Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[Cl:10][C:11]1[C:16](B(O)O)=[CH:15][CH:14]=[CH:13][N:12]=1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2].O>[Cl:10][C:11]1[C:16]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[CH:3]=2)=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: OB(O)c1cccnc1Cl
Reactant: COc1cc(I)ccn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(-c2cccnc2Cl)ccn1
Temperature: 100 °C

Procedure:
To 4-iodo-2-methoxypyridine (834 mg, 3.55 mmol), 2-chloropyridine-3-boronic acid (838 mg, 5.32 mmol), Na2CO3 (1.13 g, 10.7 mmol), Pd(OAc)2 (40 mg, 0.18 mmol) and P(tBu)3·HBF4 (104 mg, 0.36 mmol) was added dioxane (12 mL) and water (4 mL). The mixture was heated overnight at 100° C. in a sealed tube. The resulting mixture was diluted with EtOAc and extracted with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The resulting solid was triturated with MeOH and dried to yield the title compound. MS m/z=221 [M+1]+. Calc'd for C21H9ClN2O: 220.66.
Reaction SMILES: [N:1]1([C:6]([C:8]2[CH:9]=[C:10]([NH:21][C:22]3[C:31]4[C:26](=[CH:27][C:28]([Cl:32])=[CH:29][CH:30]=4)[N:25]=[CH:24][CH:23]=3)[CH:11]=[C:12]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=O)[CH:13]=2)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C(OCC)(=O)C>C1COCC1>[N:1]1([CH2:6][C:8]2[CH:9]=[C:10]([NH:21][C:22]3[C:31]4[C:26](=[CH:27][C:28]([Cl:32])=[CH:29][CH:30]=4)[N:25]=[CH:24][CH:23]=3)[CH:11]=[C:12]([CH2:14][N:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)[CH:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1cc(Nc2ccnc3cc(Cl)ccc23)cc(C(=O)N2CCCC2)c1)N1CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Clc1ccc2c(Nc3cc(CN4CCCC4)cc(CN4CCCC4)c3)ccnc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 5 %

Procedure:
To a suspension of N-{3,5-bis[(pyrrolidin-1-yl)carbonyl]phenyl}-7-chloroquinolin-4-amine (84 mg, 0.19 mmol) in 15 mL of anhydrous THF, was added portionwise LiAlH4 (71 mg, 10 eq). The reaction mixture was stirred at room temperature for 2 h and then 10 mL of ethyl acetate was added. The mixture was filtered through a celite pad. The filtrate was evaporated and the residue was purified by preparative thin-layer chromatography (DCM/MeOH/NH4OH//95/5/1) to yield expected compound (4 mg, 5%) as a yellow oil. m/z (ESI) 420.9 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:11][O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[N:7]=1.[CH3:19][NH:20][CH2:21][CH3:22]>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:20]([CH2:21][CH3:22])[CH3:19])[C:5]2[CH2:11][O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2c(n1)C(c1ccccc1)COC2
Reactant: CCNC
Solvent: CO
Product: CCN(C)c1nc(Cl)nc2c1COCC2c1ccccc1
Yield: 100.2 %

Procedure:
A solution of 2,4-dichloro-8-phenyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine (135 mg, 0.480 mmol) and excess N-methylethanamine (284 mg, 4.80 mmol) in MeOH (2 mL) was stirred at rt for 1 h. The solvent was removed in vacuum to afford 2-chloro-N-ethyl-N-methyl-8-phenyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine (146 mg, 0.481 mmol, 100% yield). LC-MS (M+H)+=304.2.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](F)=[CH:5][CH:4]=1)#[N:2].[C:14]1([N:20]2[C:24]3([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[C:23](=[O:30])[NH:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[O:30]=[C:23]1[C:24]2([CH2:25][CH2:26][N:27]([C:6]3[C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[CH2:28][CH2:29]2)[N:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:21][NH:22]1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: N#Cc1ccc(F)c2ccccc12
Product: N#Cc1ccc(N2CCC3(CC2)C(=O)NCN3c2ccccc2)c2ccccc12
Yield: 15.6 %

Procedure:
The title compound (7 mg, 16% yield) was prepared as described for 196MBT2-4 from 1-cyano-4-fluoronaphthalene (20 mg, 0.117 mmol) and 1-phenyl-1,3,8-triazaspiro-[4,5]decan-4-one (108 mg, 0.468 mmol).
Reaction SMILES: [C:1]([C:3]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]=2)[CH:8]=[C:7]1[C:20]([O:22]CC)=O)([CH3:5])[CH3:4])#[N:2]>[Ni].O>[CH3:4][C:3]1([CH3:5])[N:6]2[C:14]3[CH:13]=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:11]=[CH:10][C:9]=3[CH:8]=[C:7]2[C:20](=[O:22])[NH:2][CH2:1]1
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)n(C(C)(C)C#N)c2c1
Agent: [Ni]
Solvent: O
Product: CCOC(=O)c1ccc2cc3n(c2c1)C(C)(C)CNC3=O
Temperature: 50 °C
Reaction time: 18 h
Yield: 115.4 %

Procedure:
A mixture of diethyl 1-(2-cyanopropan-2-yl)-1H-indole-2,6-dicarboxylate (9.3 g, 23.3 mmol) and Raney Ni (4 g of 50% wet catalyst) and water (5 mL) water is heated to 50° C. under 250 psi of H2. The mixture is stirred for 18 h. LCMS shows complete reaction with high purity. The mixture is filtered through Celite, keeping the catalyst wet until properly disposed. The solvent was removed under reduced pressure to afford the title compound (7.7 g, 95%) as a white solid.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].Cl>C1(C)C=CC=CC=1.CN(C=O)C>[C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: BrC1CCCC1
Reactant: Oc1ccc(Sc2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: c1ccc(Sc2ccc(OC3CCCC3)cc2)cc1
Reaction time: 16 h
Yield: 100 %

Procedure:
A solution was prepared by combining 11.3 g of 4-hydroxyphenyl phenyl sulfide which had been synthesized according to the well-known formulation, 8.2 g of bromocyclopentane, 7.6 g of potassium carbonate, and 40 g of DMF. The solution was aged at 80° C. for 16 hours. The aged solution was cooled to room temperature, to which 100 g of 5 wt % dilute hydrochloric acid was added to quench the reaction. To the solution, 150 g of toluene was added for extraction. The organic layer was separated and washed with water. It was combined with 5 wt % sodium hydroxide aqueous solution. The organic layer was separated and washed with water again. On subsequent concentration in vacuum, 13.8 g of the target compound, 4-cyclopentyloxyphenyl phenyl sulfide was obtained as oily matter. Yield 100%.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]3[CH2:14][C:13](=[O:15])[NH:12][C:9]3=[N:10][CH:11]=2)=[CH:2]1.[C:16]([O:19][CH:20](OCC)OCC)(=O)[CH3:17]>>[CH2:16]([O:19][CH:20]=[C:14]1[C:8]2[C:9](=[N:10][CH:11]=[C:6]([C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)[CH:7]=2)[NH:12][C:13]1=[O:15])[CH3:17]
Reactant: O=C1Cc2cc(-c3ccsc3)cnc2N1
Reactant: CCOC(OCC)OC(C)=O
Product: CCOC=C1C(=O)Nc2ncc(-c3ccsc3)cc21

Procedure:
This compound was synthesized from 5-(3-thienyl)-1H-pyrrolo[2,3-b]pyridin-2-one and diethoxymethyl acetate according to Procedure A. 1H NMR 400 MHz (DMSO-d6): δ 10.89 (s, 1H); 8.33 (s, 1H); 7.88 (s, 1H); 7.84 (s, 1H); 7.79 (s, 1H); 7.62 (m, 1H); 7.49 (d, 1H); 4.40 (m, 2H); 1.36 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:28])=[C:4]([CH:19]=[N:20][C:21]([O:23][Si](C)(C)C)=[CH2:22])[C:5]([O:8][CH2:9][CH2:10][O:11][Si](C(C)(C)C)(C)C)=[CH:6][CH:7]=1.C(OC([N:36]1[C:44]2[C:39](=[CH:40][CH:41]=[C:42]([Cl:45])[CH:43]=2)/[C:38](=[CH:46]/[C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([Cl:53])[CH:48]=2)/[C:37]1=[O:54])=O)(C)(C)C.CO>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([F:28])=[C:4]([CH:19]2[C:38]3([C:39]4[C:44](=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=4)[NH:36][C:37]3=[O:54])[CH:46]([C:47]3[CH:52]=[CH:51][CH:50]=[C:49]([Cl:53])[CH:48]=3)[CH2:23][C:21](=[O:22])[NH:20]2)[C:5]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Cl)cc21
Reactant: C=C(N=Cc1c(OCCO[Si](C)(C)C(C)(C)C)ccc(Br)c1F)O[Si](C)(C)C
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2c(OCCO)ccc(Br)c2F)N1
Temperature: 140 °C
Reaction time: 0.75 h
Yield: 65.6 %

Procedure:
To a solution of 1-{3-bromo-2-fluoro-6-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-phenyl}-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 183c in toluene (30 mL) was added E/Z-6-chloro-3-(3-chlorobenzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 24a (0.5 g, 1.28 mmol). The reaction mixture was stirred under nitrogen in a sealed tube at 140° C. for 45 min. After the solution was cooled to room temperature, methanol (10 mL) was added. The reaction mixture was filtered through a short pad of celite gel and washed with ethyl acetate. The filtrate was concentrated. The residue was dissolved in dichloromethane (20 mL) and trifluoroactic acid (15 mL) was added. After the reaction mixture was stirred at room temperature for 1 h, the mixture was concentrated. The residue was partitioned between saturated NaHCO3 solution and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over Na2SO4 and concentrated. The residue was dissolved in tetrahydrofuran (10 mL) and tetrabutylammonium fluoride solution (1M in THF, 10 mL) was added. The reaction mixture was stirred at room temperature for 10 min, then poured into water and extracted with ethyl acetate. The combined organic layer was dried over MgSO4 and concentrated. The residue was purified by chromatography to give racemic (2′R,3R,4′S)-2′-[3-bromo-2-fluoro-6-(2-hydroxy-ethoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a yellow solid (Yield 0.4 g, 65.6%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:18]=[CH:17][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15]Cl)=[CH:5][CH:4]=1.C[O:22][C:23](=[O:36])[CH2:24][O:25][C:26]1[CH:34]=[CH:33][C:32]([SH:35])=[C:31]2[C:27]=1[CH2:28][CH2:29][CH2:30]2>>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:18]=[CH:17][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][S:35][C:32]2[CH:33]=[CH:34][C:26]([O:25][CH2:24][C:23]([OH:36])=[O:22])=[C:27]3[C:31]=2[CH2:30][CH2:29][CH2:28]3)=[CH:5][CH:4]=1
Reactant: COC(=O)COc1ccc(S)c2c1CCC2
Reactant: FC(F)(F)c1ccc(COc2ccccc2CCl)cc1
Product: O=C(O)COc1ccc(SCc2ccccc2OCc2ccc(C(F)(F)F)cc2)c2c1CCC2

Procedure:
The title compound was prepared in the manner analogous to Example 1F using 81B and 12C. MS m/z 503 (M+1).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:11]([NH2:13])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CCN(CC)CC.C1C=CC2N(O)N=NC=2C=1.O.[C:32](O)(=[O:36])[C:33]([CH3:35])=[O:34].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[O:34]=[C:33]([CH3:35])[C:32]([NH:13][C:11](=[O:12])[C@H:3]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[NH2:2])=[O:36]
Reactant: CC(=O)C(=O)O
Reactant: NC(=O)[C@@H](N)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)C(=O)NC(=O)[C@@H](N)Cc1ccccc1
Yield: 65.1 %

Procedure:
A suspension of HCl.H-Phe-NH2 (1.0 g, 4.98 mmol) in DCM (49 mL) was neutralized with Et3N (0.69 mL, 4.98 mmol) at 4° C. To this mixture were added HOBt.H2O (0.76 g, 4.98 mmol), pyruvic acid (0.52 mL, 7.47 mmol), and EDC.HCl (1.05 g, 5.47 mmol), and the mixture was stirred at 4° C. for 30 min and at room temperature for 2 h. After removal of the solvent in vacuo, the residue was dissolved in AcOEt, successively washed with 10% citric acid, 5% NaHCO3 and saturated NaCl for three times, dried over Na2SO4, and concentrated in vacuo to obtain 0.76 g (65%) of the title compound as a white solid: mp 138-140° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.34 (d, J=8.6 Hz, 1H), 7.52 (s, 1H), 7.24-7.19 (m, 6H), 4.45-4.37 (m, 1H), 3.11 (dd, J=4.2, 13.8 Hz, 1H), 2.96 (dd, J=9.5, 13.8 Hz, 1H), 2.26 (s, 3H); HRMS (EI): m/z 234.1008 (M+) (calcd for C12H14N2O3: 234.1004).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][I:5].I.CN(CCI)P(Cl)(Cl)=O.[CH3:16][C:17]1([CH3:32])[O:21][CH:20]([CH2:22][CH2:23][P:24]([Cl:31])(N(C)CCBr)=[O:25])[CH2:19][O:18]1>>[CH3:16][C:17]1([CH3:32])[O:21][CH:20]([CH2:22][CH2:23][P:24]([Cl:31])([N:2]([CH3:1])[CH2:3][CH2:4][I:5])=[O:25])[CH2:19][O:18]1
Reactant: CN(CCBr)P(=O)(Cl)CCC1COC(C)(C)O1
Reactant: CNCCI
Agent: CN(CCI)P(=O)(Cl)Cl
Agent: I
Product: CN(CCI)P(=O)(Cl)CCC1COC(C)(C)O1
Yield: 61 %

Procedure:
This compound was prepared using N-methyl-N-2-iodoethylamine.HI via N-methyl-N-(2-iodoethyl)phosphoramidic dichloride, as described for 16a (10 mmol scale). The crude product was purified by chromatography (1:4 EtOAc:hexanes) which afforded 16c as a pale yellow oil (2.50 g, 61%): Rf 0.67 (1:1 EtOAc:hexanes); 1H NMR (CDCl3) 4.27(m, 3H), 4.10(t, 1H, J=6.52 Hz), 3.59(t, 1H, J=7.38 Hz), 3.44(m, 2H), 3.26(t, 2H, J=7.56 Hz), 2.78(d, 3H, J=12.89 Hz), 2.00(dt, 2H, J=6.02 Hz), 1.38(d, 6H, J=15.48 Hz)ppm; 31P NMR (CDCl3) -8.46, -8.69 ppm (1:1 ratio of diastereomers).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH:9]([OH:39])[CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17](=[O:38])[NH:18][CH:19]([CH2:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:12]1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:32]1([CH2:31][CH2:30][CH2:29][CH:19]([NH:18][C:17]([CH:13]2[CH2:14][CH2:15][CH2:16][N:11]([CH2:10][CH:9]([OH:39])[CH:8]([NH2:7])[CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:12]2)=[O:38])[CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(O)CN1CCCC(C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(Cc1ccccc1)C(O)CN1CCCC(C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.3 %

Procedure:
(1-Benzyl-2-hydroxy-3-{3-[4-phenyl-1-(3-phenyl-propyl)-butylcarbamoyl]-piperidine-1-yl}-propyl)-carbamic acid tert-butyl ester (19) (194.4 mg; 0.3 mmol) is dissolved in methylene chloride (5 mL) at ambient temperature. Trifluoroacetic acid (5 mL) is added in a slow stream, and the solution is stirred for 90 minutes at ambient temperature. The solution is concentrated in vacuo at 40° C. The residue is slurried in a mixture of methylene chloride (10 mL) and water (100 mL), then potassium carbonate is added until the slurry is alkaline. The slurry is diluted with water (50 mL) then extracted with methylene chloride (3×50 mL). The organic extracts are dried over MgSO4, filtered, and concentrated in vacuo affording the desired product (150 mg) as an oil.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[NH2:8].[CH2:22]1C[O:25][CH2:24][CH2:23]1.C(O)C#C>CCOC(C)=O.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.[Cu]I>[NH2:8][C:7]1[C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])=[CH:3][C:2]=1[C:22]#[C:23][CH2:24][OH:25]
Reactant: Nc1c(I)cc(-c2ccccc2C(F)(F)F)cc1[N+](=O)[O-]
Reactant: C1CCOC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#CCO
Solvent: CCOC(C)=O
Product: Nc1c(C#CCO)cc(-c2ccccc2C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
3-Iodo-5-nitro-2′-trifluoromethyl-biphenyl-4-ylamine (466 mg, 1.14 mmol, as prepared in Example 9, step A), (Ph3P)2PdCl2 (0.05 eq., 40.1 mg, 0.057 mmol), and CuI (0.05 eq., 10.2 mg, 0.054 mmol) were placed in a 40 mL vial equipped with a magnetic stir bar. The vial was evacuated and backflushed with Ar, and anhydrous THF (6 mL) and TEA (4.0 eq., 0.64 mL, 4.56 mmol) were added via syringe. Propargyl alcohol (4 eq., 0.270 mL, 4.56 mmol) was added via syringe, and the reaction was stirred at RT for 16 h. The solution was diluted with EtOAc (20 mL) and filtered. The solvent was removed under reduced pressure, and the crude product was purified by column chromatography on a 24-g SiO2 pre-packed column eluting with EtOAc/hexanes, 0:1 to 3:2, v/v over 20 min, yielding 279 mg (73%) of the title compound. 1H-NMR (400 MHz, CDCl3) δ: 8.10 (d, J=2.0 Hz, 1H), 7.73 (d, J=7.6 Hz, 1H), 7.53-7.59 (m, 1H), 7.53 (d, J=1.8 Hz, 1H), 7.43-7.51 (m, 1H), 7.29 (d, J=7.6 Hz, 1H), 6.82 (br. s., 2H), 4.59 (s, 2H).
Reaction SMILES: [OH:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[CH2:4][C:3]1=[O:14].[C:15]([O:18][C:19](=O)[CH3:20])(=O)[CH3:16]>CCOC(OCC)(OCC)C1C=CC=CC=1>[C:3]([O:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[C:4](=[C:15]([O:18][CH2:19][CH3:20])[C:16]2[CH:9]=[CH:10][CH:5]=[CH:6][CH:7]=2)[C:3]1=[O:14])(=[O:14])[CH3:4]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1Cc2ccc([N+](=O)[O-])cc2N1O
Agent: CCOC(OCC)(OCC)c1ccccc1
Product: CCOC(=C1C(=O)N(OC(C)=O)c2cc([N+](=O)[O-])ccc21)c1ccccc1

Procedure:
300 mg of 1-hydroxy-6-nitro-2-indolinone are dissolved in 4.0 ml of acetic anhydride and 4.0 ml of triethyl orthobenzoate, stirred for 6 hours at 110° C., concentrated by evaporation and purified through a silica gel column with methylene chloride as eluant.
Reaction SMILES: Br.Br[C:3]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[N:6][NH:5][C:4]=1[NH2:14].[C:15]([N:23]=[C:24]=[S:25])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1C=CC=CC=1.O1CCOCC1>O.CS(C)=O>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:7]1[C:3]2[S:25][C:24]([NH:23][C:15](=[O:22])[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:14][C:4]=2[NH:5][N:6]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Nc1[nH]nc(-c2ccccn2)c1Br
Agent: Br
Solvent: c1ccncc1
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: O=C(Nc1nc2[nH]nc(-c3ccccn3)c2s1)c1ccccc1
Temperature: 95 °C
Yield: 62.9 %

Procedure:
A mixture of 4-bromo-5-pyridin-2-yl-2H-pyrazol-3-ylamine hydrobromide salt (300 mg, 0.94 mmol), benzoyl isothiocyanate (0.15 mL, 1.12 mmol), pyridine (0.24 mL, 2.97 mmol), 1,4-dioxane (2 mL), and DMSO (2 mL) was heated at 95° C. overnight. The mixture was added to an excess of water, and the resulting precipitate was filtered, and recrystallized from EtOH to afford 190 mg (63%) of N-(3-pyridin-2-yl-1H-pyrazolo[3,4-d]thiazol-5-yl)-benzamide as an off-white solid. 1H NMR (d6-DMSO) δ: 8.85 (s, 1H), 8.02 (m, 4H), 7.51 (m, 3H), 7.21 (m, 1H); HPLC/MS m/z: 322 [MH]+.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[C:12]([CH3:23])=[N:11][C:10]=2[OH:24])[CH:5]=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+].O>CCO.CCOC(C)=O.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.C(COC)OC>[CH3:20][O:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:21][CH3:22])[C:12]([CH3:23])=[N:11][C:10]([OH:24])=[C:9]2[CH2:8][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([C:30]2[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)[N:7]=1
Reactant: COc1cc2c(C)nc(O)c(Cc3cccc(Br)n3)c2cc1OC
Reactant: COc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2cccc(Cc3c(O)nc(C)c4cc(OC)c(OC)cc34)n2)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of 4-((6-bromopyridin-2-yl)methyl)-6,7-dimethoxy-1-methylisoquinolin-3-ol CCH 34150 (59 mg, 152 μmol) in EtOH (0.9 mL) in a 20 mL microwave vial equipped with a magnetic stirrer were added 4-methoxyphenylboronic acid (23 mg, 151 μmol), Pd(PPh3)2Cl2 (10 mg, 14 μmol), a 2 N aq. Na2CO3 solution (0.30 mL, 0.60 mmol), H2O (2.7 mL) and dimethoxyethane (3.5 mL) and the resulting mixture was stirred at 140° C. for 25 min. After cooling to RT, the mixture was diluted with EtOAc (30 mL) and the solution was filtered through a celite plug, then washed with brine (10 mL). The organic phase was isolated and the celite plug was then further washed with CH2Cl2 (50 mL) and the resulting organic layer was washed with brine (20 mL). The organic layers were then combined, dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 94:6) provided 39 mg of 6,7-dimethoxy-4-((6-(4-methoxyphenyl)pyridin-2-yl)methyl)-1-methylisoquinolin-3-ol. This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (1.0 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afford 6,7-dimethoxy-4-((6-(4-methoxyphenyl)pyridin-2-yl)methyl)-1-methylisoquinolin-3-ol dihydrochloride 13 as a brown solid (45 mg, 61% yield).
Reaction SMILES: [C:1]([C:3]1[N:7]([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)[CH:6]=[N:5][C:4]=1[C:17]([NH2:19])=[O:18])#[CH:2].[OH-].[Na+]>Cl>[C:1]([C:3]1[NH:7][CH:6]=[N:5][C:4]=1[C:17]([NH2:19])=[O:18])#[CH:2]
Reactant: C#Cc1c(C(N)=O)ncn1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C#Cc1[nH]cnc1C(N)=O
Temperature: 100 °C
Yield: 37.6 %

Procedure:
A solution of 200 mg (0.75 mmol) of 5-ethynyl-1-β-D-ribofuranosylimidazole-4-carboxamide in 5 ml of 1N hydrochloric acid solution was heated under reflux at 100° C. for 4 hours. After the reaction, the reaction solution was neutralized with 1N sodium hydroxide solution, silica gel powder was added, and the solvent was evaporated. The residue was adsorbed onto a silica gel column (2.7×11 cm), eluted with a 0-16% ethanolchloroform solvent mixture, and crystallized from an ethanol-hexane solvent mixture to obtain 38 mg of pale yellow crystals of 5-ethynylimidazole-4-carboxamide (yield: 37.6%).
Reaction SMILES: C[O:2][C:3](=[O:36])[C@@H:4]([NH:11][C:12](=[O:35])[CH:13]([C:24](=[O:34])[N:25]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:26])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[NH:23])[NH2:22])=[CH:17][CH:16]=1)[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.C(#N)C.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].ClCCl>>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[CH2:27]([N:25]([CH3:26])[C:24]([CH:13]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[NH:22])[NH2:23])=[CH:17][CH:16]=1)[C:12]([NH:11][C@@H:4]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[C:3]([OH:36])=[O:2])=[O:35])=[O:34])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)[C@@H](NC(=O)C(Cc1ccc(C(=N)N)cc1)C(=O)N(C)Cc1ccccc1)C1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC#N
Product: CN(Cc1ccccc1)C(=O)C(Cc1ccc(C(=N)N)cc1)C(=O)N[C@H](C(=O)O)C1CCCCC1
Temperature: 25 °C
Reaction time: 168 h

Procedure:
22.1 g (44.8 mmol) of the above [2-(R,S)-(Benzyl-methyl-carbamoyl)-3-(4-carbamimidoyl-phenyl)-propionylamino]-(S)-cyclohexyl-acetic acid methyl ester was suspended in water/concentrated hydrochloric acid (1/1, 40 ml) and acetonitrile (40 ml) was added to give a solution. The reaction mixture was stirred at room temperature for 7 days. The reaction mixture was concentrated in vacuo and the residue was purified on silica gel with dichloromethane/methanol/TFA as solvent to give the desired product.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:11](=[N:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:12])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[C:20](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:20][O:1][N:2]=[C:3]([C:11](=[N:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH3:12])[C:4]([O:6][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: CC(=Nc1ccccc1)C(=NO)C(=O)OC(C)(C)C
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: CON=C(C(=O)OC(C)(C)C)C(C)=Nc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.5 %

Procedure:
To a solution of tert-butyl 2-hydroxyimino-3-phenyliminobutyrate (1.0 g) in acetone (10 ml) was added potassium carbonate (0.63 g) and dimethyl sulfate (0.43 ml) under ice-cooling. The mixture was stirred at the same temperature for 30 minutes and stirred at ambient temperature for 4 hours. The resulting suspension was poured into ice-water and extracted with diisopropyl ether. The organic layer was washed with water, dried over magnesium sulfate, and evaporated in vacuo. The residual oil was subjected to column chromatography on silica gel give tert-butyl 2-methoxyimino-3-phenyliminobutyrate (0.68 g).