Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.C(=O)([O-])O.[Na+].Cl[CH2:15][CH:16]=O>C(O)C.O>[NH3:1].[CH3:8][C:6]1[CH:5]=[CH:4][N:3]2[CH:15]=[CH:16][N:1]=[C:2]2[CH:7]=1
Reactant: Cc1ccnc(N)c1
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccn2ccnc2c1
Product: N
Yield: 100 %

Procedure:
A solution of 2-amino-4-methylpyridine (21.6 g, 0.2 mol) in ethanol (300 ml) was treated with sodium hydrogencarbonate (33.6 g, 0.4 mol) then with chloroacetaldehyde (42.4 ml of a 45 wt % solution in water, 0.3 mol) and this mixture was heated at reflux for 16 hours. The reaction was cooled then pre-adsorbed directly on to silica (200 g). Purification by dry flash chromatography, eluting with dichloromethane/methanol/conc. ammonia (95:4.5:0.5) gave 7-methylimidazo[1,2-α]pyridine as an oil (26.4 g, 100%) which crystallised on standing. 1H NMR (400 MHz, CDCl3) δH 2.39 (3H, s), 6.62 (1H, d, J 7), 7.37 (1H, s), 7.49 (1H, s), 7.55 (1H, s), 8.00 (1H, d, J 7); m/z (ES+) 132 (M++H).
Reaction SMILES: [C:1]([O:16][CH2:17][CH2:18][N:19]([C:38](=[O:45])[CH2:39][CH2:40][CH2:41][N:42]([CH3:44])[CH3:43])[CH2:20][CH2:21][O:22][C:23](=[O:37])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[Br:46][CH2:47][CH2:48][OH:49]>C(#N)C>[Br-:46].[C:23]([O:22][CH2:21][CH2:20][N:19]([CH2:18][CH2:17][O:16][C:1](=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:38](=[O:45])[CH2:39][CH2:40][CH2:41][N+:42]([CH2:47][CH2:48][OH:49])([CH3:43])[CH3:44])(=[O:37])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: OCCBr
Reactant: CCCCCCCCCCCCCC(=O)OCCN(CCOC(=O)CCCCCCCCCCCCC)C(=O)CCCN(C)C
Solvent: CC#N
Product: CCCCCCCCCCCCCC(=O)OCCN(CCOC(=O)CCCCCCCCCCCCC)C(=O)CCC[N+](C)(C)CCO
Product: [Br-]
Temperature: 80 °C
Reaction time: 8 h

Procedure:
In a sealed system, ((4-(dimethylamino)butanoyl)azanediyl)bis(ethane-2,1-diyl) ditetradecanoate (300 mg, 0.469 mmol) was dissolved in ACN (5 mL) and 2-bromoethanol (500 uL) was added. The reaction vessel was flushed with inert gas and then sealed. Reaction was heated to 80° C. and stirred overnight, then concentrated. Purification by silica gel chromatography with a DCM/MeOH gradient yielded 4-(bis(2-(tetradecanoyloxy)ethyl)amino)-N-(2-hydroxyethyl)-N,N-dimethyl-4-oxobutan-1-aminium bromide (140 mg). LCMS ESI+: m/z 684.4 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23]O)=[CH:19][CH:18]=3)=[O:16])[C:10](=[O:25])[CH:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.S(Cl)([Cl:36])=O>C(Cl)Cl.O>[Cl:36][CH2:23][C:20]1[CH:21]=[CH:22][C:17]([C:15](=[O:16])[CH2:14][N:11]2[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:5]3[CH:26]=[CH:27][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:9][C:10]2=[O:25])=[CH:18][CH:19]=1
Reactant: O=C(Cn1ccc(OCc2ccc(F)cc2)cc1=O)c1ccc(CO)cc1
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Cn1ccc(OCc2ccc(F)cc2)cc1=O)c1ccc(CCl)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To 1.20 g (3.27 mmol) 4-(4-fluoro-benzyloxy)-1-[2-(4-hydroxymethyl-phenyl)-2-oxo-ethyl]-1H-pyridin-2-one (preparation 31.1) in 20 mL DCM is added 0.29 mL (3.59 mmol) pyridine and 0.26 mL (3.59 mmol) thionylchloride at 0° C. The reaction mixture is stirred 1 h at 0° C., is warmed to RT and is then diluted with water. The organic phase is washed with saturated aqueous KHSO4-solution and then with water, dried over MgSO4, filtered over charcoal and the solvent is evaporated.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([Br:8])[C:6]=1[Br:7].C(O)(=O)C.[ClH:13].[CH2:14]=O>O>[Cl:13][CH2:1][C:2]1[S:3][C:4]([CH3:14])=[C:5]([Br:8])[C:6]=1[Br:7]
Reactant: Cl
Reactant: C=O
Reactant: Cc1scc(Br)c1Br
Solvent: O
Solvent: CC(=O)O
Product: Cc1sc(CCl)c(Br)c1Br
Temperature: 70 °C

Procedure:
A solution of 11.7 g. of 2-methyl-3,4-dibromo-thiophene in 30 ml. of acetic acid was added to 60 ml. of concentrated hydrochloric acid. After dropping in 4.1 g of a 37% aqueous solution of formaldehyde the mixture was heated to 70° C. for one hour. The reaction mixture was cooled, diluted with water and extracted with ether. The combined organic phases were washed with water, sodium bicarbonate and water, dried over sodium sulfate, filtered and evaporated to give 2-chloromethyl-3,4-dibromo-5-methyl-thiophene.
Reaction SMILES: [CH3:1][C:2]1OC2C(C=C)=CC=CC=2C=1C.[CH2:14]([O:16][C:17]([C:19]1[O:20][C:21]2[C:28](Br)=[CH:27][CH:26]=[CH:25][C:22]=2[C:23]=1[CH3:24])=[O:18])[CH3:15]>>[CH2:14]([O:16][C:17]([C:19]1[O:20][C:21]2[C:28]([CH:1]=[CH2:2])=[CH:27][CH:26]=[CH:25][C:22]=2[C:23]=1[CH3:24])=[O:18])[CH3:15]
Reactant: CCOC(=O)c1oc2c(Br)cccc2c1C
Reactant: C=Cc1cccc2c(C)c(C)oc12
Product: C=Cc1cccc2c(C)c(C(=O)OCC)oc12

Procedure:
This compound is obtained according to the process described in Example 6 for the preparation of 2,3-dimethyl-7-ethenylbenzofuran, by using 2-ethyloxycarbonyl-3-methyl-7-bromobenzofuran as starting material.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:10][NH:11][C:12]([NH2:14])=[S:13])=[CH:4][CH:3]=1.Br[CH:24]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=1)[C:25](OCC)=[O:26]>C(O)C.C(N(C(C)C)CC)(C)C>[C:18]([O:17][C:16](=[O:22])[NH:15][C@@H:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH2:10][NH:11][C:12]1[S:13][C:24]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=2)=[C:25]([OH:26])[N:14]=1)([CH3:19])([CH3:21])[CH3:20]
Reactant: CCOC(=O)C(Br)c1ccc(F)c(F)c1
Reactant: CC(C)(C)OC(=O)N[C@H](CNC(N)=S)Cc1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H](CNc1nc(O)c(-c2ccc(F)c(F)c2)s1)Cc1ccc(Cl)cc1
Temperature: 120 °C

Procedure:
A mixture of (S)-tert-butyl 3-(4-chlorophenyl)-1-thioureidopropan-2-ylcarbamate (0.585 g, 1.70 mmol) and ethyl 2-bromo-2-(3,4-difluorophenyl)acetate (0.500 g, 1.79 mmol) in ethyl alcohol (2 mL) and diisopropylethylamine (0.3 mL) in a sealed vial (Biotage microwave vial, 5 mL) with a magnetic stirring bar was heated in a microwave oven (Initiator, Biotage) at 120° C. for 15 minutes. After cooling to ambient temperature, the volatiles were removed in vacuum. The residue was partitioned between EtOAc and water. The combined organic portions were washed with brine. The crude product was purified by flash column chromatography (20% of EtOAc in hexanes for 5 minutes, 20% to 100% of EtOAc in hexanes over 23 minutes). The product was obtained as a white solid, 0.201 g, 24%. 1H NMR (300 MHz, CD3OD) δ 1.22-1.39 (m, 9H), 2.52-2.97 (m, 2H), 3.35-3.60 (m, 1H), 3.64-3.85 (m, 1H), 3.92-4.24 (m, 1H), 7.11-7.46 (m, 7H). LCMS (API-ES): 496.1/498.1 (M++H), chloro pattern.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([OH:3])=[O:2].[CH2:12]([Mg]Cl)[C:13]([CH3:16])([CH3:15])[CH3:14]>C1COCC1.CCCCCC>[CH3:12][C:13]([CH3:16])([CH3:15])/[CH:14]=[CH:8]/[C:7]1[CH:10]=[CH:11][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=1
Reactant: CC(C)(C)C[Mg]Cl
Reactant: O=Cc1ccc(C(=O)O)cc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)/C=C/c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled (0° C.) and well stirred suspension of 4-carboxy benzaldehyde (2.0 g, 13.32 mmol) in anhydrous THF (90 mL) is added 33.3 mmol of neopentyl magnesium chloride in hexane during 20 minutes and the mixture is stirred at the same temperature for an additional two hours before being quenched with satyrated ammonium chloride solution. Most of the THF is evaporated and the aqueous mixture is treated with conc. HCl (50 mL) and the mixture is heated to reflux for 2 hours. The mixture is then cooled to ambient temperature and extracted with methylene chloride (2×100 mL), the organic layer is dried over sodium sulfate and concentrated to obtain the desired compound.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].[Li]CCCC.C([O:17][C:18](=O)[CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[N:24]=1)CCC>C1COCC1>[CH3:4][O:3][P:2]([CH2:1][C:18](=[O:17])[CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)[N:24]=1)(=[O:7])[O:5][CH3:6]
Reactant: CCCCOC(=O)CCCCc1cccc(NCc2ccc(OC)cc2)n1
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(CNc2cccc(CCCCC(=O)CP(=O)(OC)OC)n2)cc1
Reaction time: 0.75 h
Yield: 89 %

Procedure:
A solution of dimethyl methylphosphonate (2.48 g, 20 mmol) in anhydrous THF (30 mL) was cooled to −78° and treated dropwise with 2.5 M n-BuLi (8.0 mL). After stirring at −78° for 45 min, a solution of ester 6-6 (1.85 g, 5.0 mmol) in THF (10 mL) was added dropwise and the resulting solution stirred for 30 min at −78°, quenched with sat. NH4Cl (25 mL), then extracted with ethyl acetate (3×75 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated to afford a yellow oil. Chromatography on silica gel (5% MeOH/CH2Cl2) afforded 6-7 as a yellow oil in 89% yield.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1C(O)=O.C1C=CC(OP(OC2C=CC=CC=2)(N=[N+]=[N-])=O)=CC=1.[N:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH2:45][CH:44]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[OH:52])[NH:43][N:42]=2)[CH:36]=1.C[N:54]([CH:56]=[O:57])C>ClCCCl>[OH:52][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=1[CH:44]1[N:43]([C:56]([NH:54][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[O:57])[N:42]=[C:41]([C:37]2[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=2)[CH2:45]1
Reactant: Oc1ccccc1C1CC(c2cccnc2)=NN1
Reactant: CN(C)C=O
Reactant: Cc1onc(-c2ccccc2)c1C(=O)O
Agent: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: ClCCCl
Product: Cc1onc(-c2ccccc2)c1NC(=O)N1N=C(c2cccnc2)CC1c1ccccc1O
Temperature: 90 °C
Reaction time: 16 h
Yield: 8.6 %

Procedure:
To a solution of 5-methyl-3-phenylisoxazole-4-carboxylic acid (29.7 mg, 0.146 mmol) in DCE (1 mL) was added a solution of TEA (14.8 mg, 0.146 mmol) in DCE (0.5 mL) at rt followed by the addition of a solution of diphenylphosphonic azide (40.2 mg, 0.146 mmol) in DCE (0.5 mL). The reaction mixture was heated at 90° C. for 2 h and then the solution was allowed to cool to rt and further to below −30° C., whereupon a solution of 2-(3-pyridin-3-yl-4,5-dihydro-1H-pyrazol-5-yl)phenol (35.0 mg, 0.146 mmol) in DMF (0.5 mL) was added. The mixture was shaken at rt for 16 h. The residue was partitioned between water (4 mL) and DCM (3 mL). The aqueous solution was extracted with DCM. The organic solutions were combined, dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by RP-HPLC to give 5-(2-hydroxyphenyl)-N-(5-methyl-3-phenylisoxazol-4-yl)-3-pyridin-3-yl-4,5-dihydro-1H-pyrazole-1-carboxamide (5.53 mg, 8.6%). LCMS: (AAC) ES+ 440.3.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[C:7]3[CH:22]=[CH:21][C:20]([Cl:23])=[N:19][C:8]=3[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])=[N:10][CH2:11][CH:5]2[NH:4][NH:3]1.CN(C)C=O.[H-].[Na+].Cl[CH2:32][C:33]#[N:34]>C(Cl)(Cl)Cl.O>[O:1]=[C:2]1[N:6]2[C:7]3[CH:22]=[CH:21][C:20]([Cl:23])=[N:19][C:8]=3[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])=[N:10][CH2:11][C:5]2=[N:4][N:3]1[CH2:32][C:33]#[N:34]
Reactant: O=C1NNC2CN=C(c3ccccc3Cl)c3nc(Cl)ccc3N12
Reactant: N#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: N#CCn1nc2n(c1=O)-c1ccc(Cl)nc1C(c1ccccc1Cl)=NC2
Reaction time: 0.08 h

Procedure:
20 grams of 1-keto-6-(o-chlorophenyl)-8-chloro-1,3-dihydro-4H-s-triazolo-(4,3-a)-pyrido-(2,3-f)-(1,4)-diazepine were dissolved in 100 ml. of dimethyl formamide, 1.8 grams of sodium hydride (about 80%) added with cooling, further stirred for 5 minutes, then 5 grams of chloroacetonitrile added (the temperature increased from 30° C. to about 50° C.) and stirring continued for 30 minutes. Then it was poured into about 1 liter of water, shaken with chloroform, the chloroform paste washed with dilute aqueous sodium hydroxide and subsequently with water, dried, suction filtered over a silica gel layer and evaporated. The chloroform residue crystallized upon triturating with methanol and was recrystallized from methanol. M.P. 198°-200° C.; Yield 8 grams.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:17]([CH3:18])[CH2:16][C:15]2[C:14](Cl)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[CH:24]2.C1CCN2C(=NCCC2)CC1>CC#N>[C:1]([O:5][C:6]([N:8]1[CH:17]([CH3:18])[CH2:16][C:15]2[C:14]([O:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[NH:26][CH:25]=[CH:24]4)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1Cc2c(Cl)ncnc2CN1C(=O)OC(C)(C)C
Reactant: Oc1ccc2[nH]ccc2c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC1Cc2c(ncnc2Oc2ccc3[nH]ccc3c2)CN1C(=O)OC(C)(C)C
Temperature: 80 °C

Procedure:
A solution of (±)-4-chloro-6-methyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylic acid tert-butyl ester (220 mg, 0.77 mmol), 5-hydroxy indole (155 mg, 1.16 mmol) and MeCN (10 mL) is treated with DBU (0.2 mL, 1.16 mmol) and heated at 80° C. for 4 h. The volume is reduced in vacuo and the residue is separated via FCC (5-90% EtOAc/heptane) to give the title compound. MS (ESI) m/z 381.3 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])O.[Na+].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>C1COCC1.O>[OH:9][C:4]1[CH:3]=[C:2]([NH:1][C:16](=[O:17])[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=[C:6]([OH:8])[CH:5]=1
Reactant: Nc1cc(O)cc(O)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1cc(O)cc(O)c1)OCc1ccccc1
Reaction time: 3 h

Procedure:
To a mixture of 5-aminobenzene-1,3-diol (0.60 g, 3.7 mmole) and sodium hydrogencarbonate (1.4 g, 16 mmole) in THF/water (15 mL, 1:1 v/v) was added dropwise benzyl chloroformate 1.6 mL, 11 mmole). After 3 h at rt, THF was removed under vacuum and the remaining aqueous layer was extracted with ethyl acetate. Purification by column chromatography over silica gel provided benzyl N-(3,5-dihydroxyphenyl)carbamate. 1H NMR (CD3OD): δ 7.42-7.25 (m, 5H), 6.46 (d, 2H, J=2.4 Hz), 5.97-5.94 (m, 1H), 5.14 (s, 2H).
Reaction SMILES: [C@@H:1]12[CH2:9][CH2:8][C:7](=[O:10])[C@@H:6]1[CH2:5][CH2:4][C:3](=[O:11])[NH:2]2.[CH3:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[C:13]1([CH3:12])[CH:21]=[CH:20][C:16]([C:17]([N:2]2[C:3](=[O:11])[CH2:4][CH2:5][C@@H:6]3[C@H:1]2[CH2:9][CH2:8][C:7]3=[O:10])=[O:18])=[CH:15][CH:14]=1
Reactant: O=C1CC[C@H]2C(=O)CC[C@H]2N1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(=O)N2C(=O)CC[C@H]3C(=O)CC[C@H]32)cc1
Yield: 65.9 %

Procedure:
In 20 ml of dichloromethane were dissolved 0.3 g of Compound 6b obtained in Example 11 and 0.39 g of 4-methylbenzoyl chloride. Thereto was added dropwise 0.38 ml of triethylamine with ice cooling. The mixture was reacted at room temperature for 12 hours. The reaction mixture was washed with 0.1N hydrochloric acid, with 0.1N aqueous solution of NaOH and then with water, and dried over anhydrous sodium sulfate. After dried, the solvent was removed and the residue was recrystallized to obtain 0.35 g of Compound mentioned above (yield: 66%). Table 6 shows analytical data.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][C@@H:14]([CH3:16])[NH:13][CH2:12][C@@H:11]2[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][C:19]1[O:23][C:22]([C:24]([Cl:26])=[O:25])=[CH:21][CH:20]=1>C1C=CC=CC=1>[ClH:26].[C:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][C@@H:14]([CH3:16])[N:13]([C:24]([C:22]3[O:23][C:19]([CH3:18])=[CH:20][CH:21]=3)=[O:25])[CH2:12][C@@H:11]2[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(C(=O)Cl)o1
Reactant: C[C@@H]1CN(CCCc2ccccc2)[C@@H](C)CN1
Solvent: c1ccccc1
Product: Cc1ccc(C(=O)N2C[C@H](C)N(CCCc3ccccc3)C[C@H]2C)o1
Product: Cl

Procedure:
The compound was obtained by following the same process as in Example 2 from a mixture of trans-1-(3-phenylpropyl)-2,5-dimethylpiperazine, 5-methyl-2-furoyl chloride and benzene.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:14](=O)([O-])[O-].[K+].[K+].CI.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(C(=O)O)c2[nH]ccc2c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)cc2cc[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 101 %

Procedure:
To 5-methyl-1H-indole-7-carboxylic acid (1.1 g), potassium carbonate (1.3 g) was added DMF (22 mL), and then methyl iodide (1.3 mL) was added thereto under ice-cooling. After stirring at room temperature overnight, the reaction mixture was adjusted to pH 3 by adding a 10% aqueous citric acid solution. The mixture was extracted with ethyl acetate, and the obtained organic layer was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate: 95/5-85/15) to obtain methyl 5-methyl-1H-indole-7-carboxylate (1.2 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][C@H:10]2[CH2:15][CH2:14][CH2:13]N[CH2:11]2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH:16](NC(C)C)(C)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[Br:1][C:2]1[C:3]([NH:9][C@H:10]2[CH2:11][CH2:16][CH2:13][CH:14]([S:24]([CH3:23])(=[O:26])=[O:25])[CH2:15]2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(N[C@H]2CCCNC2)n1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)NC(C)C
Solvent: ClCCl
Product: CS(=O)(=O)C1CCC[C@H](Nc2nc(Cl)ncc2Br)C1
Temperature: 20 °C
Reaction time: 2 h
Yield: 68.9 %

Procedure:
A solution of (5-bromo-2-chloro-pyrimidin-4-yl)-(S)-piperidin-3-yl-amine (3.5 g, 12.2 mmol) and diisopropylamine (6 g, 46 mmol) in dichloromethane was cooled to 5° C. and treated with methansulfonyl chloride (2.1 g, 18 mmole). After stirring at 20° C. for 2 hours, the reaction was concentrated purified by silica gel chromatography to give 3.1 g (43% from step 1) of (5-Bromo-2-chloro-pyrimidin-4-yl)-((S)-3-methanesulfonyl-cyclohexyl)-amine.
Reaction SMILES: [F:1][C:2]1[CH:3]=C([CH:7]=[C:8]([F:17])[C:9]=1[N:10]([CH2:14][CH2:15][OH:16])[CH2:11][CH2:12][OH:13])C#N.[OH-:18].[Na+].[CH2:20]([OH:22])[CH3:21]>>[F:1][C:2]1[CH:3]=[C:21]([CH:7]=[C:8]([F:17])[C:9]=1[N:10]([CH2:14][CH2:15][OH:16])[CH2:11][CH2:12][OH:13])[C:20]([OH:18])=[O:22]
Reactant: CCO
Reactant: [OH-]
Reactant: N#Cc1cc(F)c(N(CCO)CCO)c(F)c1
Agent: [Na+]
Product: O=C(O)c1cc(F)c(N(CCO)CCO)c(F)c1
Yield: 87 %

Procedure:
A solution of the 3.5-Difluoro-4-[bis(2-hydroxyethyl) amino]benzonitrile (3.15 g, 13 mmol) and NaOH (5.2 g, 0.13 mol) in aqueous ethanol (65 ml, 50%) was refluxed for 2.5 hours. The solution was then partitioned between EtOAc (800 ml) and HCl (330 ml, 0.4 M), the aqueous layer washed with EtOAc (3×150 ml), the combined organic layers dried (MgSO4) and evaporated to dryness. The solid recrystallized from EtOAc (100 ml) to give 2.94 g (87%) of pure white crystals: mp 146.5-150° C.; 1H NMR δ 3.3 (t, 4H, CH2N), 3.46 (q, 4H, CH2O, J=5.5 Hz), 4.49 (t, 2H, OH, J=5 Hz), 7.44 (d, 2H, H2+6, J=10.5 Hz), 13.1 (bs, 1H, CO2H); 19F NMR δ −117.3 (d, 2F, F3+5, J=9.5 Hz); MS m/z 284 (M+Na+, 15), 262 (M+H+, 100), 230 (M-CH2OH, 40). Anal. (C11H13NO4F2) C,H,N.
Reaction SMILES: C([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2)(O)=O.P([Cl:23])(OCC)([O:17][CH2:18]C)=O.[CH2:24]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)/[CH:25]=[C:26](/[CH2:28][CH2:29][CH:30]=[C:31]([CH3:33])[CH3:32])\[CH3:27].C(=O)(O)[O-].[Na+]>O1CCCC1.C(N(CC)CC)C>[ClH:23].[CH2:24]([N:34]1[CH2:35][CH2:36][N:37]([C:18]([C:5]2[CH:4]=[CH:13][CH:12]=[C:11]3[C:6]=2[CH2:7][CH2:8][C:9](=[O:14])[NH:10]3)=[O:17])[CH2:38][CH2:39]1)/[CH:25]=[C:26](/[CH2:28][CH2:29][CH:30]=[C:31]([CH3:32])[CH3:33])\[CH3:27]
Reactant: CC(C)=CCC/C(C)=C/CN1CCNCC1
Reactant: O=C1CCc2cc(C(=O)O)ccc2N1
Reactant: CCOP(=O)(Cl)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)=CCC/C(C)=C/CN1CCN(C(=O)c2cccc3c2CCC(=O)N3)CC1
Product: Cl

Procedure:
1.6 Grams of 6-carboxy-3,4-dihydrocarbostyril and 0.8 ml of triethylamine were suspended in 10 ml of THF (tetrahydrofuran), to this suspension was added dropwise 10 ml of THF solution containing 1.0 g of diethyl chlorophosphate at room temperature under stirring, then the whole mixture was stirred at room temperature for 3 hours. Then to this reaction mixture was added dropwise 10 ml of THF solution containing 1.4 g of geranylpiperazine, then the whole reaction mixture was stirred further at room temperature for 10 hours. After the reaction was finished, the crystals formed in the reaction mixture were removed by filtration, then the mother liquor was concentrated. To the residue thus obtained was added an aqueous solution saturated with sodium bicarbonate, then extracted with chloroform. The organic layer was washed with water and an aqueous solution saturated with sodium chloride, and dried with anhydrous sodium sulfate, then the solvent was removed by evaporation. The residue was converted into hydrochloride by adding ethanol-concentrated hydrochloric acid. Recrystallized from ethanol-water to obtain 1.08 g of 5-(4-geranyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyril.hydrochloride.monohydrate. Colorless needle-like crystals. Melting point: 265°-266° C. (dec.).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[CH:3]([C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=1)/[CH:4]=[CH:5]/[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][NH2:17])=[CH:8][CH:7]=1.[F:29][C:30]([F:36])([F:35])[CH2:31][C:32](O)=[O:33].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>C(Cl)Cl.O>[F:29][C:30]([F:36])([F:35])[CH2:31][C:32]([NH:17][CH2:16][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6](/[CH:5]=[CH:4]/[CH:3]([C:18]2[CH:19]=[C:20]([Cl:26])[C:21]([Cl:25])=[C:22]([Cl:24])[CH:23]=2)[C:2]([F:1])([F:27])[F:28])=[CH:7][CH:8]=1)=[O:33]
Reactant: NCc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)c2ccccc12
Reactant: O=C(O)CC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(CC(F)(F)F)NCc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)c2ccccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (E)-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)naphthalen-1-yl)methanamine (0.1 g, 0.22 mmol) in CH2Cl2 (8 mL) were added 3,3,3-trifluoropropanoic acid (0.032 g, 0.24 mmol), HOBt.H2O (52 mg, 0.33 mmol), EDC.HCl (0.065 g, 0.33 mmol) and DIPEA (0.044 g, 0.45 mmol), and the resultant reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with water and extracted with EtOAc (3×30 mL). The combined EtOAc layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; 15% EtOAc in n-hexane) afforded the title compound as a gummy material (60 mg, 50%): mp 151-153° C.; 1H NMR (400 MHz, CDCl3) δ 8.06 (m, 1H), 7.61 (m, 4H), 7.48 (s, 2H), 7.44 (d, J=8.0 Hz, 1H), 7.38 (m, 1H), 6.42 (m, 1H), 5.92 (br s, 1H), 4.92 (m, 2H), 4.24 (m, 1H), 3.12 (m, 2H); ESIMS m/z 554.04 ([M−H]−).