Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:28])[CH:5]=[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][N:23]([CH:25]3[CH2:27][CH2:26]3)[CH3:24])[CH:17]=2)=[CH:10][CH:9]=1)[CH3:7])C.[OH-].[K+]>C(O)C.O1CCCC1>[CH:25]1([N:23]([CH2:22][C:18]2[CH:17]=[C:16]([C:15]#[C:14][C:11]3[CH:12]=[CH:13][C:8]([C:6]([CH3:7])=[CH:5][C:4]([OH:28])=[O:3])=[CH:9][CH:10]=3)[CH:21]=[CH:20][CH:19]=2)[CH3:24])[CH2:26][CH2:27]1
Reactant: CCOC(=O)C=C(C)c1ccc(C#Cc2cccc(CN(C)C3CC3)c2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(=CC(=O)O)c1ccc(C#Cc2cccc(CN(C)C3CC3)c2)cc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 31.5 %

Procedure:
A solution of 3-(4-{3-[(cyclopropyl-methyl-amino)-methyl]-phenylethynyl}-phenyl)-but-2-enoic acid ethyl ester (Intermediate 93, 0.17 g, 0.46 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with a 3.4M solution of potassium hydroxide (1 mL, 3.4 mmol) and the resulting reaction mixture was stirred at ambient temperature for 36 h. The reaction mixture was extracted with diethyl ether, and the aqueous phase was neutralized with 10% aqueous hydrochloric acid and evaporated to a solid. The solid was subjected to flash column chromatography using ethyl acetate as the eluent to afford the title product as a white solid (0.05 g, 32%). 1H NMR (300 MHz, CDCl3): δ 7.49-7.43(m, 4H), 7.32-7.20(m, 4H), 5.93(s, 1H), 3.70(s, 2H), 2.29(s, 3H), 2.17 (s, 3H), 1.76-1.73(m, 1H), 0.50-0.48(m, 4H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]#[N:16])[CH:10]=2)[N:6]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:3]2[CH:4]=[C:5]([C:7]#[C:8][C:9]3[CH:14]=[CH:13][N:12]=[C:11]([C:15]#[N:16])[CH:10]=3)[N:6]=[C:2]2[CH3:1])=[CH:20][CH:19]=1
Reactant: Cc1nc(C#Cc2ccnc(C#N)c2)c[nH]1
Reactant: OB(O)c1ccc(F)cc1
Product: Cc1nc(C#Cc2ccnc(C#N)c2)cn1-c1ccc(F)cc1

Procedure:
The title compound, MS: m/e=303.1 (M+H+), was prepared in accordance with the general method of example 7 from 4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine-2-carbonitrile and 4-fluorobenzene boronic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9](=O)[C:10]([N:15]1C(=O)C2C(=CC=CC=2)C1=O)=[CH:11][N:12](C)[CH3:13].C[NH:28]N>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[C:10]([NH2:15])=[CH:11][N:12]([CH3:13])[N:28]=1
Reactant: CN(C)C=C(C(=O)c1cc(Cl)ccc1Cl)N1C(=O)c2ccccc2C1=O
Reactant: CNN
Solvent: CCO
Product: Cn1cc(N)c(-c2cc(Cl)ccc2Cl)n1
Temperature: 0 °C
Yield: 38.1 %

Procedure:
To an ice-cooled solution of 2-(3-(2,5-Dichlorophenyl)-1-(dimethylamino)-3-oxoprop-1-en-2-yl)isoindoline-1,3-dione (0.050 g, 0.13 mmol) in ethanol (6 mL) was added 40% aqueous methylhydrazine solution (45 mg, 0.39 mmol). The mixture was then heated at reflux for 3 hours. The reaction mixture was then concentrated and purified by flash column chromatography to afford 3-(2,5-dichlorophenyl)-1-methyl-1H-pyrazol-4-amine as a solid (12 mg, 38% yield). 1H NMR (400 MHz, CDCl3): 7.50 (d, J=3.6 Hz, 1H), 7.38 (d, J=8.8 Hz, 1H), 7.28 (m, 1H), 7.06 (s, 1H), 3.86 (s, 3H), 2.98 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]#[N:14])=[CH:5]2.F[B-](F)(F)F.[CH3:20][O+](C)C.[OH-].[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:20])[C:6]([C:13]#[N:14])=[CH:5]2
Reactant: N#Cc1cc2cc(Br)ccc2[nH]c1=O
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1nc2ccc(Br)cc2cc1C#N

Procedure:
A suspension of 6-bromo-3-cyano-2-[1H]-quinolone (14.6 g) in dichloromethane (150 cm3) was stirred under nitrogen with trimethyloxonium tetrafluoroborate (10.35 g) for 2 days. A solution of 2M sodium hydroxide (100 cm3) was added and the aqueous phase was extracted with dichloromethane (3×200 cm3). The dried (MgSO4) extracts were concentrated in vacuo and the residue chromatographed on silica (Merck "MK 60.9385") eluting with hexane:ethyl acetate, 4:1, to give a solid which was recrystallised from ethyl acetate to afford 6-bromo-3-cyano-2-methoxyquinoline, m.p. 169°-172°, (1.96 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1>C(COC)OC.C(OC(=O)C)C>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH:34]([C:33]3[CH:36]=[CH:37][C:30]([Cl:29])=[CH:31][CH:32]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[S:15]2(=[O:17])=[O:16])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(NC1CCN(Cc2ccccc2)CC1)c1ccccc1
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: O=S1(=O)c2ccccc2C(c2ccc(Cl)cc2)N1C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 65.7 %

Procedure:
To a solution of 19.16 g (58.1 mmol) of N-(1-benzylpiperidin-4-yl)-benzene sulfonamide in 300 mL of dimethoxyethane at 0° C. was added 46.4 mL (116.1 mmol) of a n-butyllithium (2.5 M) slowly via addition funnel. The mixture was stirred using an overhead stirrer for 45 minutes at 0° C., then 9.61 g (63.9 mmol) of p-chlorobenzaldehyde was added in one portion. The mixture was allowed to warm to room temperature, diluted with 1 liter of ethylacetate and washed 2×500 mL of water followed by 500 mL of brine. The organic phase was separated, dried (MgSO4), and concentrated in vacuo. The residue was flash chromatographed over 300 g of silica gel (eluted with ethylacetate:heptane-2:1) to afford 17.3 g of product as an orange paste.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]3[NH:19][C:18]4[C:13](=[N:14][C:15]([F:21])=[N:16][C:17]=4[NH2:20])[N:12]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.C1C(=O)N([I:29])C(=O)C1.C(O)(C(F)(F)F)=O>>[F:21][C:15]1[N:14]=[C:13]2[C:18]([NH:19][C:11]([CH2:10][C:8]3[C:7]([I:29])=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)=[N:12]2)=[C:17]([NH2:20])[N:16]=1
Reactant: Nc1nc(F)nc2nc(Cc3ccc4c(c3)OCO4)[nH]c12
Reactant: O=C1CCC(=O)N1I
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(F)nc2nc(Cc3cc4c(cc3I)OCO4)[nH]c12

Procedure:
A solution of 8-Benzo[1,3]dioxol-5-ylmethyl-2-fluoroadenine (50 mg, 0.17 mmol), NIS (94 mg, 0.4 mmol), TFA (20 mg, 13.4 L, 0.17 mmol) in CH2C12 (200 L) was stirred at room temperature overnight. After solvent removal, the desired product 18 (6 mg, 8.5%) was purified by silica gel column chromatography (CHC13:EtOAc at 9:1 to 4:6). 1H NMR (400 MHz, DMSO-d6) 7.6 (bs, 2H), 7.38 (s, 1H), 6.95 (s, 1H), 6.03 (s, 2H), 4.12 (s, 2H); MS m/z 414.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:13]([CH2:14][CH:15]([C:21]([O:23]CC)=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][N:11]=[C:10]1[S:26][CH2:27][CH2:28][CH3:29].C(=O)([O-])[O-].[Na+].[Na+].C(O)C.Cl>O>[C:16]([CH:15]([CH2:14][C:13]1[N:9]([CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:10]([S:26][CH2:27][CH2:28][CH3:29])=[N:11][CH:12]=1)[C:21]([OH:23])=[O:22])([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCCSc1ncc(CC(C(=O)OCC)C(=O)OCC)n1Cc1ccccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCSc1ncc(CC(C(=O)O)C(=O)OCC)n1Cc1ccccc1Cl
Yield: 39.7 %

Procedure:
A solution of diethyl [1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]methylmalonate (0.62 g, 1.41 mmol), sodium carbonate (1.5 g, 14.2 mol), ethanol (10 mL) and water (10 mL) was stirred at 25° C. for 18 hours, then heated for 15 minutes on a steam bath. The mixture was cooled, neutralized with aqueous hydrochloric acid solution, and the product was extracted into methylene chloride, washed with water, dried and concentrated to 0.425 g of product. Crystallization from ethyl acetate/hexane provided 0.23 g (55%) of 2-carbethoxy-3-[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]propanoic acid; mp 118°-120° C.
Reaction SMILES: [Cl:1]N1C=C(Cl)CN(Cl)N1.CN(C)C=O.[Cl:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[C:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1)[C:22]([CH:33](O)[CH3:34])=[CH:21]2.O>C(Cl)Cl>[Cl:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[C:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1)[C:22]([CH:33]([Cl:1])[CH3:34])=[CH:21]2
Reactant: ClC1=CN(Cl)NN(Cl)C1
Reactant: CC(O)c1cc2cccc(Cl)c2nc1-c1cccc(F)c1
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CC(Cl)c1cc2cccc(Cl)c2nc1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1,3,5-Trichlorotriazine (94 mg, 510 μmol) was added to dimethylformamide (0.04 mL, 510 μmol) at 25° C. After the formation of a white solid (10 min), DCM (3 mL) was added, followed by 1-(8-chloro-2-(3-fluorophenyl)quinolin-3-yl)ethanol (140.0 mg, 464 μmol), made from procedure K. After the addition, the mixture was stirred at room temperature for 4 h. Water (10 mL) was added, and then diluted with DCM (10 mL), the organic phase was washed with 15 mL of a saturated solution of NaHCO3, followed by water and brine. The organic layers were dried and concentrated. Purification of the residue by flash chromatography over silica gel, using 10% hexane in EtOAc, gave 8-chloro-3-(1-chloroethyl)-2-(3-fluorophenyl)quinoline, Mass Spectrum (ESI) m/e=320.0 (M+1).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:17])[C:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9](I)=[N:8][CH:7]=2)[CH2:3][CH2:2]1.CC1(C)C(C)(C)OB(/[CH:26]=[CH:27]/[C:28]([O:30]CC)=[O:29])O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.[Cl-].[Cl-].[Pd+2]>[CH:1]1([NH:4][C:5]([C:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9](/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29])=[N:8][CH:7]=2)=[O:17])[CH2:3][CH2:2]1
Reactant: O=C(NC1CC1)c1cnc(I)cc1C(F)(F)F
Reactant: CCOC(=O)/C=C/B1OC(C)(C)C(C)(C)O1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=C(O)/C=C/c1cc(C(F)(F)F)c(C(=O)NC2CC2)cn1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
N-Cyclopropyl-6-iodo-4-(trifluoromethyl)nicotinamide (125 mg, 0.34 mmol) and ethyl (2E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (93 mg, 0.41 mmol) were dissolved in 2 ml of 1,4-dioxane and admixed under argon with sodium carbonate (180 mg, 1.72 mmol) and bis(tricyclohexylphosphine)palladium(II) dichloride. The reaction mixture was heated in a microwave (CEM Discover) at 120° C. (80 W) for 10 min. Then the reaction mixture was filtered through kieselguhr, and the filtrate was taken up in ethyl acetate, washed with hydrochloric acid (1 M), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was taken up in 1.5 ml of ethanol, admixed with sodium hydroxide solution (1M) and stirred at room temperature overnight. Then the reaction mixture was added to ice-cold dilute hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure.
Reaction SMILES: [CH2:1]([C:3]1([C:13]2[C:21]3[C:16](=[C:17]([N+:22]([O-])=O)[CH:18]=[CH:19][CH:20]=3)[N:15]([CH3:25])[CH:14]=2)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2]>[Pd].C(O)C>[CH2:1]([C:3]1([C:13]2[C:21]3[C:16](=[C:17]([NH2:22])[CH:18]=[CH:19][CH:20]=3)[N:15]([CH3:25])[CH:14]=2)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCC1(c2cn(C)c3c([N+](=O)[O-])cccc23)CCc2cc(F)ccc21
Agent: [Pd]
Solvent: CCO
Product: CCC1(c2cn(C)c3c(N)cccc23)CCc2cc(F)ccc21
Yield: 71.6 %

Procedure:
Hydrogenate a mixture of 3-(1-ethyl-5-fluoro-indan-1-yl)-1-methyl-7-nitro-1H-indole (0.26 g, 0.77 mmol) and 5% palladium on carbon (26 mg) in ethanol (50 ml) at 60 psi at room temperature overnight. Filter catalyst and concentrate under high vacuum to obtain the title compound as oil (0.17 g, 71%). NMR (400 MHz, CDCl3): δ 0.83 (t, 3H), 2.05 (m, 1H), 2.25 (m, 2H), 2.60 (m, 1H), 2.96 (m, 2H), 3.72 (broad s, 2H, NH2), 4.02 (s, 3H), 6.43 (m, 2H), 6.76 (d, 2H), 6.83 (t, 1H), 6.97 (d, 1H), 7.02 (m, 1H).
Reaction SMILES: C(OC([NH:8][CH:9]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:10]1[CH:11]=[C:12]([CH:25]=[CH:26][CH:27]=1)[O:13][CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)=O)(C)(C)C.[ClH:34].O1CCOCC1>CO>[ClH:34].[NH2:8][C@@H:9]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:10]1[CH:11]=[C:12]([CH:25]=[CH:26][CH:27]=1)[O:13][CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(COc2cccc(C(NC(=O)OC(C)(C)C)c3ccccc3)c2)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1ccc(COc2cccc([C@@H](N)c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
To a solution of methyl 4-((3-(((tert-butoxycarbonyl)amino)(phenyl)methyl)-phenoxy)methyl)benzoate (3.21 g, 7.20 mmol) in methanol (36 mL) was added hydrogen chloride in dioxane (4 M, 9.0 mL, 36 mmol). The reaction mixture was stirred at RT for 16 hours. The solvent was removed at reduced pressure to afford the title compound (2.65 g, >95%).
Reaction SMILES: C([O:4][C@H:5]1[C@@H:43]([CH2:44][O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[O:42][C@H:8]([O:9][C@H:10]2[C@H:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][N:12]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[C@@H:11]2[CH2:33][O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C@H:7]([O:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C@H:6]1[O:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)(=O)C>[CH2:54]([O:53][C@@H:7]1[C@@H:6]([O:61][CH2:62][C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=2)[C@@H:5]([OH:4])[C@@H:43]([CH2:44][O:45][CH2:46][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[O:42][C@@H:8]1[O:9][C@H:10]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:13][N:12]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[C@@H:11]1[CH2:33][O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: CC(=O)O[C@@H]1[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H](O[C@@H]2[C@@H](COCc3ccccc3)N(C(=O)OCc3ccccc3)C[C@H]2OCc2ccccc2)O[C@@H]1COCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(OCc1ccccc1)N1C[C@@H](OCc2ccccc2)[C@H](O[C@H]2O[C@H](COCc3ccccc3)[C@H](O)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H]1COCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 82.8 %

Procedure:
The compound (0.98 g, 1.06 mmol) synthesized in Example 20 (20a) was dissolved in methanol (20 mL) and potassium carbonate (147 mg, 1.06 mmol) was added thereto, followed by stirring of the mixture at room temperature for 14 hours. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with saturated aqueous sodium hydrogencarbonate (10 mL) and saturated brine (10 mL). After the organic layer was dried with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane:ethyl acetate, 4:1, V/V) to obtain the desired title compound (772.4 mg, 83%) as a colorless oil.
Reaction SMILES: FC(F)(F)[C:3]1[CH:8]=[C:7]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH:6]=[CH:5][N:4]=1.[Cl:19]C1C=C([N+]([O-])=O)C=CN=1>>[Cl:19][C:3]1[CH:8]=[C:7]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH:6]=[CH:5][N:4]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: Nc1ccc(Cc2ccnc(C(F)(F)F)c2)cc1
Product: Nc1ccc(Cc2ccnc(Cl)c2)cc1

Procedure:
4-(2-Chloro-pyridin-4-ylmethyl)-phenylamine was prepared by a method analogous to that described for 4-(2-trifluoromethyl-pyridin-4-ylmethyl)-phenylamine (Intermediate 2P), starting from ethyl (4-nitrophenyl) acetate and 2-chloro-4-nitro-pyridine. 1H NMR (CHCl3-d) δ 8.23 (dd, J=5.1, 0.5 Hz, 1H), 7.11 (m, 1H), 7.01 (m, 1H), 6.95 (m, 2H), 6.65 (m, 2H), 3.83 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Mg].CI.[CH3:13][S:14]SC.Cl>C(OCC)C.O>[F:8][C:6]1[CH:5]=[CH:4][C:3]([CH3:9])=[C:2]([S:14][CH3:13])[CH:7]=1
Reactant: Cc1ccc(F)cc1Br
Reactant: CSSC
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: O
Solvent: CI
Product: CSc1cc(F)ccc1C

Procedure:
To a solution of 2-bromo-4-fluorotoluene (45 g) in dry diethyl ether (500 ml) is added magnesium (for Grignard reagent, 7 g), and the mixture is refluxed with stirring. To the reaction mixture is added methyl iodide (1 ml), by which the reaction initiates vigorously, and then the mixture is stirred for 30 minutes after taking off the heating bath. Thereafter, the reaction becomes mild, and then the reaction mixture is refluxed for 30 minutes. After allowing to cool, dimethyl disulfide (24 ml) is added to the reaction mixture, and the mixture is refluxed for 3 hours. After allowing to cool, water and 10% hydrochloric acid are added to the reaction mixture, and the mixture is extracted with diethyl ether. The extract is washed with water (500 ml×3), dried over anhydrous sodium sulfate and then the solvent is distilled off. The resulting residue is distilled under reduced pressure to give 4-fluoro-2-methylthiotoluene (30 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2C(=O)[O:14][C:12](=O)[C:11]3=[CH:17][CH:18]=[CH:19][CH:20]=[C:10]23)=[CH:5][CH:4]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[CH:20]=[CH:19][CH:18]=[CH:17][C:11]=2[C:12]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:14])=[CH:7][CH:8]=1
Reactant: C1CCNCC1
Reactant: COc1ccc(-n2c(=O)oc(=O)c3ccccc32)cc1
Solvent: CN(C)C=O
Product: COc1ccc(Nc2ccccc2C(=O)N2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
A mixture of 15 g (0.052 mole) of N-(4-methoxyphenyl)isatoic anhydride and 10 ml (0.11 mole) of piperidine in 50 ml of dimethylformamide was stirred at room temperature for two hours. The reaction mixture was concentrated in vacuo and the residue recrystallized from 75 ml of isopropyl alcohol to give 13.8 g of 1-[2-(4-methoxyphenylamino)benzoyl]piperidine, colorless powder, m.p. 106°-108° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:17][CH2:18][CH:19]([OH:25])[C:20]([O:22]CC)=O)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-:26][C:27]#[N:28].[K+]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:17][CH2:18][CH:19]2[O:25][C:27](=[O:26])[NH:28][C:20]2=[O:22])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#C[O-]
Reactant: CCOC(=O)C(O)CCc1ccc(OC)c(OCc2ccccc2)c1
Agent: [K+]
Product: COc1ccc(CCC2OC(=O)NC2=O)cc1OCc1ccccc1

Procedure:
In substantially the same manner as in Working Example 34, ethyl 4-(3-benzyloxy-4-methoxyphenyl)-2-hydroxybutanoate was reacted with potassium cyanate (KCNO) to obtain 5-[2-(3-benzyloxy-4-methoxyphenyl)ethyl]-2,4-oxazolidinedione as an oily product.
Reaction SMILES: C(O)(=O)/C=C\C(O)=O.[CH2:9]([N:11]1[CH2:15][CH:14]([N:16]2C(=O)[C:19]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]3[C:17]2=[O:26])[CH2:13][N:12]1[CH2:27][CH3:28])[CH3:10].[F:29]C1C=CC(C(Cl)=O)=CC=1>>[F:29][C:23]1[CH:22]=[CH:19][C:18]([C:17]([NH:16][CH:14]2[CH2:15][N:11]([CH2:9][CH3:10])[N:12]([CH2:27][CH3:28])[CH2:13]2)=[O:26])=[CH:25][CH:24]=1
Reactant: CCN1CC(N2C(=O)c3ccccc3C2=O)CN1CC
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: O=C(O)/C=C\C(=O)O
Product: CCN1CC(NC(=O)c2ccc(F)cc2)CN1CC

Procedure:
The title compound was prepared as described in Example 2 of U.S. Pat. No. 4,207,327 from 1,2-diethyl-4-phthalimidopyrazolidine maleate and p-fluorobenzoyl chloride, m.p. 114°-116° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([CH2:18]Br)[C:12]=2[F:20])[CH:9]=1)[C:5]#[N:6].[N-:21]=[N+:22]=[N-:23].[Na+]>CS(C)=O.CCOC(C)=O>[N:21]([CH2:18][C:13]1[C:12]([F:20])=[C:11]([O:10][C:8]2[CH:7]=[C:4]([CH:3]=[C:2]([Br:1])[CH:9]=2)[C:5]#[N:6])[C:16]([Cl:17])=[CH:15][CH:14]=1)=[N+:22]=[N-:23]
Reactant: N#Cc1cc(Br)cc(Oc2c(Cl)ccc(CBr)c2F)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1cc(Br)cc(Oc2c(Cl)ccc(CN=[N+]=[N-])c2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
3-bromo-5-{[3-(bromomethyl)-6-chloro-2-fluorophenyl]oxy}benzonitrile (2.25 g, 5.36 mmol) and sodium azide (0.349 g, 5.36 mmol) were combined in DMSO (10 mL) and stirred overnight at 25° C. The reaction mixture was diluted with EtOAc, washed 4× with water, dried over MgSO4, filtered and concentrated to dryness to give 3-{[3-(azidomethyl)-6-chloro-2-fluorophenyl]oxy}-5-bromobenzonitrile (2.04 g, 5.35 mmol, 100% yield) as a clear oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.93 (t, 1H), 7.48-7.63 (m, 4H), 4.60 (s, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[C:9]2[C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH3:23])[CH:21]=2)[N:16]([CH2:24][C:25]([O:27]CC)=[O:26])[C:15]=1[CH3:30])([O-:3])=[O:2].[OH-].[Na+]>C1COCC1>[N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[C:9]2[C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH3:23])[CH:21]=2)[N:16]([CH2:24][C:25]([OH:27])=[O:26])[C:15]=1[CH3:30])([O-:3])=[O:2]
Reactant: CCOC(=O)Cn1c(C)c(-c2ccnc3c([N+](=O)[O-])cccc23)c2cc(C)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)c(-c1ccnc3c([N+](=O)[O-])cccc13)c(C)n2CC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product of Example 40 step b) (0.50 g) was suspended in THF (10 ml) and to it added 1M sodium hydroxide (1.24 ml) for the mixture to be stirred overnight at room temperature to complete the reaction. The solution was evaporated to dryness and purified by Reverse Phase Preparative HPLC to give the title compound as a yellow solid (0.31 g).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:18]([F:19])=[CH:17][C:13]([C:14](N)=[O:15])=[C:12]([NH:20][C@H:21]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[CH3:22])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[OH-:30].[K+]>CCO>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:18]([F:19])=[CH:17][C:13]([C:14]([OH:15])=[O:30])=[C:12]([NH:20][C@H:21]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[CH3:22])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1C(N)=O)c1ccc(F)cc1
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1C(=O)O)c1ccc(F)cc1
Temperature: 95 °C

Procedure:
(S)-6-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)nicotinamide (Example 2; 1.0 g, 2.5 mmol) was dissolved in a 10% aqueous EtOH solution (10 ml) at 25° C., followed by addition of solid KOH (2.8 g, 50.0 mmol). The reaction solution was heated to 95° C. for 4 days, cooled to 25° C., and extracted with DCM (2×50 ml). The aqueous layer was then acidified to pH 3. The resulting solid (0.55 g), was collected by filtration and dried under vacuum to give the title compound. MS: Calcd.: 399. Found: [M+H]+ 400.