Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:25])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:16]=2)=[CH:9][CH:8]=1)C.[OH-].[Li+].Cl>C(O)C.O1CCCC1>[C:21]([C:17]1[CH:16]=[C:15]([C:14]#[C:13][C:10]2[CH:11]=[CH:12][C:7](/[CH:6]=[CH:5]/[C:4]([OH:25])=[O:3])=[CH:8][CH:9]=2)[CH:20]=[CH:19][CH:18]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CCOC(=O)/C=C/c1ccc(C#Cc2cccc(C(C)(C)C)c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)c1cccc(C#Cc2ccc(/C=C/C(=O)O)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
A solution of (E)-3-[4-(3-tert-butyl-phenylethynyl)-phenyl]-acrylic acid ethyl ester (Intermediate 103, 0.015 g, 0.047 mmol) in ethanol (2 mL) and tetrahydrofuran (2 mL) was treated with a 2M solution of lithium hydroxide (1 mL, 2 mmol) and the resulting reaction mixture was stirred at ambient temperature overnight. The reaction mixture was neutralized with 10% aqueous hydrochloric acid and evaporated in vacuo to a solid that was washed with water and hexane and dried to afford the title product as a white solid (0.012 g, 85%). 1H NMR (300 MHz, CDCl3): δ 7.78 (d, 1H, J=16.2 Hz), 7.59–7.26 (m, 8H), 6.47 (d, 1H, J=16.2 Hz), 1.34 (s, 9H).
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][NH:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.C(OC(=O)C)(=O)C>>[C:6]1([C:4]2[O:13][C:1](=[O:12])[CH2:2][N:3]=2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(O)CNC(=O)c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: O=C1CN=C(c2ccccc2)O1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
Separately, 2.08 g (0.0116 mol) of hippuric acid was added to 5.7 ml (0.0604 mol) of acetic anhydride and stirred at 80° C. for 10 minutes to obtain a solution of 2-phenyl-2-oxazolin-5-one. This solution was cooled to -20° C. and added with 1.65 g of anhydrous sodium acetate.
Reaction SMILES: Cl.CO.[C:4]([Cl:7])(=O)C.CO.[NH:10]1[CH2:18][C@H:16]([OH:17])[CH2:15][C@H:11]1[C:12]([OH:14])=[O:13]>C(OCC)C>[ClH:7].[CH3:4][O:13][C:12](=[O:14])[C@@H:11]1[CH2:15][C@@H:16]([OH:17])[CH2:18][NH:10]1
Reactant: CC(=O)Cl
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: COC(=O)[C@@H]1C[C@@H](O)CN1
Temperature: 25 °C
Yield: 88.8 %

Procedure:
To a solution of hydrogen chloride-methanol prepared from acetyl chloride (19 ml, 270 mmol) and methanol (170 ml) was added L-hydroxyproline (25 g, 190 mmol), and the reaction mixture refluxed for 7 hours with stirring, cooled to room temperature. The mixture was stirred at 5° C. for 1 hour after addition of diethyl ether (340 ml). The resulting precipitate was collected by filtration, washed with a solution of diethyl ether-methanol (2:1, 50 ml), and dried under nitrogen for 4 hours to afford the title compound (30.64 g, 89% yield).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([Cl:32])=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][N:37]([CH3:47])[C:38](=[O:46])[CH2:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[ClH:32].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:43]3[CH2:42][CH2:41][N:40]([CH2:39][C:38]([N:37]([CH3:47])[CH3:36])=[O:46])[CH2:45][CH2:44]3)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(F)cc2)[C@@H](c2ccc(F)cc2)N1C(=O)Cl
Reactant: CN(C)C(=O)CN1CCNCC1
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(F)cc2)[C@@H](c2ccc(F)cc2)N1C(=O)N1CCN(CC(=O)N(C)C)CC1
Product: Cl

Procedure:
2-{4-[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-fluoro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N,N-dimethyl-acetamide hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-fluoro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12a) and N,N-dimethyl-2-piperazin-1-yl-acetamide (Oakwood Products) in an analogous manner as described in example 25. LR-MS: 632.8 [(M+H)+]
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][CH2:16][OH:17])[O:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([O:38][CH3:39])[C:35]=1[O:36][CH3:37])[C:30](Cl)=[O:31].CN(C1C=CC=CN=1)C.[N+:49]([C:52]1[CH:57]=[CH:56][C:55]([S:58](Cl)(=[O:60])=[O:59])=[CH:54][CH:53]=1)([O-:51])=[O:50].Cl>C(Cl)Cl.O>[N+:49]([C:52]1[CH:53]=[CH:54][C:55]([S:58]([O:17][CH2:16][CH2:15][C:9]2([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[O:14][CH2:13][CH2:12][N:11]([C:30](=[O:31])[C:29]3[CH:28]=[C:27]([O:26][CH3:25])[C:35]([O:36][CH3:37])=[C:34]([O:38][CH3:39])[CH:33]=3)[CH2:10]2)(=[O:60])=[O:59])=[CH:56][CH:57]=1)([O-:51])=[O:50]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CNCCO1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCOC(CCOS(=O)(=O)c3ccc([N+](=O)[O-])cc3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To a solution of 2-[2-(3,4-dichlorophenyl)morpholin-2-yl]ethanol (5 g, 18.0 mmol) in methylene chloride (25 ml) was added triethylamine (7.5 ml, 54.0 mmol) under a nitrogen stream, the resulting mixture was cooled to 0-5° C., then a solution of 3,4,5-trimethoxybenzoyl chloride (4.2 g, 18.4 mmol) in methylene chloride (20 ml) was further added dropwise at below 10° C. After the resulting mixture was stirred at 0-5° C. for one hour, dimethylaminopyridine (0.22 g, 1.8 mmol) was further added. Subsequently, a solution of 4-nitrobenzenesulfonyl chloride (4.8 g, 21.6 mmol) in methylene chloride (10 ml) was further added dropwise at below 10° C., and the resulting mixture was stirred at room temperature for 30 minutes. After completion of the reaction, to the reaction mixture were added successively water (50 ml) and concentrated hydrochloric acid (5 ml), and the resulting mixture was partitioned. The separated organic layer was washed with water twice (50 ml each) and evaporated to dryness. Subsequently, to the obtained residue was added toluene (45 ml), and the resulting mixture was refluxed to dissolve the residue. The solution thus obtained was cooled to 0-5° C. over about one hour, and stirred at the same temperature for one hour. The crystals precipitated were collected by filtration and dried at 50° C. for 15 hours in vacuo to afford the title compound [11.2 g, yield: 94.9%] as a pale yellow crystalline solid.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]3[CH:12]=[N:13][CH:14]=[C:15]([C:18]=3[NH:19][C:20]3[C:21]([CH3:29])=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][CH:24]=[CH:23]4)[C:16]#[N:17])=[CH:8][C:7]=2[CH:30]=1)=[O:2].[OH:31][CH2:32][CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CN1C(=O)CCC1>[OH:31][CH2:32][CH:33]1[CH2:38][CH2:37][N:36]([CH2:1][C:3]2[CH:4]=[CH:5][C:6]3[O:10][C:9]([C:11]4[CH:12]=[N:13][CH:14]=[C:15]([C:18]=4[NH:19][C:20]4[C:21]([CH3:29])=[C:22]5[C:26](=[CH:27][CH:28]=4)[NH:25][CH:24]=[CH:23]5)[C:16]#[N:17])=[CH:8][C:7]=3[CH:30]=2)[CH2:35][CH2:34]1.[OH:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]3[CH:12]=[N:13][CH:14]=[C:15]([C:18]=3[NH:19][C:20]3[C:21]([CH3:29])=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][CH:24]=[CH:23]4)[C:16]#[N:17])=[CH:8][C:7]=2[CH:30]=1
Reactant: OCC1CCNCC1
Reactant: Cc1c(Nc2c(C#N)cncc2-c2cc3cc(C=O)ccc3o2)ccc2[nH]ccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1c(Nc2c(C#N)cncc2-c2cc3cc(CN4CCC(CO)CC4)ccc3o2)ccc2[nH]ccc12
Product: Cc1c(Nc2c(C#N)cncc2-c2cc3cc(CO)ccc3o2)ccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
To a suspension of 5-(5-formyl-1-benzofuran-2-yl)-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile (200 mg, 0.51 mmol) in a mixture of CH2Cl2 (10 mL) and NMP (1 mL) at room temperature under nitrogen was added 4-(hydroxymethyl)piperidine (176 mg, 1.53 mmol) followed by glacial acetic acid (153 mg, 2.55 mmol) and the reaction mixture was stirred at room temperature for 0.5 h. Sodium triacetoxyborohydride (540 mg, 2.55 mmol) was added in portions at 0° C. and the resulting mixture was stirred at room temperature overnight. The reaction mixture was partitioned between CH2Cl2 and saturated aqueous sodium bicarbonate, and the aqueous layer was extracted with CH2Cl2. The combined organic phases were washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (MeOH/CH2Cl2, 3% to 20%) to give 128 mg (51%) of 5-(5-{[4-(hydroxymethyl)piperidin-1-yl]methyl}-1-benzofuran-2-yl)-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile 392 as a yellow solid and 23.8 mg of 5-[5-(hydroxymethyl)-1-benzofuran-2-yl]-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile 481 as a yellow solid. Compound 392: HPLC retention time: 6.4 min.(g); melting range: 196-199° C.; and HRMS: 395.15023. Compound 481: HPLC retention time: 8.9 min.(g); MS: 395.3 (M+H); melting range: 232-234° C.; and HRMS: 395.15023.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Na+].Cl>O.O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:27]=[CH:26][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(-c2ccc(OC[C@H](CC3CCCCC3)NC(=O)OC(C)(C)C)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H](COc1ccc(-c2ccc(C(=O)O)cc2)cc1)CC1CCCCC1
Yield: 81.7 %

Procedure:
A solution of methyl (S)-4-[4-[2-(tert-butoxycarbonylamino)-3-cyclohexylpropyloxy]phenyl]benzoate (0.28 g) in a mixed solvent of methanol (14 ml) and tetrahydrofuran (3 ml) was treated with 1N-sodium hydroxide aqueous solution, and the mixture was refluxed for 16 hours. After cooling, water was added to the mixture, and the acidity of the mixture was adjusted to pH 1 with 1N-hydrochloric acid. The resulting precipitate was filtered, washed with water and dried under reduced pressure to give (S)-4-[4-[2-(tert-butoxycarbonylamino)-3-cyclohexylpropyloxy]phenyl]benzoic acid (222 mg) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[Cl:15][C:16]1[CH:17]=[C:18]([OH:23])[CH:19]=[CH:20][C:21]=1[Cl:22].O>CN(C=O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([O:23][C:18]2[CH:19]=[CH:20][C:21]([Cl:22])=[C:16]([Cl:15])[CH:17]=2)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc(Oc2ccc(Br)cn2)cc1Cl
Temperature: 90 °C
Yield: 99.5 %

Procedure:
To a solution of 2,5-dibromopyridine (2.412 g, 10.18 mmol) in DMF (50 mL) was added K2CO3 (5.22 g, 37.8 mmol) and 3,4-dichlorophenol (2.66 g, 16.3 mmol). The mixture was heated at 90° C. for 18 h then allowed to cool to room temperature (rt). Water was added and the mixture was extracted with DCM. Purification by FCC provided the desired product (3.23 g, 100%). 1H NMR (400 MHz, CDCl3): 8.21 (dd, J=2.5, 0.8 Hz, 1H), 7.81 (dd, J=8.3, 3.0 Hz, 1H), 7.45 (d, J=8.8 Hz, 1H), 7.26 (d, J=1.5 Hz, 1H), 7.00 (dd, J=9.0, 2.5 Hz, 1H), 6.88 (dd, J=8.8, 0.8 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][N:15]3[C:18]([C:21]([F:24])([F:23])[F:22])=[N:19][N:20]=[C:14]3[CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7](Cl)[C:6]=12.[NH3:25].CC(O)C>>[Br:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][N:15]3[C:18]([C:21]([F:24])([F:23])[F:22])=[N:19][N:20]=[C:14]3[CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH2:25])[C:6]=12
Reactant: N
Reactant: FC(F)(F)c1nnc2n1CCN(c1nc(Br)c3c(Cl)nccn13)C2
Solvent: CC(C)O
Product: Nc1nccn2c(N3CCn4c(nnc4C(F)(F)F)C3)nc(Br)c12
Temperature: 120 °C

Procedure:
To a 75 ml sealed vessel was charged with 7-(1-bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (595 mg, 1.408 mmol) along with ammonia in IPA (2N, 0.704 ml, 1.408 mmol). The vessel was sealed with screw cap and heated in an oil bath of 120° C. for 18 hrs overnight. LC-MS showed complete conversion of starting material to product. The mixture was then cooled to room temperature, solid (gel) precipitated and was filtered, washed with IPA and dried to afford 1-bromo-3-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)imidazo[1,5-a]pyrazin-8-amine (250 mg). The filtrate was concentrated and the residue was purified by MPLC (12 g silica gel, 0 to 10% methanol in methylenechloride, 28 CV) to afford another batch of product. Totally 1-bromo-3-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)imidazo[1,5-a]pyrazin-8-amine (386 mg, 0.957 mmol, 68.0% yield) was obtained. LC-MS: C12H10BrF3N8,402. found 403.08 [M+H]+, RT=1.09 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:4][C:3]=1[C:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([OH:17])[CH3:16].NC1C=CC(C2C=CC=C(Cl)C=2)=CC=1[C:39](=[O:41])C.C([Mg]Br)C1C=CC=CC=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>>[CH2:18]([C:15]1([CH3:16])[O:17][C:39](=[O:41])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=3)=[CH:4][C:3]1=2)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(=O)c1cc(-c2cccc(Cl)c2)ccc1N
Reactant: CC(O)(Cc1ccccc1)c1cc(-c2cccc(Cl)c2)ccc1N
Agent: Br[Mg]Cc1ccccc1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: CC1(Cc2ccccc2)OC(=O)Nc2ccc(-c3cccc(Cl)c3)cc21
Yield: 30 %

Procedure:
A mixture of 1-(4-amino-3′-chloro-biphenyl-3-yl)-1-benzyl-ethanol (prepared from 1-(4-amino-3′-chloro-biphenyl-3-yl)-ethanone and benzylmagnesium bromide according to procedure described previously, 0.14 g, 0.42 mmol) and triphosgene (0.04 g, 0.14 mmol) in dry TRF (10 mL) was stirred under a blanket of nitrogen for 10 minutes. THF was removed and the residue purified via flash chromatography (silica gel, 35% ethyl acetate/hexane) to give 4-benzyl-6-(3-chloro-phenyl)-4-methyl-1,4 -dihydro-benzo[d][1,3]oxazin-2-one (0.045 g, 30%) as an off-white solid: mp 187-188° C.; 1H-NMR (DMSO-d6) δ10.1 (s, 1H), 7.70 (t, 1H, J=2.3 Hz), 7.6 (d, 1H, J=8.0 Hz), 7.58-7.53 (m, 2H), 7.46 (t, 1H, J=8.0 Hz), 7.38 (d, 1H, J=8.0 Hz), 7.22-7.17 (m, 3H), 7.06-7.0 (m, 2H), 6.84 (d, 1H, J=9.14 Hz), 3.24 (d, 1H, J=14.3), 3.06 (d, 1H, J=14.3 Hz), 1.68 (s, 3H), MS (ESI) m/z 364 ([M+H]+,100%), Anal. Calc. For C22H18CINO2: C, 72.63; H, 4.99; N, 3.85. Found: C, 71.82; H, 5.09; N,3.58.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]#[N:8])[S:5][CH:6]=1.[CH3:9][C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[CH2:15][C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C:21]([C:23]1[CH:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][CH:24]=1)=[O:22]>>[CH3:9][C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[CH2:15][C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C:21]([C:23]1[CH:28]=[CH:27][C:26]([C:2]2[CH:3]=[C:4]([C:7]#[N:8])[S:5][CH:6]=2)=[CH:25][CH:24]=1)=[O:22]
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: N#Cc1cc(Br)cs1
Product: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(-c2csc(C#N)c2)cc1

Procedure:
The title compound is prepared in a manner substantially analogous General Procedure A using 4-bromo-thiophene-2-carbonitrile (CAS 18791-99-6) and [2-(S)-(2-(R)-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone to give the title compound. (150 mg, 30% yield). MS (ES+) 380.2 (M+H)+
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5]Br.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:15]([O:17][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([F:26])[CH:20]=1)[CH3:16]>CC(C)=O>[CH2:15]([O:17][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])=[C:21]([F:26])[CH:20]=1)[CH3:16]
Reactant: BrCCCCBr
Reactant: CCOC(=O)c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc(OCCCCBr)c(F)c1
Yield: 80 %

Procedure:
1,4-Dibromobutane (2.34 g, 10.8 mmol), potassium carbon-ate (1.86 g, 13.5 mmol) and potassium iodide (90 mg, 0.5 mmol) were added to a solution of 3-fluoro-4-hydroxy-benzoic acid ethyl ester from Example E27 (11.0 g, 5.4 mmol) in acetone (25 ml) and the mixture was heated at reflux for 20 h. The solid was filtered off, washed with EtOAc and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 15% EtOAc:85% hexane) to yield the title compound (1.38 g, 80%).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH:13]1([CH2:16][C:17]([OH:19])=[O:18])[CH2:15][CH2:14]1.Br[CH2:21][CH2:22][CH2:23][Cl:24]>C1COCC1.C(OCC)C>[Cl:24][CH2:23][CH2:22][CH2:21][CH:16]([CH:13]1[CH2:15][CH2:14]1)[C:17]([OH:19])=[O:18]
Reactant: O=C(O)CC1CC1
Reactant: ClCCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Product: O=C(O)C(CCCCl)C1CC1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
n-Butyl lithium (2.64 M solution in hexane, 3.8 ml) was added dropwise to a solution of diisopropylamine (1.5 ml) in THF (15 ml) at −30° C., and the reaction solution was stirred at the same temperature for 15 minutes. The reaction solution was cooled to −78° C. Then, a solution of cyclopropylacetic acid (CAS No. 5239-82-7, 500 mg) in THF (3 ml) was added dropwise and the reaction solution was further stirred at room temperature for three hours. The reaction solution was cooled to 0° C., and then 1-bromo-3-chloropropane (CAS No. 109-70-6, 0.55 ml) was added dropwise. The reaction solution was stirred at the same temperature for 10 minutes and at room temperature for further one hour. Ice water and diethyl ether were added to the reaction solution, and the aqueous layer was separated. Then, 5 N hydrochloric acid (3 ml) and ethyl acetate were added to the aqueous layer, and the organic layer was separated. The resulting ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain crude 5-chloro-2-cyclopropyl-valeric acid (550 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[C:15]1([C:21]([C:25]2[CH:30]=[N:29][CH:28]=[CH:27][N:26]=2)=CC=O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH2:31](C(C)=O)[CH3:32].[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38]>O1CCCC1.C(Cl)Cl>[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:28]3[N:29]=[C:21]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:25]4[N:26]([CH:31]=[CH:32][CH:30]=4)[CH:27]=3)[CH2:9][CH2:8]2)=[CH:13][CH:14]=1
Reactant: O=CC=C(c1ccccc1)c1cnccn1
Reactant: Cc1ccc(CN2CCNCC2)cc1
Reactant: CCC(C)=O
Agent: O=C(O)C(=O)O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccc(CN2CCN(c3cn4cccc4c(-c4ccccc4)n3)CC2)cc1
Temperature: 66 °C
Reaction time: 3 h

Procedure:
A solution of 1-(4-methylbenzyl)piperazine (9.5 g) in tetrahydrofuran (50 cc) is added in the course of 10 minutes at a temperature in the region of 20° C. to a stirred solution of 3-phenyl-3-pyrazinylpropenal (1 g) in tetrahydrofuran (50 cc), and the mixture is left with stirring for 3 hours at a temperature in the region of 66° C. After the solution is cooled to a temperature in the region of 20° C., the reaction mixture is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. A residue is obtained which is dissolved in methylene chloride (10 cc). The solution obtained is poured onto silica (200 g) contained in a column 3.5 cm in diameter. Elution is performed with a mixture (500 cc) of methylene chloride and methanol (99.5:0.5 by volume) and the corresponding eluate is evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The oil obtained is dissolved in boiling methyl ethyl ketone (20 cc). A solution of oxalic acid (0.25 g) in boiling methyl ethyl ketone (20 cc) is added. After the mixture is cooled to a temperature in the region of 20° C., the precipitate formed is separated by filtration and then recrystallized in boiling isopropyl alcohol (80 cc). 3-[4-(4-Methylbenzyl)-1-piperazinyl]-1-phenylpyrrolo[1,2-a]pyrazine oxalate (0.4 g), m.p. 128° C., is thereby obtained.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]3[CH:22]=[C:21]([F:23])[C:20]([F:24])=[C:19]([F:25])[CH:18]=3)[CH:13]=2)C=1)(=O)=O.[C:28]([CH:30]1[CH2:35][CH2:34][CH:33]([CH2:36][CH2:37][CH3:38])[CH2:32][CH2:31]1)#[CH:29].O.[CH3:40]N(C)C=O>C(N(CC)CC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu](I)I>[CH2:28]([C@H:30]1[CH2:35][CH2:34][C@H:33]([C:36]#[C:37][C:38]2[C:9]3[C:14](=[CH:13][C:12]([C:17]4[CH:18]=[C:19]([F:25])[C:20]([F:24])=[C:21]([F:23])[CH:22]=4)=[CH:11][CH:10]=3)[CH:15]=[CH:16][CH:7]=2)[CH2:32][CH2:31]1)[CH2:29][CH3:40]
Reactant: CN(C)C=O
Reactant: O=S(=O)(Oc1ccc2cc(-c3cc(F)c(F)c(F)c3)ccc2c1)C(F)(F)F
Reactant: C#CC1CCC(CCC)CC1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Product: CCC[C@H]1CC[C@H](C#Cc2cccc3cc(-c4cc(F)c(F)c(F)c4)ccc23)CC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
25.0 g of 6-(3,4,5-trifluorophenyl)naphthalene-2-yl trifluoromethanesulfonate and 1-ethynyl-4-propylcyclohexane were dissolved in a mixture of 125 ml of N,N-dimethylformamide and 25 ml of triethylamine. To the solution were then added 0.7 g of tetrakis(triphenylphosphine)palladium and 0.2 g of copper iodide (I). The reaction mixture was then stirred at a temperature of 50° C. for 3 hours. The reaction solution was then allowed to cool to room temperature. To the reaction solution was then added 150 ml of water. The reaction solution was extracted with 200 ml of toluene, washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was then distilled off. The residue was then recrystallized from ethanol to obtain 17.6 g of 2-(trans-4-propylcyclohexyl)ethynyl-6-(3,4,5-trifluorophenyl)naphthalene.
Reaction SMILES: [C:1]([C:3]1[O:7][N:6]=[CH:5][CH:4]=1)#[N:2].[NH2:8][C:9]1[S:10][C:11]([Cl:19])=[CH:12][C:13]=1[C:14](OCC)=O.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:14]1[C:13]2[CH:12]=[C:11]([Cl:19])[S:10][C:9]=2[N:8]=[C:1]([C:3]2[O:7][N:6]=[CH:5][CH:4]=2)[N:2]=1
Reactant: N#Cc1ccno1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cc(Cl)sc1N
Product: Clc1cc2c(Cl)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 477, the reaction of 5-cyanoisoxazole and 2-amino-5-chloro-3-ethoxycarbonyl-thiophene, and the subsequent reaction with POCl3 yields 4-chloro-2-(isoxazol-5-yl)-6-chloro-thieno-[2,3-d]-pyrimidine