Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:18]([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH:13]=[C:12]2I.[Cl:29][C:30]1[CH:35]=[CH:34][N:33]=[C:32]([Sn](CCCC)(CCCC)CCCC)[N:31]=1.N#N>CN(C=O)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:29][C:30]1[CH:35]=[CH:34][N:33]=[C:32]([C:12]2[C:11]3[C:15](=[CH:16][CH:17]=[C:9]([C:3]4[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=4[F:8])[CH:10]=3)[N:14]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:13]=2)[N:31]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccc(Cl)n1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4c(F)cccc4F)ccc32)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nccc(Cl)n3)c3cc(-c4c(F)cccc4F)ccc32)cc1
Temperature: 80 °C
Yield: 25.7 %

Procedure:
To a solution of 5-(2,6-difluorophenyl)-3-iodo-1-tosyl-1H-indole (2.0 g, 3.92 mmol) and 4-chloro-2-tributylstannanyl-pyrimidine (2.38 g, 5.98 mmol) in DMF (60 mL) was bubbled N2 for 15 min and added CuI (0.898 g, 4.71 mmol) and Pd(PPh3)4 (0.226 g, 0.196 mmol). The reaction mixture was heated at 80° C. for 1 h and cooled to RT. The reaction mixture was quenched with water and precipitate was formed. The resulting precipitate was collected by filtration, washed with water, and dried to yield crude product. Purification by silica gel column chromatography, eluting with 10% EtOAc in hexanes obtained the title compound (0.50 g, 26%). MS (ESI, pos. ion) m/z: 496.0 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][CH2:5][NH:6][C:7](=[O:30])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:22][C:23]2[CH:28]=[CH:27][C:26](Br)=[CH:25][CH:24]=2)[CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:10][CH:9]=1.[CH:32]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)([CH3:34])[CH3:33]>>[F:19][C:18]([F:21])([F:20])[CH2:17][CH2:16][CH2:15][CH:14]([C:11]1[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:31])=[O:30])=[CH:13][CH:12]=1)[O:22][C:23]1[CH:24]=[CH:25][C:26]([C:38]2[CH:39]=[CH:40][C:35]([CH:32]([CH3:34])[CH3:33])=[CH:36][CH:37]=2)=[CH:27][CH:28]=1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CCCC(F)(F)F)Oc2ccc(Br)cc2)cc1
Reactant: CC(C)c1ccc(B(O)O)cc1
Product: CC(C)c1ccc(-c2ccc(OC(CCCC(F)(F)F)c3ccc(C(=O)NCCC(=O)O)cc3)cc2)cc1

Procedure:
The title compound is prepared in a manner substantially similar to Example 128 starting from 3-{4-[1-(4-bromo-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylamino}-propionic acid methyl ester and 4-isopropyl phenyl boronic acid. MS: 526.2 [M−H]−.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])(C)(C)C.Cl.Br[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:18])=[C:10]([C:16]#[C:17][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[CH:11]=1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: Brc1ccncc1
Agent: Cl
Product: O=C(O)COc1ccc(Cl)cc1C#Cc1ccncc1

Procedure:
Following the general method as outlined in Example 10, starting from tert-butyl(4-chloro-2-ethynylphenoxy)acetate (Intermediate 3) and 4-bromopyridine hydrochloride (Fluka), the title compound was obtained as a yellow solid after purification by precipitation in dioxane.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:23][CH:22]=1)[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.[OH-].[Na+]>CO>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]([N:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:35])=[O:2])[C:21]2[CH:22]=[CH:23][C:24]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:25][CH:26]=2)=[O:20])=[CH:14][CH:15]=1
Reactant: COC(=O)CCCCCCCN(C(=O)c1ccc(Cl)cc1)c1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCCCCCCN(C(=O)c1ccc(Cl)cc1)c1ccc(OCc2ccccc2)cc1

Procedure:
As described in example 1(b), the reaction is carried out with 7.4 g (15 mmol) of 8-[4-chloro-N-(4-benzyloxyphenyl)-benzamido]-caprylic acid methyl ester, 1 g (23 mmol) of sodium hydroxide and 200 cc. of methanol. Reaction time: 48 hours, reaction temperature: 25° C. The crude product is used in the next reaction step without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=O)=[O:10])=[CH:5][CH:4]=1.[C:20]([CH2:22][C:23]([NH2:25])=[S:24])#[N:21]>N1CCCCC1.C(O)C>[CH3:1][N:2]([CH3:19])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:10])[NH:25][C:23](=[S:24])[C:22]([C:20]#[N:21])=[C:11]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C(=O)C(=O)c2ccccc2)cc1
Reactant: N#CCC(N)=S
Solvent: CCO
Solvent: C1CCNCC1
Product: CN(C)c1ccc(C2(O)NC(=S)C(C#N)=C2c2ccccc2)cc1

Procedure:
A mixture of 10.1 g. p-dimethylaminobenzil, 3.2 g. cyanothioacetamide, 10 drops of piperidine and 100 ml. ethanol is stirred for 12 hours at ambient temperature. The precipitated product is filtered off with suction, washed with chloroform and recrystallised from ethanol. There are obtained 6.0 g. of the desired product in the form of yellow crystals; m.p. 184°-185° C. (decomp.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)O)=[CH:4][CH:3]=1.S(Cl)([Cl:18])=O>ClCCl>[Cl:18][CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: OC(c1ccccc1)c1ccc(F)cc1
Solvent: ClCCl
Product: Fc1ccc(C(Cl)c2ccccc2)cc1
Yield: 95.2 %

Procedure:
In dichloromethane (30 mL), (±)-(4-fluorophenyl)phenylmethanol (2.1 g, 10 mmol) synthesized in Production Example 195 was dissolved, and thionyl chloride (5.1 g, 42 mmol) was added dropwise thereto at a room temperature. After the completion of the dropping, the mixture was heated under reflux, and the completion of the reaction was confirmed by TLC. After the completion of the reaction, the reaction mixture was concentrated, diluted with ethyl acetate, and washed with water. The organic layer was dried over magnesium sulfate, and the solvent was distilled off. Thus the title compound (2.1 g, 94%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[N:16]=[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[S:18][CH:19]=1)/[CH:6]=[CH:7]/[CH:8]=O.[S:26]1[CH2:30][C:29](=[O:31])[NH:28][C:27]1=[O:32]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[N:16]=[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[S:18][CH:19]=1)[CH:6]=[CH:7][CH:8]=[C:30]1[S:26][C:27](=[O:32])[NH:28][C:29]1=[O:31]
Reactant: COc1cc(/C=C/C=O)ccc1OCc1csc(-c2ccccc2)n1
Reactant: O=C1CSC(=O)N1
Product: COc1cc(C=CC=C2SC(=O)NC2=O)ccc1OCc1csc(-c2ccccc2)n1
Yield: 49 %

Procedure:
According to the same manner as that described in Example 1, (E)-3-methoxy-4-(2-phenyl-4-thiazolylmethoxy)-cinnamaldehyde was condensed with 2,4-thiazolidinedione to give 5-[3-methoxy-4-(2-phenyl-4-thiazolylmethoxy)-cinnamylidene]-2,4-thiazolidinedione (yield: 49%). This product was recrystallized from chloroform-methanol. Yellow needles, mp: 248-249° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][C:12]([CH:14]3[CH2:18][CH2:17][CH2:16][NH:15]3)=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1.[N:19]1([C:24]2[N:29]=[C:28]([C:30](=O)[CH3:31])[CH:27]=[C:26]([CH3:33])[N:25]=2)[CH:23]=[CH:22][N:21]=[CH:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCOCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][C:12]([CH:14]3[CH2:18][CH2:17][CH2:16][N:15]3[CH:30]([C:28]3[CH:27]=[C:26]([CH3:33])[N:25]=[C:24]([N:19]4[CH:23]=[CH:22][N:21]=[CH:20]4)[N:29]=3)[CH3:31])=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(NCc1ccc2c(c1)OCO2)C1CCCN1
Reactant: CC(=O)c1cc(C)nc(-n2ccnc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(C(C)N2CCCC2C(=O)NCc2ccc3c(c2)OCO3)nc(-n2ccnc2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 8.1 %

Procedure:
Pyrrolidine-2-carboxylic acid (benzo[1,3]dioxol-5-ylmethyl)-amide (85 mg, 0.34 mmol) was dissolved in dioxane (2.5 mL). Next, TsOH monohydrate (30 mg) and the 1-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-ethanone (69 mg, 0.34 mmol) were added and the reaction mixture was microwaved for 20 mins at 130° C. Upon completion of heating, the solution was allowed to return to room temperature and the sodium triacetoxyborohydride (145 mg, 0.68 mmol) was added to the reaction vessel and it was allowed to stir at room temperature for an additional 16 hours. After this period, the solution was concentrated under vacuum, diluted in ethyl acetate (50 mL) and transferred to a separatory funnel. The organic layer was washed with 1M NaOH (50 mL), dried over Na2SO4 and concentrated down by vacuum to afford the crude product. This material was purified by Flash Chromatography (0-40% ACN/DCM gradient) to afford 12 mg (8%) of 1-[1-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-ethyl]-pyrrolidine-2-carboxylic acid (benzo[1,3]dioxol-5-ylmethyl)-amide. Product isolated as a mixture of diasteromers; [M+H]+ 435.03.
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:71]=[CH:70][C:67]([C:68]#[N:69])=[CH:66][CH:65]=1>>[C:68]([C:67]1[CH:70]=[CH:71][C:64]([NH:63][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:36])([CH3:35])[CH3:37])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Br:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[CH:65][CH:66]=1)#[N:69]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Br)ccc12
Reactant: N#Cc1ccc(N)cc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C#N)cc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Br)ccc12

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-bromo-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 92 (0.4 g, 0.66 mmol), was reacted with diisopropylethylamine (0.77 g, 5.9 mmol), diphenylphosphinic chloride (0.62 g, 2.6 mmol), then reacted with 4-aminobenzonitrile (Aldrich) (0.31 g, 2.6 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-bromo-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-phenyl)-amide as a off white foam (Yield 0.18 g, 45%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[O:8])[CH:2]=1.[C:9]([Mg]Cl)#[CH:10]>C1COCC1>[OH:8][CH:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[C:9]#[CH:10]
Reactant: C#C[Mg]Cl
Reactant: O=Cc1cccnc1
Solvent: C1CCOC1
Product: C#CC(O)c1cccnc1

Procedure:
3-Hydroxy-3-(3-pyridinyl)-1-propyne was prepared according to Method A above using 3-pyridine carboxaldehyde (0.428 g, 4 mmol) (Aldrich) in THF (20 mL) and ethynylmagnesium chloride (5 mmol, 10 mL, 0.5M solution in tetrahydrofuran) (Aldrich). (Yield 440 mg, 83%).
Reaction SMILES: [ClH:1].[CH2:2]([C:5]1[N:6]=[C:7]([NH2:10])[NH:8][CH:9]=1)[C:3]#[CH:4].[N:11]([CH2:14][C:15]1[CH:19]=[CH:18][S:17][CH:16]=1)=[N+:12]=[N-:13]>>[ClH:1].[S:17]1[CH:18]=[CH:19][C:15]([CH2:14][N:11]2[CH:4]=[C:3]([CH2:2][C:5]3[N:6]=[C:7]([NH2:10])[NH:8][CH:9]=3)[N:13]=[N:12]2)=[CH:16]1
Reactant: [N-]=[N+]=NCc1ccsc1
Reactant: C#CCc1c[nH]c(N)n1
Agent: Cl
Product: Nc1nc(Cc2cn(Cc3ccsc3)nn2)c[nH]1
Yield: 44 %

Procedure:
4-Prop-2-ynyl-1H-imidazol-2-ylamine hydrochloride (0.096 (0.061 mmol) was reacted with 3-azidomethyl thiophene (0.102 g, 0.732 mmol) following the general procedure for click reactions outlined above to produce 4-(1-Thiophen-3-ylmethyl-1H-[1,2,3]triazol-4-ylmethyl)-1Himidazol-2-ylamine hydrochloride (0.079 g, 44%) of a pale yellow solid. 1H NMR (300 MHz, CD3OD) δ 8.18 (s, 1H), δ 7.44 (s, 1H), δ7.30 (d, 1H), δ 6.98 (d, 1H), δ 6.53 (s, 1H), δ 5.57 (s, 2H), δ 3.95 (s, 2H) ppm; 13C (75 MHz, CD3OD) δ 145.7, 145.1, 143.7, 139.7, 129.8, 121.8, 111.5, 109.8, 109.2, 52.7, 21.5 ppm; HRMS (ESI) calcd for C11H12N6S (M+) 260.0919. found 260.0919.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.[CH2:23]([NH2:27])[CH2:24][CH2:25][CH3:26]>C(Cl)Cl>[CH2:23]([NH:27][C:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=1)=[O:10])[CH2:24][CH2:25][CH3:26]
Reactant: O=C(O)c1cccc(Cl)n1
Reactant: CCCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCCCNC(=O)c1cccc(Cl)n1
Reaction time: 16 h
Yield: 47.6 %

Procedure:
6-Chloro-pyridine-2-carboxylic acid (500 mg, 3.17 mmol), EDC.HCl (1.34 g, 6.98 mmol) and HOBN (1.42 g, 7.93 mmol) were dissolved in DCM (30 mL) and NEM (914 mg, 7.93 mmol) and n-butylamine (376 μL, 3.81 mmol) were added. The reaction mixture was stirred for 16 h, washed with sat aq NaHCO3 (2×20 mL), 1 M aq HCl (2×20 mL), brine (20 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography to give the title compound (321 mg, 48%) as a colourless liquid. LCMS (ES+): 213.5 [MH]+.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C([O:12][C:13]([C:15]1[S:16][C:17]([N:20]2[CH2:25][CH2:24][N:23]([C:26](=[O:37])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:36])([F:35])[F:34])[CH2:22][CH2:21]2)=[N:18][N:19]=1)=O)C>>[CH2:1]([NH:9][C:13]([C:15]1[S:16][C:17]([N:20]2[CH2:21][CH2:22][N:23]([C:26](=[O:37])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:36])([F:35])[F:34])[CH2:24][CH2:25]2)=[N:18][N:19]=1)=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCOC(=O)c1nnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)s1
Reactant: CCCCCCCCN
Product: CCCCCCCCNC(=O)c1nnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)s1

Procedure:
Following the procedure as described in Example 3, making variations only as required to use n-octylamine in place of isoamylamine to react with 5-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl][1,3,4]thiadiazole-2-carboxylic acid ethyl ester, the title compound was obtained as a white solid (0.040 g, yield 66%). 1H NMR (300 MHz, CDCl3) δ 7.73-7.7 (m, 1H), 7.63-7.51 (m, 2H), 7.34-7.31 (m, 1H), 7.05 (br. t, 1H), 4.06-4.01 (m, 1H), 3.90-3.81 (m, 1H), 3.75-3.6 (m, 2H), 3.53-3.5 (m, 2H), 3.42-3.28 (m, 4H), 1.59-1.52 (m, 2H), 1.4-1.18 (m, 10H), 0.84 (t, J=5.7 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 174.5, 167.5, 158.2, 156.0, 133.9, 133.9, 132.4, 129.6, 129.0, 127.5, 126.9, 126.8, 126.7, 125.3, 121.7, 49.5, 48.9, 45.9, 40.7, 39.6, 31.7, 29.4, 29.1, 29.11, 26.8, 22.6, 14.0. MS (ES+) m/z 498 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[CH:8]=[CH:7]2.[Li+].C[Si]([N-:18][Si](C)(C)C)(C)C>>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH2:18])[CH:8]=[CH:7]2
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: Clc1ccc2cccc(Br)c2n1
Agent: [Li+]
Product: Nc1ccc2cccc(Br)c2n1

Procedure:
Other cyclic amides of the present invention can be prepared such as the 3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-ones 16 as described in Scheme 9. Substituted amines are coupled to the 8-bromo-2-chloroquinoline through treatment with base, such as LiHMDS, at a temperature of about RT, to afford the desired 8-bromoquinolin-2-amine 13. The bromo compound 13 is converted to the boronic acid 14 via treatment with a palladium catalyst, such as Pd(dppf)2Cl2, bis(pinacolato)diboron, and a base such as KOAc, at a temperature higher than RT, preferably above about 75° C., more preferably at about at 115° C. Coupling of the boronic acid 14 with the protected 7-bromo-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one 11 such as in the presence of a palladium catalyst, such as Pd2(dba)3 or bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)-dichloro-palladium(H), and dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine and a base such as K3PO4, at a temperature higher than RT, preferably above about 75° C., more preferably at about at 130° C., gave the protected 7-(quinolin-8-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one 15. Deprotection, such as with acid, at a temperature higher than RT, preferably at about 50° C., affords the desired 7-(quinolin-8-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one 16.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[C:4]([C:6]1[C:11]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:17]=2)(=[O:15])=[O:14])=[CH:10][C:9]([Cl:27])=[CH:8][N:7]=1)=O.[Si]([N:36]=[C:37]=[O:38])(C)(C)C>C1COCC1.CC(O)=O>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([S:13]([NH:12][C:11]2[C:6]([C:4]3[C:3]4[C:2](=[CH:31][CH:30]=[CH:29][CH:28]=4)[NH:1][C:37](=[O:38])[N:36]=3)=[N:7][CH:8]=[C:9]([Cl:27])[CH:10]=2)(=[O:15])=[O:14])=[CH:17][C:18]=1[C:23]([F:24])([F:25])[F:26]
Reactant: C[Si](C)(C)N=C=O
Reactant: Nc1ccccc1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=c1nc(-c2ncc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c2ccccc2[nH]1
Temperature: 65 °C

Procedure:
To a stirred solution of N-[2-(2-amino-benzoyl)-5-chloro-pyridin-3-yl]-4-chloro-3-trifluoromethyl-benzenesulfonamide (48 mg, 0.097 mmol) in anhydrous THF (2 mL) and AcOH (400 μL) was added TMS isocyanate (32 μL, 0.22 mmol) and the resulting mixture was heated at 65° C. overnight. The crude reaction mixture was directly purified by HPLC to provide 4-Chloro-N-[5-chloro-2-(2-oxo-1,2-dihydro-quinazolin-4-yl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide. 1H NMR (400 MHz, CDCl3) δ 10.50 (br s, 1 H), 8.58 (d, J=2.4 Hz, 1 H), 8.19 (d, J=2.4 Hz, 1 H), 8.06 (d, J=7.6 Hz, 1 H), 7.92 (d, J=2.4 Hz, 1 H), 7.80-7.76 (m, 1 H), 7.65 (dd, J=8.4, 2.4 Hz, 1 H), 7.41 (d, J=8.0 Hz, 1 H), 7.23-7.22 (m, 2 H); Mass spectrum m/z: 515.0 (M+H).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9]([NH:11][NH2:12])=[S:10].[F:13][C:14]([F:24])([F:23])[C:15]1[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][CH:16]=1>>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9](=[S:10])[NH:11][N:12]=[CH:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]([F:13])([F:23])[F:24])=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: NNC(=S)NC1CC2C=CC1C2
Product: FC(F)(F)c1ccc(C=NNC(=S)NC2CC3C=CC2C3)cc1

Procedure:
The title compound was prepared from a mixture of N1-bicyclo[2.2.1]hept-5-en-2-ylhydrazine-1-carbothioamide (100 mg, 0.56 mmol) and α,α,α-trifluoro-p-tolualdehyde (76 μL, 0.56 mmol) similar to Example 3 and isolated as a white solid (60 mg, 32%). 1H NMR (CDCl3): 9.14 (s, 1H), 7.78 (s, 1H), 7.73 (d, J=8.7 Hz, 2H), 7.67 (d, J=8.7 Hz, 2H), 7.46 (d, J=7.2 Hz, 1H), 6.25-6.14 (m, 2H), 4.30-4.26 (m, 1H), 3.07 (s, 1H), 2.98 (s, 1H), 1.96-1.88 (m, 1H), 1.69 (d, J=9.0 Hz, 1H), 1.51 (d, J=8.7 Hz, 1H), 1.46-1.40(m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].[C:13]1([CH2:19]O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.CN(C=O)C>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([O:7][CH2:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:6]
Reactant: COc1ccc(C(=O)O)cc1N
Reactant: OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)OCc2ccccc2)cc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
3-amino-4-methoxybenzoic acid (20 g, 120 mmol), phenylmethanol (12.94 g, 120 mmol), DMAP (14.62 g, 120 mmol), and EDC (22.94 g, 120 mmol) were dissolved in DMF (100 ml). The reaction was stirred at RT for 2 hours. The reaction mixture was filtered, and the mother liquor was diluted with water and extracted with EtOAc. The organic phase was extracted with water, dried over Na2SO4 and evaporated under vacuum. The crude product was crystallized in EtOAc. The mother liquor are purified by flash chromatography (Petroleum Ether/EtOAc 80/20). The overall amount of the desired product was 16 g (Yield: 52%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[SH:11].CS[C:14](SC)=[C:15]([C:18]1[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=1)[C:16]#[N:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C1C=CN=CC=1.C(O)C.C(Cl)Cl>[C:6]([C:5]1[CH:9]=[CH:10][C:2]2[NH:1][C:14](=[C:15]([C:18]3[N:23]=[C:22]([C:24]([F:26])([F:25])[F:27])[CH:21]=[CH:20][N:19]=3)[C:16]#[N:17])[S:11][C:3]=2[CH:4]=1)([OH:8])=[O:7]
Reactant: Nc1ccc(C(=O)O)cc1S
Reactant: CSC(SC)=C(C#N)c1nccc(C(F)(F)F)n1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Product: N#CC(=C1Nc2ccc(C(=O)O)cc2S1)c1nccc(C(F)(F)F)n1
Temperature: 160 °C
Yield: 44.5 %

Procedure:
A mixture of 4-amino-3-mercaptobenzoic acid (768 mg, 4.5 mmol), 3,3-bis(methylthio)-2-(4-trifluoromethylpyrimidin-2-yl)acrylonitrile (1.45 g, 5.0 mmol, 1.1 eq.), 4-dimethylaminopyridine (550 mg, 4.5 mmol, 1 eq.), and potassium carbonate (622 mg, 4.5 mmol, 1 eq.) in ethanol (20 mL) was heated at 160° C. for 0.4 hr in a microwave. The mixture was cooled to room temperature, diluted with DCM, and washed with 1M hydrochloric acid. The DCM fraction was decanted, filtered, and concentrated under vacuum to give 2-[6-carboxybenzothiazol-2(3H)-ylidene]-2-(4-trifluoromethyl-pyrimidin-2-yl)acetonitrile (729 mg, 40% yield) as a brown solid.
Reaction SMILES: Cl[C:2]1[N:19]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=2)[NH2:30])[CH2:23][CH2:22]1>>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][NH:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:30][C:29]3[CH:31]=[CH:32][CH:33]=[C:27]([N:24]4[CH2:23][CH2:22][N:21]([CH3:20])[CH2:26][CH2:25]4)[CH:28]=3)[N:19]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: Fc1ccccc1CNc1cccn2nc(Cl)nc12
Reactant: CN1CCN(c2cccc(N)c2)CC1
Product: CN1CCN(c2cccc(Nc3nc4c(NCc5ccccc5F)cccn4n3)c2)CC1

Procedure:
N(8)-(2-Fluoro-benzyl)-N(2)-[3-(4-methyl-piperazin-1-yl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-fluoro-benzyl)-amine (0.3227 g, 1.166 mmol) and 3-(4-methylpiperazin-1-yl)aniline (223 mg, 1.17 mmol) in a manner analogous to Example 2d. Product isolated as a red foam (102.96 mg, 20.5%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.19 (s, 1H), 7.98 (d, J=7.3 Hz, 1H), 7.43-7.06 (m, 7H), 6.74 (t, J=14.3, 7.1 Hz, 1H), 6.46 (d, J=8.6 Hz, 1H), 6.35 (m, 2H), 4.59 (d, J=6.4 Hz, 2H), 3.11 (s, 4H), 2.45 (s, 4H), 2.22 (s, 3H). MS=432 (MH)+.
Reaction SMILES: O=O.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[C:14]([CH3:16])[CH3:15])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1.CO>O1CCCC1.[Rh]>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C@H:10]([CH:14]([CH3:16])[CH3:15])[C:11]([OH:13])=[O:12])=[CH:8][CH:9]=1
Reactant: CC(C)=C(C(=O)O)c1ccc(Cl)cc1
Agent: [Rh]
Agent: O=O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)[C@H](C(=O)O)c1ccc(Cl)cc1
Reaction time: 0.25 h
Yield: 95.1 %

Procedure:
Rhodium-catalyzed hydrogenation. --A catalyst solution was prepared in a glove box (O2 content <1 ppm) by dissolving 0.0482 g (0.1 19 mmol) of [Rh(COD)2 ]BF4 and 0.0858 g (0.1 19 mmol) of (R,S)-BPPFA-EPIP in 20 ml of tetrahydrofuran and stirring at 20° for 15 minutes. Then, 5.0 g (23.74 mmol) of 2-(p-chlorophenyl)-3-methylcrotonic acid, 13 ml of methanol, 33 ml of tetrahydrofuran were placed in a 185 ml autoclave and the catalyst solution prepared above was added. The autoclave was sealed and the hydrogenation was carried out at 20° while stirring and under a constant pressure of 50 bar. The conversion was 100% after 18 hours. The hydrogenation solution was evaporated at 50°/20 mbar and the residue was distilled in a bulb tube oven at 150°/0.2 mbar. There were obtained 4.8 g (96%) of (S)-2-(p-chlorophenyl)-3-methylbutyric acid as a colorless oil which crystallized out at RT; chemical purity 99.9 GC area %; 97.6% ee.