Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH3:13].[I-:14].[K+].[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22]>CC(=O)CC>[I-:14].[CH2:2]([N+:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: Cc1ccccn1
Reactant: CCCCC#CCCCCCCCl
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCC#CCCCCCC[n+]1ccccc1C
Yield: 85 %

Procedure:
12-Chloro-dodec-5-yne (1 mmol) was mixed with potassium iodide (3 mmol) and 2-picoline (3 mmol) in butanone. room temperature. The butanone was removed in a vacuum, and the resulting residue was partitioned between water and ethyl ether. The aqueous layer was washed extensively with ether until no 2-picoline was left in the aqueous layer. The resulting aqueous solution of the product was extracted with chloroform. The chloroform was removed to afford the product (85%). 1HNMR (300 MHz, CDCl3, ppm) 9.62 (d, 1H), 8.39 (dd, 1H), 7.99 (m, 1H), 7.91 (d, 1H), 4.88 (t, 2H), 2.97 (s, 3H), 2.12-2.20 m, 4H), 1.90-2.00 (m, 2H), 1.32-1.58 (m, 8H), 0.88 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:25]=[C:24]([O:26][C@H:27]3[C@H:31]4[O:32][CH2:33][C@@H:34]([OH:35])[C@H:30]4[O:29][CH2:28]3)[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=1.[N:44]1([S:48]([CH3:58])(=[O:57])=[N:49][C:50]2[CH:55]=[CH:54][C:53](Br)=[CH:52][CH:51]=2)[CH2:47][CH2:46][CH2:45]1>>[N:44]1([S:48](=[N:49][C:50]2[CH:55]=[CH:54][C:53]([C:11]3[CH:12]=[CH:13][C:8]([C:7]4[N:6]=[C:5]5[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:42])([CH3:41])[CH3:43])[C:24]([O:26][C@H:27]6[C@H:31]7[O:32][CH2:33][C@@H:34]([OH:35])[C@H:30]7[O:29][CH2:28]6)=[N:25][C:4]5=[CH:3][C:2]=4[Cl:1])=[CH:9][CH:10]=3)=[CH:52][CH:51]=2)([CH3:58])=[O:57])[CH2:45][CH2:46][CH2:47]1
Reactant: CS(=O)(=Nc1ccc(Br)cc1)N1CCC1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)OC1(C)C
Product: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2cc(Cl)c(-c3ccc(-c4ccc(N=S(C)(=O)N5CCC5)cc4)cc3)nc21

Procedure:
The title compound is prepared from (3R,3aR,6R,6aR)-6-(6-chloro-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridin-2-yloxy)hexahydrofuro[3,2-b]furan-3-ol and N-[azetidin-1-yl(methyl)oxo-λ6-sulfanylidene]-4-bromoaniline following a procedure analogous to that described for Intermediate 3 (Step 3). LC (method 1): tR=1.12 min; Mass spectrum (ESI+): m/z=712 [M+H]+.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]([S:14]([N:17]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH2:18][C:19]([OH:21])=[O:20])(=[O:16])=[O:15])=[CH:11][CH:12]=2)[C:7]([NH:29][C:30]([NH2:32])=[NH:31])=[N:6][CH:5]=1.[H-].[Na+].[C:35](OC(=O)CN(S(C1C=C2C(C(Cl)=CN=C2Cl)=CC=1)(=O)=O)CC1C=CC=CN=1)([CH3:38])([CH3:37])[CH3:36]>COCCOC>[C:35]([O:20][C:19](=[O:21])[CH2:18][N:17]([S:14]([C:10]1[CH:9]=[C:8]2[C:13]([C:4]([Cl:3])=[CH:5][N:6]=[C:7]2[NH:29][C:30]([NH2:32])=[NH:31])=[CH:12][CH:11]=1)(=[O:15])=[O:16])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)([CH3:38])([CH3:37])[CH3:36]
Reactant: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)N(CC(=O)O)Cc3ccccn3)cc12
Reactant: CC(C)(C)OC(=O)CN(Cc1ccccn1)S(=O)(=O)c1ccc2c(Cl)cnc(Cl)c2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)CN(Cc1ccccn1)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Temperature: 60 °C

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-(2-pyridylmethyl)glycine dihydrochloride ##STR25## Guanidine hydrochloride (293 mg, 3.07 mmol was added in one portion to a stirred suspension of NaH (57 mg, 80% dispersion by wt in mineral oil, 1.92 mmol) in DME (10 mL) and the mixture was heated at 60° C. under N2 for 30 min. A solution of N-[(1,4-dichloro-7-isoquinolinyl)sulphonyl]-N-(2-pyridylmethyl)glycine t-butyl ester (370 mg, 0.78 mmol) in DME (10 mL) was added and the mixture heated at 90° C. for 1 h. The solvents were evaporated in vacuo, the residue was dissolved with EtOAc (200 mL), and washed with aqueous NH4Cl (150 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by column chromatography upon silica gel using pentane-EtOAc (100:0 to 20:80) as eluant to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-(2-pyridylmethyl)glycine t-butyl ester (120 mg, 0.24 mmol) as a pale yellow foam.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8]O)[CH:5]=[N:4][CH:3]=[N:2]1.S(Cl)([Cl:12])=O>>[Cl:12][CH2:8][CH2:7][CH2:6][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=S(Cl)Cl
Reactant: OCCCn1cncn1
Product: ClCCCn1cncn1

Procedure:
3-(1H-1,2,4-triazol-1-yl)-1-propanol (0.160 g, 1.3 mmol) was refluxed in thionylchloride (3 ml) for 2 h. The recation mixture was evaporated yielding the title product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]([NH:16][C@H:17]([C:22]([O:24]C)=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])[CH:8]=[CH:7]2)([O-])=O.[C:26]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[C:26]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:31]=[CH:30][C:29]([S:32]([NH:1][C:4]2[CH:12]=[C:11]3[C:10](=[CH:6][CH:5]=2)[N:9]([CH2:13][C:14]([NH:16][C@H:17]([C:22]([OH:24])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])[CH:8]=[CH:7]3)(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)Cn1ccc2cc([N+](=O)[O-])ccc21
Product: CC(C)C[C@H](NC(=O)Cn1ccc2cc(NS(=O)(=O)c3ccc(-c4ccccc4)cc3)ccc21)C(=O)O

Procedure:
The title compound was prepared from methyl N-[(5-nitro-1H-indol-1-yl)acetyl]-L-leucinate and biphenyl-4-sulfonyl chloride following the procedures of Example 10 Step 4 and Step 5: MS (ESI) m/z 520; MS (ESI) m/z 518.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([NH:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[CH3:14])=[O:4].S(Cl)([Cl:20])(=O)=O.O>C(Cl)(Cl)Cl>[Cl:20][C:9]1[C:10]([O:12][CH3:13])=[CH:11][C:6]([NH:5][C:3](=[O:4])[C:2]([F:15])([F:16])[F:1])=[C:7]([CH3:14])[CH:8]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1ccc(C)c(NC(=O)C(F)(F)F)c1
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cc(NC(=O)C(F)(F)F)c(C)cc1Cl
Reaction time: 8 h

Procedure:
To a solution of 2,2,2-Trifluoro-N-(5-methoxy-2-methylphenyl)acetamide (8.16 g) in chloroform (35 mL) was added sulfuryl chloride (3.12 mL) under ice-cooling, and the mixture was stirred overnight. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. To the residue was added hexane, and the mixture was stirred at room temperature for 1 hour. The precipitate was collected by filtration, washed with hexane, and then dried under reduced pressure to obtain the title compound (7.02 g). 1H-NMR (CDCl3) δ ppm: 2.23 (3H, s), 3.90 (3H, s), 7.24 (1H, s), 7.59 (1H, s), 7.60-7.82 (1H, br).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].C[O:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15]C)[C:8]=1[CH:9]=[O:10]>ClCCl>[OH:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[C:8]=1[CH:9]=[O:10]
Reactant: COc1cccc(OC)c1C=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=Cc1c(O)cccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.1 %

Procedure:
Into a 3000-mL three neck round-bottom flask, was placed a solution of AlCl3 (240 g, 1.80 mol, 3.00 equiv) in dichloromethane (1200 mL). A solution of 2,6-dimethoxybenzaldehyde (100 g, 601.78 mmol, 1.00 eq) in dichloromethane (800 ml) was added to the reaction mixture dropwise at 0° C. The resulting solution was stirred overnight at room temperature, and then it was quenched with 200 mL of diluted HCl (2M). The resulting solution was extracted with 2×200 mL of dichloromethane. The combined organic layers were concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:200-1:50) as eluent to furnish 40 g (48%) of 2,6-dihydroxybenzaldehyde as a yellow solid. 1HNMR (300 MHz, DMSO-d6) δ 11.25 (s, 2H), 10.25 (s, 1H), 7.36 (m, 1H), 6.36 (d, J=8.4 Hz 2H); MS (ESI) m/z 139 [M+H]+.
Reaction SMILES: Cl[CH:2]([NH:8][C:9](=[O:11])[CH3:10])[C:3]([Cl:7])([Cl:6])[CH2:4][Cl:5].[NH:12]1[CH:16]=[N:15][CH:14]=[N:13]1.C(N(CC)CC)C.O>O1CCCC1>[NH:8]([CH:2]([N:12]1[CH:16]=[N:15][CH:14]=[N:13]1)[C:3]([Cl:7])([Cl:6])[CH2:4][Cl:5])[C:9]([CH3:10])=[O:11]
Reactant: CC(=O)NC(Cl)C(Cl)(Cl)CCl
Reactant: c1nc[nH]n1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NC(n1cncn1)C(Cl)(Cl)CCl
Yield: 66 %

Procedure:
3.6 gm of N-(1,2,2,3-tetrachloro-n-propyl)-acetamide were dissolved in 30 ml of tetrahydrofuran, and, while stirring, the resulting solution was added dropwise to a solution of 1.05 gm of 1,2,4-triazole and 1.8 gm of triethylamine in 20 ml of tetrahydrofuran. Subsequently, the reaction mixture was stirred for 2 hours at room temperature, then water was added, and the tetrahydrofuran was distilled off in vacuo. The oil thus obtained as a residue crystallized after some time and was recrystallized from methanol/water, yielding 2.7 gm of the compound of the formula ##STR5## having a melting point of 135° C.
Reaction SMILES: C1C2C(COC(=O)[NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:25][C@@H:26]([CH2:30][S:31][C:32]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]([NH2:29])=[O:28])=[O:24])C3C(=CC=CC=3)C=2C=CC=1.CCN(C(C)C)C(C)C>CN(C)C=O>[NH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:25][C@@H:26]([CH2:30][S:31][C:32]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:27]([NH2:29])=[O:28])=[O:24]
Reactant: NC(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)CCCCCNC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NCCCCCC(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(N)=O

Procedure:
678 mg (0.97 mmol) of the compound of example 20A was dissolved in 7 ml dimethyl formamide and 0.19 ml (1.94 mmol) DIEA was added. After one hour reaction time, the raw product was purified by preparative RP-HPLC on a C18 column with a water methanol gradient from 9/1 to 1/9. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 457 mg (0.93 mmol, 95% of theory) of the desired product.
Reaction SMILES: CCCCCC.[H-].[Na+].[CH3:9][O:10][C:11]([CH2:13]P(OC)(OC)=O)=[O:12].[Cl:20][C:21]1[CH:31]=[C:30]([CH2:32][CH2:33][CH3:34])[CH:29]=[C:28]([CH:35]=O)[C:22]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C1COCC1>[Cl:20][C:21]1[CH:31]=[C:30]([CH2:32][CH2:33][CH3:34])[CH:29]=[C:28](/[CH:35]=[CH:13]/[C:11]([O:10][CH3:9])=[O:12])[C:22]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCCc1cc(Cl)c(C(=O)OCC)c(C=O)c1
Reactant: COC(=O)CP(=O)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCc1cc(Cl)c(C(=O)OCC)c(/C=C/C(=O)OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
To a suspension of hexane-washed sodium hydride (0.14 g of 60% suspension in mineral oil, 3.45 mmol) in 20 mL of THF was added trimethyl phosphonoacetate (0.56 mL, 3.45 mmol). The resulting mixture was stirred for 30 min at ambient temperature, at which time a white slurry was obtained. To this slurry was added ethyl 2-chloro-6-formyl-4-propylbenzoate (0.80 g, 3.14 mmol) dropwise in 5 mL of THF. The resulting solution was stirred at ambient temperature for 1 h, at which time the mixture had become homogeneous. The reaction mixture was quenched with water and extracted with ethyl acetate. The organics were washed sequentially with 1N HCl, sat'd aq NaHCO3 and brine, dried (MgSO4), filtered through a pad of silica gel and concentrated in vacuo to afford 0.92 g (95%) of the title compound which was sufficiently pure to be used without purification. 1H NMR (CDCl3): δ 7.58 (d, 1H, J=15.9 Hz), 7.25 (s, 1H), 7.18 (s, 1H), 6.33 (d, 1H, J=15.9 Hz), 4.40 (q, 2H, J=7.2 Hz), 3.73 (s, 3H), 2.52 (t, 2H, J=7.5 Hz), 1.60-1.52 (m, 2H), 1.35 (t, 3H, J=7.1 Hz), 0.88 (t, 3H, J=7.4 Hz). LRMS (ESI): 333.1 (M+H+Na)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[C:15]2[O:14][CH2:13][CH2:12][C:11]=2[C:10]([OH:16])=[CH:9][CH:8]=1)[CH3:2].Cl[CH2:22][C:23]1[N:24]=[C:25]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH3:36])=[CH:31][CH:30]=2)[O:26][C:27]=1[CH3:28].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[C:15]2[O:14][CH2:13][CH2:12][C:11]=2[C:10]([O:16][CH2:22][C:23]2[N:24]=[C:25]([C:29]3[CH:30]=[CH:31][C:32]([CH2:35][CH3:36])=[CH:33][CH:34]=3)[O:26][C:27]=2[CH3:28])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(-c2nc(CCl)c(C)o2)cc1
Reactant: CCOC(=O)C(Cc1ccc(O)c2c1OCC2)OCC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCOC(=O)C(Cc1ccc(OCc2nc(-c3ccc(CC)cc3)oc2C)c2c1OCC2)OCC

Procedure:
In analogy to the procedure described in example 120 f], [rac]-2-ethoxy-3-(4-hydroxy-2,3-dihydro-benzofuran-7-yl)-propionic acid ethyl ester (example 125 a]) was reacted with 4-chloromethyl-2-(4-ethyl-phenyl)-5-methyl-oxazole (example 122 a]) in the presence of potassium carbonate and potassium iodide to yield [rac]-2-ethoxy-3-{4-[2-(4-ethyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2,3-dihydro-benzofuran-7-yl}-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 120 f] to yield [rac]-2-ethoxy-3-{4-[2-(4-ethyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2,3-dihydro-benzofuran-7-yl}-propionic acid as white solid.
Reaction SMILES: N#N.[CH3:3][O:4][C:5]([C:7]1[N:8]=[CH:9][O:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([O:20]C(C)(C)C)=[O:19])[CH:13]=1)=[O:6]>C(O)(C(F)(F)F)=O>[CH3:3][O:4][C:5]([C:7]1[N:8]=[CH:9][O:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([OH:20])=[O:19])[CH:13]=1)=[O:6]
Reactant: COC(=O)c1ncoc1-c1cccc(C(=O)OC(C)(C)C)c1
Agent: N#N
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ncoc1-c1cccc(C(=O)O)c1

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-(3-tert-butoxycarbonyl-phenyl)-oxazole-4-carboxylic acid methyl ester (1.00 g, 3.30 mmol) in TFA (13.3 mL) was stirred at rt for 45 min. The TFA was removed under reduced pressure and the residue was triturate in Et2O, filtered and washed with Et2O to give the title compound as a white powder. LC-MS-conditions 02: tR=0.79 min, [M+H]+=248.20.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:28][N:29]1[C:33]([C:34]([OH:36])=O)=[CH:32][C:31]([CH3:37])=[N:30]1.C(N(C(C)C)CC)(C)C.[CH3:47][O:48][C:49]1[CH:50]=[C:51]([NH:59][C:60]2[N:61]=[CH:62][C:63]3[CH2:69][NH:68][CH2:67][CH2:66][C:64]=3[N:65]=2)[CH:52]=[C:53]([O:57][CH3:58])[C:54]=1[O:55][CH3:56]>CN(C=O)C.CCOC(C)=O>[CH3:28][N:29]1[C:33]([C:34]([N:68]2[CH2:67][CH2:66][C:64]3[N:65]=[C:60]([NH:59][C:51]4[CH:50]=[C:49]([O:48][CH3:47])[C:54]([O:55][CH3:56])=[C:53]([O:57][CH3:58])[CH:52]=4)[N:61]=[CH:62][C:63]=3[CH2:69]2)=[O:36])=[CH:32][C:31]([CH3:37])=[N:30]1
Reactant: Cc1cc(C(=O)O)n(C)n1
Reactant: COc1cc(Nc2ncc3c(n2)CCNC3)cc(OC)c1OC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(Nc2ncc3c(n2)CCN(C(=O)c2cc(C)nn2C)C3)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
A solution of (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (0.035 g, 0.079 mmol) in anhydrous DMF (2 mL) was treated sequentially with 1,3-dimethyl-1H-pyrazole-5-carboxylic acid (0.014 g, 0.103 mmol) and diisopropylethylamine (0.035 mL, 0.159 mmol). The reaction mixture was allowed to stir for 30 minutes at room temperature. After 30 minutes, N-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine, Intermediate 1 (0.025 g, 0.079 mmol) was added to the reaction mixture. The reaction was allowed to stir for 3 hours at room temperature. The reaction mixture was then diluted with EtOAc and washed three times with brine. The combined aqueous layers were then washed twice with EtOAc. The organic layers were combined, dried over anhydrous Na2SO4(s), filtered and concentrated in vacuo. The crude product was then purified over silica using a MeOH/CHCl3 gradient affording the final product in 52% yield (0.018 g, 0.041 mmol).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[S:27]([NH:30][C@H:31]([C:33]([O:35]C(C)(C)C)=[O:34])[CH3:32])(=[O:29])=[O:28])=[CH:17][C:16]=2[F:40])=[CH:11][N:10]=1>C(Cl)Cl>[NH2:8][C:9]1[N:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[S:27]([NH:30][C@H:31]([C:33]([OH:35])=[O:34])[CH3:32])(=[O:29])=[O:28])=[CH:17][C:16]=2[F:40])=[CH:13][N:14]=1
Reactant: C[C@H](NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)nc2)c(F)c1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)nc2)c(F)c1)C(=O)O
Reaction time: 2 h
Yield: 98.9 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a solution of tert-butyl N-{[4′-(2-aminopyrimidin-5-yl)-3′-fluorobiphenyl-2-yl]sulfonyl}-L-alaninate (80 mg, 0.17 mmol) in DCM (1 mL) at rt. After 2 hours, the solution was concentrated to dryness and purified by HPLC to afford the title compound (70 mg, 89%). MS (ESI): mass calcd. for C19H17FN4O4S, 416.10; m/z found, 417.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.72 (s, 2H), 8.10 (dd, J=8.0, 1.2, 1H), 7.66 (m, 1H), 7.61-7.53 (m, 2H), 7.37 (m, 3H), 3.73 (q, J=7.2, 1H), 1.31 (d, J=7.2, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[N:24][C:25]=1[O:26][CH3:27]>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:22]3[CH:23]=[N:24][C:25]([O:26][CH3:27])=[C:20]([F:19])[CH:21]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: COc1ncc(B(O)O)cc1F
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3cnc(OC)c(F)c3)cccc2c1N
Yield: 48.3 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (126 mg, 0.408 mmol) and (5-fluoro-6-methoxypyridin-3-yl)boronic acid (138 mg, 0.81 mmol) were reacted to afford the title compound (70 mg, 48% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.22 (t, J=6.0 Hz, 1H), 8.45 (d, J=7.6 Hz, 1H), 8.29 (d, J=1.9 Hz, 1H), 8.13 (dd, J=11.9, 1.9 Hz, 1H), 7.95 (apparent d, J=7.0 Hz, 1H), 7.80 (apparent t, J=8.0 Hz, 1H), 4.03 (s, 3H), 3.31 (apparent q, J=7.0 Hz, 2H), 1.60 (apparent sextet, J=7.0 Hz, 2H), 0.91 (t, J=7.0 Hz, 3H). MS APCI, m/z=356 (M+H) HPLC 1.99 min.
Reaction SMILES: [OH-].[Na+].[CH2:3]1[C:8]2[NH:9][C:10]3[C:15]([C:16](=[O:17])[C:7]=2[CH2:6][C:5]2[NH:18][C:19]4[C:24]([C:25](=[O:26])[C:4]1=2)=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=[CH:12][CH:11]=3.[N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O.[Na+]>CO>[CH:22]1[CH:23]=[C:24]2[C:25]([C:4]3[C:5]([NH:18][C:19]2=[CH:20][CH:21]=1)=[CH:6][C:7]1[C:16]([C:15]2[C:10]([NH:9][C:8]=1[CH:3]=3)=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:17])=[O:26]
Reactant: O=c1c2c([nH]c3ccccc13)Cc1c([nH]c3ccccc3c1=O)C2
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12

Procedure:
79 Parts of methanol and 12 parts of a 50% NaOH aqeuous solution were fully stirred in a flask of stainless steel. 10 Parts of the 6,13-dihydroquinacridone obtained in Example 9 and 10 parts of sodium m-nitrobenzenesulfonate were gradually added, and the mixture was refluxed at 70° to 75° C. for 3 to 5 hours. The mixture was cooled until it had a temperature of 40° C. or lower, and the mixture was filtered. The resultant cake was washed with hot water until the wash water was colorless and transparent, and dried, to give 9.78 parts (98.4% of the theoretical yield) of an unsubstituted quinacridone. The quinacridone was measured for a purity by IR and absorbance to show 99.2% of quinacridone and 0.8% of 6,13-dihydroquinacridone. The quinacridone had a specific surface area of 22.8 m2 /g.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1.Cl[C:15]1[N:20]=[C:19]([N:21]([CH3:23])[CH3:22])[CH:18]=[CH:17][N:16]=1.O>ClC(Cl)Cl>[CH3:22][N:21]([CH3:23])[C:19]1[CH:18]=[CH:17][N:16]=[C:15]([CH2:1][NH:2][CH:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]2)[N:20]=1
Reactant: CN(C)c1ccnc(Cl)n1
Reactant: CCOC(=O)N1CCC(NC)CC1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)N1CCC(NCc2nccc(N(C)C)n2)CC1
Temperature: 120 °C
Yield: 60.2 %

Procedure:
A mixture of ethyl 4-(methylamino)-1-piperidinecarboxylate (111.75 g) and 2-chloro-N,N-dimethyl-4-pyrimidinamine (47.3 g) is stirred and heated in an oil-bath for 22 hours at 120° C. The reaction mixture is cooled and the product is taken up in trichloromethane (500 ml). Water (300 ml) is added and the layers are separated. The organic phase is washed with water (200 ml), dried, filtered and evaporated. The residue solidifies on triturating in petroleumether. The product is filtered off and crystallized from diisopropyl ether (390 ml). After cooling to 0° C., the product is filtered off and dried, yielding 55.5 g (59.7%) of ethyl 4-[[4-dimethylamino-2-pyrimidinyl]methylamino]-1-piperidinecarboxylate (intermediate 1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][C:9]1[S:10][C:11](Br)=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].C(OC([N:23]1[C:27]2=[N:28][CH:29]=[CH:30][CH:31]=[C:26]2[C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24]1)=O)(C)(C)C.ClCCl.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][C:9]1[S:10][C:11]([C:25]2[C:26]3[C:27](=[N:28][CH:29]=[CH:30][CH:31]=3)[NH:23][CH:24]=2)=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)c2cccnc21
Reactant: CC(C)(C)OC(=O)NCc1ccc(Br)s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCc1ccc(-c2c[nH]c3ncccc23)s1
Temperature: 110 °C

Procedure:
Into a vial was dissolved (5-bromo-thiophen-2-ylmethyl)-carbamic acid tert-butyl ester (115 mg, 0.000394 mol; Maybridge), 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (119 mg, 0.000346 mol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (28 mg, 0.000034 mol; Strem) in 1,4-dioxane (6.0 mL, 0.077 mol; Acros). To this was added 2.0 M of sodium carbonate in water (1.5 mL). The reaction was purged with Ar and sealed. The reaction was heated at 110° C. under an atmosphere of Argon for 2 hours. The reaction was diluted with methylene chloride and washed with water. The organic layer was dried with magnesium sulfate, filtered and evaporated. The residue was taken up in DMSO and purified by preparative HPLC to yield the title compound in 33.4 mg yield (22%) as the TFA salt. MS m/z=330.15 (M+1). 1H NMR (400 MHz, CDCl3)™ ppm 13.919 (s, 1H) 8.703 (dd, J=7.9, 1.1 Hz, 1H) 8.246 (dd, J=5.7, 1.0 Hz, 1H) 7.676 (d, J=1.7 Hz, 1H) 7.464 (dd, J=7.9, 5.8 Hz, 1H) 7.111 (d, J=3.6 Hz, 1H) 6.985 (d, J=3.6 Hz, 1H) 4.981 (s (br), 1H) 4.508 (d, J=5.7 Hz, 2H) 1.485 (s, 9H).