Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[F:18][C:19]1[CH:20]=[C:21]([CH:31]([NH:33][C:34]([C:36]2[N:37]=[C:38](Cl)[O:39][CH:40]=2)=[O:35])[CH3:32])[CH:22]=[C:23]([F:30])[C:24]=1[NH:25][S:26]([CH3:29])(=[O:28])=[O:27].C([O-])([O-])=O.[Cs+].[Cs+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:30][C:23]1[CH:22]=[C:21]([CH:31]([NH:33][C:34]([C:36]2[N:37]=[C:38]([C:5]3[CH:4]=[C:3]([C:2]([F:17])([F:16])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=3)[O:39][CH:40]=2)=[O:35])[CH3:32])[CH:20]=[C:19]([F:18])[C:24]=1[NH:25][S:26]([CH3:29])(=[O:28])=[O:27]
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(NC(=O)c1coc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 19.3 %

Procedure:
3,5-Bis(trifluoromethyl)benzeneboronic acid (67 mg, 0.26 mmol) and 2-chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylaminophenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted using Pd(PPh3)2Cl2 (7 mg, 0.01 mmol), Cs2CO3 (127 mg, 0.39 mmol) as described above to give the title compound (14 mg, 19%) after purification by flash chromatography on silica gel (% EtOAc in hexane=12%˜80%).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].CC(C)=O.C1(O)C=CC=CC=1.[CH3:18][C:19]1[N:24]=[C:23]2[N:25]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([CH2:38][CH2:39][CH3:40])[CH:32]=3)[C:26]([CH2:28][CH3:29])=[N:27][C:22]2=[C:21]([CH3:41])[CH:20]=1.Br[CH:43]([C:48]1[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=1)[C:44]([O:46][CH3:47])=[O:45]>>[C:44]([CH:43]([C:48]1[CH:49]=[CH:50][C:51]([Cl:54])=[CH:52][CH:53]=1)[O:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][N:25]2[C:23]3=[N:24][C:19]([CH3:18])=[CH:20][C:21]([CH3:41])=[C:22]3[N:27]=[C:26]2[CH2:28][CH3:29])=[CH:32][C:33]=1[CH2:38][CH2:39][CH3:40])([O:46][CH3:47])=[O:45]
Reactant: COC(=O)C(Br)c1ccc(Cl)cc1
Reactant: CCCc1cc(Cn2c(CC)nc3c(C)cc(C)nc32)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: Oc1ccccc1
Product: CCCc1cc(Cn2c(CC)nc3c(C)cc(C)nc32)ccc1OC(C(=O)OC)c1ccc(Cl)cc1
Yield: 50 %

Procedure:
Using the K2CO3 /acetone conditions for phenol alkylation described in Step A of Example 4; 5,7-dimethyl-2-ethyl-3-[4-hydroxy-3-propylphenyl methyl]-3H-imidazo[4,5-b]pyridine (Step A, Example 8) was alkylated with methyl 2-bromo-2-(4-chlorophenyl)acetate. Standard workup and purification by flash chromatography afforded a 50% yield of the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][CH:6]=[N:7][CH:8]=1)=O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([S:16](/[N:19]=[CH:1]/[C:3]2[CH:4]=[N:5][CH:6]=[N:7][CH:8]=2)(=[O:17])=[O:18])=[CH:14][CH:15]=1
Reactant: O=Cc1cncnc1
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=S(=O)(/N=C/c1cncnc1)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 80.9 %

Procedure:
To a solution of 5-formyl pyrimidine (68, 1.0 g, 9.3 mmol) and 4-chlorobenzene sulfonamide (1.95 g, 10.2 mmol) in toluene (20 mL) was added 4 Å molecular sieves (1.0 g) and MP-TsOH (1.0 g). Dean-stark apparatus with reflux condenser was affixed to reaction vessel and reaction was heated at reflux for 18 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was taken up in EtOAc and filtered through Celite. The filtrate was concentrated in vacuo to yield 2.12 g (81%) 69 as a light brown solid, 1H NMR (CDCl3) δ 9.42 (s, 1H), 9.25 (s, 2H), 9.15 (s, 1H), 7.98 (d, 2H), 7.57 (d, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@:19]([CH2:27][C:28](O)=[O:29])([C:22]4[S:23][CH:24]=[CH:25][CH:26]=4)[O:18][C:17]3=[O:31])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@:19]([CH2:27][CH2:28][OH:29])([C:22]4[S:23][CH:24]=[CH:25][CH:26]=4)[O:18][C:17]3=[O:31])[CH3:15])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CC[C@](CC(=O)O)(c2cccs2)OC1=O
Solvent: C1CCOC1
Product: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CC[C@](CCO)(c2cccs2)OC1=O
Yield: 40 %

Procedure:
A solution of 2-((S)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-2-oxo-6-(thiophen-2-yl)-1,3-oxazinan-6-yl)acetic acid (218 mg, 0.5 mmol) in THF anhydrous (10 mL) was added BH3 (3.0 mL) at 0□ and then stirred at reflux for 2 h. Then the reaction mixture quenched by water and separated, extracted with EtOAc twice. The organic phases was dried over Na2SO4, filtered and concentrated to afford the residue, which was purified by TLC to give (S)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(2-hydroxyethyl)-6-(thiophen-2-yl)-1,3-oxazinan-2-one (85 mg, 40%). LC-MS Method 3 tR=1.35, min, m/z=426, 448; 1H NMR (CD3OD): 1.50 (m, 3H), 2.15 (m, 2H), 2.30 (m, 1H), 2.40 (m, 1H), 2.60 (m, 1H), 3.15 (m, 1H), 3.45 (m, 1H), 3.70 (m, 1H), 5.60 (m, 1H), 6.90 (m, 1H), 7.00 (m, 1H), 7.10 (m, 4H), 7.35 (m, 3H), 7.55 (m, 2H).
Reaction SMILES: I[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:3]=1.[Cl:22][C:23]1[N:28]=[C:27](Cl)[CH:26]=[CH:25][N:24]=1>>[Cl:22][C:23]1[N:28]=[C:27]([C:2]2[N:3]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=2)[CH:26]=[CH:25][N:24]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(I)n2)cc1
Reactant: Clc1ccnc(Cl)n1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)n3)n2)cc1

Procedure:
The title compound was prepared from 2-iodo-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example A.4) (1.0 g, 2.39 mmol) and 2,4-dichloro-pyrimidine (0.356 g, 2.39 mmol) according to the general procedure IVc. Obtained as an off-white solid (0.49 g, 50%). MS (EI) 404.1 [(M)+]; mp 152° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][C:24]=2[NH2:29])[CH:3]=1.[NH2:30][C:31]1[C:32]([C:38](O)=[O:39])=[N:33][C:34]([Br:37])=[CH:35][CH:36]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>CN1C(=O)CCC1>[NH2:30][C:31]1[C:32]([C:38]([NH:29][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][C:23]=2[C:4]2[CH:3]=[C:2]([CH3:1])[N:7]=[C:6]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH:5]=2)=[O:39])=[N:33][C:34]([Br:37])=[CH:35][CH:36]=1
Reactant: Cc1cc(-c2ccncc2N)cc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Reactant: Nc1ccc(Br)nc1C(=O)O
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN1CCCC1=O
Product: Cc1cc(-c2ccncc2NC(=O)c2nc(Br)ccc2N)cc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Yield: 35 %

Procedure:
Method 27 was followed using 6-methyl-N2,N2-di-BOC-4,4′-bipyridine-2,3′-diamine (1.0 equiv.), 3-amino-6-bromopicolinic acid (1.0 equiv.), EDC (1.0 equiv.), HOAt (1.0 equiv.) in NMP (0.48M) to yield 3-amino-6-bromo-N-(2′-(di-BOC-amino)-6′-methyl-4,4′-bipyridin-3-yl)picolinamide (35%). LCMS (m/z): 599.1/601.1 (MH+); LC Rt=3.69 min.
Reaction SMILES: [C:1]([NH:3][C:4](=[O:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)#[N:2].C1COCC1.Br[CH2:19][C:20]([N:22]([CH2:27][C:28]([N:30]1[CH2:39][CH2:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31]1)=[O:29])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:21]>CN(C=O)C.CC(C)([O-])C.[K+]>[CH2:31]1[C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:38][CH2:39][N:30]1[C:28](=[O:29])[CH2:27][N:22]([CH2:23][CH:24]([CH3:25])[CH3:26])[C:20]([CH2:19][N:3]([C:1]#[N:2])[C:4](=[O:12])[CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:21]
Reactant: CC(C)CN(CC(=O)N1CCc2ccccc2C1)C(=O)CBr
Reactant: N#CNC(=O)Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)CN(CC(=O)N1CCc2ccccc2C1)C(=O)CN(C#N)C(=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 12.2 %

Procedure:
To a stirred solution of N-cyano-2-phenyl-acetamide (0.15 g, 0.9 mmol) (see Example 1) in DMF (5.0 mL), potassium tert-butoxide (0.9 mL of a 1.0 M THF solution, 0.9 mmol) was added dropwise at 0° C., under argon. The resulting mixture was stirred at 0° C. for 20 min, then at ambient temperature for 15 min. After this time, the resulting anion was added dropwise to a stirred solution of the 2-bromo-N-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-2-oxo-ethyl]-N-isobutyl-acetamide (0.34 g, 0.9 mmol) from above in DMF (5.0 mL) at room temperature, under argon. Upon complete addition, the reaction was stirred at room temperature for 1.5 h, then warmed to 40° C. for 6 h. The reaction was cooled to room temperature and stirred for 48 h after which time it was concentrated to dryness. The resulting residue was dissolved in EtOAc and washed with 5% citric acid (aqueous). The layers were separated and the aqueous phase was extracted with EtOAc (2×). The combined organics were dried (MgSO4), filtered and concentrated to give the crude product which was purified via reverse phase HPLC (C18 column, 20-100% CH3CN/H2O over 20 min at a flow rate of 20 mL/min, UV detection was at 220 nm). Retention time of the product was 16 min. Product-containing fractions were concentrated to give 49 mg (12%) of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[C:11](=[O:12])[C:10]([CH3:13])=[N:9][N:8]=[C:7]1[N:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]([NH:20]C(=O)OC(C)(C)C)[CH2:15]1)#[N:2].Cl.C([O-])(O)=O.[Na+]>ClCCl.CO>[NH2:20][C@@H:16]1[CH2:17][CH2:18][CH2:19][N:14]([C:7]2[N:6]([CH2:5][C:4]3[CH:28]=[CH:29][CH:30]=[CH:31][C:3]=3[C:1]#[N:2])[C:11](=[O:12])[C:10]([CH3:13])=[N:9][N:8]=2)[CH2:15]1
Reactant: Cc1nnc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)n(Cc2ccccc2C#N)c1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1nnc(N2CCC[C@@H](N)C2)n(Cc2ccccc2C#N)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-tert-butyl 1-(4-(2-cyanobenzyl)-6-methyl-5-oxo-4,5-dihydro-1,2,4-triazin-3-yl)piperidin-3-ylcarbamate (7, 13 mg) in dichloromethane (0.5 mL) was added HCl in methanol (20%) (1 mL) and the mixture was stirred at RT for 2 h. The mixture was carefully neutralized with NaHCO3 (aq, saturated), and extracted with CH2Cl2 (50 mL×3). The combined extracts were dried over Na2SO4 and concentrated to give the crude product. This was purified by column chromatography on silica gel, eluted with 92:6:2 dichloromethane-methanol-ammonia to provide (R)-2-((3-(3-aminopiperidin-1-yl)-6-methyl-5-oxo-1,2,4-triazin-4(5H)-yl)methyl)benzonitrile (8). MS: m/z, 325 (100%, M+1).
Reaction SMILES: Cl.C([O:6][C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[S:25][C:24]3[C:19](=[N:20][CH:21]=[CH:22][C:23]=3[Cl:26])[CH:18]=2)=[O:16])[CH2:11][CH2:10]1)=O)(C)(C)C.[CH3:27]O>>[Cl:26][C:23]1[CH:22]=[CH:21][N:20]=[C:19]2[CH:18]=[C:17]([C:15]([N:12]3[CH2:13][CH2:14][N:9]([C:7](=[O:6])[CH3:27])[CH2:10][CH2:11]3)=[O:16])[S:25][C:24]=12
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc3nccc(Cl)c3s2)CC1
Reactant: CO
Agent: Cl
Product: CC(=O)N1CCN(C(=O)c2cc3nccc(Cl)c3s2)CC1
Reaction time: 0.25 h

Procedure:
HCl (gas) was bubbled through a solution of 4-(7-chloro-thieno[3,2-b]pyridine-2-carbonyl)-piperazine-1-carboxylic acid tert-butyl ester (270 mg, 0.71 mmol) in MeOH (5 mL). After 15 min, TLC showed the reaction to be complete. The resulting HCl salt was obtained as a yellow oil (199 mg, 99%) after the solvent was removed under pressure. The title compound was prepared from the resulting HCl salt and acetyl chloride by a procedure analogous to Example 70A. MS: 325 (MH+); HPLC Rf: 3.62; HPLC purity: 95%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH2:6][C:7](=O)[CH3:8].Cl.[Cl:14][C:15]1[CH:16]=[C:17]([NH:21]N)[CH:18]=[CH:19][CH:20]=1>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][C:6]1[C:18]2[C:17](=[CH:16][C:15]([Cl:14])=[CH:20][CH:19]=2)[NH:21][C:7]=1[CH3:8]
Reactant: NNc1cccc(Cl)c1
Reactant: CC(=O)COc1cccc(Br)c1
Agent: Cl
Solvent: CC#N
Product: Cc1[nH]c2cc(Cl)ccc2c1Oc1cccc(Br)c1

Procedure:
1-(3-Bromo-phenoxy)-propan-2-one (5.95 g, 26 mmol) and 3-chlorophenylhydrazine hydrochloride (4.65 g, 26 mmol) were combined in ACN (100 mL) and the reaction was heated to reflux for 1 hour. After cooling the reaction was worked-up using standard procedures then purified using silica gel chromatography to give a 3:4 mixture of separable regioisomers of which the minor component was the title compound.
Reaction SMILES: IC.[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH2:14][OH:15])[CH:8]=[CH:7]2.[H-].[Na+].[CH3:18]N(C=O)C>O>[Br:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:14][O:15][CH3:18])[CH:10]=2)[CH:5]=1
Reactant: CN(C)C=O
Reactant: OCc1ccc2cc(Br)ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COCc1ccc2cc(Br)ccc2c1

Procedure:
Iodomethane (18.96 g, 133.6 mmol) was added dropwise to ice-cooled mixture of (6-bromo-naphthalen-2-yl)-methanol (15.84 g, 66.8 mmol), sodium hydride 60% in oil (3.84 g, 100.2 mmol), and DMF (100 ml). Water was added and the product was filtered. Yield 16.7 g (99%).
Reaction SMILES: [N+:1](=[CH2:3])=[N-:2].[O:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9](Cl)=[O:10]>CCOCC>[N+:1](=[CH:3][C:9]([C:5]1[O:4][CH:8]=[CH:7][CH:6]=1)=[O:10])=[N-:2]
Reactant: O=C(Cl)c1ccco1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: [N-]=[N+]=CC(=O)c1ccco1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
N-Nitroso-N-methylurea (16.14 g, 61.53 mmol) was treated with a concentrated NaOH aqueous solution to produce diazomethane. The diazomethane was combined with dry ether (100 ml), dried over KOH, and the resulting ethereal solution was cooled in an ice-salt bath. A solution of furan-2-carbonyl chloride (1.6 g, 12.3 mmol) in dry ether (25 ml) was then added very slowly to the diazomethane solution. The reaction mixture was stirred overnight at room temperature. The solvent was evaporated to dryness (under an argon atmosphere, and keeping the water bath temperature below 25° C.), and the resulting crude material was purified by column chromatography using 230-400 mesh silica gel and 1% triethylamine in DCM solvent system. Evaporation of solvent yielded 2-diazo-1-(furan-2-yl)ethanone as a yellow oil (900 mg, 49%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([C:11]([OH:13])=[O:12])=[CH:4][C:3]=1[N:14]1[C:18](=[O:19])[C:17]([CH3:20])=[C:16]([CH3:21])[C:15]1=[O:22].[H][H]>[Ni].O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([C:11]([OH:13])=[O:12])=[CH:4][C:3]=1[N:14]1[C:15](=[O:22])[C:16]([CH3:21])=[C:17]([CH3:20])[C:18]1=[O:19]
Reactant: [H][H]
Reactant: CC1=C(C)C(=O)N(c2cc(C(=O)O)c([N+](=O)[O-])cc2F)C1=O
Agent: [Ni]
Solvent: C1CCOC1
Product: CC1=C(C)C(=O)N(c2cc(C(=O)O)c(N)cc2F)C1=O
Yield: 92.6 %

Procedure:
67.8 g of N-(2-fluoro-5-carboxy-4-nitrophenyl)-2,3-dimethylmaleic acid imide are hydrogenated using hydrogen in the presence of 14 g of Raney nickel catalyst in 1000 ml of tetrahydrofuran at a temperature of 20°-25° under normal pressure. When the stoichiometric amount of hydrogen has been consumed, the catalyst is separated off and the solution is concentrated by evaporation. 56.7 g of N-(2-fluoro-5-carboxy-4-aminophenyl)-2,3-dimethylmaleic acid imide having a melting point of 270° are thus obtained.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C:13]2([C:16]([F:19])([F:18])[F:17])[CH2:15][CH2:14]2)(=O)=O)=CC=1.[C-:20]#[N:21].[K+].O>CN(C=O)C>[F:19][C:16]([F:17])([F:18])[C:13]1([CH2:12][C:20]#[N:21])[CH2:14][CH2:15]1
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OCC2(C(F)(F)F)CC2)cc1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCC1(C(F)(F)F)CC1
Temperature: 60 °C
Yield: 39.4 %

Procedure:
Treat a solution of (1-(trifluoromethyl)cyclopropyl)methyl 4-methylbenzenesulfonate (12 g, 40.8 mmol) in DMF (150 mL) with potassium cyanide (3.5 g, 53 mmol) and heat at 50-70° C. for 3 days. Treat the mixture with water, extract with EtOAc (3×), wash the combined organics with water, then brine, dry and concentrate under reduced pressure to give the title compound (2.4 g, 39% yield). 1H NMR (400 MHz, CDCl3): δ 2.81 (s, 2H), 1.24-1.18 (m, 2H), 0.95-0.92 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][C:6]1[CH:18]=[CH:17][C:9]([C:10]([CH:12]=[CH:13][C:14]([OH:16])=[O:15])=[O:11])=[CH:8][CH:7]=1.[CH3:22][C:23]1C=CC(OC2C=CC(C(C=CC(O)=O)=O)=CC=2)=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][C:6]1[CH:18]=[CH:17][C:9]([C:10]([CH:12]=[CH:13][C:14]([O:16][CH2:22][CH3:23])=[O:15])=[O:11])=[CH:8][CH:7]=1
Reactant: Cc1ccc(Oc2ccc(C(=O)C=CC(=O)O)cc2)cc1
Reactant: O=C(O)C=CC(=O)c1ccc(Oc2cccc(Cl)c2)cc1
Product: CCOC(=O)C=CC(=O)c1ccc(Oc2cccc(Cl)c2)cc1

Procedure:
The procedure in Example 17(1) was followed, except that 6.05 g of 3-[4-(3-chlorophenoxy)benzoyl]acrylic acid were used in place of 3-[4-(4-methylphenoxy)benzoyl]acrylic acid, to give 5.78 g of ethyl 3-[4-(3-chlorophenoxy)benzoyl]acrylate in the form of an oil.
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][C:6]([NH:7][C:8]2[S:9][C:10]3[N:18]=[CH:17][CH:16]=[CH:15][C:11]=3[C:12](=[O:14])[N:13]=2)=[CH:5][CH:4]=1)#[N:2].[H-].[Li+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([N:13]1[C:12](=[O:14])[C:11]2[CH:15]=[CH:16][CH:17]=[N:18][C:10]=2[S:9][C:8]1=[N:7][C:6]1[CH:19]=[CH:20][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: N#Cc1ccc(Nc2nc(=O)c3cccnc3s2)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Li+]
Product: N#Cc1ccc(N=c2sc3ncccc3c(=O)n2Cc2ccccc2)cc1
Yield: 70.1 %

Procedure:
The reaction procedure of Example 11 was followed except that 900 mg (3.21 mmol) of 2-(4-cyanoanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 28 mg of lithium hydride and 604 mg of benzyl bromide were used. The resulting residue was then purified through silica gel column chromatography (eluant: chloroform) to obtain 834 mg of 3-benzyl-2-[(4-cyanophenyl)imino]-2,3-dihydro-4H-pyrido[3,2-e]-1,3-thiazin-4-one (70%, recrystallized from a mixture of ether and hexane) as a low polarity substance and 103 mg of 2-[N-benzyl-N-(4-cyanophenyl)-N-propylamino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one (10%, recrystallized from ether) as a high polarity substance.
Reaction SMILES: [Mg].[F:2][C:3]([F:12])([F:11])[C:4]1[CH:5]=[C:6](Br)[CH:7]=[CH:8][CH:9]=1.O1CCCC1.[CH3:18][CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:24][CH:23]=1)=[O:21]>C(O)(=O)C>[F:2][C:3]([F:12])([F:11])[C:4]1[CH:5]=[C:6]([C:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:24][CH:23]=2)([OH:21])[CH2:19][CH3:18])[CH:7]=[CH:8][CH:9]=1
Reactant: CCC(=O)c1ccc(OCc2ccccc2)cc1
Reactant: FC(F)(F)c1cccc(Br)c1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCC(O)(c1ccc(OCc2ccccc2)cc1)c1cccc(C(F)(F)F)c1

Procedure:
To a Grignard reactant prepared from 1.46 g. of magnesium turnings and 13.5 g. of 3-trifluoromethyl-bromobenzene in 34 ml. of dry tetrahydrofurane a solution of 9.61 g. of 4-benzyloxy-propiophenone in 50 ml. of dry tetrahydrofurane is added dropwise, under moderate reflux. The reaction mixture is slightly boiled for a further hour. The progress of the reaction can be monitored by thin layer chromatography. After termination of the reaction the reaction mixture is cooled and poured onto a mixture of glacial acetic acid and ice. The solvent phase is washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is distilled off in vacuo. 15 g. of the named compound are obtained, which can be recrystallized from n-heptane. Melting point: 50°-51° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C:7]=3[C:6]=2[CH:5]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([CH3:29])[CH2:28][O:27]2)=[CH:22][CH:21]=1.O>CN(C=O)C>[Cl:3][C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:29][C:26]([C:23]3[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=3)([OH:27])[CH3:28])[C:8]3[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C:7]=3[C:6]=2[CH:5]=1
Reactant: CC1(c2ccc(F)cc2)CO1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCc2c(n(CC(C)(O)c3ccc(F)cc3)c3ccc(Cl)cc23)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 45.5 %

Procedure:
The title compound was prepared by following general procedure 5. To a stirred suspension of sodium hydride (61 mg, 0.254 mmol) in 5 mL of DMF, 9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.2 g, 0.852 mmol) was added and stirred at RT for 5 min. 2-(4-Fluorophenyl)-2-methyloxirane (194 mg, 1.27 mmol) was added slowly dropwise and stirred at RT for 14 h. The reaction was monitored by TLC and LCMS. After completion of the reaction, water was added, extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, evaporated under reduced pressure and purified by reverse phase chromatography to afford 150 mg of (1-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-2-(4-fluorophenyl)propan-2-ol) as the TFA salt. 1H NMR (DMSO-d6, TFA salt) δ (ppm): 7.40 (s, 1H), 7.30-7.18 (m, 3H), 7.0-6.80 (m, 3H), 4.40-4.25 (d, 2H), 4.25-4.15 (d, 2H), 3.40-3.20 (d, 2H), 3.20-3.00 (m, 4H), 2.90 (s, 3H), 1.50 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:12]=[C:11]([S:13][C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17]([OH:19])=O)[NH:10][N:9]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([N:33]2[CH2:36][CH:35]([NH:37]C(=O)OC(C)(C)C)[CH2:34]2)(=[O:32])=[O:31])=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:25]=[CH:26][C:27]([S:30]([N:33]2[CH2:36][CH:35]([NH:37][C:17](=[O:19])[C:16]3[CH:20]=[CH:21][CH:22]=[C:14]([S:13][C:11]4[NH:10][N:9]=[C:8]([NH:7][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=5)[CH:12]=4)[CH:15]=3)[CH2:34]2)(=[O:31])=[O:32])=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)NC1CN(S(=O)(=O)c2ccc(F)cc2)C1
Reactant: O=C(O)c1cccc(Sc2cc(Nc3ccccn3)n[nH]2)c1
Product: O=C(NC1CN(S(=O)(=O)c2ccc(F)cc2)C1)c1cccc(Sc2cc(Nc3ccccn3)n[nH]2)c1
Yield: 36.9 %

Procedure:
3-(3-(Pyridine-2-ylamino)-1H-pyrazol-5-ylthio)benzoic acid (0.050 g, 0.160 mmol) and tert-butyl 1-(4-fluoro-phenylsulfonyl)azetidin-3-ylcarbamate (0.063 g, 0.19 mmol) were treated as described in Example 3, except that the mixture was purified on Prep HPLC (MeCN/H2O/0.1% TFA). This afforded the title material (0.031 g, 30%, trifluoroacetic acid salt) as a solid. 1H NMR 400 MHz DMSO-d6 δ (ppm): 3.72 (2H, dd, J=8.46, 6.44 Hz), 4.00 (2 H, t, J=8.08 Hz), 4.35-4.52 (1 H, m), 6.43 (1 H, s), 6.91-7.03 (1 H, m), 7.18 (1 H, d, J=8.08 Hz), 7.34-7.40 (1 H, m), 7.44 (1 H, t, J=7.71 Hz), 7.50-7.59 (2 H, m), 7.60-7.69 (2 H, m), 7.82-7.98 (3 H, m), 8.20 (1 H, d, J=4.55 Hz), 8.96 (1 H, d, J=6.06 Hz), 10.62 (1 H, br.s). HPLC ret. time (Condition B): 4.125 min.; 91%. LCMS (+ESI, M+H+) m/z 525. HRMS: calc. 525.1179, found 525.1191.
Reaction SMILES: F[C:2]1[C:3]([CH3:15])=[C:4]([CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12])[C:5]([OH:7])=[O:6].[CH2:16]([NH2:19])[CH:17]=[CH2:18].S(=O)(=O)(O)O>O>[CH2:16]([NH:19][C:2]1[C:3]([CH3:15])=[C:4]([CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12])[C:5]([OH:7])=[O:6])[CH:17]=[CH2:18]
Reactant: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1F
Reactant: C=CCN
Agent: O=S(=O)(O)O
Solvent: O
Product: C=CCNc1c(S(C)(=O)=O)ccc(C(=O)O)c1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4.0 g (17 mmol) of 3-fluoro-2-methyl-4-(methylsulfonyl)benzoic acid were dissolved in 12.9 ml (172 mmol) of allylamine. The mixture was heated at reflux for 5 days and allowed to stand for 2 days. 10 ml (134 mmol) of allylamine and 15 ml of water were added, and the mixture was heated at reflux for 14 days, cooled to RT, added to ice, acidified with 10% strength sulfuric acid and extracted twice with ethyl acetate. The combined organic phases were dried over MgSO4, and the solvent was removed under reduced pressure. The residue was crystallized from diethyl ether. This gave 4.2 g of a yellow solid of a purity of 88%.