Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][C:7](SC)=[N:8][CH:9]=2)[NH:4][N:3]=1.ClC1C=C(C=CC=1)C(OO)=O.[CH2:24]([NH2:27])[CH2:25][CH3:26]>C1COCC1>[Br:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([NH:27][CH2:24][CH2:25][CH3:26])=[N:8][CH:9]=2)[NH:4][N:3]=1
Reactant: CSc1ncc2c(Br)n[nH]c2n1
Reactant: CCCN
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCOC1
Product: CCCNc1ncc2c(Br)n[nH]c2n1
Temperature: 40 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
To a mixture of 3-bromo-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidine (0.49 g, 2.0 mmol) in THF (5 mL) was added meta-chloroperoxybenzoic acid (0.52 g, 99%, 3 mmol) at room temperature. The white mixture was stirred for 2 h and n-propylamine (0.82 mL, 10 mmol) was added at 0° C. The resulting solution was heated at 40° C. for 12 h. After removal of the solvent, MeOH was added and the mixture was filtered. The white solid was washed with MeOH (3×) and dried to provide 3-bromo-N-propyl-1H-pyrazolo[3,4-d]pyrimidin-6-amine (0.45 g, 88%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 13.19 (bs, 1H), 8.63 (s, 1H), 7.69 (bs, 1H), 3.29-3.17 (m, 2H), 1.61-1.49 (m, 2H), 0.88 (t, J=7.4 Hz, 3H); 13C NMR (100 MHz, DMSO-d6) δ 161.61, 156.98, 152.71, 120.06, 106.66, 42.68, 21.72, 11.47; MS m/z 256.1 [M+1].
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][Mg]Br.[CH2:7]([O:9][C:10]([C:12]1[C:13](OS(C(F)(F)F)(=O)=O)=[N:14][C:15]2[C:20]([C:21]=1[CH3:22])=[CH:19][CH:18]=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)=[O:11])[CH3:8].CCOC(C)=O.CCCCCC>C1COCC1.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:7]([O:9][C:10]([C:12]1[C:13]([CH:1]=[C:2]([CH3:6])[CH3:3])=[N:14][C:15]2[C:20]([C:21]=1[CH3:22])=[CH:19][CH:18]=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)=[O:11])[CH3:8]
Reactant: CC(C)=C[Mg]Br
Reactant: CCOC(=O)c1c(OS(=O)(=O)C(F)(F)F)nc2cc(C(F)(F)F)ccc2c1C
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C=C(C)C)nc2cc(C(F)(F)F)ccc2c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.9 %

Procedure:
5.6 ml (2.8 mmol, 2M in THF) (2-methylprop-1-enyl)magnesium bromide was added in drops at 0° C. to a solution of 600 mg (1.4 mmol) 4-methyl-7-(trifluoromethyl)-2-(trifluoromethylsulfonyl-oxy)quinoline-3-carboxylic acid ethyl ester and 75 mg (0.1 mmol) Ni(dppp)Cl2 in THF (10 ml). The mixture was subsequently stirred for 16 h at RT and thereafter quenched at 0° C. with a sat. aq. NH4Cl sol. It was then extracted with EtOAc and the organic phase was washed with water and brine, dried over Na2SO4 and concentrated in a vacuum. After CC (EtOAc/hexane 1:19) of the residue, 200 mg (0.6 mmol, 43%) 4-methyl-2-(2-methylprop-1-enyl)-7-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester was obtained.
Reaction SMILES: Br[C:2]1[C:3](=[O:32])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]1)[CH:5]=2.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[F:59][C:60]1[CH:61]=[C:62](B(O)O)[CH:63]=[CH:64][C:65]=1[O:66][CH3:67]>>[F:17][C:15]1[CH:16]=[C:11]([C:10]2[C:9]3[C:4](=[CH:5][C:6]([O:19][CH2:20][CH2:21][CH:22]4[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]4)=[CH:7][CH:8]=3)[C:3](=[O:32])[C:2]=2[C:62]2[CH:63]=[CH:64][C:65]([O:66][CH3:67])=[C:60]([F:59])[CH:61]=2)[CH:12]=[C:13]([F:18])[CH:14]=1
Reactant: COc1ccc(B(O)O)cc1F
Reactant: CS(=O)(=O)N1CCC(CCOc2ccc3c(c2)C(=O)C(Br)=C3c2cc(F)cc(F)c2)CC1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: COc1ccc(C2=C(c3cc(F)cc(F)c3)c3ccc(OCCC4CCN(S(C)(=O)=O)CC4)cc3C2=O)cc1F
Yield: 67 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(3,5-difluorophenyl)-6-{2-[1-(methylsulfonyl)piperidin-4-yl]ethoxy}-1H-inden-1-one obtained in Step 3 of Example 100 as a starting material instead of 6-(2-morpholino ethoxy)-2-bromo-3-phenyl-1H-inden-1-one, 3-fluoro-4-methoxyphenylboronic acid instead of 3-pyridinylboronic acid, and being purified by silica gel column chromatography (EtOAc/hexanes=1:1) to obtain the title compound (67%).
Reaction SMILES: [Cl:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][CH:10]=3)[NH:8][C:4]=2[CH:3]=1.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[Cl:19][C:18]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:7]([C:9]3[CH:10]=[CH:11][C:12]([CH:15]=[O:16])=[CH:13][CH:14]=3)=[N:6][C:5]=2[CH:17]=1
Reactant: CCOC(=O)CBr
Reactant: O=Cc1ccc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)cc1
Product: CCOC(=O)Cn1c(-c2ccc(C=O)cc2)nc2cc(Cl)c(Cl)cc21

Procedure:
Ethyl [5,6-dichloro2-(4-formylphenyl)benzimidazol-1-yl]acetate was prepared from 5,6-dichloro-2-(4-formylphenyl)benzimidazole obtained in Example 13 and ethyl bromoacetate by following General Procedure 3.
Reaction SMILES: [NH2:1][C@H:2]([CH2:21][OH:22])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1.C([O-])(=O)C.[Na+].[N:28]#[C:29]Br.[OH-].[Na+]>CO>[NH2:28][C:29]1[O:22][CH2:21][C@H:2]([CH2:3][CH2:4][C:5]2[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:20])[C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)=[CH:9][CH:10]=2)[N:1]=1
Reactant: N[C@H](CO)CCc1ccc(NC(=O)c2ccc(Cl)cc2)cc1
Reactant: N#CBr
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC1=N[C@@H](CCc2ccc(NC(=O)c3ccc(Cl)cc3)cc2)CO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.6 %

Procedure:
To a stirred suspension of N-[4-((S)-3-Amino-4-hydroxy-butyl)-phenyl]-4-chloro-benzamide (250 mg) and sodium acetate (124 mg) in methanol (10 ml) was added dropwise a solution of cyanogen bromide (100 mg) in methanol (3 ml). The resulting pale yellow solution was then stirred at room temperature for 16 h. The reaction mixture was poured into 1 N aq. NaOH and extracted twice with dichloromethane/THF. The combined organic layers were washed with sat. aq. NaCl, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel; eluant: 0% to 100% EtOAc in heptane, then 0% to 30% MeOH in EtOAc) to afford N-{4-[2-((S)-2-amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-4-chloro-benzamide (150 mg, 56%) as a white solid. MS (ISP): 346.1 ([{37Cl}M+H]+), 344.2 ([{35Cl}M+H]+).
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[N:11]([CH3:18])[C:10](=[O:19])[C:9]12[CH2:21][CH2:20]1)=O.CN(C=O)C.O.C([O-])([O-])=O.[K+].[K+]>CO>[NH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[N:11]([CH3:18])[C:10](=[O:19])[C:9]12[CH2:20][CH2:21]1
Reactant: CN1C(=O)C2(CC2)c2cc(NC(=O)C(F)(F)F)c([N+](=O)[O-])cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)C2(CC2)c2cc(N)c([N+](=O)[O-])cc21
Temperature: 50 °C
Reaction time: 12 h
Yield: 70.6 %

Procedure:
2,2,2-Trifluoro-N-(1′-methyl-6′-nitro-2′-oxo-spiro[cyclopropane-1,3′-indole]-5′-yl)-acetamide (2 g) is dissolved in MeOH (15 ml), DMF (10 ml) and water (6.1 ml). Freshly powdered K2CO3 (2.9 g; 21 mmol) is added and the reaction is stirred at 50° C. for 12 h. After completion of the reaction the mixture is poured into water and the precipitate is collected by filtration and washed with 2-propanol and tertbutylmethyl ether. The compound (1 g) is obtained as a red solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:18][CH2:17][CH2:16][C@@H:15]2[CH2:19][OH:20])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:21]>CCO.O1CCOCC1>[ClH:21].[ClH:21].[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH2:18][CH2:17][CH2:16][C@@H:15]2[CH2:19][OH:20])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC[C@@H]2CO)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: OC[C@H]1CCCN1C1CCNCC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
A solution of 8.80 g (30.9 mmol) of 4-((R)-2-hydroxymethyl-pyrrolidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester in 200 ml of EtOH was treated at RT with 15.5 ml (62.0 mmol) of hydrochloric acid in 1,4-dioxane (4 molar) and the mixture was heated up to 100° C. After two hours, the solvents were evaporated and the residue was re-crystallized from MeOH/MeCN and Et2O to give 6.53 g (82%) of the title compound as off-white solid. MS: 185.1 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8]N)[N:3]=1.CCO.[CH3:13][C:14]([CH2:16][CH3:17])=O>C(O)COCCO>[Br:1][C:2]1[N:3]=[C:4]2[NH:8][C:14]([CH3:13])=[C:16]([CH3:17])[C:5]2=[CH:6][CH:7]=1
Reactant: CCC(C)=O
Reactant: NNc1cccc(Br)n1
Solvent: OCCOCCO
Solvent: CCO
Product: Cc1[nH]c2nc(Br)ccc2c1C
Yield: 15.7 %

Procedure:
A suspension of 2-bromo-6-hydrazinopyridine (32,5 g, 0.17 mol) in abs EtOH was treated with ethyl methyl ketone (20 ml, 0.22 mol) for 1 h at reflux. The reaction mixture was allowed to cool and treated with additional ethyl methyl ketone (10+3+1 ml) until all starting material had dissapeared according to TLC. The reaction mixture was taken up in 150 ml diethylene glycol and the EtOH evaporated at reduced pressure at 70° C. The remaining solution was deaerated and heated to reflux for 22h. The reaction mixture was cooled and paritioned between 1250 ml CH2Cl2 and 1000 ml 2M HCl (reextracted with 250 ml CH2Cl2). The organic layer was washed with further 500 ml 2M HCl and 500 ml H2O dried over MgSO4, and evaporated. Chromatography (silica, CH2Cl2 /diethyl ether; 95/5) afforded 6 g 6-bromo-2,3-dimethyl-pyrrolo[2,3-b] pyridine. Recrystallization from 120 ml abs EtOH gave 4,2 g (11%). (1H-NMR, 500 MHz, CDCl3) 2.19(s,3H), 2.42(s,3H), 7.16(d, 1H), 7.59(d, 1H), 9.12(b, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([CH3:15])[C:9]=2[Br:16])=[O:5])[CH3:2].[C:17]([O:21][C:22]([N:24]1[CH2:28][C@H:27]([CH3:29])OS1(=O)=O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C@H:27]([CH3:29])[CH2:28][NH:24][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([CH3:15])[C:9]=2[Br:16])=[O:5])[CH3:2]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Reactant: CCOC(=O)c1cc2ccc(C)c(Br)c2[nH]1
Product: CCOC(=O)c1cc2ccc(C)c(Br)c2n1[C@H](C)CNC(=O)OC(C)(C)C

Procedure:
The title compound, ISP-MS: m/e=439.1 and 441.3 (M+), was prepared in accordance with the general method of example 12b) from 7-bromo-6-methyl-1H-indole-2-carboxylic acid ethyl ester and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([C:12]2[NH:16][C:15]([CH3:17])=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[CH:4][CH:3]=1.[CH:19]1([CH2:22]Br)[CH2:21][CH2:20]1>>[CH:19]1([CH2:22][N:16]2[C:12]([C:10](=[O:11])[CH2:9][CH2:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:13][C:14]([CH3:18])=[C:15]2[CH3:17])[CH2:21][CH2:20]1
Reactant: BrCC1CC1
Reactant: Cc1cc(C(=O)CCc2ccc(F)cc2)[nH]c1C
Product: Cc1cc(C(=O)CCc2ccc(F)cc2)n(CC2CC2)c1C
Yield: 64.8 %

Procedure:
The title compound was prepared as a pale yellow oil in 64.8% yield in a similar procedure to that described in Referential Example 97 by using 5-[3-(4-fluorophenyl)propionyl]-2,3-dimethylpyrrole and cyclopropylmethyl bromide.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:17]1[S:21][C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:19]([CH3:27])[CH:18]=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:17]2[S:21][C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:19]([CH3:27])[CH:18]=2)[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1sc(Br)cc1C
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Product: CCOC(=O)c1sc(-n2ccc(OCc3ccccc3)cc2=O)cc1C
Yield: 26 %

Procedure:
Following the procedure as described in Example 3, making variations only as required to use 4-(benzyloxy)pyridin-2(1H)-one in place of 4-aminopyridin-2(1H)-one to react with ethyl 5-bromo-3-methylthiophene-2-carboxylate in place of N-benzyl-2-bromo-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 26% yield: 1H NMR (300 MHz, CDCl3) δ 7.55 (d, J=7.8 Hz, 1H), 7.44-7.36 (m, 5H), 6.87 (s, 1H), 6.13 (dd, J=7.8, 2.7 Hz, 1H), 6.07 (d, J=2.7 Hz, 1H), 5.04 (s, 2H), 4.32 (q, J=7.1 Hz, 2H), 2.55 (s, 3H), 1.36 (t, J=7.1 Hz, 3H); MS (ES+) m/z 370.2 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH:15]([C:17](=[O:19])[NH2:18])[N:14]([CH2:20][CH2:21][CH2:22][C:23](OC(C)(C)C)=[O:24])[C:13](=[O:30])[C@@H:12]1[CH3:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[CH2:34]1[C:36]2([CH2:41][CH2:40][NH:39][CH2:38][C@H:37]2[OH:42])[CH2:35]1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([C:17](=[O:19])[NH2:18])[N:14]([CH2:20][CH2:21][CH2:22][C:23]([N:39]2[CH2:40][CH2:41][C:36]3([CH2:34][CH2:35]3)[C@H:37]([OH:42])[CH2:38]2)=[O:24])[C:13](=[O:30])[C@@H:12]1[CH3:31])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@@H]1CNCCC12CC2
Reactant: C[C@H]1C(=O)N(CCCC(=O)OC(C)(C)C)C(C(N)=O)CN1C(=O)OCc1ccccc1
Agent: Cl
Product: C[C@H]1C(=O)N(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)[C@@H](C(N)=O)CN1C(=O)OCc1ccccc1
Yield: 22 %

Procedure:
In analogy to the procedure described in example 120 step D, (2S,5RS)-4-(3-tert-butoxycarbonyl-propyl)-5-carbamoyl-2-methyl-3-oxo-piperazine-1-carboxylic acid benzyl ester was first hydrolysed with HCl and then coupled with (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride (intermediate 2). The two diasterioisomers could be separated by flash column chromatography (SiO2, EtOAc/MeOH 1:0-9:1) affording first (2S,5R)-5-carbamoyl-4-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-4-oxo-butyl]-2-methyl-3-oxo-piperazine-1-carboxylic acid benzyl ester in 22% yield as an amorphous white solid, MS: 487.30 (MH+) and then (2S,5S)-5-carbamoyl-4-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-4-oxo-butyl]-2-methyl-3-oxo-piperazine-1-carboxylic acid benzyl ester in 20% yield as a colorless foam MS: 487.30 (MH+).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[C:13]([F:15])[C:12]([CH3:16])=[C:11]2[C:6]=1[CH2:7][CH2:8][CH2:9][C:10]2=O)(=[O:3])[CH3:2].[H][H]>[C].[Pd].CO>[C:1]([NH:4][C:5]1[CH:14]=[C:13]([F:15])[C:12]([CH3:16])=[C:11]2[C:6]=1[CH2:7][CH2:8][CH2:9][CH2:10]2)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)Nc1cc(F)c(C)c2c1CCCC2=O
Agent: [Pd]
Solvent: CO
Product: CC(=O)Nc1cc(F)c(C)c2c1CCCC2
Temperature: 50 °C
Reaction time: 18 h
Yield: 80.8 %

Procedure:
In a 50-ml autoclave, 1.0 g of 5-acetylamino-7 -fluoro-8-methyl-l-tetralone and 10 ml of methanol were charged. To the resulting mixture, 0.5 g of 10% palladium-carbon was added. The hydrogen pressure was increased to 40 kg/cm2 at room temperature, under which the resulting mixture was stirred at 50° C. for 18 hours. After the completion of the reaction, the reaction mixture was filtered. The catalyst so obtained was washed with chloroform and then the filtrate was concentrated under reduced pressure. To the residue, isopropyl ether was added. The crystals so precipitated were collected by filtration, followed by drying under reduced pressure, whereby 0.76 g of the title compound was obtained.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[CH:9][O:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[CH3:20][O:21][C:22](=[O:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH2:28].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:20][O:21][C:22](=[O:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[CH:9][O:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COc1ccc(-c2coc3ncnc(Cl)c23)cc1
Reactant: COC(=O)CCCCCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)CCCCCNc1ncnc2occ(-c3ccc(OC)cc3)c12
Temperature: 25 °C

Procedure:
Dissolve 7.1 g (27.2 mol) 4-chloro-5-(4-methoxyphenyl)furo[2,3-d]pyrimidine in 250 ml acetonitrile and add 5.9 g (32.7 mmol) 6-aminohexanoic acid methyl ester hydrochloride and 9.4 g (68.1 mmol) potassium carbonate. Heat the mixture under reflux for 18 hours and then filter after cooling to room temperature. Mix the residue three times in 50 ml water each time, filter and dry under vacuum. 4.1 g (41% of theor.) of the title compound is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](=O)[NH:7][C:6]=2[CH:17]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[N:7][C:6]=2[CH:17]=1
Reactant: O=C1Nc2cc(Cl)ccc2Cc2ccccc21
Reactant: C1CNCCN1
Product: Clc1ccc2c(c1)N=C(N1CCNCC1)c1ccccc1C2

Procedure:
3-Chloro-5,11-dihydro-dibenzo[b,e]azepin-6-one (189JO59) (25 mg, 0.1 mmol) and piperazine were reacted according to GP4 to give 2.2 mg of the title compound (189JO60). MS(ESI) 312 (MH+). Purity for MH+ (UV/MS) 100/100.
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]1=[O:13].[CH3:14][O:15][C:16]([C:18]1[CH:33]=[CH:32][C:21]([C:22]([C:24]2[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=2)=[O:23])=[CH:20][CH:19]=1)=[O:17].CS(C)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:14][O:15][C:16]([C:18]1[CH:33]=[CH:32][C:21]([C:22]([C:24]2[CH:25]=[CH:26][C:27]([CH2:28][O:13][C:3]3[N:4]=[C:5]4[CH:12]=[CH:11][CH:10]=[CH:9][N:6]4[C:7](=[O:8])[C:2]=3[CH3:1])=[CH:30][CH:31]=2)=[O:23])=[CH:20][CH:19]=1)=[O:17]
Reactant: COC(=O)c1ccc(C(=O)c2ccc(CBr)cc2)cc1
Reactant: CC1C(=O)N=C2C=CC=CN2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)c2ccc(COc3nc4ccccn4c(=O)c3C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-methylpyrido[1,2-a]pyrimidine-2,4-dione (2.20 g, 12.5 mmol) and 4-(4-methoxycarbonylbenzoyl)benzyl bromide (7.04 g, 12.7 mmol) in DMF (40.0 ml)-DMSO (20.0 ml) was added potassium carbonate (3.92 g, 28.4 mmol) and the mixture was stirred at room temperature overnight. This reaction mixture was diluted with water and the resulting crystals were collected by filtration, dissolved in ethyl acetate, and dried over MgSO4. The solvent was then distilled off under reduced pressure and the residue was re-crystallized from ethyl acetate to provide colorless needles.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][CH:24]([C:27]([OH:30])([CH3:29])[CH3:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:31][C:32]1[N:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[OH:30][C:27]([CH:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:35]3[CH:36]=[N:37][C:32]([CH3:31])=[CH:33][CH:34]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1)([CH3:29])[CH3:28]
Reactant: CC(C)(O)C1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Reactant: Cc1ccc(B(O)O)cn1
Product: Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CCC(C(C)(C)O)C2)cn1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 113 using 5-bromo-6-(3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 113.1) and (6-methylpyridin-3-yl)boronic acid to afford an off-white amorphous solid. HPLC (Condition 4) tR=4.38 min, UPLC-MS (Condition 7) m/z=501.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.00 (d, J=16.03 Hz, 6H) 1.55-1.80 (m, 2H) 1.95-2.12 (m, 1H) 2.48 (s, 3H) 2.99-3.20 (m, 3H) 3.22-3.35 (m, 1H) 4.26 (s, 1H) 7.32 (dd, J=8.21, 5.86 Hz, 3H) 7.67 (dd, J=7.82, 2.35 Hz, 1H) 7.78-7.89 (m, 2H) 7.96 (d, J=2.35 Hz, 1H) 8.47 (d, J=2.35 Hz, 1H) 8.72 (d, J=2.35 Hz, 1H) 10.13 (s, 1H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.I.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C.[CH3:33][C:34]([CH3:54])([CH3:53])[C:35]([N:37]1[C:45]2[C:40](=[CH:41][C:42]([NH:46][CH:47]3[CH2:52][CH2:51][CH2:50][NH:49][CH2:48]3)=[CH:43][CH:44]=2)[CH:39]=[N:38]1)=[O:36].Cl>CN(C=O)C>[CH3:33][C:34]([CH3:54])([CH3:53])[C:35]([N:37]1[C:45]2[C:40](=[CH:41][C:42]([NH:46][CH:47]3[CH2:52][CH2:51][CH2:50][N:49]([C:6](=[O:8])[C:5]4[CH:9]=[CH:10][CH:11]=[C:3]([S:2][CH3:1])[CH:4]=4)[CH2:48]3)=[CH:43][CH:44]=2)[CH:39]=[N:38]1)=[O:36]
Reactant: CSc1cccc(C(=O)O)c1
Reactant: CC(C)(C)C(=O)n1ncc2cc(NC3CCCNC3)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: I
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1cccc(C(=O)N2CCCC(Nc3ccc4c(cnn4C(=O)C(C)(C)C)c3)C2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 53.3 %

Procedure:
To a solution of 3-(methylthio)benzoic acid (200 mg, 1.2 mmol) in DMF (4.5 mL) was added in succession N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydroiodide (345 mg, 1.75 mmol) 1-hydroxybenzotriazole hydrate (186 mg, 1.2 mmol) and diisopropylethylamine (0.630 mL, 3.6 mmol). After stirring at room temperature for 10 min, 2,2-dimethyl-1-(5-(piperidin-3-ylamino)-1H-indazol-1-yl)propan-1-one (300 mg, 1.0 mmol) was added in one portion. The solution was stirred under a nitrogen atmosphere overnight. The solution was poured into 1.0 M HCl (20 mL), extracted twice with EtOAc, and the organic phases were washed with 10% NaOH, dried over Na2SO4 and evaporated. Chromatography of the residue on silica gel, eluting with EtOAc/heptane, gave the title compound as a pale yellow foam (240 mg, 53%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[F:9].[N:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.O.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>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:13]2[CH:14]=[CH:15][N:10]=[CH:11][CH:12]=2)=[CH:4][C:3]=1[F:9]
Reactant: Fc1cc(I)ccc1Br
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Fc1cc(-c2ccncc2)ccc1Br
Temperature: 25 °C
Yield: 21.9 %

Procedure:
1-Bromo-2-fluoro-4-iodobenzene (300 mg, 0.997 mmol), 4-pyridineboronic acid (147 mg, 1.196 mmol), Na2CO3(211 mg, 1.994 mmol) and tetrakis(triphenylphosphine)palladium (230 mg, 0.199 mmol) in 3.3 mL of 1:1 Dioxane/water were heated to 100° C. for 20 h. The reaction was slowly warmed to room temperature, diluted with water and extracted with EtOAc. The organic phase was separated, dried (Na2SO4) and evaporated to dryness, giving an oil. This material was chromatographed on silica gel, eluting with 0-10% ethyl acetate in hexanes to give 4-(4-bromo-3-fluorophenyl)pyridine (55 mg) as an off-white solid.
Reaction SMILES: I.[Cl:2][C:3]1[CH:15]=[CH:14][C:13]2[C:8]3[N:9]=[C:10]([NH2:12])[S:11][C:7]=3[CH2:6][C:5]=2[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1>O1CCCC1>[Cl:2][C:3]1[CH:15]=[CH:14][C:13]2[C:8]3[N:9]=[C:10]([NH:12][C:23](=[O:30])[C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[S:11][C:7]=3[CH2:6][C:5]=2[CH:4]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: Nc1nc2c(s1)Cc1cc(Cl)ccc1-2
Agent: Cl
Agent: I
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: O=C(Nc1nc2c(s1)Cc1cc(Cl)ccc1-2)c1ccncc1
Temperature: 80 °C
Reaction time: 20 h
Yield: 26.5 %

Procedure:
A mixture of 6-Chloro-8H-indeno[1,2-d]thiazol-2-ylamine hydroiodide 10 (80 mg; 0.23 mmol), potassium carbonate (138 mg; 1.0 mmol) and isonicotinoyl chloride hydrochloride (89 mg; 0.5 mmol) in dry tetrahydrofuran was heated to 80° C. in a sealed tube. After 20 hr., the mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was diluted with methylene chloride and washed with water. The organic layer was dried (sodium sulfate), filtered and concentrated in vacuo. The crude product was purified by reverse phase HPLC (eluent: acetonitrile/water/0.1% trifluoroacetic acid) to provide 20 mg of N-(6-Chloro-8H-indeno[1,2-d]thiazol-2-yl)-isonicotinamide 11 as the trifluoroacetate salt. EI-HRMS m/e calcd for C16H10ClN3OS (M+) 327.0233, found 327.0217.