Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH2:12]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)[CH2:13][CH2:14][CH3:15]>>[CH2:12]([C:16]1[CH:17]=[CH:18][C:19]([NH:20][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])=[CH:21][CH:22]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCc1ccc(N)cc1
Reactant: O=C(O)Cc1ccccc1Br
Product: CCCCc1ccc(Nc2ccccc2CC(=O)O)cc1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 4-butylaniline to yield 2-[(4-butylphenyl)amino]phenylacetic acid.
Reaction SMILES: [F:1][C:2]([F:55])([F:54])[C:3]1[CH:4]=[C:5]([CH:47]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:49]=1)[C:6]([N:8]1[CH2:12][C@@:11]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][C:25]3([C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:29][C@@H:28]3[O:36][CH2:37][C:38]([N:40]([CH3:46])[CH2:41][CH2:42][CH2:43][NH:44][CH3:45])=[O:39])[CH2:24][CH2:23]2)([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:10][CH2:9]1)=[O:7].[NH2:56][C:57]1[N:62]=[CH:61][C:60]([C:63]([OH:65])=O)=[CH:59][CH:58]=1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C)C=O.CN(C)C1C=CN=CC=1>[NH2:56][C:57]1[CH:58]=[CH:59][C:60]([C:63]([N:44]([CH2:43][CH2:42][CH2:41][N:40]([C:38](=[O:39])[CH2:37][O:36][C@@H:28]2[C:25]3([CH2:26][CH2:27][N:22]([CH2:21][CH2:20][C@:11]4([C:13]5[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=5)[O:10][CH2:9][N:8]([C:6](=[O:7])[C:5]5[CH:47]=[C:48]([C:50]([F:51])([F:52])[F:53])[CH:49]=[C:3]([C:2]([F:54])([F:1])[F:55])[CH:4]=5)[CH2:12]4)[CH2:23][CH2:24]3)[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29]2)[CH3:46])[CH3:45])=[O:65])=[CH:61][N:62]=1
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: CNCCCN(C)C(=O)CO[C@H]1Cc2ccccc2C12CCN(CC[C@@]1(c3ccc(F)cc3)CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CO1)CC2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(CCCN(C)C(=O)c1ccc(N)nc1)C(=O)CO[C@H]1Cc2ccccc2C12CCN(CC[C@@]1(c3ccc(F)cc3)CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CO1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
The compound (200 mg, 0.257 mmol) obtained in Example 1k was dissolved in methylene chloride (3 mL)-N,N-dimethylformamide (2 mL), 6-aminopyridine-3-carboxylic acid (36 mg, 0.257 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (74 mg, 0.386 mmol) and 4-dimethylaminopyridine (4 mg, 0.0258 mmol) were added, and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=40:1, v/v) to give the title compound (196 mg; yield, 85%) as a white solid.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[Cl:5][CH2:6][C:7](=O)[C:8](=[O:10])[CH3:9]>C(O)C>[ClH:5].[NH2:1][C:2]1[S:3][CH:6]=[C:7]([C:8](=[O:10])[CH3:9])[N:4]=1
Reactant: NC(N)=S
Reactant: CC(=O)C(=O)CCl
Solvent: CCO
Product: CC(=O)c1csc(N)n1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.7 %

Procedure:
To a stirred mixture of thiourea (8.87 g, 115 mmol) in ethanol (20.9 mL) was added 1-chloro-2,3-butanedione (13.90 g, 115 mmol) dropwise, a slight exothermic reaction resulted. The mixture was stirred at ambient temperature for 1 hour. The reaction mixture was filtered and the precipitate washed with ethyl ether (2×). The tan solid was air dried then dried under high vacuum overnight to give 1-(2-amino-thiazol-4-yl)-ethanone hydrochloride as a tan solid (21.5 g, 97%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.C1C(=O)N([Cl:18])C(=O)C1>ClCCCl>[Cl:18][C:3]1[C:2]([F:1])=[CH:7][C:6]([O:8][CH3:9])=[CH:5][C:4]=1[OH:10].[Cl:18][C:7]1[C:6]([O:8][CH3:9])=[CH:5][C:4]([OH:10])=[CH:3][C:2]=1[F:1]
Reactant: COc1cc(O)cc(F)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCCl
Product: COc1cc(O)c(Cl)c(F)c1
Product: COc1cc(O)cc(F)c1Cl
Temperature: 25 °C
Yield: 36 %
Yield: 15 %

Procedure:
Under a nitrogen atmosphere, 3-fluoro-5-methoxyphenol (50-1) (15 g, 106 mmol) was diluted in DCE (150 mL, 0.7 M). To this solution NCS (15.5 g, 116 mmol) was added, and the reaction mixture was heated to reflux for 4 hours. The reaction was then cooled to room temperature and quenched with water (100 mL). The aqueous layer was then extracted with methylene chloride (3×50 mL). The organic extracts were dried over sodium sulfate and concentrated. Silica gel chromatography (1%-30% EtOAc/Hexanes) gave 2-chloro-3-fluoro-5-methoxyphenol (50-2) (6.7 g, 36%) and 4-chloro-3-fluoro-5-methoxyphenol (50-3) (2.8 g, 15%). LCMS (ES) m/z 177.2 (M)+. The starting material, 3-fluoro-5-methoxyphenol (50-1), was also recovered (4.3 g).
Reaction SMILES: [ClH:1].[CH3:2][CH:3]([NH2:18])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.CO[C:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]=1>C(O)C>[ClH:1].[CH3:2][CH:3]([N:18]=[C:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27]1)[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: CC(N)c1ccc(CCc2ccccc2)cc1
Reactant: COC1=NCCCCC1
Agent: Cl
Solvent: CCO
Product: CC(N=C1CCCCCN1)c1ccc(CCc2ccccc2)cc1
Temperature: -20 °C
Reaction time: 96 h
Yield: 76 %

Procedure:
A mixture of 15.0 g of α-methyl-ρ-phenethylbenzylamine hydrochloride and 25 ml of O-methylcaprolactim is stirred into a slurry and allowed to stand at room temperature for 4 days with occasional stirring. Small portions of absolute ethanol are added to keep the slurry stirrable. The mixture is then cooled to -20° C., the precipitate is collected, washed with small portions of absolute ether and recrystallized from a mixture of acetone-methanol to yield 15.7 g (76% yield) of the desired product, M.P. 230°-231.5° C.
Reaction SMILES: CO[C:3]([C:5]1[S:9][C:8]([CH2:10][CH:11]([C:13]2[C:14]([CH2:19][CH2:20][CH2:21][CH3:22])=[N:15][O:16][C:17]=2[CH3:18])O)=[N:7][CH:6]=1)=[O:4].[CH2:23]([CH2:25][NH2:26])[OH:24]>>[OH:24][CH2:23][CH2:25][NH:26][C:3]([C:5]1[S:9][C:8](/[CH:10]=[CH:11]/[C:13]2[C:14]([CH2:19][CH2:20][CH2:21][CH3:22])=[N:15][O:16][C:17]=2[CH3:18])=[N:7][CH:6]=1)=[O:4]
Reactant: NCCO
Reactant: CCCCc1noc(C)c1C(O)Cc1ncc(C(=O)OC)s1
Product: CCCCc1noc(C)c1/C=C/c1ncc(C(=O)NCCO)s1
Yield: 35 %

Procedure:
As described for example 124b, 2-[2-(3-butyl-5-methyl-isoxazol-4-yl)-2-hydroxy-ethyl]-thiazole-5-carboxylic acid methyl ester (90 mg, 0.29 mmol) was converted, using ethanolamine instead of isopropylamine, to the title compound (35 mg, 35%) which was obtained as a light yellow solid after purification by chromatography (silica, 0 to 10% methanol in dichloromethane). MS: m/e=336.3 [M+H]+.
Reaction SMILES: [C:1]([N:4]1[CH:11]=[C:10]([F:12])[C:8](=[O:9])[NH:7][C:5]1=[O:6])(=[O:3])[CH3:2].[H-].[Na+].Br[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:18](=[O:19])[O:17]1.O>CN(C=O)C>[C:1]([N:4]1[CH:11]=[C:10]([F:12])[C:8](=[O:9])[N:7]([CH:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:18](=[O:19])[O:17]2)[C:5]1=[O:6])(=[O:3])[CH3:2]
Reactant: O=C1OC(Br)c2ccccc21
Reactant: CC(=O)n1cc(F)c(=O)[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)n1cc(F)c(=O)n(C2OC(=O)c3ccccc32)c1=O
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
In 8 ml of DMF was dissolved 3.44 g of 1-acetyl-5-fluorouracil and 0.80 g of sodium hydride (60% content) was added to the stirred solution mentioned above under ice cooling. Then, a solution of 4.69 g of 3-bromophthalide in 7 ml of DMF was added dropwise to the mixture. After completion of the dropwise addition, the mixture was stirred for 3.5 hours at room temperature. Then, 100 ml of water was added to the mixture and the mixture was extracted with chloroform. The chloroform layer was washed with water and dried over anhydrous sodium sulfate and then, the solvent was distilled off. The residue was washed twice with 25 ml each of n-hexane to obtain crude N1 -acetyl-N3 -phthalidyl-5-fluorouracil. To this product were added 50 ml of 0.05N hydrochloric acid and 50 ml of ethanol and the mixture was refluxed for 15 minutes. After the solvent was distilled off, water was added to the residue and the colorless crystal produced was collected by filtration. After washing with water and drying, the product was heated with 15 ml of chloroform under reflux for 3 minutes. After filtration while hot, there was obtained 2.65 g (50%) of colorless crystal. This was recrystallized from methanol to obtain colorless needles having a melting point of 234°-237°.
Reaction SMILES: [CH2:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].S(Cl)([Cl:16])=O.Cl.S(=O)=O>C1(C)C=CC=CC=1>[CH2:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:16])=[O:10])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=S(Cl)Cl
Reactant: CCCCc1ccc(C(=O)O)cc1
Agent: Cl
Agent: O=S=O
Solvent: Cc1ccccc1
Product: CCCCc1ccc(C(=O)Cl)cc1

Procedure:
A mixture of 1.1 g. of p-n-butyl benzoic acid, 2.5 g. of thionylchloride, 5 ml. of toluene and a small amount of zeolite was refluxed for about 4 hours to react them. After the reaction, excess of thionylchloride, dissolved hydrogen-chloride gas, sulfur dioxide gas, and toluene were vaporized to remove them by a rotary evaporator. A crude p-n-butyl benzoylchloride was obtained as a residue. On the other hand, 1.1 g. of 2,3-dichloroaniline was dissolved in 10 ml. of acetone and 1.3 g. of potassium carbonate was gradually added with stirring to suspend it.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[O:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=1)[C:6](=[O:21])[CH:5]2[C:22]1[C:30]([OH:31])=[CH:29][C:25]2[O:26][CH2:27][O:28][C:24]=2[CH:23]=1.[CH2:32]=[O:33].O.[OH-].[Li+]>O1CCCC1.O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[O:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=1)[C:6](=[O:21])[C:5]2([C:22]1[C:30]([OH:31])=[CH:29][C:25]2[O:26][CH2:27][O:28][C:24]=2[CH:23]=1)[CH2:32][OH:33]
Reactant: O=C1C(c2cc3c(cc2O)OCO3)c2cc(F)ccc2N1Cc1ccc(C(F)(F)F)o1
Reactant: C=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2ccc(F)cc2C1(CO)c1cc2c(cc1O)OCO2
Temperature: 0 °C
Reaction time: 4 h
Yield: 16.6 %

Procedure:
A mixture of 5-fluoro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-{[5-(trifluoromethyl)-2-furyl]methyl}-1,3-dihydro-2H-indol-2-one (3.64 g, 8.41 mmol), para-formaldehyde (2.52 g, 84.1 mmol) and lithium hydroxide monohydrate (1.06 g, 25.2 mmol) in tetrahydrofuran (84.0 mL) and water (10.0 mL) was stirred at 0° C. for 4 h. After the solvent was removed in vacuo, the residue was dissolved in ethyl acetate (100 mL), washed with 10% aqueous HCl (3×25.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography eluting with ethyl acetate/hexanes (50%) to give the title compound (0.65 g, 59%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ 9.11 (s, 1H), 7.12 (d, 1H), 6.99-6.87 (m, 3H), 6.80 (dd, 1H), 6.48 (d, 1H), 6.23 (s, 1H), 5.89 (d, 2H), 5.09 (br, 1H), 4.97 (ABq, 2H), 4.01 (ABq, 2H); 13C NMR (75 MHz, DMSO-d6) δ 176.1, 160.5; MS (ES+) m/z 466.2 (M+1), 448.2 (M−17).
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[N:10][N:9]=[C:8]2[SH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:14][C:15]([O-:17])=[O:16].[Na+].[OH-].[Na+].Cl>O.C(O)C>[C:15]([CH2:14][S:12][C:8]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:11]=[N:10][N:9]=1)([OH:17])=[O:16]
Reactant: Sc1nncn1-c1ccccc1
Reactant: O=C([O-])CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CSc1nncn1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.7 %

Procedure:
Into 500 ml of ethanol were suspended 53 g (0.3 mol) of 4-phenyl-3-mercapto-1,2,4-triazole and 44.1 g (0.36 mol) of sodium chloroacetate. Thereto was added an aqueous solution prepared by dissolving 15.5 g (0.36 mol) of sodium hydroxide (purity, 93%) into 60 ml of water. This mixture was kept at 50° C. for 3 hours to-react the reactants. The reaction mixture was allowed to cool to room temperature, neutralized by dropwise adding 31 ml (0.36 mol) of concentrated hydrochloric acid, and then cooled to 10° C. or lower with ice. The resulting precipitate was taken out by filtration. To the precipitate was added 1.5 l of ethanol. This mixture was heated, and the insoluble matter was taken out by filtration. Thereafter recrystallization was conducted with cooling to obtain 32.3 g (0.14 mol) of the desired mercaptoacetic acid derivative. Yield, 45.8%.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.N1C=CN=C1.[C:17]([Si:21]([CH3:24])([CH3:23])Cl)([CH3:20])([CH3:19])[CH3:18]>CN(C)C=O>[C:17]([Si:21]([CH3:24])([CH3:23])[O:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: OCCOc1ccc(O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.4 %

Procedure:
To a solution of 4-(2-hydroxy-ethoxy)-phenol (4.2 g, 27 mmol) in anhydrous N,N-dimethylformamide (30 mL) at 0° C. was added imidazole (2.1 g, 31 mmol) and tert-butyldimethylchlorosilane (4 g, 27 mmol). The reaction mixture was then stirred at 0° C. for 1 h. The mixture was partitioned between ethyl acetate and water. Organic layer was separated, aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc:hexanes=1;4) to give 4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-phenol as a colorless oil (5.1 g, 70%)
Reaction SMILES: Cl.[NH2:2][C:3]12[CH2:10][CH2:9][C:6]([C:11]([O:13][CH3:14])=[O:12])([CH2:7][CH2:8]1)[CH2:5][CH2:4]2.C([O-])([O-])=O.[Na+].[Na+].[C:21](=O)([O:30]N1C(=O)CCC1=O)[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCOCC1.O.CCOC(C)=O>[CH2:23]([O:22][C:21]([NH:2][C:3]12[CH2:4][CH2:5][C:6]([C:11]([O:13][CH3:14])=[O:12])([CH2:9][CH2:10]1)[CH2:7][CH2:8]2)=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)C12CCC(N)(CC1)CC2
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)C12CCC(NC(=O)OCc3ccccc3)(CC1)CC2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 100.1 %

Procedure:
To a solution of methyl 4-aminobicyclo[2.2.2]octane-1-carboxylate hydrochloride (1.16 g, 5.29 mmol, Prime Organics) in 1,4-dioxane (15 mL) was added a solution of Na2CO3 (0.90 g, 8.49 mmol) in water (15 mL). The reaction mixture was stirred for about 5 min at ambient temperature. Benzyl 2,5-dioxopyrrolidin-1-yl carbonate (1.32 g, 5.29 mmol) was added and the reaction mixture was stirred at ambient temperature for about 72 h. The reaction mixture was diluted with EtOAc (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concd under reduced pressure to give methyl 4-(benzyloxycarbonylamino)bicyclo[2.2.2]octane-1-carboxylate (1.68 g, 95%): LC/MS (Table 1, Method a) Rt=2.44 min; MS m/z: 318 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]1[CH2:11][CH2:12][CH2:13][CH:14]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]1=[CH:5]2.CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH:41]([CH3:43])[CH3:42])=[C:36]([C:44]([F:47])([F:46])[F:45])[CH:35]=1>CCOC(C)=O.O>[CH:41]([O:40][C:37]1[CH:38]=[CH:39][C:34]([CH2:33][O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]2[CH2:11][CH2:12][CH2:13][CH:14]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]2=[CH:5]3)=[CH:35][C:36]=1[C:44]([F:45])([F:46])[F:47])([CH3:43])[CH3:42]
Reactant: CCOC(=O)CC1CCCn2c1cc1cc(O)ccc12
Reactant: CC(C)Oc1ccc(CCl)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1CCCn2c1cc1cc(OCc3ccc(OC(C)C)c(C(F)(F)F)c3)ccc12
Temperature: 50 °C
Yield: 80.5 %

Procedure:
Ethyl 2-(2-hydroxy-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate (0.107 g, 0.391 mmol) was dissolved in anhydrous DMF (3.91 mL, 0.391 mmol). Cesium carbonate (0.166 g, 0.509 mmol) was added followed by 4-(chloromethyl)-1-isopropoxy-2-(trifluoromethyl)benzene (0.122 mL, 0.587 mmol) to give a suspension. The reaction was heated at 50° C. for 5 h. The solvent was evaporated in vacuo to give a residue which was dissolved in EtOAc (50 mL) and water (20 mL). The organic layer was washed with water (20 mL), brine (20 mL), and dried over MgSO4. The solvent was evaporated in vacuo to give an oil which was purified by silica gel column chromatography to give the title compound as an oil (0.154 g). LCMS m/z=490.4 [M+H]+; 1H NMR (400 MHz, Acetonitrile-d3) δ ppm 1.24 (t, J=7.14 Hz, 3H), 1.32 (d, J=6.06 Hz, 6H), 1.50-1.64 (m, 1H), 2.1 (m, 3H), 2.55 (dd, J=15.73, 8.02 Hz, 1H), 2.86 (dd, J=15.66, 5.94 Hz, 1H), 3.33-3.47 (m, 1H), 3.79-3.88 (m, 1H), 4.06-4.21 (m, 3H), 4.74 (dt, J=12.09, 6.02 Hz, 1H), 5.04 (s, 2H), 6.13 (s, 1H), 6.81 (dd, J=8.78, 2.46 Hz, 1H), 7.04 (d, J=2.40 Hz, 1H), 7.16 (d, J=8.59 Hz, 1H), 7.19 (d, J=8.84 Hz, 1H), 7.62 (d, J=8.59 Hz, 1H), 7.66 (d, J=1.89 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([F:20])[CH:16]=3)[CH:11]2[CH3:21])=[N:4][C:5]([Cl:9])=[N:6][C:7]=1[CH3:8].[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1>CN(C)C=O>[ClH:9].[CH3:1][C:2]1[C:3]([N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([F:20])[CH:16]=3)[CH:11]2[CH3:21])=[N:4][C:5]([NH:27][C:26]2[CH:28]=[CH:29][C:23]([F:22])=[CH:24][CH:25]=2)=[N:6][C:7]=1[CH3:8]
Reactant: Nc1ccc(F)cc1
Reactant: Cc1nc(Cl)nc(N2CCc3cc(F)ccc3C2C)c1C
Solvent: CN(C)C=O
Product: Cc1nc(Nc2ccc(F)cc2)nc(N2CCc3cc(F)ccc3C2C)c1C
Product: Cl
Yield: 61.1 %

Procedure:
The same procedures as in Step 2 of Example 3 above were repeated using 5,6-dimethyl-2-chloro-4-(1-methyl-6-fluoro-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine (0.1 g, 0.33 mmol), dimethylformamide (5 ml), and 4-fluoroaniline (0.08 ml, 0.84 mmol) to afford 84 mg (61%) of the titled compound.
Reaction SMILES: [Cl:1][CH:2]([Cl:6])[C:3]([NH2:5])=[O:4].[P:7]([Cl:12])(Cl)(Cl)(Cl)[Cl:8].C(O)=[O:14]>C(Cl)(Cl)(Cl)Cl>[Cl:8][P:7]([Cl:12])([NH:5][C:3](=[O:4])[CH:2]([Cl:6])[Cl:1])=[O:14]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=CO
Reactant: NC(=O)C(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(NP(=O)(Cl)Cl)C(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
A reaction mixture consisting of 2,2-dichloroacetamide (6.4 g, 50 mmol), phosphorus pentachloride (10.4 g, 50 mmol), and carbon tetrachloride (50 mL) was stirred under nitrogen while heated at reflux for 30 minutes. A clear solution resulted, which was cooled to room temperature. Formic acid (1.9 mL, 50 mmol) was added dropwise with stirring, and formation of a white precipitate was observed. The stirring was continued for 1 hour at ambient temperature. The white solid was separated by filtration, rinsed with carbon tetrachloride, and dried in vacuum over phosphorus pentoxide at ambient temperature. A yield of 10 g (82%) of N-(dichlorophosphinyl)-2,2-dichloroacetamide was obtained.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([OH:13])=[O:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[N:45]12[CH2:52][CH2:51][CH:48]([CH2:49][CH2:50]1)[C@@H:47](O)[CH2:46]2>C1COCC1>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([O:13][C@@H:47]2[CH:48]3[CH2:51][CH2:52][N:45]([CH2:50][CH2:49]3)[CH2:46]2)=[O:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(C(C(=O)O)c2ccccc2)CC1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(=O)N1CCN(C(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)CC1
Temperature: 25 °C
Yield: 64.5 %

Procedure:
2-(4-Acetylpiperazin-1-yl)-2-phenylacetic acid (238 mg, 0.91 mmol) was suspended in dry THF (9 ml) and, with stirring at room temperature under nitrogen atmosphere, DCC (374 mg, 1.81 mmol), HOBT (245 mg, 1.81 mmol) and (R)-quinuclidin-3-ol (231 mg, 1.81 mmol) were sequentially added. The reaction was reacted at the same temperature for three days. The solvent was evaporated and the crude was purified by flash chromatography (DCM/MeOH/NH4OH=97/3/0.3). The product was suspended in THF/Acetonitrile (2/1; 10 ml) and the white solid was filtered off. The colourless solution was evaporated obtaining (R)-quinuclidin-3-yl 2-(4-acetylpiperazin-1-yl)-2-phenylacetate (218 mg, 64.7% yield) as a off-white spongy solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[CH:2]1.[CH2:8](O)[CH2:9][OH:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[O:7]1[CH2:8][CH2:9][O:10][CH:6]1[C:3]1[CH:4]=[CH:5][S:1][CH:2]=1
Reactant: O=Cc1ccsc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: c1cc(C2OCCO2)cs1
Temperature: 25 °C

Procedure:
A solution of 28.04 g (250 mmol) of 3-thiophenecarboxaldehyde, 20.2 g (330 mmole) of ethyleneglycol, 10 mg (0.05 mmole) of p-toluenesulfonic acid monohydrate and 25 ml of benzene was heated to reflux untill the calculated amount of water was removed via a Dean-Stark trap (5 hours). The reaction mixture was allowed to cool to room temperature and was washed with 30 ml of saturated NaHCO3 solution. The organic layer was dried over MgSO4 and the solvent was removed by evaporation to give the title compound as a clear colorles oil.
Reaction SMILES: O=[CH:2][CH2:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:8]=[C:7]([C:21]#[N:22])[N:6]=1.[NH2:23][CH2:24][C:25]([OH:27])=[O:26].[OH2:28].C([BH3-])#N>CO.C(O)(=O)C>[F:18][C:17]([F:20])([F:19])[C:13]([OH:26])=[O:28].[C:25]([CH2:24][NH:23][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:18])[F:20])[CH:12]=2)[N:8]=[C:7]([C:21]#[N:22])[N:6]=1)([OH:27])=[O:26].[C:25]([CH2:24][NH:23][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:18])[F:20])[CH:12]=2)[N:8]=[C:7]([C:21]#[N:22])[N:6]=1)([OH:27])=[O:26]
Reactant: NCC(=O)O
Reactant: N#Cc1nc(CCC=O)cc(-c2cccc(C(F)(F)F)c2)n1
Reactant: O
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CO
Product: N#Cc1nc(CCCNCC(=O)O)cc(-c2cccc(C(F)(F)F)c2)n1
Product: O=C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of 4-(3-oxo-propyl)-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile (50 mg) in methanol (1 mL) was added glycine (25 mg), followed by water (100 μL) and acetic acid (12 μL). The mixture was stirred at room temperature for five minutes then solid supported cyanoborohydride (77 mg, 2.57 mmol/g) was added and stirring continued overnight. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to yield crude product. Purification by preparative-HPLC afforded the TFA salt of 4-[3-(carboxymethyl-amino)-propyl]-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:20]=[C:21]([C:25]([OH:27])=O)[N:22]([CH3:24])[CH:23]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1.[CH3:35][N:36]([CH3:41])[CH2:37][CH2:38][NH:39][CH3:40]>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:20]=[C:21]([C:25]([N:39]([CH2:38][CH2:37][N:36]([CH3:41])[CH3:35])[CH3:40])=[O:27])[N:22]([CH3:24])[CH:23]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]2)[N:3]=1
Reactant: CNCCN(C)C
Reactant: CC1Cc2ccc(-c3cc(C(=O)O)n(C)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Product: CC1Cc2ccc(-c3cc(C(=O)N(C)CCN(C)C)n(C)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 87A, Step 9 starting from 4-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-1-methyl-1H-pyrrole-2-carboxylic acid (Example 87A, Step 8) and N,N,N′-trimethylethane-1,2-diamine. LCMS (M+H)+: m/z=546.4.