Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2([C:23]([OH:25])=[O:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH2:12][CH2:11]1)=O)(C)(C)C.[CH3:26][C:27]1[CH:28]=[CH:29][C:30]([S:33]([OH:36])(=[O:35])=[O:34])=[CH:31][CH:32]=1.O.CCN(CC)CC>CC(O)C>[CH3:26][C:27]1[CH:28]=[CH:29][C:30]([S:33]([OH:36])(=[O:35])=[O:34])=[CH:31][CH:32]=1.[NH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2([C:23]([OH:25])=[O:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)NCC1CCN(CC2(C(=O)O)CCOCC2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Solvent: O
Product: NCC1CCN(CC2(C(=O)O)CCOCC2)CC1
Temperature: 60 °C
Reaction time: 7 h
Yield: 87.5 %

Procedure:
In a 300 mL, 3-necked round bottom flask under N2, 4-[(4-{[(tert-butoxycarbonyl)amino]methyl}piperidin-1-yl)methyl]tetrahydro-2H-pyran-4-carboxylic acid (10 g, 28 mmol, Step 11) was placed and a solution of p-TsOH H2O (16 g, 84 mmol) in IPA (150 mL) was poured at room temperature. The resulting mixture was stirred at 60° C. for 7 h under N2 and Et3N (8.6 mL, 62 mmol) was added dropwise slowly during the period of 2 hr with seeding. The white precipitate was formed during the addition of Et3N. The resulting white suspension was stirred at 60° C. for 3 h, at 50° C. for 5 h and at room temperature for 10 h. The suspension was filtered and the obtained solid was washed with IPA (100 mL), dried at 50° C. for 5 h to give 10.5 g (87%) of the titled compound as white powder.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[CH3:15].CCCCCC.C1(S(N([F:41])S(C2C=CC=CC=2)(=O)=O)(=O)=O)C=CC=CC=1>C1COCC1>[F:41][C:10]1[C:5]([O:4][CH2:3][O:2][CH3:1])=[C:6]([CH3:15])[CH:7]=[CH:8][C:9]=1[O:11][CH2:12][O:13][CH3:14]
Reactant: COCOc1ccc(C)c(OCOC)c1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCOc1ccc(C)c(OCOC)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
To a solution of 2,4-bis(methoxymethoxy)-1-methyl-benzene (WO2012/076877 Intermediate 150, 2000 mg, 9.4233 mmol) in dry THF (20 mL) butyllithium 1.6M in hexane (6.77 ml, 10.84 mmol) was slowly added and the reaction mixture was stirred for 30 minutes at room temperature. The reaction was cooled to −15° C. and it was added (via cannulation) to a solution of N-(benzenesulfonyl)-N-fluoro-benzenesulfonamide (3565.8 mg, 11.308 mmol) in dry THF (10 mL) at −15° C. The reaction mixture was stirred for 30 minutes at the same temperature. The reaction was quenched with brine (5 ml) diluted with water (20 ml) and extracted with ethyl acetate (2×30 ml). The organic layer was dried (Na2SO4), filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a SNAP 50 g as column and cyclohexane/ethyl acetate from 100:0 to 80:20 as eluent affording the title compound (1950 mg) as colourless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=3)=[C:13]([C:23]([OH:25])=O)[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2].Cl.[F:27][C:28]1[CH:33]=[CH:32][C:31]2[C:34]3([CH2:40][O:41][C:30]=2[CH:29]=1)[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=3)=[C:13]([C:23]([N:37]3[CH2:38][CH2:39][C:34]4([C:31]5[CH:32]=[CH:33][C:28]([F:27])=[CH:29][C:30]=5[O:41][CH2:40]4)[CH2:35][CH2:36]3)=[O:25])[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn2c(Nc3cccc(C)c3)c(C(=O)O)cnc12
Reactant: Fc1ccc2c(c1)OCC21CCNCC1
Agent: Cl
Product: CCOC(=O)c1cnn2c(Nc3cccc(C)c3)c(C(=O)N3CCC4(CC3)COc3cc(F)ccc34)cnc12
Yield: 64.3 %

Procedure:
In the same manner as in Example 21, step 5 and using 3-ethoxycarbonyl-7-(3-methylphenylamino)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.130 g, 0.382 mmol) obtained in step 2 and 6-fluoro-2H-spiro[benzofuran-3,4′-piperidine]hydrochloride (0.087 g, 0.420 mmol), the title compound (0.130 g, 64%) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](Cl)=[O:9])[S:5][C:6]=1[Br:7].Cl.[CH2:12]([O:14][NH2:15])[CH3:13].Cl>N1C=CC=CC=1.O1CCCC1>[CH2:12]([O:14][NH:15][C:8]([C:4]1[S:5][C:6]([Br:7])=[C:2]([Br:1])[CH:3]=1)=[O:9])[CH3:13]
Reactant: O=C(Cl)c1cc(Br)c(Br)s1
Reactant: CCON
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCONC(=O)c1cc(Br)c(Br)s1
Reaction time: 0.5 h

Procedure:
At room temperature, 6.8 g of 4.5-dibromothiophene-2-carboxylic chloride is stirred, in portions, into 6.8 g of O-ethylhydroxylamine hydrochloride in 10 ml of pyridine and 80 ml of tetrahydrofuran. After 30 minutes, dilute hydrochloric acid was added, and the product was filtered off and washed with water. Yield: 5.8 g; m.p.: 117-119° C.
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[CH:3][CH2:2]1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.C[O-:21].[Na+].O>CN(C)C=O>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[C:2]2[C:3](=[O:21])[NH:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[S:1]2)=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: C1=Nc2ccccc2SC1
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2SC1=Cc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 85.6 %

Procedure:
A solution of 2H-1,4-benzothiazine-3(4H-one (2 g) and 4-chlorobenzaldehyde (2.6 g) in dimethylformamide (15 ml) was treated with sodium methylate (0.98 g). The temperature of the mixture rose spontaneously. After cooling to room temperature, the reaction mixture was stirred and heated at 110° C. with a continuous removal of a low boiling substance for 3 hours. The reaction mixture was cooled to 30° C., and poured onto 100 ml of iced water. The resulted yellow solid was filtered and recrystallized from a mixture of dimethylformamide and isopropyl alcohol. 2-(4-Chlorophenylmethylidene)-2H-1,4-benzothiazine-3(4H)-one (3.3 g) was obtained as yellow crystals. m.p. 245-248° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]([CH3:12])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)(=O)=O.C[N:19](C)[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][C:28]=2N(C)C)[CH:23]=CC=1.[NH2:34]C1C=CC(Cl)=C(C=1)C#N>ClCCl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:28]3[C:29]([C:20]#[N:19])=[C:24]([CH3:23])[CH:25]=[CH:26][C:27]=3[NH:34][C:10]=2[CH3:12])=[CH:4][CH:3]=1
Reactant: CC(=O)CSc1ccc(Cl)cc1
Reactant: N#Cc1cc(N)ccc1Cl
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: CCN(CC)CC
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc2[nH]c(C)c(Sc3ccc(Cl)cc3)c2c1C#N
Reaction time: 2 h
Yield: 12.5 %

Procedure:
A stirred solution of 1-[(4-chlorophenyl)thio]-acetone (6.14 g) in dry dichloromethane (150 ml) at −78° C. was treated with sulphuryl chloride (2.25 ml). After 30 min a prepared solution of N,N,N′,N′-tetramethyl-1,8-naphthalenediamine (6.01 g) and 5-amino-2-chloro-benzonitrile (3.89 g) in dry dicholoromethane (80 ml) was added dropwise over 30 min. The mixture was stirred for a further 2 hours, after which triethylamine (4.26 ml) was added and the reaction allowed to reach room temperature. The reaction mixture was diluted with dichloromethane (200 ml), washed with water, 1N HCl and brine. The organic phase was dried (MgSO4), evaporated in vacuo, and the residue purified by flash column chromatography eluting with iso-hexane and ethyl acetate (1:1) to give the sub-title compound (1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][NH:5][C:6](=[O:9])[C:7]=1[Cl:8].C(N(CC)C(C)C)(C)C.[CH3:19][O:20][CH2:21]Br.O>C(Cl)Cl>[Cl:8][C:7]1[C:6](=[O:9])[N:5]([CH2:19][O:20][CH3:21])[N:4]=[CH:3][C:2]=1[Cl:1]
Reactant: O=c1[nH]ncc(Cl)c1Cl
Reactant: COCBr
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCn1ncc(Cl)c(Cl)c1=O
Reaction time: 22 h
Yield: 74.8 %

Procedure:
To a stirred solution of 4,5-dichloropyridazin-6-one (5.00 g, 30.3 mmol) and N,N-diisopropylethylamine (7.92 mL, 45.5 mmol) in methylenechloride (50 mL) was added slowly, bromomethyl methyl ether (4.79 mL, 60.6 mmol) at room temperature (water-bath). The reaction was stirred for 22 h and was then concentrated. Purification by column chromatography (1% MeOH in CH2Cl2) gave 4.74 g (74.8%) of 4,5-dichloro-2-methoxymethyl-2H-pyridazin-3-one.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]=1[CH2:17][C:18]#[N:19].N.[H][H]>C(O)CC.[Ni]>[NH2:19][CH2:18][CH2:17][CH:3]1[CH:2]([CH3:1])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1c(CC#N)n(-c2ccccc2)c2ccccc12
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CCCO
Product: CC1c2ccccc2N(c2ccccc2)C1CCN

Procedure:
To a solution of 83 g of 3-methyl-1-phenyl-2-indole acetonitrile in 340 ml of n-propanol there are added 100 ml of concentrated aqueous ammonia and two spoons of Raney nickel. The mixture is hydrogenated at 60° and normal pressure. After the hydrogen take-up is complete, filtration is effected and the filtrate is made slightly acid with glacial acetic acid under cooling. After the addition of water, washing with diethyl ether is effected and the aqueous phase is made alkaline with dilute ammonia. The latter is extracted with methylene chloride and the extract is concentrated by evaporation after washing with water and drying over sodium sulphate. The residue, 2-aminoethyl-3-methyl-1-phenylindole, is then converted into the hydrochloride. M.Pt. 202°-207° (from acetone/diethyl/ether).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=O)[NH:5][CH:6]=1.Br[CH2:10]/[CH:11]=[CH:12]/[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[N:5]([CH:6]=1)[CH:10]=[CH:11][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7]2
Reactant: CCOC(=O)/C=C/CBr
Reactant: O=Cc1cc(Br)c[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccn2cc(Br)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.7 %

Procedure:
A mixture of 4-bromo-1H-pyrrole-2-carbaldehyde (1.00 g, 5.75 mmol), (E)-ethyl 4-bromobut-2-enoate (1.555 mL, 11.49 mmol), and potassium carbonate (1.74 g, 12.6 mmol) in DMF (20 mL) was stirred overnight at room temperature under a nitrogen atmosphere. Following reaction, the solution was extracted with ethyl acetate (2×100 mL) and water (100 mL). The organic layers were combined, dried over sodium sulfate, concentrated, and purified via silica gel flash chromatography, eluting with a gradient of 10-30% EtOAc and hexane to give, upon removal of solvent, the title compound as a purple solid (350 mg, 23%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.32 (t, J=7.40 Hz, 3H), 4.31 (q, J=5.40 Hz, 2H), 6.92 (s, 1H), 7.02-7.03 (m, 1H), 7.93 (s, 1H), 8.13 (s, 1H), 8.28-8.29 (m, 1H). ESI-MS m/z [M+H]+ calc'd for C11H10BrNO2, 268. found, 268.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=1.[Li][C:11](C)(C)C.CCCCC.[C:20]([O:24][CH2:25][CH3:26])(=[O:23])[CH:21]=[O:22]>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([O:8][CH3:9])[C:5]([C:21]([OH:22])([CH3:11])[C:20]([O:24][CH2:25][CH3:26])=[O:23])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C=O
Reactant: [Li]C(C)(C)C
Reactant: COc1cccc(Cl)n1
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(O)c1ccc(Cl)nc1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a solution of 2-chloro-6-methoxypyridine (100 g, 696 mmol) in anhydrous THF (1.0 L) was added a solution of tert-BuLi in pentane (1.3 M, 640 mL, 836 mmol) at −68° C. dropwise. The reaction mixture was stirred for 30 min at this temperature. To the reaction mixture was added a solution of ethyl glyoxalate (109 g, 940 mmol) in THF (400 mL) was added dropwise below −60° C. over 1.5 h, and the resulting mixture was stirred at this temperature for 1 h. The reaction mixture was poured into ice water (10 L), extracted with EtOAc (10 L), dried over Na2SO4, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether→petroleum ether EtOAc=5:1) to afford ethyl 2-(6-chloro-2-methoxypyridin-3-yl)-2-hydroxypropanoate (360 g, 50%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 1.20 (t, 3H), 1.75 (s, 3H), 3.95 (s, 3H), 4.20 (q, 2H), 6.95 (d, 1H), 7.67 (d, 1H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][C@H:9]([N:12]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:10][OH:11])=[O:4].[F:38][C:39]([F:45])([F:44])[CH2:40][C:41](O)=[O:42]>>[NH2:26][C:23]1[CH:22]=[CH:21][C:20]([S:17]([N:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[C@H:9]([CH2:10][OH:11])[CH2:8][CH2:7][CH2:6][NH:5][C:3]([C@@H:2]([NH:1][C:41](=[O:42])[CH2:40][C:39]([F:45])([F:44])[F:38])[CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][CH:29]=2)=[O:4])(=[O:19])=[O:18])=[CH:25][CH:24]=1
Reactant: CC(C)CN([C@H](CO)CCCNC(=O)[C@@H](N)Cc1cccc2ccccc12)S(=O)(=O)c1ccc(N)cc1
Reactant: O=C(O)CC(F)(F)F
Product: CC(C)CN([C@H](CO)CCCNC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)CC(F)(F)F)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was prepared from (2S,4S)-2-amino-N-{4-[(4-amino-benzenesulfonyl)-isobutyl-amino]-5-hydroxy-pentyl}-3-naphthalen-1-yl-propionamide (see example 8) as described in general procedure E using 3,3,3-trifluoropropionic acid. The final product was obtained in 76% yield.
Reaction SMILES: [OH:1][CH:2]([C:7]1[CH:8]=[CH:9][C:10]([C:13](=O)[CH2:14][CH2:15][C:16](=O)[CH:17]([N:25]2[C:29]3=[N:30][CH:31]=[CH:32][C:33]([O:34][CH3:35])=[C:28]3[CH:27]=[N:26]2)[CH2:18][CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[N:11][CH:12]=1)[C:3]([OH:6])([CH3:5])[CH3:4].C([O-])(=O)C.[NH4+:42].C(O)(=O)C.C(=O)([O-])O.[Na+]>C(O)C>[CH3:35][O:34][C:33]1[CH:32]=[CH:31][N:30]=[C:29]2[N:25]([CH:17]([C:16]3[NH:42][C:13]([C:10]4[N:11]=[CH:12][C:7]([CH:2]([OH:1])[C:3]([CH3:5])([OH:6])[CH3:4])=[CH:8][CH:9]=4)=[CH:14][CH:15]=3)[CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[N:26]=[CH:27][C:28]=12
Reactant: COc1ccnc2c1cnn2C(CC1CCOCC1)C(=O)CCC(=O)c1ccc(C(O)C(C)(C)O)cn1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccnc2c1cnn2C(CC1CCOCC1)c1ccc(-c2ccc(C(O)C(C)(C)O)cn2)[nH]1
Temperature: 25 °C
Reaction time: 6 h
Yield: 69.8 %

Procedure:
A mixture of 1-[5-(1,2-dihydroxy-2-methylpropyl)pyridin-2-yl]-5-(4-methoxy-1H-pyrazolo[3,4-b]pyridin-1-yl)-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (265 mg), ammonium acetate (200 mg), acetic acid (0.20 mL) and ethanol (10 mL) was stirred at room temperature for 6 hr. The reaction solution was poured into aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to give the title compound (178 mg, yield 58%) as a colorless amorphous solid from the fraction eluted with ethyl acetate. MS: 492 (MH+).
Reaction SMILES: C([C:4]1([C:13]#[N:14])[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)(=O)C.[Br:15]Br.[CH2:17]([O:19]CC)[CH3:18]>[Cl-].[Al+3].[Cl-].[Cl-]>[Br:15][CH2:18][C:17]([CH:12]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]1[C:13]#[N:14])=[O:19]
Reactant: CC(=O)C1(C#N)Cc2ccccc2C1
Reactant: CCOCC
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Product: N#CC1Cc2ccccc2C1C(=O)CBr

Procedure:
2-Acetyl-2,3-dihydro-1H-indene-2-carbonitrile (32.9 g) was dissolved in diethyl ether (33 ml). Aluminium chloride (0.17 g) was added. Bromine (28.4 g) was added dropwise at room temperature and the disappearance of the bromine colour was observed. The ether solution was washed with a Na2CO3 -solution and with water, dried over MgSO4, and evaporated. 35.7 g of crude product was obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.[C:20]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)#[N:21]>>[O:17]1[CH2:18][CH2:19][N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([C:25]3[CH:26]=[CH:27][C:22]([C:20]#[N:21])=[CH:23][CH:24]=3)[N:3]=2)[CH2:15][CH2:16]1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Clc1nc(N2CCOCC2)nc(N2CCOCC2)n1
Product: N#Cc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Yield: 50 %

Procedure:
The title compound was prepared by following the procedure of example 473 step 2 using 4,4′-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholine and 4-cyanophenyl-boronic acid. Yield 86 mg, 50% yield; HPLC: Rt=2.60 min; MS 353 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)(O)[CH:9]=[CH2:10])=[CH:4][CH:3]=1.[OH-:18].[Na+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:9][CH2:10][OH:18])=[CH:4][CH:3]=1
Reactant: C=CC(O)(c1ccc(Cl)cc1)c1cccnc1
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: OCC=C(c1ccc(Cl)cc1)c1cccnc1

Procedure:
1-(4-Chlorophenyl)-1-(3-pyridyl)-2-propen-1-ol (0.33 g) was stirred in 25 ml 2 M sulfuric acid overnight at 50° C. The reaction mixture was made alkaline with 45% sodium hydroxide and extracted with ether. The ethereal layer was dried (MgSO4) and evaporated to give 0.30 g of the title compound as an oil. 1H NMR (CDCl3) revealed an approximate Z/E ratio of 60/40:δ3.8 (Br, OH), 4.20 and 4.25 (two doublets, allyl), 6.37 and 6.30 (two triplets, vinyl), 6.9-7.6 (aromatic) and 8.3-8.6 (multiplet, 2,6-pyridyl). This crude product was used directly in the oxidation step according to Example K.
Reaction SMILES: C[O:2][C:3]1[CH:10]=[C:9]([O:11]C)[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].[C:13](Cl)(=[O:15])[CH3:14].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[C:13]([C:8]1[C:9]([OH:11])=[CH:10][C:3]([OH:2])=[C:4]([CH:7]=1)[CH:5]=[O:6])(=[O:15])[CH3:14]
Reactant: CC(=O)Cl
Reactant: COc1ccc(C=O)c(OC)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cc(C=O)c(O)cc1O
Temperature: 0 °C

Procedure:
To a mixture of 49.8 g of 2,4-dimethoxybenzaldehyde, 23.6 ml of acetyl chloride, and 1000 ml of methylene chloride cooled to approximately 0° C. were added 119.7 g of aluminum chloride with stirring under a nitrogen atmosphere. The reaction was allowed to warm to room temperature while stirring overnight. The mixture was added to a slurry of ice and concentrated hydrochloric acid. The organic layer was separated and washed with a saturated sodium chloride solution, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by high pressure liquid chromatography over silica gel eluting with a 0-40% ethyl acetate in hexane gradient. The appropriate fractions were pooled and concentrated to provide 5.85 g of the desired title intermediate, m.p.=142°-143° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:6]=1[OH:12])[CH2:2][CH2:3][CH3:4].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].CC(C)=O>C1C=CC=CC=1.CCCCCC>[CH2:13]([O:12][C:6]1[CH:7]=[CH:8][C:9]([Br:11])=[CH:10][C:5]=1[CH2:1][CH2:2][CH2:3][CH3:4])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: CCCCc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCCCCC
Solvent: c1ccccc1
Product: CCCCc1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 85.6 %

Procedure:
A mixture comprising 31.12 g of the above phenol, 18.81 g of benzyl bromide, 18.24 g of potassium carbonate and 300 ml of acetone, was stirred at room temperature for 2 days. Acetone was distilled off, and water was added to the residue. The mixture was extracted with benzene. The benzene layer was washed with a saturated sodium chloride aqueous solution, and dried over sodium sulfate. Then, the solvent was distilled off to obtain a pale yellow oily substance. This substance was subjected to silica gel column chromatography by using benzene-n-hexane (1:9, v/v) as the developer, whereby 30.07 g of (2-n-butyl-4-bromophenyl) benzyl ether was obtained as a colorless oily substance.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].[OH-].[CH2:7]([N+:14](C)(C)C)[C:8]1C=CC=C[CH:9]=1.C(#N)C=C>C(O)(=O)C>[CH2:1]([O:5][CH:8]([CH3:9])[C:7]#[N:14])[CH2:2][CH2:3][CH3:4]
Reactant: C[N+](C)(C)Cc1ccccc1
Reactant: CCCCO
Agent: [OH-]
Solvent: C=CC#N
Solvent: CC(=O)O
Product: CCCCOC(C)C#N
Yield: 74 %

Procedure:
A mixture of 148 grams (2.0 moles) of n-butanol and 2.0 grams of 40% benzyltrimethylammonium hydroxide (Triton B) is combined in a 1 liter 4-neck round bottom flask stirred at reflux while 106 grams (2.0 moles) of acrylonitrile is added at a rate such that the temperature does not exceed 45° C. The mixture is stirred an hour after all the acrylonitrile has been added, made acidic with acetic acid, and fractionated under vacuum through a Vigreux column. The product boils at 75° C./2 mm (literature value: 98° C./20 mm). The product totalled 188.0 grams of 99.0% pure material which constituted a 74.0% yield. The density of the product was determined to be 0.93 grams/ml. The nuclear magnetic resonance and infrared spectra were obtained and were determined to be consistent with the expected structure of the product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.F[C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].C1(C)C=CC=CC=1.CC(N(C)C)=O>C(OCC)(=O)C>[O:11]=[C:7]1[C:8]2[C:4](=[CH:3][C:2]([O:1][C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: N#Cc1ccc(F)cc1
Reactant: O=C1CCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: N#Cc1ccc(Oc2ccc3c(c2)CCC3=O)cc1
Reaction time: 4 h
Yield: 51.3 %

Procedure:
Combine 5-Hydroxyindanone (2.0 g, 13.50 mmol), 4-Fluorobenzonitrile (1.55 g, 12.80 mmol), K2CO3 (2.65 g, 19.20 mmol) and toluene/DMA (20 ml/40 ml), reflux under Nitrogen using a Dean-Stark Trap. After 4.0 hours, cool the reaction to room temperature and add Ethyl Acetate. Wash several times with 10% LiCl and Brine solution, then dry the organic layer over Na2SO4 follow by concentration. Flash chromatograph using 4/1 then 1/1 hexanes/ethyl acetate eluant to afford 1.64 g, 6.57 mmol (49% yield) of the title compound: 1H NMR (500 MHz, CDCl3); 2.7-2.8 (2H, m), 3.1-3.2 (2H, m), 7.0-7.1 (2H, m), 7.1-7.2 (2H, m), 7.6-7.7 (2H, m), 7.7-7.8 (1H, m); MS m/z 250 (M+1).
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)[CH2:2][CH3:3].C=O.[C:24]([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[CH2:19]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]#[N:16])=[CH:17][CH:18]=1)[CH3:24])[CH2:20][CH3:21]
Reactant: [BH3-]C#N
Reactant: CCCN(CCC)CCCCNCc1ccc(C#N)cc1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)CCCCN(C)Cc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.8 %

Procedure:
309 mg (1.07 mmol) of 4-[(4-dipropylaminobutyl)amino]methylbenzonitrile (2a) was added dropwise in a 100 ml recovery flask, and dissolved in 9.2 ml of anhydrous methanol. 0.134 ml of a formaldehyde aqueous solution (35%) was then added to the solution. 201.7 mg of sodium cyanoborohydride was then added to the mixture. After the addition of acetic acid to adjust the mixture to pH 5.0, the mixture was stirred at room temperature for 24 hours. 1 mol/l sodium hydroxide aqueous solution was then added to the mixture, followed by extraction with chloroform. The extract was dried over magnesium sulfate and concentrated, thereby obtaining 296.2 mg of 4-[(4-dipropylaminobutyl)methylamino]methylbenzonitrile (2b) was obtained as a colorless oily substance (yield: 92%).