(Cc3ccc(C(C)C)cc3)c(C)cc(C)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a mixed solution of 3-ethyl-7-(4-isopropylbenzyl)-4,6-dimethyl-3-propyl-1-benzofuran obtained in Reference Example 183 (941 mg, 2.94 mmol) in trifluoroacetic acid (5 mL) was added dropwise triethylsilane (0.94 mL, 5.87 mmol), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, which was extracted with ethyl acetate, and then the organic layer was washed with a saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain 940 mg (yield 99%) of the title compound. Oily matter.
Reaction SMILES: [O:1]=[S:2]1(=[O:29])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][CH2:24][CH2:25][CH2:26][NH2:27])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:28])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.[O:30]1[CH2:33][C:32](=O)[CH2:31]1.C(N(C(C)C)C(C)C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[O:29]=[S:2]1(=[O:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][CH2:24][CH2:25][CH2:26][NH:27][CH:32]3[CH2:33][O:30][CH2:31]3)[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:28])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: O=C1COC1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCCN)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCCNC3COC3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.9 %

Procedure:
To a stirred of N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]propane-1,3-diamine (84 mg, 0.2 mmol, prepared in analogy to Example 9-3), oxetan-3-one (15 mg, 0.21 mmol) and ethyldiisopropylamine (43 μL, 0.25 mmol) in dichloromethane (10 mL) was added molecular sieves (4 Å, 84 mg) followed by sodium triacetoxyborohydride (63.6 mg, 0.3 mmol). After being stirred at room temperature overnight, another batch of sodium triacetoxyborohydride (63.6 mg, 0.3 mmol) was added and the mixture was heated under reflux for 2 hours. The reaction mixture was cooled, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC to afford 26 mg of N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-N′-(oxetan-3-yl)propane-1,3-diamine as a white solid. MS obsd. (ESI+) [(M+H)+] 467, 1H NMR (400 MHz, CD3OD) δ ppm 8.05 (d, J=7.6 Hz, 1 H), 7.87 (d, J=7.6 Hz, 1 H), 7.34 (s, 1 H), 7.68 (t, J=14.8 Hz, 1 H), 7.58-7.51 (m, 2 H), 7.45 (d, 1 H), 5.99 (s, 1 H), 5.24 (s, 2 H), 4.85 (t, J=3.3 Hz, 2 H), 4.85 (t, J=13.6 Hz, 2 H), 4.55 (m, 4 H), 4.06-4.00 (m, 1 H), 3.67 (s, 2 H), 3.50 (t, J=13.2 Hz, 2 H), 2.74 (t, J=13.6 Hz, 2 H), 2.45 (s, 3 H), 1.98-1.91 (m, 2 H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][C:12]#[N:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1>[F:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][CH:3]=1)[C:6]([CH2:11][CH2:12][NH2:13])=[CH:7][NH:8]2
Reactant: N#CCc1c[nH]c2cc(F)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NCCc1c[nH]c2cc(F)ccc12
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
Combine 2-(6-fluoro-1H-indol-3-yl)acetonitrile (165 g, 0.925 mol) and THF (1.32 L). Slowly add 1M solution of BH3 (2.042 L, 1,832 Kg, 0.131 mol) in THF over about 40 minutes. When the addition is complete, heat to reflux within 1 hour. After 1 hour at reflux, cool to room temperature and the reaction mixture, over about 25 minutes, to a well-stirred 15% aqueous solution of NaOH (1.9 L, 9.5 mol). After addition, slowly and gradually heat to 50° C. After 1 hour, heat 60° C. After 30 minutes, heat to reflux for 1 hour. Cool to room temperature and stir overnight, decant the alkaline aqueous layer and replace by water. Heat to 30° C. under a pressure of 200 mbars in order to distill the THF until about 2.5 kg of distilate is removed. Extract the mixture with dichloromethane. Slowly add to the combined organic layers over a 25 minutes a mixture of 37% aqueous HCl (143 g) and water (220 g) and stir to give a solid. After 1 hour, collect the solid by filtration, wash with of dichloromethane, aid dry overnight to afford of the hydrochloride salt of the title compound.
Reaction SMILES: [H-].[Na+].[N:3]1([C:9](OC(C)(C)C)=O)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.BrC[C:18]1[CH:22]=[N:21][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:19]=1>CN(C)C=O>[C:23]1([N:20]2[N:21]=[C:22]([CH2:9][N:3]3[CH2:4][CH2:5][NH:6][CH2:7][CH2:8]3)[CH:18]=[N:19]2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: BrCc1cnn(-c2ccccc2)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(-n2ncc(CN3CCNCC3)n2)cc1
Reaction time: 0.25 h

Procedure:
To a stirred suspension of 0.28 g (0.71 mmol) of sodium hydride (60% mineral oil dispersion) in 5 mL anhydrous N,N-dimethylformamide at 0° C. was added 0.12 g (0.65 mmol) tert-butyl 1-piperazine-carboxylate. The resulting mixture was stirred under an atmosphere of nitrogen for 15 min and then allowed to warm to ambient temperature at which point 0.14 g (0.59 mmol) of 4-(bromomethyl)-2-phenyl-2H-1,2,3-triazole was added. After 4 h, quench the reaction with 25 mL cold water and extract the resulting solution with 25 mL ethyl acetate. The organic layer was washed with water (2×25 mL), dried over magnesium sulfate, filtered and evaporated in vacuo to afford the title compound which was purified by reverse-phase HPLC (TMC Pro-Pac C18; 10-100% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient). LC/MS: m/z (ES) 344.0 (MH)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][C:5]([Cl:9])=[C:6]([CH3:8])[N:7]=1.[NH3:10]>>[NH2:10][C:2]1[CH:3]=[N:4][C:5]([Cl:9])=[C:6]([CH3:8])[N:7]=1
Reactant: Cc1nc(Cl)cnc1Cl
Reactant: N
Product: Cc1nc(N)cnc1Cl
Temperature: 135 °C

Procedure:
A mixture of 3,6-dichloro-5-methylpyrazine (5 g, 30.7 mmol) in ethanolic ammonia solution (50 ml) was heated for 8 hours in a high-pressure cell at 135° C. The solvent was then removed by evaporation and the residue dissolved in chloroform (40 ml). The organic solution was washed with water (2×25 ml) dried (MgSO4) and the volatiles removed by evaporation. The crude solid was semi-purified by column chromatography on silica gel eluting with dichloromethane/methanol (95:5) to the title compound (1.3 g, 31%) as a 10:17 mixture with its regioisomer. NMR: 2.06 (s, 3H), 2.18 (s, 3H), 6.2 (br s, 4H), 6.74 (s, 1H), 7.26 (s, 1H); m/z: 143 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][N:11]2[C:15](=[O:16])[C:14]3=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]3[C:12]2=[O:21])=[C:4]([C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:3]=1>O1CCCC1.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][CH2:10][N:11]2[C:15](=[O:16])[C:14]3=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]3[C:12]2=[O:21])=[C:4]([C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:3]=1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1C#CCN1C(=O)c2ccccc2C1=O
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1cc(Cl)ccc1C=CCN1C(=O)c2ccccc2C1=O

Procedure:
A mixture of 2.0 g (5 mmole) of 1-[4-chloro-2-benzoylphenyl]-3-phthalimidopropyne and 0.1 g of prehydrogenated 10% palladium on barium sulfate in 50 ml of tetrahydrofuran was hydrogenated at room temperature and atmospheric pressure until 85 ml of hydrogen was absorbed. The catalyst was removed by filtration and the filtrate was concentrated at reduced pressure to dryness. The residue was crystallized from ether to give a white solid, mp 70°-72° C. Recrystallization from ether gave colorless prisms, mp 70°-72° C.