Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].Br[CH2:14][C:15]([O:17][CH3:18])=[O:16]>>[O:12]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10](=[O:11])[N:2]1[O:1][CH2:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: COC(=O)CBr
Product: COC(=O)CON1C(=O)c2ccccc2C1=O
Yield: 56 %

Procedure:
The title compound was prepared from 2-hydroxyisoindoline-1,3-dione and methyl 2-bromoacetate in 56% yield using the same procedure as described in the synthesis of intermediate G. LCMS (method B): [MH]+=236, tR=1.82 min.
Reaction SMILES: [OH:1][N:2]=[C:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1.C([Li])CCC.I[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([CH3:27])[C:22]([O:24]CC)=[O:23])=[CH:17][CH:16]=1.Cl.[OH-].[Na+]>O1CCCC1.CO.O.CCCCCC>[OH:1][N:2]=[C:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH:21]([CH3:27])[C:22]([OH:24])=[O:23])=[CH:19][CH:20]=1
Reactant: ON=C1CCCC1
Reactant: CCOC(=O)C(C)c1ccc(CI)cc1
Agent: Cl
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: CO
Solvent: O
Product: CC(C(=O)O)c1ccc(CC2CCCC2=NO)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56.8 %

Procedure:
To a solution of 2.0 g of hydroxyiminocyclopentane in 30 ml of tetrahydrofuran was added 28 ml of 15% n-hexane solution of n-butyllithium at room temperature. After the mixture was stirred for 30 minutes at the same temperature, a solution of 6.0 g of ethyl 2-(4-iodomethylphenyl)propionate in 20 ml of tetrahydrofuran was added and stirring was continued for further 10 minutes at room temperature. The reaction mixture was poured into a mixture of 80 ml of ice-water and 20 ml of concentrated hydrochloric acid, extracted with ether, the solvent removed by distillation to afford a residue, to which 1.0 g of sodium hydroxide and 40 ml of methanol were added and the mixture was allowed to stand at room temperature overnight. To the reaction mixture was added 30 ml of water, methanol was removed by distillation, and the residual aqueous layer was shaken with ether and then acidified with hydrochloric acid. Extraction of the acidified layer with ether and decoloration of the product through a silica gel column afforded 2.8 g of the desired compound, which by recrystallization from a mixture of ether and n-hexane yielded colorless crystals, m.p. 146°-148° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[C:9]([NH:10][CH:11]([CH2:14]OS(C)(=O)=O)[CH2:12][CH3:13])=[CH:8][C:7]([CH3:20])=[N:6][C:5]=1[O:21][C:22]1[C:27]([CH3:28])=[CH:26][C:25]([Cl:29])=[CH:24][C:23]=1[CH3:30].[I-].[Na+].[CH2:34]([NH2:36])[CH3:35].C(N(CC)CC)C>C(#N)C>[CH3:1][O:2][C:3](=[O:31])[C:4]1[C:9]([NH:10][CH:11]([CH2:14][NH:36][CH2:34][CH3:35])[CH2:12][CH3:13])=[CH:8][C:7]([CH3:20])=[N:6][C:5]=1[O:21][C:22]1[C:27]([CH3:28])=[CH:26][C:25]([Cl:29])=[CH:24][C:23]=1[CH3:30]
Reactant: CCN
Reactant: CCC(COS(C)(=O)=O)Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C(=O)OC
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCNCC(CC)Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C(=O)OC
Temperature: 70 °C
Reaction time: 6 h

Procedure:
A solution of 2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-methanesulfonyloxymethyl-propylamino)-6-methyl-nicotinic acid methyl ester in acetonitrile was treated with sodium iodide, ethylamine and triethylamine. The resulting mixture was heated to 70° C. overnight, then 85° C. for 6 hrs, then 100° C. overnight until tic showed no starting material. The resulting mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, dried, concentrated, and purified to give the title compound as an oil. 1H NMR(CDCl3) d 8.06(d, 1H), 7.02(s, 2H), 6.31(s, 1H), 3.88(s, 3H), 3.86(m,1H), 2.85(m, 4H), 2.12(s,3H), 2.07(s, 6H), 1.64(m, 1H), 1.60(m, 1H), 1.27(m, 3H), .99(t, 3H)
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1)=[C:2]=[S:3].[CH2:11]([S:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([C:26](O)=[O:27])[CH:20]=[CH:19]2)[CH2:12][CH2:13][CH3:14].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1>[CH2:11]([S:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([C:26]([S:10][C:7]1[CH:8]=[CH:9][C:4]([N:1]=[C:2]=[S:3])=[CH:5][CH:6]=1)=[O:27])[CH:20]=[CH:19]2)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCSc1ccc2cc(C(=O)O)ccc2c1
Reactant: S=C=Nc1ccc(S)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Product: CCCCSc1ccc2cc(C(=O)Sc3ccc(N=C=S)cc3)ccc2c1

Procedure:
Quantities: compound 3 (0.64 g, 2.0 mmol), compound 13 (0.33 g, 1.9 mmol), 4-(dimethylamino)pyridine (0.10 g, 0.80 mmol), N,N'-dicyclohexylcarbodiimide (0.50 g, 2.4 mmol).
Reaction SMILES: [OH:1][C:2]([C:5]1[O:9][N:8]=[C:7]([CH:10]=[C:11]([C:14]#[N:15])[C:12]#[N:13])[CH:6]=1)([CH3:4])[CH3:3].[CH2:16]([Mg]Br)[CH3:17].Cl>O1CCOCC1.O1CCCC1.[Cu]I>[OH:1][C:2]([C:5]1[O:9][N:8]=[C:7]([CH:10]([CH:11]([C:12]#[N:13])[C:14]#[N:15])[CH2:16][CH3:17])[CH:6]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(O)c1cc(C=C(C#N)C#N)no1
Reactant: CC[Mg]Br
Agent: [Cu]I
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CCC(c1cc(C(C)(C)O)on1)C(C#N)C#N
Reaction time: 1 h

Procedure:
1.02 g of {[5-(1-hydroxy-1-methylethyl)-isoxazol-3-yl]methylidene}malononitrile was dissolved in 50 ml of 1,4-dioxane. Thereto, 0.05 g of copper(I) iodide was added and ml of a 3 M solution of ethylmagnesium bromide in tetrahydrofuran was then added under ice-cooling. The mixture was stirred for 1 hour under ice-cooling. The reaction mixture was added to 0.1 M hydrochloric acid and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.40 g of {1-[5-(1-hydroxy-1-methylethyl)-isoxazol-3-yl]propyl}malononitrile.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].CI.[C:9]([N:13]1[C:17](O)=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[N:14]1)([CH3:12])([CH3:11])[CH3:10].O>CN(C)C=O>[C:9]([N:13]1[C:17]([O:4][CH3:1])=[CH:16][C:15]([C:19]([F:21])([F:22])[F:20])=[N:14]1)([CH3:12])([CH3:10])[CH3:11]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)n1nc(C(F)(F)F)cc1O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(F)(F)F)nn1C(C)(C)C
Reaction time: 15 h
Yield: 99.7 %

Procedure:
15.0 g (108.4 mmoles) of anhydrous potassium carbonate and 19.3 g (135.5 mmoles) of methyl iodide were added, at room temperature, to a solution of 18.8 g (90.3 mmoles) of 1-tert-butyl-3-trifluoromethyl-1H-pyrazol-5-ol dissolved in 100 ml of N,N-dimethylformamide. The mixture was stirred for 15 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with diethyl ether. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 20.0 g (yield: 99.8%) of 1-tert-butyl-5-methoxy-3-trifluoromethyl-1H-pyrazole.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][CH2:7][NH:8][C:9]2[C:10]3[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[CH:4][CH:3]=1.[C:32]1([N:38]=[C:39]=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(#N)C>[C:18]1([C:17]2[C:10]3[C:9]([NH:8][CH2:7][CH2:6][C:5]4[CH:30]=[CH:31][C:2]([NH:1][C:39]([NH:38][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)=[O:40])=[CH:3][CH:4]=4)=[N:14][CH:13]=[N:12][C:11]=3[O:15][C:16]=2[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccc(CCNc2ncnc3oc(-c4ccccc4)c(-c4ccccc4)c23)cc1
Reactant: O=C=Nc1ccccc1
Solvent: CC#N
Product: O=C(Nc1ccccc1)Nc1ccc(CCNc2ncnc3oc(-c4ccccc4)c(-c4ccccc4)c23)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.2 %

Procedure:
To a solution of N-(4-aminophenethyl)-5,6-diphenylfuro[2,3-d]pyrimidin-4-amine (0.195 g) in acetonitrile (10 mL) was added phenyl isocyanate (0.063 g). After stirring at room temperature for 16 h, the reaction mixture was concentrated and the residue was partitioned between water and ethyl acetate. The organic layer was concentrated and the crude compound was purified by silica gel column chromatography using a mixture of hexanes:ethyl acetate (1:1), to give 1-(4-(2-(5,6-diphenylfuro[2,3-d]pyrimidin-4-ylamino)ethyl)phenyl)-3-phenylurea (0.240 g, 95%). 1H-NMR (CDCl3, 300 MHz): δ 8.42 (s, 1 H), 7.58 (brs, 1 H), 7.43-7.39 (m, 5 H), 7.33-7.18 (m, 11 H), 7.03-6.98 (m, 1 H), 6.86-6.83 (m, 2 H), 4.67 (t, 1 H), 3.63 (q, 2 H), 2.66 (t, 2 H). LC-MS (ESI) m/z 526.2 (M+H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][C:8]=1[O:17][CH3:18].[N:19]([O-:21])=[O:20].[Na+].C(O)(=O)C.[N+]([O-])(O)=O>O>[CH3:18][O:17][C:8]1[C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])=[CH:16][C:15]([N+:19]([O-:21])=[O:20])=[C:10]([CH:9]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: O=N[O-]
Reactant: COC(=O)c1ccc(OCCCCCl)c(OC)c1
Agent: [Na+]
Solvent: O
Solvent: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COC(=O)c1cc(OC)c(OCCCCCl)cc1[N+](=O)[O-]
Temperature: 40 °C
Yield: 934.8 %

Procedure:
In a 50 mL volume glass flask equipped with a stirrer, a thermometer and a dropping funnel were placed 10.1 g (36.7 mmol) of methyl 4-(4-chlorobutoxy)-3-methoxybenzoate (purity: 98%) obtained in Example II-18, 0.25 g (3.67 mmol) of sodium nitrite, and 12.5 mL of acetic acid. The resulting mixture was heated to 40° C. under stirring. To the reaction mixture was dropwise added slowly 115.4 g (146.8 mmol) of nitric acid (60 wt. %), and the mixture was heated at 40-50° C. for 5 hours. After the reaction was complete, 20 mL of water was added to the reaction mixture, and the aqueous mixture was cooled to 20° C., precipitating a crystalline product. The crystalline product was collected by filtration, washed successively with 30 mL of water and 30 mL of n-heptane, and dried under reduced pressure, to give 10.9 g (isolated yield: 92.0%, purity: 99% in terms of area percentage determined by high performance liquid chromatography) of methyl 5-methoxy-4-(4-chlorobutoxy)-2-nitrobenzoate as a white crystalline product.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])=[C:6]2[C:10]([CH3:11])=[CH:9][N:8]([CH3:12])[C:7]=12.[Br:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25]>>[Br:21][C:22]1[CH:23]=[C:24]([NH:25][C:2]2[N:3]=[CH:4][C:5]([C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[O:14])=[C:6]3[C:10]([CH3:11])=[CH:9][N:8]([CH3:12])[C:7]=23)[CH:26]=[CH:27][CH:28]=1
Reactant: Nc1cccc(Br)c1
Reactant: Cc1cn(C)c2c(Cl)ncc(C(=O)N3CCOCC3)c12
Product: Cc1cn(C)c2c(Nc3cccc(Br)c3)ncc(C(=O)N3CCOCC3)c12

Procedure:
Prepared in a similar manner to Example 4(d) from 1-(7-chloro-1,3-dimethyl-1H-pyrrolo[2,3-c]pyridine-4-yl)-1-morpholin-4-yl-methanone (100 mg) and 3-bromoaniline (74 ul) to give 1-[7-(3-bromo-phenylamino)-1,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-4-yl]-1-morpholin-4-yl-methanone (93 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][S:11]([CH2:14][CH3:15])(=[O:13])=[O:12])[CH3:9])=[CH:4][CH:3]=1.Cl.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23]Cl)[CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([N:10]([CH2:23][C:19]2[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=2)[S:11]([CH2:14][CH3:15])(=[O:13])=[O:12])[CH3:9])=[CH:6][CH:7]=1
Reactant: ClCc1cccnc1
Reactant: CCS(=O)(=O)NC(C)c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)N(Cc1cccnc1)C(C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
N-(1-(4-Bromophenyl)ethyl)-N-ethylsulfonylamine (1.25 g, 4.28 mmol), and (0.75 g, 4.6 mmol) of 3-picolyl chloride hydrochloride, and (5.1 g, 37 mmol) of potassium carbonate were dissolved in 40 ml DMF. Additional 3-picolyl chloride hydrochloride (0.75 g, 4.6 mmol) was added after 30 minutes and the mixture stirred 20 h at room temperature. The mixture was diluted with 120 ml ethyl acetate and 60 ml of water and transferred to a separatory funnel. The organic layer was separated and washed twice with water. The organic layer was again separated and dried over sodium sulfate, filtered, and concentrated in vacuo to afford a dark oil. The oil was purified by radial chromatography on a 6 micron silica plate eluting with 1 to 4% methanol/dichloromethane to afford after concentration of fractions the title compound. MS calcd. 383.2; MS (M+1) 384.1.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:10])[CH:3]=1.[CH3:11][Mg]I.[Mg].CI>C(OCC)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH3:11])=[C:4]([F:10])[CH:3]=1
Reactant: C[Mg]I
Reactant: O=Cc1ccc(Br)cc1F
Agent: [Mg]
Solvent: CI
Solvent: CCOCC
Product: CC(O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 4-bromo-2-fluorobenzaldehyde (5 g, 24.62 mmol) in diethyl ether (10 ml) was added to an ice-cold solution of methylmagnesium iodide prepared from magnesium (1.7 g, 73.88 mmol) and methyliodide (4.58 ml, 73.88 mmol) in diethyl ether (50 ml). The mixture was warmed stirred at RT, for 12 h, and cooled to 0° C., quenched with dil. 6N HCl and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford the title compound as red colour liquid (5 g, 94%), 1H-NMR (δ ppm, CDCl3, 400 MHz): δ7.40 (t, J=8.2 Hz, 1H), 7.30 (dd, J=8.3. 1.7 Hz, 1H), 7.21 (dd, J=9.9, 1.9 Hz, 1H), 5.17 (q, J=6.4 Hz, 1H), 1.49 (d, J=6.5 Hz, 3H).
Reaction SMILES: O.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[O:16][C:17]1[CH:22]=[C:21]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[N:25]([CH3:34])[C:24]2=[O:35])[C:20]([F:36])=[CH:19][C:18]=1[N+:37]([O-])=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[NH2:37][C:18]1[CH:19]=[C:20]([F:36])[C:21]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:31])([F:33])[F:32])[N:25]([CH3:34])[C:24]2=[O:35])=[CH:22][C:17]=1[O:16][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][C:10]=1[O:9][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3cnccc3OCc3ccccc3)c([N+](=O)[O-])cc2F)c1=O
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3cnccc3OCc3ccccc3)c(N)cc2F)c1=O
Temperature: 45 °C
Reaction time: 3 h
Yield: 84.7 %

Procedure:
To a mixture of 0.55 g of an iron powder, 3 ml of acetic acid and 0.3 ml of water was added a solution of 0.548 g of 4-benzyloxy-3-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}pyridine in 0.5 ml of acetic acid and 3 ml of ethyl acetate dropwise. After completion of the addition, the mixture was stirred for 3 hour at 40-50° C. The mixture was poured into water, then, the mixture was filtrated through Celite, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution, and saturated saline, dried over anhydrous magnesium sulfate, and concentrated to obtain 0.438 g of 3-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-benzyloxypyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][CH:11]=[N:10][C:9]=2[CH2:13]O)=[CH:4][CH:3]=1.S(Cl)([Cl:17])=O>>[Cl:17][CH2:13][C:9]1[N:10]=[CH:11][O:12][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: OCc1ncoc1-c1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Product: ClCc1ncoc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
269 mg (0.77 mmol) of the compound from Example 38A are initially charged in 0.43 ml (5.85 mmol) of thionyl chloride. The reaction mixture is stirred at RT for 12 h, and excess thionyl chloride is then removed under reduced pressure. The residue is taken up in 5 ml of ethyl acetate and washed once with 2 ml of sat. aqueous sodium bicarbonate solution. The organic phase is dried over magnesium sulfate and the solvent is removed on a rotary evaporator. The product obtained is used without further purification in the subsequent reactions.
Reaction SMILES: [NH:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH3:8].[OH-].[Na+].[F:11][C:12]([F:23])([F:22])[C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[CH:15][CH:14]=1>O>[CH3:8][N:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:2]1=[N:1][C:20]([NH:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]([F:11])([F:22])[F:23])=[CH:18][CH:17]=1)=[O:21]
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: CN1CCCCC1=N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN1CCCCC1=NC(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The hydrochloride salt of 2-imino-1 -methylpiperidine (7.60 g.; 0.068 mole) is converted to free base by adding 7 ml. of NaOH (50%) to an aqueous slurry (using a minimal amount of water) of the salt and then extracting with benzene. After drying over K 2 CO 3, the benzene solution is filtered through diatomaceous earth. A benzene solution of 12.73 g. (0.068 mole) of p-trifluoromethylphenylisocyanate [prepared according to Inukai and Maki, Kogyo Kagaku Zasshi, 67 (5) 807-9 (1964[ is added to the above solution slowly. After 4 hours of stirring at room temperature, the benzene is evaporated in vacuo to give a solid residue. Repeated recrystallizations of the solid from methanol yields the pure product, 1-(1 -methyl-2 -piperidylidene)-3-(4-trifluoromethylphenyl)urea, m.p. = 154 -155° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][CH2:16][C:17]([OH:19])=O)[C:12]2[C:7](=[CH:8][C:9]([CH3:20])=[CH:10][CH:11]=2)[N:6]=1)=[O:4].FC1C(O)=C(F)C(F)=C(F)C=1F.Cl.[C:34]([C@@H:36]1[CH2:40][CH2:39][CH2:38][NH:37]1)#[N:35].C(N1CCOCC1)C>CN(C=O)C.C(Cl)Cl.C(Cl)CCl>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][CH2:16][C:17]([N:37]2[CH2:38][CH2:39][CH2:40][C@H:36]2[C:34]#[N:35])=[O:19])[C:12]2[C:7](=[CH:8][C:9]([CH3:20])=[CH:10][CH:11]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1cc(OCC(=O)O)c2ccc(C)cc2n1
Reactant: N#C[C@@H]1CCCN1
Agent: CCN1CCOCC1
Agent: Cl
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1cc(OCC(=O)N2CCC[C@H]2C#N)c2ccc(C)cc2n1

Procedure:
To a solution of 1000 mg 4-Carboxymethoxy-7-methyl-quinoline-2-carboxylic acid methyl ester in 5 ml DMF were added 956 mg pentafluorophenol and 994 mg EDC. The mixture was stirred under exclusion of moisture until LCMS indicated complete conversion to the corresponding pentafluorophenolester. (S)-2-Cyano-pyrrolidine hydrochloride (437 mg) was mixed with 1.3 ml N-ethylmorpholine and 10 ml DMF and this mixture added dropwise to the solution of the pentafluorophenolester. After 12 h the reaction mixture was diluted with DCM and washed with aqueous LiCl (4%) and saturated aqueous NaHCO3. The crude product obtained after evaporation of the solvent was purified by flash chromatography on silica eluting with ethyl acetate/heptane gradient. Yield: 772 mg.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[CH:4][C:3]=1[NH:12][C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:29][C:30]1[N:35]=[C:34]([CH3:36])[CH:33]=[CH:32][N:31]=1>C1COCC1>[Cl:29][C:30]1[N:35]=[C:34]([CH2:36][C:6]([C:5]2[CH:10]=[CH:11][C:2]([F:1])=[C:3]([NH:12][C:13](=[O:14])[O:15][CH2:16][CH:17]=[CH2:18])[CH:4]=2)=[O:8])[CH:33]=[CH:32][N:31]=1
Reactant: Cc1ccnc(Cl)n1
Reactant: C=CCOC(=O)Nc1cc(C(=O)OC)ccc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCOC(=O)Nc1cc(C(=O)Cc2ccnc(Cl)n2)ccc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
To a solution of methyl 4-fluoro-3-{[(2-propen-1-yloxy)carbonyl]amino}benzoate (60 g, 237 mmol) in dry THF (500 mL) at −10° C., LiHMDS (1M in THF, 735 mmol, 735 mL) was added dropwise and the solution was allowed to stir for 1 h at 0° C. A solution of 2-chloro-4-methylpyrimidine (30.5 g, 237 mmol) in THF (50 mL) was then added dropwise to the solution of ester and base at 0° C. over 20 min. The solution was allowed to stir 1 h at rt. TLC showed the reaction was complete. The reaction was quenched by addition of the saturated aqueous NH4Cl (200 mL) at 0° C. The reaction mixture was extracted with EtOAc (500 mL×3). The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by flash column on silica gel, eluting with DCM. This solution was evaporated to obtain a solid. The orange solid was triturated with a small amount of EtOAc and filtered, rinsing with diethyl ether to give the title compound (69.8 g, 81.6% yield). 1H NMR (400 MHz, CDCl3) δ ppm 13.66 (br, 0.55H), 8.79-8.83 (m, 0.36H), 8.53-8.61 (m, 0.91H), 8.33-8.37 (m, 0.59H), 7.65-7.72 (m, 0.40H), 7.50-7.57 (m, 0.59H), 7.26-7.30 (m, 0.35H), 7.08-7.19 (m, 1H), 6.92-7.12 (br, 1H), 6.87-6.92 (m, 0.64H), 5.90-6.21 (m, 1.5H), 5.39 (d, J=18.1 Hz, 1H), 5.29 (d, J=10.4 Hz, 1H), 4.70 (d, J=5.5 Hz, 2H), 4.44 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]1[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[OH:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:30][C:31](=[O:45])[C@@H:32](OS(C1C=CC(C)=CC=1)(=O)=O)[CH3:33].C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]1[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[O:28][C@@H:32]([C:31]([OH:45])=[O:30])[CH3:33])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](C)OS(=O)(=O)c1ccc(C)cc1
Reactant: O=C(OCc1ccccc1)N1CCc2ccccc2C1c1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H](Oc1ccc(Cl)cc1C1c2ccccc2CCN1C(=O)OCc1ccccc1)C(=O)O
Temperature: 65 °C
Reaction time: 18 h

Procedure:
To a solution of (±)-1-(5-chloro-2-hydroxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (192 mg, 0.30 mmol, 1.0 eq.) in MeCN (1 mL), (S)-2-(toluene-4-sulfonyloxy)-propionic acid methyl ester (80 mg, 0.30 mmol, 1.0 eq.) and potassium carbonate anhydrous (83 mg, 0.60 mmol, 2.0 eq.) were added and the mixture was heated to 65° C. for 18 hours. (S)-2-(Toluene-4-sulfonyloxy)-propionic acid methyl ester (40 mg, 0.15 mmol, 0.5 eq.) was added again and the mixture was heated at 90° C. for 4 hours. The mixture was allowed to cool to r.t. and extracted with Et2O (2×), dried over MgSO4, filtered, and concentrated in vacuo. To a solution of the crude ester in THF (1.3 mL), 1M aq. NaOH soln. (0.38 mL) was added. The solution was stirred at r.t. for 18 hours. The solution was diluted with water (2 mL) and 1M aq. HCl soln. (0.38 mL) followed by DCM. The mixture was shaked then the layers were separated and the aq. phase was extracted with DCM (2×). The comb. org. phases were concentrated in vacuo. The crude mixture, redissolved in DMF (1.2 mL), was purified by prep. HPLC (column: Atlantis, 19×50 mm, 5 um, UV/MS, acidic conditions) to give the desired acid.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:9])([F:8])[C:5]([NH2:7])=[O:6].I[CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[CH:16].[Cl-].[NH4+]>CN(C=O)C.CCOCC>[F:3][C:4]([F:9])([F:8])[C:5]([NH:7][CH2:16][CH2:15][CH2:14][CH2:13][C:12]#[CH:11])=[O:6]
Reactant: NC(=O)C(F)(F)F
Reactant: C#CCCCCI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C#CCCCCNC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.1 %

Procedure:
To a solution of sodium hydride (60% oil, 2.55 g, 63.6 mol) in DMF (50 ml), trifluoroacetamide (8.99 g, 79.6 mmol) was added portionwise as about 10 portions with ice cooling. Subsequently, a solution of 6-iodo-1-hexyne (3.31 g, 15.9 mmol) in DMF (15 ml) was added to the reaction mixture. The reaction mixture was stirred at room temperature for four hours. The reaction mixture was added with saturated aqueous ammonium chloride (100 ml) and ether (100 ml) for extraction. The ether layer was dried over magnesium sulfate, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent; hexane-ethyl acetate mixed solvent) to afford 2.0 g of 6-trifluoroacetamido-1-hexyne (yield; 65.4%).