Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[Na+].[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:30]2[C:35](=[O:36])[CH2:34][CH:33]([C:37]3[S:38][CH:39]=[CH:40][CH:41]=3)[CH2:32][C:31]=2OCC)[NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)=[O:18])=[CH:11][CH:10]=1)#[N:8].O>C(#N)C>[O:18]=[C:17]1[NH:16][CH:15]([C:12]2[CH:11]=[CH:10][C:9]([C:7]#[N:8])=[CH:14][CH:13]=2)[C:30]2[C:35](=[O:36])[CH2:34][CH:33]([C:37]3[S:38][CH:39]=[CH:40][CH:41]=3)[CH2:32][C:31]=2[N:19]1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[CH:21]=1
Reactant: CCOC1=C(C(NC(=O)Nc2cccc(C(F)(F)F)c2)c2ccc(C#N)cc2)C(=O)CC(c2cccs2)C1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CC(c2cccs2)C3)cc1
Temperature: 25 °C

Procedure:
Sodium tert-butoxide (108 mg, 1.13 mmol) is added to a solution of 1-((4-cyanophenyl)-(2-ethoxy-6-oxo-4-(thiophen-2-yl)cyclohex-1-enyl)methyl)-3-(3-(trifluoromethyl)phenyl)-urea (intermediate 21, 507 mg, 0.94 mmol) in acetonitrile (6 mL) and the mixture is stirred at room temperature over night. Water is added and the mixture is extracted with ethyl acetate. The organic layer is dried over Na2SO4 and concentrated under reduced pressure. The residue is purified two times by reversed phase HPLC (first purification: Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% TFA; second purification: Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% NH3). Yield: 31 mg; ESI mass spectrum [M+H]+=494, Retention time HPLC: 1.18 min, 1.20 min (1:1 mixture of diastereomers) (V011_S01).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([F:12])[CH:6]=1)[CH2:3][OH:4].C([O-])(=O)C.[Na+].[N:18]#[C:19]Br>CO>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([CH:2]2[CH2:3][O:4][C:19]([NH2:18])=[N:1]2)=[CH:6][C:7]=1[F:12]
Reactant: N#CBr
Reactant: NC(CO)c1ccc(Br)c(F)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: NC1=NC(c2ccc(Br)c(F)c2)CO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.2 %

Procedure:
To a stirred, cooled (0° C.) solution of (RS)-2-amino-2-(4-bromo-3-fluoro-phenyl)-ethanol (3.26 g) and sodium acetate (2.22 g) in methanol (25 ml) was added dropwise a solution of cyanogen bromide (1.52 g) in methanol (10 ml) over 10 min. The mixture was then allowed to warm to at r.t. and stirring continued for 16 h. The mixture was concentrated in vacuo and the residue was resuspended in water and made basic by addition of 1 M aq sodium hydroxide solution. The mixture was then extracted twice with dichloromethane and the combined organic phases were dried over sodium sulphate and concentrated in vacuo. The residue was triturated in dichloromethane and the resultign crystals washed with ether to give (RS)-4-(4-bromo-3-fluoro-phenyl)-4,5-dihydro-oxazol-2-ylamine (1.09 g, 30%) as a white solid. MS (ISP): 261.0 ([{81Br}M+H]+), 258.9 ([{79Br}M+H]+).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH:12]([CH3:14])[CH3:13])[CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:25]=[CH:26][N:27]=1)[C:19](N(OC)C)=[O:20].BrC1C=C(C(C2C3C(Cl)=NC=NC=3N(C(C)C)C=2)=O)C=NC=1>>[Cl:11][C:9]1[C:10]2[C:2]([C:19]([C:18]3[CH:25]=[CH:26][N:27]=[C:16]([Cl:15])[CH:17]=3)=[O:20])=[CH:3][N:4]([CH:12]([CH3:14])[CH3:13])[C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: CON(C)C(=O)c1ccnc(Cl)c1
Reactant: CC(C)n1cc(Br)c2c(Cl)ncnc21
Agent: CC(C)n1cc(C(=O)c2cncc(Br)c2)c2c(Cl)ncnc21
Product: CC(C)n1cc(C(=O)c2ccnc(Cl)c2)c2c(Cl)ncnc21

Procedure:
The title compound was prepared from 5-Bromo-4-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine (6.5 g, 23.7 mmol) and 2-Chloro-N-methoxy-N-methyl-isonicotinamide (5.7 g, 28.4 mmol) by procedures analogous to those described for the preparation of (5-Bromo-pyridin-3-yl)-(4-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone. MS: 295.8 (MH−); HPLC Rf: 2.0 min. (HPLC method 2); HPLC purity: 100%.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[S:7].Cl[CH2:15][S:16][C:17]#[N:18]>>[S:16]([CH2:15][O:8][C:6](=[S:7])[C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:1])([F:12])[F:13])[CH:4]=1)[C:17]#[N:18]
Reactant: OC(=S)c1cccc(C(F)(F)F)c1
Reactant: N#CSCCl
Product: N#CSCOC(=S)c1cccc(C(F)(F)F)c1
Yield: 69 %

Procedure:
23 g (0.1 mol) of the K salt of 3-trifluoromethyl thiobenzoic acid and 14.3 g (0.13 mol) of chloromethyl thiocyanate were reacted and processed as in Example 1 B. 19 g of a yellowish oil having a density of 1.4 (this corresponds to a yield of 69% of the theoretical conversion).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:19])[CH:14]=3)[O:9]2)[CH:5]=[CH:6][CH:7]=1.OC1C=CC(O)=CC=1C(=O)C.[F:31][C:32]([F:42])([F:41])C1C=CC=CC=1C=O>>[OH:19][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[O:9][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:2][C:3]=1[C:32]([F:42])([F:41])[F:31])[CH2:17][C:16]2=[O:18]
Reactant: O=Cc1ccccc1C(F)(F)F
Reactant: O=C1CC(c2cccc(F)c2)Oc2ccc(O)cc21
Agent: CC(=O)c1cc(O)ccc1O
Product: O=C1CC(c2ccccc2C(F)(F)F)Oc2ccc(O)cc21

Procedure:
6-Hydroxy-2-(2-trifluoromethylphenyl)chroman-4-one was prepared as described for 2-(3-fluorophenyl)-6-hydroxychroman-4-one in Example 9(a) starting from 3.0 g of 2′,5′-dihydroxyacetophenone and 3.0 ml of 2-trifluoromethylbenzaldehyde. The product was triturated from ethanol. 1H NMR (300 MHz, d6-DMSO) δ: 9.48 (s, 1H), 8.07 (m, 1H), 7.86-7.79 (m, 2H), 7.66 (m, 1H), 7.15 (d, 1H, J 3.0 Hz), 7.06 (dd, 1H, J 8.8, 3.0 Hz), 6.95 (d, 1H, J 8.8 Hz), 5.70 (dd, 1H, J 13.8, 2.4 Hz), 3.38 (dd, 1H, J −16.9, 13.8 Hz), 2.66 (dd, 1H, J −16.9, 3.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]([CH3:12])[CH2:10][OH:11].C(N(CC)CC)C.N1C=CC=CC=1.S(=O)(=O)=O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]([CH3:12])[CH:10]=[O:11]
Reactant: CC(CO)c1c(Cl)cccc1Cl
Agent: O=S(=O)=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: c1ccncc1
Product: CC(C=O)c1c(Cl)cccc1Cl
Reaction time: 1 h

Procedure:
To a stirred solution of 2-(2,6-dichlorophenyl)propan-1-ol (278 mg, 1.4 mmol) in DMSO (6 ml) was added triethylamine (1.1 ml, 8.1 mmol) followed by pyridine-sulphur trioxide (322 mg, 2.0 mmol). After 1 h more pyridine-sulphur trioxide (161 mg, 1.0 mmol) was added and the mixture stirred for a further 1 h. The mixture was partitioned between EtOAc (3×20 ml) and water (20 ml). The combined organic layers were washed with brine (20 ml) then separated and dried (Na2SO4). The solvent was evaporated and the residue azeotroped with toluene (2×20 ml). The aldehyde was used directly without further purification. 1H NMR (250 MHz, CDCl3) δ 1.51 (3H, d, J=7.0 Hz), 4.17 (1H, q, J=7.0 Hz), 7.20 (1H, t, J=8.0 Hz), 7.33 (2H, d, J=8.5 Hz).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[CH:13][C:6]2[NH:7]C(=O)[O:9][C:10](=O)[C:5]=2[CH:4]=1.[CH:17]1([C:22](=O)[CH2:23][C:24]#[N:25])[CH2:21][CH2:20][CH2:19][CH2:18]1.C(N(CC)CC)C.Cl>CN(C=O)C>[CH:17]1([C:22]2[C:23]([C:24]#[N:25])=[C:10]([OH:9])[C:5]3[C:6](=[CH:13][CH:14]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=3)[N:7]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: N#CCC(=O)C1CCCC1
Reactant: O=c1[nH]c2ccc(C(F)(F)F)cc2c(=O)o1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1c(C2CCCC2)nc2ccc(C(F)(F)F)cc2c1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 32.6 %

Procedure:
A mixture of 6-trifluoromethyl-1H-benzo[d][1,3]oxazine-2,4-dione (1.5 g, 4.22 mmol), 3-cyclopentyl-3-oxopropanenitrile (579 mg, 4.22 mmol), triethylamine (5.98 g, 8.23 ml, 59.1 mmol) and DMF (638 μl) was stirred for 72 h at room temperature. 1N HCl was added and the reaction mixture was extracted with EtOAc. The combined extracts were washed with brine, dried with Na2SO4 and evaporated. The remaining residue was triturated in EtOAc (8 ml) for 3 h. The solid was filtrated off and washed two times with EtOAc to afford the title compound (421 mg, 24%) as white solid. MS (ESI): 307.5 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[C@H:10]([CH:18]=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[C@H:10]([CH2:18][N:30]2[CH2:31][CH2:32][CH:27]([C:24]3[CH:23]=[CH:22][C:21]([F:20])=[CH:26][CH:25]=3)[CH2:28][CH2:29]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(C2CCNCC2)cc1
Reactant: O=C[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccsc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: Fc1ccc(C2CCN(C[C@@H]3CN(Cc4ccccc4)C[C@H]3c3ccsc3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1.0 g (16.4 mmol) of 1-benzyl-3-(S)-formyl-4-(R)-(3-thienyl)pyrrolidine and 2.94 g (23.4 mmol) of 4-(4-fluorophenyl)piperidine in 50 mL of 1,2-dichlorethane was added 4.96 g (23.4 mmol) of sodium triacetoxyborohydride and the solution was stirred at rt for 16 h. The reaction was poured into 50 mL of saturated NaHCO3 solution and the mixture was extracted with CH2Cl2. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica, acetone:hexanes, 1:3) to afford the title compound. 1H NMR (CDCl3) δ6.97-7.10 (m, 4H), 3.72 (d, 1H, J=13.1 hz), 3.64 (d, 1H, J=13.0 Hz), 3.11-3.14 (m, 1H); Mass Spectrum (ESI) m/e 435 (M+1); [α]D=−13.3 (c.=0.06, CHCl3)
Reaction SMILES: [BH4-].[Na+].[Cl:3][CH2:4][C:5]([NH:7][CH:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[O:10][CH2:9]1)=[O:6].O.Cl>CO>[Cl:3][CH2:4][C:5]([NH:7][C@H:8]1[C@H:17]([OH:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[O:10][CH2:9]1)=[O:6]
Reactant: O=C(CCl)NC1COc2ccccc2C1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(CCl)N[C@@H]1COc2ccccc2[C@H]1O
Yield: 99.3 %

Procedure:
Sodium borohydride (0.9 g, 23.8 mol) was added to a solution of 2-chloro-N-(4-oxo-chroman-3-yl)-acetamide (3.5 g, 14.6 mmol) in methanol (30 ml). When the reaction was complete (checked by thin layer chromatography), excess reagent was decomposed by the addition of water and pH was adjusted to 5-6 with 3N aqueous hydrochloric acid. The solution was partitioned between water and chloroform. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; 5-10% methanol in chloroform) to afford 2-chloro-N-((3RS,4RS)-trans-4-hydroxychroman-3-yl)-acetamide (3.5 g, 14.5 mmol, 99%) as white crystals.
Reaction SMILES: Cl.[C:2]1([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:11][C:10]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[N:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:36]([O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:37]>CN(C)C1C=CN=CC=1.ClCCl>[C:39]1([O:38][C:36]([N:9]2[C@H:8]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]2[NH:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)=[O:37])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: Fc1ccc(CNC2=N[C@@H](c3ccccc3)[C@@H](c3ccccc3)N2)cc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Oc1ccccc1)N1C(NCc2ccc(F)cc2)=N[C@@H](c2ccccc2)[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
To a solution of (cis-4,5-diphenyl-4,5-dihydro-1H-imidazol-2-yl)-(4-fluorobenzyl)amine (86) (100 mg, 0.26 mmol), triethylamine (0.091 mL, 0.656 mmol), 4-dimethylamino-pyridine (10 mg) in dichloromethane (10 mL) is added phenyl chloroformate (0.033 mL, 0.262 mmol), and the mixture is stirred at RT overnight. The reaction mixture is diluted with dichloromethane and washed with water, and the organic layer is dried (MgSO4), filtered, and evaporated. The residue is purified by chromatography on silica gel; gradient elution with heptane: EtOAc (70:30-60:40) gives 100 mg of the product 123. 1H NMR (CDCl3) δ 7.50-7.40 (m, 2H), 7.40-7.10 (m, 6H), 7.10-6.90 (m, 8H), 6.90-6.80 (m, 2H), 6.70-6.60 (m, 2H), 5.75-5.55 (m, 2H), 4.75-4.55 (m, 2H); MS: m/z 466 (M++1)
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[CH:9]=1.[CH2:18]([C:20]1[NH:21][CH:22]=[CH:23][N:24]=1)[CH3:19]>>[ClH:2].[Cl:17][C:12]1[CH:11]=[C:10]([C:8]2[CH:7]=[N:6][CH:5]=[C:4]([CH2:3][N:21]3[CH:22]=[CH:23][N:24]=[C:20]3[CH2:18][CH3:19])[CH:9]=2)[CH:15]=[CH:14][C:13]=1[Cl:16]
Reactant: CCc1ncc[nH]1
Reactant: ClCc1cncc(-c2ccc(Cl)c(Cl)c2)c1
Agent: Cl
Product: CCc1nccn1Cc1cncc(-c2ccc(Cl)c(Cl)c2)c1

Procedure:
The title compound, MS: m/e=332.2 (M+H+) was obtained as an orange solid (49% yield) by the reaction of 3-chloromethyl-5-(3,4-dichloro-phenyl)-pyridine hydrochloride (1:1) with 2-ethylimidazole, using sodium hydride and triethylamine as base followed by formation of the hydrochloride salt.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[C:12]([Cl:17])=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-].[Na+].S(OC)(O[CH3:24])(=O)=O.O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([C:8]([N:10]([C:11]2[C:12]([Cl:17])=[N:13][CH:14]=[CH:15][CH:16]=2)[CH3:24])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C(Nc1cccnc1Cl)c1cccnc1Cl
Reactant: COS(=O)(=O)OC
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CN(C(=O)c1cccnc1Cl)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A four-necked round-bottomed flask, equipped with a mechanical stirrer, a dropping funnel, a thermometer and an efficient reflux condenser, was charged with 268.1 g (1.0 mol) of 2-chloro-N-(2-chloro-3-pyridinyl)-3-pyridinecarboxamide, 260 ml of 50% aqueous sodium hydroxide, 1500 ml of toluene and 8.0 g (0.0352 mol) of benzyltriethylammonium chloride. Stirring was begun and a solution of 134 ml (178.5 g, 1.415 mol) of dimethyl sulphate in 1 l of toluene was added dropwise over a period of about 3 hours, whereby the temperature rose to 50°-60° C. After the addition of dimethyl sulfate was complete, stirring at 60° C. was continued for a further 2 hours. The reaction mixture was cooled to room temperature and 1 l of water was added. The layers were separated, and the aqueous phase was extracted three times with 300-ml portions of toluene. The organic layers were combined and washed successively with 300 ml of water, 300 ml of 1% aqueous acetic acid and 300 ml of water. The combined organic extracts were dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography on silica gel (0.2-0.5 mm) using as eluents successively toluene and ethyl acetate/cyclohexane/tetrahydrofuran 1/9/10 (v/v/v). The product obtained by evaporation of suitable fractions was recrystallized from acetonitrile/tert-butyl methyl ether 1/1 (v/v). It was highly soluble in dichloromethane, had a m.p. of 98°-101° C., and was identified to be 2-chloro-N-(2-chloro-3-pyridinyl)-N-methyl-3-pyridinecarboxamide. The yield was 232.5 g (82.5% of theory).
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]1[CH:11]=[N:12][C:13]([N:16]2[CH2:21][CH2:20][CH:19]([C:22]([O:24]CC)=[O:23])[CH2:18][CH2:17]2)=[N:14][CH:15]=1.C1COCC1.[OH-].[Na+]>CCO>[F:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]1[CH:11]=[N:12][C:13]([N:16]2[CH2:17][CH2:18][CH:19]([C:22]([OH:24])=[O:23])[CH2:20][CH2:21]2)=[N:14][CH:15]=1
Reactant: CCOC(=O)C1CCN(c2ncc(-c3cccc(CO)c3F)cn2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)C1CCN(c2ncc(-c3cccc(CO)c3F)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
Ethyl 1-{5-[2-fluoro-3-(hydroxymethyl)phenyl]pyrimidin-2-yl}piperidine-4-carboxylate (1.4 g) was mixed with THF (10 ml) and EtOH (15 ml), and a 1M aqueous NaOH solution (5.8 ml) was added thereto, followed by stirring at room temperature overnight. The insoluble matter was collected by filtration, and the filtrate was concentrated under reduced pressure. Water and 1M hydrochloric acid (5.8 ml) were added to the obtained residue at 0° C., followed by stirring at 0° C. for 30 minutes. The solid was collected by filtration, washed with water, and then dried at 50° C. under reduced pressure to obtain 1-{5-[2-fluoro-3-(hydroxymethyl)phenyl]pyrimidin-2-yl}piperidine-4-carboxylic acid (1.29 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[N:5]([CH3:11])[N:4]=1)[CH3:2].O1CCCC1.S(Cl)(Cl)=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][C:43]=1[Cl:44])[O:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([N:32]=[C:33]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[N:34]=2)[CH:31]=1>CN(C)C=O.CN(C)C(=O)C>[Cl:44][C:43]1[CH:42]=[CH:41][C:24]([O:25][C:26]2[CH:27]=[CH:28][C:29]3[N:30]([N:32]=[C:33]([NH:35][C:36]([CH:38]4[CH2:40][CH2:39]4)=[O:37])[N:34]=3)[CH:31]=2)=[CH:23][C:22]=1[NH:21][C:8]([C:6]1[N:5]([CH3:11])[N:4]=[C:3]([CH2:1][CH3:2])[CH:7]=1)=[O:10]
Reactant: CCc1cc(C(=O)O)n(C)n1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)ccc1Cl
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: CCc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)ccc2Cl)n(C)n1
Yield: 30.7 %

Procedure:
In the same manner as in Example 55 and using 3-ethyl-1-methyl-1H-pyrazole-5-carboxylic acid (56.5 mg, 0.366 mmol), tetrahydrofuran (5 mL), thionyl chloride (63.3 μL, 0.730 mmol), N,N-dimethylformamide (2 drops), N-[6-(3-amino-4-chlorophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (114 mg, 0.332 mmol) and N,N-dimethylacetamide (6 mL) as starting materials, the title compound (48.9 mg, 28%) was obtained as a white solid.
Reaction SMILES: C(O[C:4](=[O:16])[CH2:5][NH:6][C:7](=[O:15])[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][C:10]1=[O:14])C.[CH2:17]([NH2:21])[CH2:18][CH2:19][CH3:20]>>[CH2:17]([NH:21][C:4](=[O:16])[CH2:5][NH:6][C:7](=[O:15])[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][C:10]1=[O:14])[CH2:18][CH2:19][CH3:20]
Reactant: CCOC(=O)CNC(=O)CN1CCCC1=O
Reactant: CCCCN
Product: CCCCNC(=O)CNC(=O)CN1CCCC1=O
Yield: 96.9 %

Procedure:
9.12 g (0.04 mole) of N-(2-oxo-1-pyrrolidineacetyl)-glycine ethyl ester are heated for 12 hours under reflux with 7.7 g (0.1 mole) of n-butylamine. The reaction mixture is evaporated to dryness and the crystallized residue is washed with diethyl ether. The residual product is dried after filtration and washing with diethyl ether. 9.9 g of N-n-butyl-2-(2-oxo-1-pyrrolidineacetamido)-acetamide are thus obtained (yield: 97% of theory); M.P. 105°-106° C.
Reaction SMILES: [C:1]([O:14][CH2:15]Cl)([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[I-:17].[Na+].O>CC(C)=O>[C:1]([O:14][CH2:15][I:17])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)OCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)OCI

Procedure:
C4F9OCH2Cl (50 g, 0.175 mole, isomer ratio n/i=95:5) was combined with sodium iodide (52.5 g, 0.38 mole) in acetone (200 g) and heated to reflux overnight. Water was added and the acetone distilled from the reaction vessel using a Dean-Stark apparatus. The product was washed with water to remove residual acetone. Glc of the residue (52.6 g) revealed it to be 82.6 wt. % of the desired product C4F9OCH2I, which was further purified by distillation. The distillation fraction boiling at 110-15° C. was found to be 97.8 wt. % of the desired product with a 96/4 normal to iso ratio.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.[CH3:23][S:24][CH2:25][CH2:26]/[CH:27]=[CH:28]/[C:29]#[N:30].C1CCN2C(=NCCC2)CC1.C(#N)C>>[CH3:23][S:24][CH2:25][CH2:26][CH:27]([N:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1)[CH2:28][C:29]#[N:30]
Reactant: CSCC/C=C/C#N
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CSCCC(CC#N)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 25 °C
Reaction time: 120 h
Yield: 83.2 %

Procedure:
A mixture of 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidine (0.30 g, 0.00095 mol), (2E)-5-(methylthio)pent-2-enenitrile (0.28 g, 0.0016 mol) and DBU (45 0.00030 mol) in ACN (3 mL, 0.06 mol) was stirred at rt for 5 days. The solvent was removed by rotary evaporation to give an orange oil. The crude oil was chromatographed with 30-70 ethyl acetate/hex, to give 0.35 g of a colorless oil (83% yield).
Reaction SMILES: [CH:1]1([N:7]2[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[NH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:16]=1[CH2:17]Br>>[Cl:14][C:15]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:16]=1[CH2:17][N:8]1[C:9]([CH3:13])([CH3:12])[C:10](=[O:11])[N:7]1[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Fc1ccc(CBr)c(Cl)c1
Reactant: CC1(C)NN(C2CCCCC2)C1=O
Product: CC1(C)C(=O)N(C2CCCCC2)N1Cc1ccc(F)cc1Cl

Procedure:
2-Cyclohexyl-4,4-dimethyl-1,2-diazetidin-3-one and 2-chloro-4-fluorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2.BrN1C(=[O:18])CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[OH-].[Na+]>ClC1C=CC=CC=1.O>[OH:18][CH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2
Reactant: Cc1ccc2nccnc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Clc1ccccc1
Product: OCc1ccc2nccnc2c1
Temperature: 85 °C

Procedure:
In a 100 ml flask, 6-methyl-quinoxaline (1.25 g, 8.68 mmol) was dissolved with N-bromosuccinimide (2.32, 13.0 mmol) and benzoyl peroxide (0.15 g, 0.62 mml) in 31 g of chlorobenzene. The mixture was heated up to 85° C. to give a pale yellow solution that turned reddish with time. The solution was maintained at 85° C. for two hours and it was then cooled to −10° C. and filtered. The solution was vacuum dried to give an orange solid residue. The orange solid was then mixed with an alkaline solution prepared by dissolving 2.6 g of sodium hydroxide pellets in 50 ml of water. The mixture was gently heated to 85-95° C. to give a solution of 6-hydroxymethyl-quinoxaline that was mixed with the catalyst (5% Pt/C, 0.2 g) and maintained at that temperature with air sparging. The reaction was monitored by GCMS showing the consumption of 6-hydroxymethyl-quinoxaline and the formation of 6-quinoxalinecarboxaldehyde. After 10 hours, both compounds were completely consumed indicating the end of the reaction. The aqueous solution was cooled to room temperature and filtered. The yellow solution obtained was neutralized with 3.18 g of 96% sulfuric acid dissolved in 5 ml of water. A yellow precipitated was formed during the addition of acid. The yellow solid was filtered and air dried to give 0.67 g of dry product (45% yield). The lower yield in this experiment is attributed to a loss of bromomethyl-quinoxaline that was not recovered with from the succinimides precipitate by washings with pentane as explained in Examples 1 and 2.