Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:9]1[CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.C(N(CC)CC)C.O>ClCCl.CN(C)C1C=CN=CC=1>[S:21]([O:11][CH2:10][C@@H:9]1[CH2:12][CH2:13][CH2:14][N:8]1[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])([C:18]1[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=1)(=[O:23])=[O:22]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
A solution of N-Boc-L-prolinol (51.2 g, 254 mmol) in dichloromethane (250 mL) was cooled to 0° C., and thereto were added p-toluenesulfonylchloride (53.4 g, 280 mmol), triethylamine (30.9 g, 42.6 mL, 305 mmol), and 4-dimethylaminopyridine (5.00 g, 40.9 mmol). After stirring overnight at room temperature, to the mixture was added water, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified with silica gel column (hexane/ethyl acetate=70/30 to 30/70) to give the title compound (89.7 g, 250 mmol, 99%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[H-].[Na+].CS(O[CH:16]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17]1)(=O)=O>CN(C=O)C.CCOC(C)=O>[CH3:21][N:18]1[CH2:19][CH2:20][CH:16]([N:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]2)[CH2:17]1
Reactant: CN1CCC(OS(C)(=O)=O)C1
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1CCC(n2cc([N+](=O)[O-])cn2)C1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
4-Nitro-1H-pyrazole (0.452 g, 4.00 mmol) was dissolved in DMF (8 mL) and cooled to 0° C. NaH (0.192 g, 60% dispersion in oil, 4.80 mmol) was added and the mixture was stirred for 10 minutes. 1-Methylpyrrolidin-3-yl methanesulfonate A22 (0.717 g, 4.00 mmol) was added and the mixture was stirred for 16 hours at 100° C. The mixture was diluted with EtOAc (5 mL) and washed with sat. NH4Cl (5 mL) and water (4×5 mL). The organics were concentrated in vacuo affording a crude pale yellow oil which was purified by flash chromatography (0-30% MeOH in DCM) to give the title compound A23 as a pale yellow oil (0.575 g, 73% yield). LCMS-B: rt 1.12 min; m/z 197 [M+H]+.
Reaction SMILES: [Br:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:8][N:9]([CH3:17])[CH:10]=[N:11][C:12]1[S:13][CH:14]=[CH:15][N:16]=1>>[Br-:1].[CH3:8][N:9]([CH:10]=[N:11][C:12]1[S:13][CH:14]=[CH:15][N+:16]=1[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:17]
Reactant: CN(C)C=Nc1nccs1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)C[n+]1ccsc1N=CN(C)C
Product: [Br-]

Procedure:
prepared by reaction of ethyl bromoacetate with N,N-dimethyl-N′-thiazol-2-yl-formamidine. LC-MS: tR=0.58 min; [M+H]+=242.1.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([C:13]([F:16])([F:15])[F:14])[CH:7]=2.C(=O)([O-])[O-].[K+].[K+].Cl.[N+:24]([C:27]1[CH:32]=[CH:31][C:30]([NH:33][CH:34]2[CH2:39][CH2:38][CH:37]([O:40][CH2:41][C:42]([N:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)=[O:43])[CH2:36][CH2:35]2)=[CH:29][C:28]=1[C:50]([F:53])([F:52])[F:51])([O-:26])=[O:25]>CN(C=O)C.CCOC(C)=O>[N+:24]([C:27]1[CH:32]=[CH:31][C:30]([NH:33][CH:34]2[CH2:35][CH2:36][CH:37]([O:40][CH2:41][C:42]([N:44]3[CH2:49][CH2:48][N:47]([CH2:2][C:3]4[CH:4]=[N:5][C:6]5[C:11]([CH:12]=4)=[CH:10][CH:9]=[C:8]([C:13]([F:16])([F:15])[F:14])[CH:7]=5)[CH2:46][CH2:45]3)=[O:43])[CH2:38][CH2:39]2)=[CH:29][C:28]=1[C:50]([F:53])([F:52])[F:51])([O-:26])=[O:25]
Reactant: FC(F)(F)c1ccc2cc(CCl)cnc2c1
Reactant: O=C(COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCN(Cc2cnc3cc(C(F)(F)F)ccc3c2)CC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 34.8 %

Procedure:
To a solution of 3-chloromethyl-7-trifluoromethyl-quinoline (140 mg, 0.57 mmol, 1.1 eq.) in DMF (10 ml) was added potassium carbonate (345 mg, 2.5 mmol, 5 eq.) then 2-[4-(4-Nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-1-piperazin-1-yl-ethanone hydrochloride (233 mg, 0.5 mmol, 1 eq.) was added. The solution was stirred overnight at 70° C. and diluted with EtOAc (25 ml) and washed with water (25 ml), saturated aqueous lithium chloride (25 ml) and brine (25 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue, which was applied onto a silica gel column and eluted with methanol in dichloromethane. The semi-purified material was further purified by HPLC to afford 2-[4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-1-[4-(7-trifluoromethyl-quinolin-3-ylmethyl)-piperazin-1-yl]-ethanone as a yellow solid (111.2 mg, 30%). (CI, m/z): [M+H]+ 640; 1H NMR (400 MHz, CDCl3): δ 1.20-1.36 (m, 2H), 1.40-1.54 (m, 2H), 2.08-2.21 (m, 4H), 2.46-2.61 (m, 4H), 3.32-3.49 (m, 2H), 3.53-3.62 (m, 2H), 3.63-3.71 (m, 2H), 3.76 (s, 2H), 4.20 (s, 2H), 4.46 (d, J=7.6 Hz, 1H), 6.63 (dd, J=9.1, 2.6 Hz, 1H), 6.85 (d, J=2.5 Hz, 1H), 7.75 (dd, J=8.5, 1.6 Hz, 1H) 7.94 (d, J=8.5 Hz, 1H), 8.02 (d, J=9.0 Hz, 1H), 8.13 (d, J=1.2 Hz, 1H), 8.43 (s, 1H), 9.03 (d, J=2.1 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[K+].[K+].[C:17]([O:22][CH2:23]Cl)(=[O:21])[CH2:18][CH2:19][CH3:20]>CC(C)=O>[C:17]([O:22][CH2:23][O:10][C:8]1[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([F:1])[CH:9]=1)(=[O:21])[CH2:18][CH2:19][CH3:20]
Reactant: O=Cc1ccc(O)cc1F
Reactant: CCCC(=O)OCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCC(=O)OCOc1ccc(C=O)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
To a 500 mL dry round bottom flask a were added 2-fluoro-4-hydroxybenzaldehyde (5.60 g, 40 mmol), anhydrous K2CO3 (10.6 g, 76.9 mmol) and acetone (200 mL). The mixture was stirred at room temperature for 30 minutes. To another 500 mL dry round bottom flash b were added chloromethyl butyrate (9.33 g, 61.5 mmol), KI (14.2 g, 66.6 mmol) and acetone (150 mL). This mixture was also stirred at room temperature for 30 minutes. After the solid settled down on the glassware bottom, the top yellow acetone solution in flask b was decanted into the stirring solution in the round bottom flask a. The resulting mixture was refluxed for 4 hours. Most acetone was rotary evaporated, and the residual solid was triturated with methyl tert-butyl ether (MTBE) three times (100 mL, 50 mL, 50 mL). The MTBE extract was concentrated, and the residue was purified with a silica gel chromatography (heptane/ethyl acetate, gradient eluting) to give (3-fluoro-4-formylphenoxy)methyl butyrate (6.40 g) as a colorless oil. Yield: 43%. 1H NMR (CDCl3, 300 MHz): δ=10.18 (s, 1H), 7.80 (t, J=8.7 Hz, 1H), 6.93-6.89 (m, 1H), 6.82 (dd, J=12.3, 2.1 Hz, 1H), 5.83 (s, 2H), 2.36 (t, J=7.5 Hz, 2H), 1.64 (sextet, J=7.5 Hz, 2H), 0.92 (t, J=7.5 Hz, 3H). 13C NMR (CDCl3, 75.5 MHz): δ=185.5 (d, J=6.1 Hz), 169.7 (d, J=258.8 Hz), 162.8 (d, J=12.2 Hz), 130.2 (d, J=3.7 Hz), 119.1 (d, J=8.5Hz), 112.4 (d, J=3.1 Hz), 103.5 (d, J=24.4 Hz), 84.1, 35.7, 18.0, 13.3.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:35](Cl)(=[O:40])[CH2:36][CH:37]([CH3:39])[CH3:38]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:35](=[O:40])[CH2:36][CH:37]([CH3:39])[CH3:38])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(C)CC(=O)Cl
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)CC(C)C)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-[4′-(4-Amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (0.10 g, 0.28 mmol) and triethylamine (0.1 mL, 0.66 mmol) were combined in CH2Cl2 (2 mL). Isovaleryl chloride (0.04 mL, 0.33 mmol) was added, and the reaction was stirred at room temperature for 1 hour. After aqueous workup, the crude material was purified by silica gel chromatography (0-80% EtOAc in hexanes) to give the title compound.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:18]=[CH:17][S:16][C:5]=3[C:6](=[O:15])[NH:7][C:8]=2[C:9]([CH3:14])=[CH:10][C:11]=1[O:12][CH3:13].CC1(C)C(C)(C)OB([C:27]2[CH:32]=[CH:31][C:30]([CH:33]([CH2:43][CH3:44])[CH2:34][NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:29][CH:28]=2)O1>>[CH3:13][O:12][C:11]1[CH:10]=[C:9]([CH3:14])[C:8]2[NH:7][C:6](=[O:15])[C:5]3[S:16][CH:17]=[CH:18][C:4]=3[C:3]=2[C:2]=1[C:27]1[CH:28]=[CH:29][C:30]([CH:33]([CH2:43][CH3:44])[CH2:34][NH:35][C:36](=[O:42])[O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[CH:31][CH:32]=1
Reactant: CCC(CNC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1Br
Product: CCC(CNC(=O)OC(C)(C)C)c1ccc(-c2c(OC)cc(C)c3[nH]c(=O)c4sccc4c23)cc1
Yield: 33.1 %

Procedure:
Following General Procedure B, 9-brom-8-methoxy-6-methylthieno[2,3-c]quinolin-4(5H)-one (150 mg, 0.46 mmol) was reacted with tert-butyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butylcarbamate (240 mg, 0.64 mmol) to afford the desired product (75 mg, 33%) as a light brown solid: ESI MS m/z 493 [C28H12N2O4S+H]+.
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH2:3][C:4]#[CH:5].C(NCC)C.Br[C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1>[Cu]I>[N:25]1[CH:26]=[CH:27][CH:28]=[C:23]([C:5]#[C:4][CH2:3][CH:2]([OH:1])[CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:24]=1
Reactant: C#CCC(O)CCCCOC1CCCCO1
Reactant: Brc1cccnc1
Agent: [Cu]I
Solvent: CCNCC
Product: OC(CC#Cc1cccnc1)CCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 5.84 g (25.8 mmol) 4-hydroxy-8-(2-tetrahydropyranyloxy)-1-octyne, 4.7 ml diethylamine, 10 ml (100 mmol) 3-bromopyridine, 0.032 g copper (I) iodide, and 0.187 g bis-triphenylphosphine palladium (II) chloride is stirred at room temperature for 18 h. The solvent is evaporated and the residue taken up in ether. The ether layer is washed with saturated aqueous sodium bicarbonate, water, brine, dried, filtered and evaporated to get an amber oil which is purified by chromatography using ether as the eluent to give 1-(3-pyridyl)-4-hydroxy-8-(2-tetrahydropyranyloxy)-1-octyne; NMR (CDCl3): delta 4.6 (brs,1H), 2.6 (d,2H).
Reaction SMILES: C([C:5]1N=C(N2CCC(F)(F)C2)[C:8]2[C:9](=[N:11][N:12](CC)[N:13]=2)[N:10]=1)(C)(C)C.[F:23][C:24]1([F:44])[CH2:28][CH2:27][N:26]([C:29]2[C:30]3[N:43]=[N:42][NH:41][C:31]=3[N:32]=[C:33]([O:35][CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[N:34]=2)[CH2:25]1.ClCC1N(C)N=NN=1>>[F:44][C:24]1([F:23])[CH2:28][CH2:27][N:26]([C:29]2[C:30]3[C:31](=[N:41][N:42]([CH2:8][C:9]4[N:10]([CH3:5])[N:13]=[N:12][N:11]=4)[N:43]=3)[N:32]=[C:33]([O:35][CH2:36][C:37]([CH3:38])([CH3:39])[CH3:40])[N:34]=2)[CH2:25]1
Reactant: CC(C)(C)COc1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: Cn1nnnc1CCl
Product: Cn1nnnc1Cn1nc2nc(OCC(C)(C)C)nc(N3CCC(F)(F)C3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 7-(3,3-Difluoro-pyrrolidin-1-yl)-5-(2,2-dimethyl-propoxy)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 5-(chloromethyl)-1-methyl-1H-tetrazole. MS (m/e): 409.4 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([NH2:28])[CH:26]=4)[NH:21][CH:20]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[N+](C1C=C2C(=CC=1)NC=C2)([O-])=O.[C:41]([Cl:44])(=[O:43])[CH3:42]>C1COCC1>[ClH:44].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([NH:28][C:41](=[O:43])[CH3:42])[CH:26]=4)[NH:21][CH:20]=3)[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc(N2CCN(CCCCc3c[nH]c4ccc(N)cc34)CC2)cc1
Agent: O=[N+]([O-])c1ccc2[nH]ccc2c1
Solvent: C1CCOC1
Product: COc1ccc(N2CCN(CCCCc3c[nH]c4ccc(NC(C)=O)cc34)CC2)cc1
Product: Cl
Reaction time: 2 h

Procedure:
A solution of 3.5 g of 3-[4-(4-p-methoxyphenylpiperazino)butyl]-5-aminoindole ["D"; obtainable by reduction of the corresponding 5-nitroindole] in 35 ml of THF is treated with a solution of 0.9 g of acetyl chloride in 10 ml of THF, and the mixture is stirred for 2 hours at 50°, evaporated and worked up in a conventional manner. 3-[4-(4-p-Methoxyphenylpiperazino)butyl]-5-acetamidoindole, hydrochloride, m.p. 240° (dec.) is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11](=O)/[CH:12]=[CH:13]/N(C)C)[NH:8][CH:7]=1)=[O:5])[CH3:2].Cl.[NH2:19][C:20]([NH2:22])=[NH:21].CC[O-].[Na+]>C(O)C.O>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:12]=[CH:13][N:19]=[C:20]([NH2:22])[N:21]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: N=C(N)N
Reactant: CCOC(=O)c1c[nH]c(C(=O)/C=C/N(C)C)c1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c[nH]c(-c2ccnc(N)n2)c1
Temperature: 110 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
To a suspension of 5-((E)-3-Dimethylamino-acryloyl)-1H-pyrrole-3-carboxylic acid ethyl ester (0.25 g, 1.06 mmol) in 4 mL of ethanol, guanidine hydrochloride (0.121 g, 1.27 mmol) and sodium ethylate (0.086 g, 1.27 mmol) were added. The mixture was heated to 110° C. overnight. Then, a further amount of sodium ethylate (0.086 g, 1.27 mmol) was added to the mixture and heating to 115° C. was prolonged for additional 24 hours. The resulting mixture was cooled at room temperature and diluted with water (2 mL). The solid was isolated by filtration, washed with 10 mL of water, dried in a vacuum oven at 40° C. affording to give 0.197 g (80%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:5](=[O:6])[C:4](=[O:7])[C:3]=1[NH:8][CH2:9][CH2:10][CH2:11]O.N1C=CC=CC=1.S(Cl)([Cl:21])=O.O>C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:5](=[O:6])[C:4](=[O:7])[C:3]=1[NH:8][CH2:9][CH2:10][CH2:11][Cl:21]
Reactant: O=S(Cl)Cl
Reactant: Nc1c(NCCCO)c(=O)c1=O
Solvent: O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Nc1c(NCCCCl)c(=O)c1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
A mixture of 1-amino-2-(3-hydroxypropylamino)cyclobut-1-ene-3,4-dione (1.0 g) and pyridine (0.5 ml) in chloroform (100 ml) was cooled to 0° C. To this was added dropwise thionyl chloride (4.38 g) in chloroform (30 ml) and the reaction mixture was stirred overnight at room temperature. There was solid remaining so more thionyl chloride (4.38 g) was added, the solid slowly dissolving, and the reaction mixture was left to stand for 60 hours. The mixture was evaporated under reduced pressure to afford an oily residue, which on the addition of water gave a solid which was collected by filtration and dried to give the title compound (0.73 g); δppm 2.0 (2H, m), 3.5-3.8 (4H, m), 7.45 (broad m); m/e 190, 188, 152, 134, 132, 97, 96, 69.
Reaction SMILES: [NH2:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[C:15](Cl)(Cl)=[S:16]>C1COCC1.O>[F:10][C:9]1[C:2]([N:1]=[C:15]=[S:16])=[CH:3][C:4]([C:11]([F:14])([F:12])[F:13])=[C:5]([CH:8]=1)[C:6]#[N:7]
Reactant: S=C(Cl)Cl
Reactant: N#Cc1cc(F)c(N)cc1C(F)(F)F
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cc(F)c(N=C=S)cc1C(F)(F)F
Reaction time: 1 h
Yield: 87.5 %

Procedure:
To a solution of the compound 25 (660 mg, 3.25 mmol) in THF (6 mL) was added a solution of thiophosgene (1 mL, 13 mmol) in water (1 mL) slowly at room temperature. The reaction mixture was stirred for 1 h, then concentrated in vacuo. The residue was diluted with H2O. The aqueous solution was extracted with ethyl acetate. The organic layers were combined and washed with aq.NaHCO3 and brine, dried over Na2SO4, filtered and concentrated to provide the title compound 3d (700 mg, 88%) as a light yellow solid, which was used directly in next step without further purification. 1H NMR (400 MHz, CDCl3) δ7.63 (d, 1H, J=8.5 Hz), 7.57 (d, 1H, J=6.9 Hz).
Reaction SMILES: [CH:1]([N:4]([CH:29]([CH3:31])[CH3:30])[CH2:5][CH2:6][C@@H:7]([C:14]1[CH:19]=[C:18](Br)[CH:17]=[CH:16][C:15]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:3])[CH3:2].[Li]CCCC.CN([CH:40]=[O:41])C.[NH4+].[Cl-]>C(OCC)C.[Li]CCCC.O>[CH:1]([N:4]([CH:29]([CH3:31])[CH3:30])[CH2:5][CH2:6][C@@H:7]([C:14]1[CH:19]=[C:18]([CH:40]=[O:41])[CH:17]=[CH:16][C:15]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(Br)ccc1OCc1ccccc1)C(C)C
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(C=O)ccc1OCc1ccccc1)C(C)C
Reaction time: 1.5 h
Yield: 100.6 %

Procedure:
n-BuLi (2.5 M in hexane, 19 mL, 47.5 nmol) was added to a solution of to (R)-N,N-diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropanamine (prepared as described in WO 94/11337, Example 1) (8.9 g, 18.52 mmol) in dry diethyl ether (100 mL) kept at −40° C. under nitrogen atmosphere. After 1.5 hour of stirring, additional n-BuLi (10 mL, 25 mmol) was added and after 2 hours another n-BuLi (5 mL, 12.5 mmol) was added. The reaction was then stirred for 15 minutes and DMF (6 mL, 77.8 mmol) was added followed by additional DMF (5 mL, 64.8 mmol) after 20 minutes of stirring. The temperature was allowed to rise to room temperature and after 35 minutes of stirring, NH4Cl (sat.) was added followed by water and diethyl ether. The layers were separated and the aqueous layer was extracted with diethyl ether. The combined organic layers were dried (MgSO4) and the solvent was evaporated. The residue was chromatographed on silica (toluene-triethylamine 90:10) to afford 8 g (100%) of a yellowish oil; 1H NMR (CDCl3) δ0.90 (m, 12H), 2.12-2.40 (m, 4H), 2.95 (m, 2H), 4.44 (t, 1H), 5.10 (s, 2H), 6.95 (d, 1H), 7.15-7.36 (m, 10H), 7.70 (dd, 1H), 7.91 (s, 1H), 9.88 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([B:21]2[O:25][C:24]([CH3:27])([CH3:26])[C:23]([CH3:29])([CH3:28])[O:22]2)=[CH:17][CH:16]=1>>[CH3:1][C:2]1[CH:11]=[C:10]([O:12][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([B:21]3[O:22][C:23]([CH3:29])([CH3:28])[C:24]([CH3:27])([CH3:26])[O:25]3)=[CH:19][CH:20]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Reactant: Cc1cc(O)c2ccccc2n1
Product: Cc1cc(OCc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c2ccccc2n1
Yield: 28 %

Procedure:
Alkylation of 2-Methyl-quinolin-4-ol with 2-(4-Bromomethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane was carried out according to procedures in Step 2A for Example 1C to give 2-Methyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyloxy]-quinoline in 28% yield. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.3 (s, 12 H) 2.6 (s, 3 H) 5.4 (s, 2 H) 7.0 (s, 1 H) 7.5 (m, 1 H) 7.6 (d, J=8.1 Hz, 2 H) 7.7 (m, 1 H) 7.7 (d, J=8.1 Hz, 2 H) 7.9 (d, J=8.1 Hz, 1 H) 8.1 (dd, J=8.3, 0.8 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([I:9])=[C:6]([OH:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:17][C:18]([CH3:20])=[CH2:19]>CC(C)=O.CCOC(C)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([I:9])=[C:6]([O:8][CH2:19][C:18]([CH3:20])=[CH2:17])[CH:7]=1
Reactant: C=C(C)CBr
Reactant: Oc1cc(Cl)ccc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: C=C(C)COc1cc(Cl)ccc1I

Procedure:
To a mixture of 5-chloro-2-iodophenol (1.21 g, 4.76 mmol) and K2CO3 (723 mg, 5.23 mmol) in acetone (20 mL) was added 3-bromo-2-methyl-propene (0.53 ml, 5.23 mmol), and the reaction was heated to reflux for 16 hours. The reaction was cooled, diluted with EtOAc and water, and the layers were separated. The aqueous layer was extracted with EtOAc (2×) and the combined organics were dried over MgSO4, filtered and concentrated to afford 4-chloro-1-iodo-2-((2-methylallyl)oxy)benzene which was used directly in the next step without further purification.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[CH2:29]([CH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>C1COCC1>[CH2:29]([CH:36]1[CH2:41][CH2:40][N:39]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]3[CH2:21][CH2:20][C:19]4[C:14](=[CH:15][C:16]([C:22]5[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=5)=[CH:17][CH:18]=4)[CH:13]=3)=[O:11])=[CH:5][CH:4]=2)[CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CC3)cc1
Reactant: c1ccc(CC2CCNCC2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN4CCC(Cc5ccccc5)CC4)cc2)CC3)cc1
Temperature: 25 °C

Procedure:
In THF (15 ml) was dissolved N-[4—(chloromethyl)-phenyl]-7—(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (300 mg), and to the mixture was added 4-benzylpiperidine (408 μl). The mixture was refluxed for 19 hours. The reaction mixture was cooled to room temperature, and to the mixture was added water (100 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate) and recrystallized from ethyl acetate-hexane to give N-[4—(4-benzyl-piperidinomethyl)phenyl]-7—(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (Compound 35) (259 mg) as colorless crystals.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]([C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:36])[CH2:32][CH2:33][CH2:34][Cl:35])=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22].C(=O)(O)[O-].[K+].[I-].[K+]>C1(C)C=CC=CC=1>[ClH:35].[C:21]([C:25]1[CH:26]=[CH:27][C:28]([C:31](=[O:36])[CH2:32][CH2:33][CH2:34][N:12]2[CH2:13][CH2:14][CH:9]([C:7]([OH:8])([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:10][CH2:11]2)=[CH:29][CH:30]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)c1ccc(C(=O)CCCCl)cc1
Reactant: OC(c1ccccc1)(c1ccccc1)C1CCNCC1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(C(=O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Product: Cl
Reaction time: 48 h

Procedure:
A mixture of 107 g (0.4 mole) of α,α -diphenyl-4-piperidinemethanol, 105 g (0.44 mole) of 4' -tert-butyl-4-chlorobutyrophenone, 70 g (0.7 mole) of potassium bicarbonate, and a small amount of potassium iodide in 600 ml of toluene was refluxed and stirred for 21/2 days then filtered. The filtrate was treated with charcoal, filtered through celite then treated with ethereal HCl. The resulting solid was recrystallized from methanol and isopropyl alcohol to give the desired product, M.P. 234°-235° C.