Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[N:8][C:7]([C:13]([OH:15])=[O:14])=[CH:6]2)[CH3:2].S(Cl)(Cl)=O.[C:20]1(O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[N:8][C:7]([C:13]([O:15][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:14])=[CH:6]2)[CH3:2]
Reactant: CCc1ccc2nnc(C(=O)O)cc2c1
Reactant: Oc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCc1ccc2nnc(C(=O)Oc3ccccc3)cc2c1

Procedure:
A mixture of 6-ethylcinnolin-3-yl carboxylic acid (0.606 g.) and thionyl chloride (30 ml.) was heated under reflux on a steam bath for 20 minutes. The resulting solution was evaporated under reduced pressure to give a yellow crystalline solid, to which was added a solution of phenol (1.13 g.) in dry tetrahydrofuran (20 ml.). The mixture was heated under reflux on a steam bath for 2 hours. The resulting solution was evaporated and the residue was washed by decantation with ether (2× 50 ml.). The residual brown oil was dissolved in ethyl acetate (50 ml.) and washed successively with 5% w/v aqueous sodium bicarbonate (10 ml.) and water (2× 10 ml.). The ethyl acetate solution was dried (MgSO4), filtered and evaporated, and the residual oil was applied to the top of a silica column (30 g. Kieselgel 60). Elution with a 50% v/v mixture of ethyl acetate and petroleum ether (b.p. 60°-80° C.), and evaporation of the appropriate fractions, gave crude phenyl 6-ethylcinnolin-3-yl carboxylate. The product was recrystallised from aqueous ethanol, and then had m.p. 143°-145° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.C(#N)C.C(N(CC)CC)C.[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>>[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([C:4]1[NH:5][CH:6]=[C:2]([CH3:1])[N:3]=1)=[O:21]
Reactant: Cc1c[nH]cn1
Reactant: O=C(Cl)c1ccccc1F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c[nH]c(C(=O)c2ccccc2F)n1
Temperature: 140 °C
Yield: 67.4 %

Procedure:
To a 350 mL pressure vessel was added 4-methylimidazole (12 g, 146 mmol, 1 eq.) and a stirbar. Acetonitrile (35 mL, 670 mmol, 4.6 eq.) was added. Triethylamine (59 mL, 424 mmol, 2.9 eq.) was added and the mixture was stirred until it became homogeneous. 2-fluorobenzoyl chloride (67.2 g, 424 mmol, 2.9 eq.) was added. Upon addition of the acyl chloride, the mixture became warm and viscous. The vessel was sealed and heated at 140° C. for 2 h with stirring. During heating, the mixture turned black in color. The vessel was removed from the heat, allowed to cool, and its contents were diluted with acetone (50 mL). The mixture was stirred and transferred to a 2 L round-bottomed flask containing 7% aqueous HCl (1000 mL). Charcoal was added to the flask and the mixture was heated at reflux for 1.5 h. The mixture was allowed to cool almost to room temperature and then was filtered through a Celite pad followed by a rinse with 1N HCl (˜100 mL). The filtrate was placed in an ice bath and was made alkaline with aqueous NH4OH (35%) whereupon a solid precipitate formed. The solid was filtered and washed with copious amounts of dilute NH4OH to remove triethylamine hydrochloride salts. The solid was collected and placed under high vacuum, yielding the desired ketone 1 as a brown solid (20.1 g, 67%). LC/MSD (HP Series 1100 MSD) Expected MW: 204.07, Observed M+H: 205.0, Retention time: 1.13. 1H NMR, CD3OD, Varian 400 MHz δ 7.70 (t, 1H), 7.59 (m, 1H), 7.30 (t, 1H), 7.25-6.96 (m, 2H), 2.34 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)([CH3:5])[CH3:4].[N+]([C:17]1[CH:18]=[C:19]([CH:22]=[O:23])[S:20][CH:21]=1)([O-])=O.O>CS(C)=O>[CH:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:21]2[S:20][C:19]([CH:22]=[O:23])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)([CH3:5])[CH3:4]
Reactant: O=Cc1cc([N+](=O)[O-])cs1
Reactant: CC(C)Oc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)Oc1ccc(Oc2ccc(C=O)s2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 7.9 %

Procedure:
NaH (60%, 480 mg, 12.0 mmol) was added in several portions to a stirred solution of Example 17A (1.52 g, 10.0 mmol) in DMSO (15 mL) at room temperature. After 20 min, 4-nitrothiophene-2-carbaldehyde (1.57 g, 10.0 mmol) was added in one portion. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, extracted with ether (2×). The ether layer was washed with 10% NaOH (1×), brine (1×), dried over MgSO4 and concentrated. The residue was purified on silica gel eluting with ethyl acetate: hexane gradient to give the desired product as a brown oil (206 mg, 7.8%).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11].CN(C)C=O.C(N(CC)CC)C.[N+](C1C=CC([O:44][C:45]([N:47]2[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[CH2:50][CH2:49][CH2:48]2)=O)=CC=1)([O-])=O>>[F:21][C:19]([F:22])([F:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[S:10]([NH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][NH:2][C:45]([N:47]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH2:50][CH2:49][CH2:48]1)=[O:44])(=[O:12])=[O:11]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCCc2ccccc21
Reactant: NCCCCCCNS(=O)(=O)c1ccccc1C(F)(F)F
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCCCCCCNS(=O)(=O)c1ccccc1C(F)(F)F)N1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 61 %

Procedure:
To a solution of N-(6-Aminohexyl) -2-trifluoromethylbenzene sulfonamide Hydrochloride( 0.1 g, 0.27 mmol) dimethyl formamide (3 mL) and triethylamine (0.1 g, 1 mmol) was added 3, 4-Dihydro-2H-quinoline-1-carboxylic acid 4-nitrophenyl ester (0.09 g, 0.3 mmol) and the reaction mixture was stirred at room temperature for 4 h. Solvent was evaporated and purification by preparative TLC afford the titled compound as an oil (0.08 g, 61%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].Br[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[C:17]1([CH2:16][N:1]2[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:2]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NC(=O)C1CCNCC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: NC(=O)C1CCN(Cc2ccccc2)CC1

Procedure:
123.0 g (0.96 mol) of 4-piperidinecarboxamide and 90.8 g (1.08 mol) of sodium bicarbonate are introduced under an argon atmosphere into 2 1 of dry toluene. 180.6 g, equivalent to 125.6 ml (1.056 mol), of bromomethylbenzene are added, and the mixture is heated under reflux for 5 h.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:23][C:24]2[CH:32]=[C:31]3[C:27]([CH:28]=[N:29][NH:30]3)=[CH:26][CH:25]=2)[C:5]2[C:10]([CH2:11]C)=[CH:9][N:8]([S:13]([C:16]3[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[C:6]=2[N:7]=1.[NH2:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]2[CH2:45][CH2:44][N:43]([C:46](=[O:48])[CH3:47])[CH2:42][CH2:41]2)=[CH:36][CH:35]=1.C[Si](Cl)(C)C>C(O)CCC>[NH:30]1[C:31]2[C:27](=[CH:26][CH:25]=[C:24]([NH:23][C:4]3[C:5]4[C:10]([CH3:11])=[CH:9][N:8]([S:13]([C:16]5[CH:17]=[CH:18][C:19]([CH3:20])=[CH:21][CH:22]=5)(=[O:15])=[O:14])[C:6]=4[N:7]=[C:2]([NH:33][C:34]4[CH:35]=[CH:36][C:37]([N:40]5[CH2:41][CH2:42][N:43]([C:46](=[O:48])[CH3:47])[CH2:44][CH2:45]5)=[CH:38][CH:39]=4)[N:3]=3)[CH:32]=2)[CH:28]=[N:29]1
Reactant: CCc1cn(S(=O)(=O)c2ccc(C)cc2)c2nc(Cl)nc(Nc3ccc4cn[nH]c4c3)c12
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CC(=O)N1CCN(c2ccc(Nc3nc(Nc4ccc5cn[nH]c5c4)c4c(C)cn(S(=O)(=O)c5ccc(C)cc5)c4n3)cc2)CC1
Temperature: 115 °C
Yield: 18.5 %

Procedure:
To a mixture of 2-Chloro-N-(1H-indazol-6-yl)-5-ethyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.08 g, 0.17 mmol) and 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (0.075 g, 0.34 mmol) in n-butyl alcohol (2 mL) was added TMSCl (0.011 mL, 0.086 mmol). After heating at 115° C. for 48 h, the mixture was purified by preparative HPLC to give 1-(4-(4-(4-(1H-indazol-6-ylamino)-5-methyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone (0.02 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[C:4]([F:12])[CH:3]=1.[CH3:13][C:14]1([C:17]2[S:21][C:20]([NH2:22])=[N:19][N:18]=2)[CH2:16][CH2:15]1.CN1CCOCC1.COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[Cl-]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:22][C:20]2[S:21][C:17]([C:14]3([CH3:13])[CH2:16][CH2:15]3)=[N:18][N:19]=2)=[O:11])=[C:4]([F:12])[CH:3]=1
Reactant: O=C(O)Cc1ccc(Br)cc1F
Reactant: CC1(c2nnc(N)s2)CC1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC1(c2nnc(NC(=O)Cc3ccc(Br)cc3F)s2)CC1
Reaction time: 14 h
Yield: 47.2 %

Procedure:
Combine (4-bromo-2-fluoro-phenyl)-acetic acid (3.81 g, 16.35 mmol) and 5-(1-Methyl-cyclopropyl)-[1,3,4]thiadiazol-2-ylamine (2.54 g, 16.35 mmol) in THF (45 mL). Under N2, add 4-methyl-morpholine (2.16 mL, 19.62 mmol), then 4-(4,6-dimethoxy-[1,3,5]triazin-2-yl)-4-methyl-morpholin-4-ium; chloride (5.43 g, 19.62 mmol). Stir the reaction mixture for 14 hours under N2. Extract with ethyl acetate versus water. Wash with aqueous saturated sodium chloride, dry over magnesium sulfate, filter, and concentrate. Triturate the resulting solid from ethyl acetate/hexanes, filter, and dry to give fluffy white solid as the title compound (2.86 g, 47%). MS (ES), mm/z 370, 372 (M+1).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]([CH3:9])([OH:8])[C:4]([F:7])([F:6])[F:5].C(N(CC)CC)C.[C:19](Cl)(=[O:23])[C:20]([CH3:22])=[CH2:21]>CN(C)C1C=CN=CC=1.CC(C)=O>[C:19]([O:8][C:3]([CH3:9])([C:4]([F:6])([F:5])[F:7])[C:2]([F:10])([F:11])[F:1])(=[O:23])[C:20]([CH3:22])=[CH2:21]
Reactant: CC(O)(C(F)(F)F)C(F)(F)F
Reactant: C=C(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC(C)(C(F)(F)F)C(F)(F)F
Yield: 74.8 %

Procedure:
7.3 g of 1,1,1,3,3,3-hexafluoro-2-methyl-2-propanol, 0.2 g of 4-dimethylaminopyridine, 4.9 g of triethylamine and 20 g of acetone were charged into a four-necked flask equipped with a stirrer, a thermometer and a dropping funnel, and were dissolved by stirring. Then, 4.6 g of methacrylic acid chloride was dropwise added to the resulting solution at about 5° C. over 30 minutes, followed by stirring at the same temperature for 3 hours. Thereafter, the reaction solution was washed with water, thereby obtaining 7.5 g of 1,1,1,3,3,3-hexafluoro-2-methyl-2-propyl methacrylate. The 1H-NMR data of the obtained 1,1,1,3,3,3-hexafluoro-2-methyl-2-propyl methacrylate were as follows.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[NH:32]1[CH2:37][CH2:36][CH:35]([N:38]2[CH2:43][CH2:42][N:41]([C:44]([O:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[O:45])[CH2:40][CH2:39]2)[CH2:34][CH2:33]1.[NH2:54][C:55]1[C:86]([C:87]([F:90])([F:89])[F:88])=[CH:85][C:58]([CH2:59][C@@H:60]([CH2:64][C:65](=[O:84])[N:66]2[CH2:71][CH2:70][CH:69]([N:72]3[CH2:78][CH2:77][C:76]4[CH:79]=[CH:80][CH:81]=[CH:82][C:75]=4[NH:74][C:73]3=[O:83])[CH2:68][CH2:67]2)[C:61](O)=[O:62])=[CH:57][C:56]=1[Cl:91].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:54][C:55]1[C:86]([C:87]([F:89])([F:88])[F:90])=[CH:85][C:58]([CH2:59][C@@H:60]([CH2:64][C:65](=[O:84])[N:66]2[CH2:67][CH2:68][CH:69]([N:72]3[CH2:78][CH2:77][C:76]4[CH:79]=[CH:80][CH:81]=[CH:82][C:75]=4[NH:74][C:73]3=[O:83])[CH2:70][CH2:71]2)[C:61]([N:32]2[CH2:37][CH2:36][CH:35]([N:38]3[CH2:39][CH2:40][N:41]([C:44]([O:46][CH2:47][C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)=[O:45])[CH2:42][CH2:43]3)[CH2:34][CH2:33]2)=[O:62])=[CH:57][C:56]=1[Cl:91]
Reactant: O=C(OCc1ccccc1)N1CCN(C2CCNCC2)CC1
Reactant: Nc1c(Cl)cc(C[C@@H](CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1c(Cl)cc(C[C@@H](CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCN(C(=O)OCc4ccccc4)CC3)CC2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
241 mg (0.75 mmol) TBTU, 0.62 mL (3.6 mmol) ethyldiisopropylamine and 215 mg (0.71 mmol) benzyl 4-piperidin-4-yl-piperazin-1-carboxylate were added to a solution of 390 mg (0.71 mmol) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-butanoic acid in 10 mL DMF and the reaction mixture was stirred overnight at RT. The reaction solution was poured into 80 mL 15% K2CO3 solution, stirred for 10 min at RT, the precipitated substance was suction filtered, washed with 5 mL water and dried in the air over the weekend.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[C:36]([C:41](=[NH:43])[NH2:42])[CH:37]=2)[CH:32]=1)(=O)=O.C(OCC)C>N1C=CC=CC=1>[C:1]1([CH2:7][C:8]([O:10][C:31]2[CH:40]=[CH:39][C:38]3[C:33](=[CH:34][CH:35]=[C:36]([C:41](=[NH:42])[NH2:43])[CH:37]=3)[CH:32]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Reactant: O=C(O)Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: CCOCC
Product: N=C(N)c1ccc2cc(OC(=O)Cc3ccccc3)ccc2c1
Reaction time: 0.5 h
Yield: 55.9 %

Procedure:
To a solution of 2.4 g of phenylacetic acid in 50 ml of anhydrous pyridine, while being cooled and stirred, was added 4.4 g of DCC. After 30 minutes, to the mixture was added 5.0 g of 6-amidino-2-naphthol methanesulfonate. The mixture was stirred at room temperature for 24 hours, mixed with ethyl ether, and the precipitate was collected by filtration. The precipitate was dissolved in DMF and the insolubles were filtered off. The filtrate containing the DMF-soluble substances was mixed with ethyl ether, the resulting precipitate was collected by filtration and recrystallized from a mixture of DMF and ethyl ether to obtain 3.0 g of a white powder of 6-amidino-2-naphthyl phenylacetate methanesulfonate.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH:15]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(CC)CC)C>C(#N)C>[CH:15]1([NH:21][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NC1CCCCC1
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(NC2CCCCC2)c([N+](=O)[O-])c1
Yield: 97.9 %

Procedure:
A solution of methyl 4-chloro-3-nitrobenzoate (5.00 g, 23.2 mmol), cylohexylamine (3.98 mL, 34.8 mmol), and triethylamine (4.8 ML, 35 mmol) in acetonitrile (75 mL) was reluxed for 22 h under an argon atmosphere. The reaction mixture was concentrated to a volume of ˜20 mL and the precipitated solid was filtered. The filtrate was diluted with ethyl acetate and was washed with 1M citric acid (1×) followed by saturated NaHCO3 (1×). The organic layer was dried (MgSO4) and concentrated on a rotary evaporator. The residue was purified by column chromatography (silica gel, 50-70% dichloromethane/hexanes (v/v)) to give compound 45 as a yellow solid (6.32 g, 98%). ESI-MS m/e 279.2 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[C@H:11]([CH3:16])[CH2:12][NH:13][C:14](=[O:15])[C:6]3=[CH:5][C:4]=2[CH:3]=1.[CH:17]([N:20]1[CH2:25][CH2:24][CH:23](O)[CH2:22][CH2:21]1)([CH3:19])[CH3:18].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>>[CH:17]([N:20]1[CH2:25][CH2:24][CH:23]([O:1][C:2]2[CH:10]=[CH:9][C:8]3[N:7]4[C@H:11]([CH3:16])[CH2:12][NH:13][C:14](=[O:15])[C:6]4=[CH:5][C:4]=3[CH:3]=2)[CH2:22][CH2:21]1)([CH3:19])[CH3:18]
Reactant: C[C@@H]1CNC(=O)c2cc3cc(O)ccc3n21
Reactant: CC(C)N1CCC(O)CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CNC2=O)CC1
Yield: 22 %

Procedure:
The title compound was synthesized in analogy to example 1, from (R)-8-hydroxy-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one, 1-isopropyl-piperidin-4-ol (commercially available), tributylphosphine and 1,1′-(azodicarbonyl)dipiperidine, to give the desired product as a colorless gum (22%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][CH2:13][C:14]([OH:16])=O)=[CH:9][C:4]=2[CH:3]=[CH:2]1.N1C=CN=C1.S(Cl)(Cl)=O.Cl.[NH:27]1[CH2:30][CH:29]([OH:31])[CH2:28]1.Cl>C(Cl)Cl.O.C(N(CC)CC)C>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][CH2:13][C:14]([N:27]3[CH2:30][CH:29]([OH:31])[CH2:28]3)=[O:16])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: OC1CNC1
Reactant: O=C(O)COCCc1ccc2sccc2c1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(COCCc1ccc2sccc2c1)N1CC(O)C1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
1.20 g of 2-(2-(1-benzothiophene-5-yl)ethoxy)acetic acid was dissolved in 12 ml of methylene chloride. Thereafter, 2.3 ml of triethylamine and 0.38 g of imidazole were added to the obtained solution, and the mixture was then cooled to 5° C. Thereafter, 0.41 ml of thionyl chloride was added dropwise thereto, and the obtained mixture was stirred at the same above temperature for 1 hour. The reaction mixture was cooled to −60° C., and thereafter, 0.82 ml of triethylamine and 0.72 g of 3-azetidinol hydrochloride were added thereto. The mixture was stirred at the same above temperature for 1 hour and then at a room temperature for 1.5 hours. Thereafter, water was added to the reaction mixture, and the pH thereof was adjusted to pH 1.0 by addition of 6 mol/l hydrochloric acid. Thereafter, an organic layer was separated. The organic layer was washed with a saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent was distilled away under a reduced pressure, so as to obtain a yellow oil product, 2-(2-(1-benzothiophene-5-yl)ethoxy)-1-(3-hydroxy-1-azetidinyl)-1-ethanone. (2) The above 2-(2-(1-benzothiophene-5-yl)ethoxy)-1-(3-hydroxy-1-azetidinyl)-1-ethanone was dissolved in 12 ml of tetrahydrofuran, and the obtained solution was cooled to 5° C. Thereafter, 12.7 ml of a tetrahydrofuran solution containing a 1 mol/l borane-tetrahydrofuran complex was added dropwise thereto, and the obtained mixture was stirred at a room temperature for 17 hours. Thereafter, 10 ml of acetone was added to the reaction mixture, and the obtained mixture was then stirred for 30 minutes. Thereafter, 6.0 ml of 6 mol/l hydrochloric acid was added thereto, followed by heating to reflux for 2 hours. The reaction solution was cooled, and water and ethyl acetate were added to the reaction mixture. The pH thereof was adjusted to pH 13 by addition of a 2 mol/l aqueous sodium hydroxide solution, and an organic layer was then separated. The organic layer was washed with a saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent was distilled away under a reduced pressure, so as to obtain 1.13 g of a yellow oil product, 1-(2-(2-(1-benzothiophene-5-yl)ethoxy)ethyl)-3-azetidinol.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([CH:17]=O)=[CH:13][N:12]=1.[CH2:19]([NH2:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][NH:27][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:13][N:12]=1
Reactant: NC(=O)c1ccc(F)c(-c2ccc(C=O)cn2)c1
Reactant: NCCc1ccccc1
Product: NC(=O)c1ccc(F)c(-c2ccc(CNCCc3ccccc3)cn2)c1

Procedure:
Using the method outlined in Example 60, 4-fluoro-3-(5-formylpyridin-2-yl)benzamide (Preparation 13) and phenethylamine were converted to the title compound: RT=2.30 min; m/z (ES+)=350.0 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10].[C:12]([O-:15])(=[O:14])[CH3:13].[K+]>CN(C=O)C>[C:12]([O:15][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10])(=[O:14])[CH3:13]
Reactant: CC(=O)[O-]
Reactant: O=[N+]([O-])c1ccccc1CBr
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCc1ccccc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 6 h
Yield: 88 %

Procedure:
The mixture of 1-(bromomethyl)-2-nitrobenzene dimer 59 (0.43 g, 1 mmol) and potassium acetate (0.4 g, 4 mmol) in anhydrous DMF (40 mL) was stirred at 70° C. for 6 h, and cooled to r. t. After evaporation, the residue was dispensed with ice-water, and extracted with EtOAc. The combined organic phase was washed with H2O, brine, respectively, and dried over anhydrous Na2SO4. After removing solvent, the crude product was purified by flash column chromatography (elution, hexane/EtOAc:3/1) to yield compound 62 (0.34 g, 88%) as white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[CH:5]=[CH:4][C:3]=1[NH2:12].[CH2:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1)[CH2:14][CH3:15].C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[CH:5]=[CH:4][C:3]=1[NH:12][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][C:16]([CH2:13][CH2:14][CH3:15])=[CH:17][CH:18]=1
Reactant: Cc1nc2c(Cl)c(N)ccc2s1
Reactant: CCCc1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCc1ccc(C(=O)Nc2ccc3sc(C)nc3c2Cl)cc1
Yield: 52 %

Procedure:
Reaction of 4-chloro-2-methyl-benzothiazol-5-ylamine (50 mg, 0.25 mmol) in THF (1.5 mL) with 4-propylbenzoyl chloride (90 μL, 0.56 mmol) in presence of triethylamine (0.5 mL) according to method A gave N-(4-Chloro-2-methyl-benzothiazol-5-yl)-4-propyl-benzamide (44 mg, 0.13 mmol, 52% yield) as a orange powder after crystallisation in hexane and methanol.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.[F:10][C:11]([Si](C)(C)C)([F:13])[F:12].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:10][C:11]([F:13])([F:12])[CH:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:9])=[CH:2][CH:3]=1)[OH:8]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: Cc1ccc(C=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ccc(C(O)C(F)(F)F)cc1
Yield: 125.3 %

Procedure:
According to Reference Example 8-12, by use of p-tolualdehyde (500 μL, 4.24 mmol), (trifluoromethyl)trimethylsilane (752 μL, 5.09 mmol), tetrabutylammonium fluoride (a 1.0 mol/L solution in tetrahydrofuran, 424 μL, 0.424 mmol) and tetrahydrofuran (10 mL), the mixture was stirred and reacted at room temperature for 30 minutes. Thus, 4-(2,2,2-trifluoro-1-hydroxyethyl)toluene (Compound DE) (1.01 g, yield: quantitative) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[H-].[Na+].[F:12][C:13]([F:22])([F:21])[CH2:14][CH2:15][CH:16]([C:19]#[N:20])[C:17]#[N:18]>CN(C)C=O>[CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][C:16]([CH2:15][CH2:14][C:13]([F:12])([F:21])[F:22])([C:17]#[N:18])[C:19]#[N:20])=[CH:4][CH:3]=1
Reactant: Cc1ccc(CBr)cc1
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(CC(C#N)(C#N)CCC(F)(F)F)cc1
Yield: 73.2 %

Procedure:
Using 0.19 g of 4-methylbenzyl bromide, 3 ml of N,N-dimethylformamide, 0.05 g of sodium hydride (60% in oil), and 0.17 g of (3,3,3-trifluoropropyl)malononitrile, and according to the process described in the Production Example 26, there was obtained 0.20 g of 2-(4-methylbenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (84)).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(O[Na])(C)(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: C1COCCN1
Reactant: COc1ccccc1I
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COc1ccccc1N1CCOCC1
Yield: 70 %

Procedure:
To a solution of 1-iodo-2-methoxybenzene (1 g, 4.28 mmol) in dioxane (10 mL) was added morpholine (446.8 mg, 5.12 mmol), Pd2(dba)3 (100 mg, 0.1 mmol), Xantphos (200 mg, 0.3 mmol) and t-BuONa (671 mg, 6.0 mmol). Under a N2 atmosphere the reaction mixture was heated at reflux temperature for 16 h. The solvent was then removed and the residue dissolved in ethyl acetate and washed with water. The separated organic layer was concentrated to give the crude product which was used in next step without further purification (578 mg Yield 70%). LCMS (m/z): 194.1 (M+1).