Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][C@@H:6]([NH:8][C:9]([C:11]2[S:12][C:13]([Cl:16])=[CH:14][CH:15]=2)=[O:10])[CH2:5][N:4]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[C:24](Cl)(=[O:26])[CH3:25].CCN(C(C)C)C(C)C.Cl>C(Cl)Cl>[C:24]([NH:1][CH2:2][C@@H:3]1[CH2:7][C@@H:6]([NH:8][C:9]([C:11]2[S:12][C:13]([Cl:16])=[CH:14][CH:15]=2)=[O:10])[CH2:5][N:4]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])(=[O:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1C[C@H](NC(=O)c2ccc(Cl)s2)C[C@H]1CN
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NC[C@@H]1C[C@@H](NC(=O)c2ccc(Cl)s2)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
70.0 mg (0.2 mmol) tert. Butyl (2S,4R)-2-aminomethyl-4-[(5-chloro-thiophene-2-carbonyl)-amino]-pyrrolidine-1-carboxylate are dissolved in 5 ml DCM and combined successively at −10° C. with 15.4 μl (0.2 mmol) acetyl chloride and 67 μl (0.4 mmol) DIPEA. The mixture is stirred for two hours at 0° C. Then it is made weakly acidic by the careful addition of dil. hydrochloric acid and extracted three times with ethyl acetate. The combined organic phases are dried on sodium sulphate, filtered and evaporated down i. vac.
Reaction SMILES: COC1[CH:16]=[CH:15][C:14]2[C:5](=[C:6]3[C:11](=[CH:12][N:13]=2)[CH2:10][CH2:9][CH2:8][CH2:7]3)C=1.C([S-])C.[Na+].[C:21]([O:24][C:25](=[O:27])[CH3:26])(=O)[CH3:22].P([O-])([O-])([O-])=O>CN(C=O)C>[C:25]([O:24][C:21]1[CH:16]=[CH:15][C:14]2[C:5](=[C:6]3[C:11](=[CH:12][N:13]=2)[CH2:10][CH2:9][CH2:8][CH2:7]3)[CH:22]=1)(=[O:27])[CH3:26]
Reactant: COc1ccc2ncc3c(c2c1)CCCC3
Reactant: CC(=O)OC(C)=O
Agent: CC[S-]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc2ncc3c(c2c1)CCCC3
Temperature: 160 °C
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
A mixture of 2-methoxy-7,8,9,10-tetrahydrophenanthridine (Compound 273, 48.17 g, 226 mmol) and sodium ethanethiolate (43.69 g, 520 mmol) in dry DMF was heated at 160° C. for 4 hours. After the reaction mixture was cooled to zero degrees C., acetic anhydride (63.9 mL, 678 mmol) was added and the reaction mixture was stirred for 30 minutes. The resulting thick white slurry was poured into 0.1M pH 7.5 phosphate buffer (1.6 L) and extracted with ether (3×400 mL). The combined organic layers were washed with water (3×300 mL) and brine (300 mL), dried (MgSO4), filtered through a 3 cm×3 cm plug of silica, and evaporated in vacuo. The residue was purified by recrystallization from ethyl acetate-hexanes to give 45.70 g (86 percent) of Compound 274: white crystalline solid; mp 118°-119° C.; Rf =0.39 (silica, 50 percent ethyl acetate in dichloromethane); IR (CHCl3) νmax 3018, 2938, 2861, 1758, 1507, 1369, 1193, 1174 cm-1 ; 1H NMR (300 MHz, CDCl3), 8.60 (s, 1 H, H6), 8,06 (d, J=9.0 Hz, 1 H, H4), 7.61 (d, J=2.5 Hz, 1 H, H1), 7.36 (dd, J=9.0, 2.5 Hz, 1 H, H3), 3.03 (t, J=6.0 Hz, 2 H, H7 or H10), 2.89 (t, J=6.0 Hz, 2 H, H7 or H10), 2.37 (s, 3 H, OCOCH3), 1.98-1.86 (m, 4 H, H8 and H9); 13C NMR (125 Mz, CDCl3) δ 169.5, 152.3, 148.4, 144.3, 140.9, 131.3, 130.1, 128.0, 122.9, 113.8, 27.0, 24.8, 22.2, 22.1, 21.1; MS (FAB+) m/e (rel intensity) 242 (M+H, 100), 200 (25); HRMS for C15H16NO2 (M+H), calcd 242.1181, found 242,1181. Anal. Calcd for C15H15NO2 : C, 74.67; H, 6.27; N, 5.80. Found: C, 74.66; H, 6.37; N, 5.64.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[OH:28][CH2:29][CH2:30][N:31]([CH2:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1)[CH2:32][CH2:33][OH:34]>>[OH:28][CH2:29][CH2:30][N:31]([CH2:35][C:36]1[CH:37]=[CH:38][C:39]([NH:40]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:41][CH:42]=1)[CH2:32][CH2:33][OH:34]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: Nc1ccc(CN(CCO)CCO)cc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN(CCO)CCO)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-((di-(2-hydroxy-ethyl)-amino)-methyl)-aniline Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C28H29N3O5
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[C:7]([C:18]([O-])=[O:19])=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:9][C:10]=1[CH3:11])=[O:4].CN(C1C=CC=CN=1)C.[C:39]([O:43][C:44](=[O:47])[CH2:45][NH2:46])([CH3:42])([CH3:41])[CH3:40]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:6]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[C:7]([C:18]([NH:46][CH2:45][C:44]([O:43][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:47])=[O:19])=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:9][C:10]=1[CH3:11])=[O:4]
Reactant: COC(=O)C1=C(C)NC(c2ccccc2)=C(C(=O)[O-])C1c1cccc([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)CN
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: COC(=O)C1=C(C)NC(c2ccccc2)=C(C(=O)NCC(=O)OC(C)(C)C)C1c1cccc([N+](=O)[O-])c1
Reaction time: 1 h
Yield: 100.1 %

Procedure:
More specifically, a dried methylene chloride solution containing 394 mg (1 mmol) of 1,4-dihydro-5-methoxycarbonyl-6-methyl-4-(3-nitrophenyl)-2-phenylpyridine-3-carboxylate, 309 mg (1.5 mmol) of dicyctohexylcarbodiimide and 134 mg (1.1 mmol) of dimethylaminopyridine was stirred for one hour. To this reaction mixture, 157 mg (1.2 mmol) of glycine t-butyl ester was added and the reaction mixture was refluxed for 2 hours. Insoluble components were removed from the reaction mixture by filtration and the reaction mixture was chromatographed on a silica gel column for purification, whereby 508 mg (100%) of the captioned compound was obtained as an oily material.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=[C:4]([Cl:18])[CH:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[Cl:18][C:4]1[CH:3]=[C:2]([C:24]2[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCCNC2=O
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2cc(Cl)cc3c(C)c4n(c23)CCCNC4=O)cc1

Procedure:
The title compound, off-white solid (81 mg, 91%), MS (ISP) m/z=355.4 [(M+H)+], mp 240.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-9-chloro-11-methyl-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (intermediate 13) (81.9 mg, 0.25 mmol) and commercially available 4-methoxy-phenylboronic acid (49.4 mg, 0.325 mmol).
Reaction SMILES: CO[C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH2:10])=[O:4].[NH2:11][C:12](N)=[O:13]>O>[NH:10]1[C:9]2[CH:8]=[CH:7][S:6][C:5]=2[C:3](=[O:4])[NH:11][C:12]1=[O:13]
Reactant: NC(N)=O
Reactant: COC(=O)c1sccc1N
Solvent: O
Product: O=c1[nH]c(=O)c2sccc2[nH]1
Temperature: 180 °C
Reaction time: 5 h
Yield: 94 %

Procedure:
A solid mixture of methyl-3-aminothiophene-2-carboxylate (76 g, 480 mmol) and urea (189 g, 3140 mmol) was heated, with stirring, to 180° C. for 5 h. The mixture was cooled to 90° C. and water (1000 ml) added. After stirring at room temperature for 16 h, a cream coloured solid was filtered and washed twice with further water. The solid was dried in vacuo at 40° C. to give the title compound in 94% yield, >95% purity. LC-MS m/z=169.0 [M+H]+; RT=1.29 min; LC-MS method 2. 1H NMR: δH (400 MHz, D6-DMSO) 6.90 (1H, d, J=5.5 Hz), 8.04 (1H, d, J=5.5 Hz), 11.10-11.80 (2H, b).
Reaction SMILES: CSC.S([O:9][CH3:10])(OC)(=O)=O.[C:11]1([S:17][C:18]2([C:21]([CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)=O)[CH2:20][CH2:19]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[K+]>C(O)(C)(C)C>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][CH2:23][C:21]2([C:18]3([S:17][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH2:20][CH2:19]3)[CH2:10][O:9]2)=[CH:26][CH:27]=1
Reactant: COS(=O)(=O)OC
Reactant: O=C(CCc1ccc(Cl)cc1)C1(Sc2ccccc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: CSC
Product: Clc1ccc(CCC2(C3(Sc4ccccc4)CC3)CO2)cc1
Reaction time: 14 h
Yield: 81.4 %

Procedure:
21 ml (0.29 mol) o& dimethyl sulphide and 32.5 g (0.26 mol) of dimethyl sulphate are added to 40 ml of tert.-butanol and allowed to stand at room temperature for 14 hours. A solution of 30 g (0.095 mol) of 4-chlorophenylethyl 1-phenylmercapto-cyclopropyl ketone in 90 ml of tert.-butanol are first added dropwise to the reaction mixture with stirring and 29.2 g of potassium hydroxide powder are then introduced, while the temperature of the reaction mixture is held at 20 to 30° C. The mixture is stirred for a further 3 hours at 30° C., then the dimethyl sulphide is removed under reduced pressure and the reaction mixture is then poured into 70 ml of a 1% strength aqueous hydrogen peroxide solution. The mixture is extracted with ethyl acetate. The organic phase is washed with water and concentrated by removing the solvent under reduced pressure after drying over sodium sulphate. In this manner, 25.6 g (82% of theory) of 2-(4-chlorophenylethyl)-2-(1-phenylmercapto-cyclopropyl)oxirane are obtained in the form of an oily product which is reacted further without additional purification. ##STR68##
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22]([OH:24])=O)=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:39]1([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>ClCCl>[C:48]([O:47][C:45]([N:39]1[CH2:44][CH2:43][N:42]([C:22]([C:21]2[N:20]=[C:19]([C:25]([F:27])([F:28])[F:26])[N:16]3[CH2:17][CH2:18][N:13]([C:11](=[O:12])[CH2:10][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:29][C:30]4[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=4[F:38])[CH2:14][C:15]=23)=[O:24])[CH2:41][CH2:40]1)=[O:46])([CH3:51])([CH3:49])[CH3:50]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 103.1 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (150 mg, 0.27 mmol), tert-butyl piperazine-1-carboxylate (100.6 mg, 0.54 mmol), bis(2-oxo-3-oxazolidinyl)phosphonic chloride (0.138 g, 0.54 mmol) and triethylamine (0.25 mL, 1.62 mmol) were dissolved in 6 mL of dichloromethane under stirring. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-4-{7-[3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carbonyl}-piperazine-1-carboxylic acid tert-butyl ester 13a (200 mg, yield 99%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-])=O)=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:4]=1>O1CCCC1.[C].[Pd]>[CH3:1][O:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([NH2:12])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:4]=1
Reactant: COc1nn(-c2ccccc2)c2cc([N+](=O)[O-])ccc12
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1nn(-c2ccccc2)c2cc(N)ccc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A 250-mL 3-necked round-bottom flask was purged, was added a solution of 3-methoxy-6-nitro-1-phenyl-1H-indazole (800 mg, 2.91 mmol, 1.00 equiv, 98%) in tetrahydrofuran (125 mL), palladium carbon (0.1 g), then flushed and maintained with a hydrogen atmosphere. The resulting solution was stirred for 5 min at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum to yield 3-methoxy-1-phenyl-1H-indazol-6-amine as a gray solid. MS (m/z): 240 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:44][C:45]1[CH:46]=[CH:47][C:48]([F:60])=[C:49]([C:51]23[CH2:58][CH:57]2[CH2:56][O:55][CH2:54][C:53](=[S:59])[NH:52]3)[CH:50]=1>ClCCl>[F:60][C:48]1[CH:47]=[CH:46][C:45]([NH:44][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[O:10])=[CH:50][C:49]=1[C:51]12[CH2:58][CH:57]1[CH2:56][O:55][CH2:54][C:53](=[S:59])[NH:52]2
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: Nc1ccc(F)c(C23CC2COCC(=S)N3)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(F)c(C23CC2COCC(=S)N3)c1)c1ccc(Cl)cn1
Reaction time: 0.25 h
Yield: 198.5 %

Procedure:
To a solution of 5-chloro-2-pyridinecarboxylic acid (60 mg, 0.38 mmol) and diisopropylethylamine (0.17 ml, 0.99 mmol) in dichloromethane (20 ml) at 23° C. was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (174 mg, 0.46 mmol), the mixture was stirred for 15 min, then (1SR,7RS)-1-(5-amino-2-fluoro-phenyl)-5-oxa-2-aza-bicyclo[5.1.0]octane-3-thione (intermediate B13A) (91 mg, 0.36 mmol) was added and the resulting light yellow solution was stirred for 1 h at 23° C. The reaction mixture was poured on ice cold sat. NaHCO3-solution and extracted twice with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated to give a brown solid (280 mg, 168%), which was purified by silica gel column chromatography with dichloromethane/ethyl acetate to give the title compound as a light yellow solid (147 mg, 88%). MS (ISP): m/z=392.1 [(M+H)+] and 394 [(M+2+H)+].
Reaction SMILES: C[O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([O:11][CH3:12])=[C:6]([Br:13])[CH:5]=1.[OH-].[Li+]>C1COCC1.O>[Br:13][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([F:10])[C:7]=1[O:11][CH3:12])[C:3]([OH:14])=[O:2]
Reactant: COC(=O)c1cc(F)c(OC)c(Br)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1c(F)cc(C(=O)O)cc1Br
Reaction time: 72 h
Yield: 52.8 %

Procedure:
5.8 g of the product obtained in step 2 were dissolved in 100 ml of a mixture of THF and water (9:1), 1.06 g (44.1 mmol) of lithium hydroxide were added and the mixture was stirred for 3 days. The solvent was evaporated and the residue was purified by preparative RP HPLC (water/ACN gradient). 2.9 g of the title compound were obtained.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C1COCC1.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CCOC(C)=O>[C:20]([O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(OC(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
tert-Butyl 4-hydroxypiperidine-1-carboxylate (2.0 g) was mixed with THF (20 ml), and TEA (3 ml) and benzoyl chloride (1.2 g) were added thereto, followed by stirring at room temperature for 1 hour. Water and EtOAc were added to the reaction mixture, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain tert-butyl 4-(benzoyloxy)piperidine-1-carboxylate (2.45 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20]2)=[CH:15][CH:14]=1.Cl([O-])=[O:26].[Na+].O.O.OP([O-])(O)=O.[Na+]>C(#N)C.C(O)(C)(C)C.O.CC(=CC)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:26])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:14]=[CH:15][C:16]([CH:19]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20]2)=[CH:17][CH:18]=1
Reactant: [O-][Cl+][O-]
Reactant: CN1CCC(c2ccc(-c3cc4c(C=O)c[nH]c4cc3Cl)cc2)C1
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: CC#N
Product: CN1CCC(c2ccc(-c3cc4c(C(=O)O)c[nH]c4cc3Cl)cc2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 4.1 %

Procedure:
To a solution of 6-chloro-5-[4-(1-methylpyrrolidin-3-yl)phenyl]-1H-indole-3-carbaldehyde (crude, 0.23 g, 0.68 mmol) in acetonitrile (8 mL) and tert-butanol (8 mL) was added 2-methyl-2-butene (8 mL). The reaction mixture was cooled to 0° C. and treated with a solution of sodium chlorite (683 mg, 7.50 mmol) and sodium phosphate monobasic dihydrate (1.59 g, 10.2 mmol) in water (4 mL) dropwise. The reaction mixture was stirred at room temperature for two hours and treated with additional sodium chlorite (911 mg, 10.0 mmol) and sodium phosphate monobasic dihydrate (2.12 g, 13.6 mmol) in H2O (4 mL) and 2-methyl-2-butene (2 mL). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was evaporated in vacuo and the aqueous residue was extracted with EtOAc (3×30 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified via prep-HPLC to give 6-chloro-5-[4-(1-methylpyrrolidin-3-yl)phenyl]-1H-indole-3-carboxylic acid (10 mg) as a solid. MS (ES+) 354.9 (M+H)+. 1H NMR (400 MHz, CD3OD) δ 8.01 (m, 2H), 7.59 (s, 1H), 7.3-7.5 (m, 4H), 3.40-4.00 (m, 5H), 3.06 (s, 3H), 2.1-2.7 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([CH2:11][NH:12][CH:13]=O)=[N:6][C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1[F:23].P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([F:10])[C:7]2[N:6]([CH:13]=[N:12][CH:11]=2)[C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1[F:23])=[O:24]
Reactant: COC(=O)c1cc(F)c(CNC=O)nc1Nc1ccc(Br)cc1F
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(F)c2cncn2c1Nc1ccc(Br)cc1F
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 29.2 %

Procedure:
To a suspension of 2-(4-bromo-2-fluoro-phenylamino)-5-fluoro-6-formylaminomethyl-nicotinic acid methyl ester (2.49 g, 6.2 mmol) in toluene (60 mL) was added phosphorous oxychloride (0.65 mL, 7.0 mmol). The reaction mixture was heated to 90° C. and stirred for 1.5 hour before cooling to room temperature and concentrating in vacuo. The resultant residue was dissolved in ethyl acetate and washed with water followed by a saturated aqueous solution of sodium bicarbonate and then brine. The organic phase was isolated, dried (MgSO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0% to 100%, ether in hexane) to afford the title compound as a yellow solid (692 mg, 29%). LCMS (method B): RT=3.97 min, [M+H]+=382/384.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1C1C=CC(N2CCN(S(CC(C(C)C)C(O)=O)(=O)=O)CC2)=CC=1.[OH:29][NH:30][C:31]([C:33]1([CH2:39][S:40]([N:43]2[CH2:48][CH2:47][N:46]([C:49]3[CH:54]=[CH:53][C:52](Br)=[CH:51][CH:50]=3)[CH2:45][CH2:44]2)(=[O:42])=[O:41])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)=[O:32].O1C=CC=C1B(O)O>>[OH:29][NH:30][C:31]([C:33]1([CH2:39][S:40]([N:43]2[CH2:48][CH2:47][N:46]([C:49]3[CH:54]=[CH:53][C:52]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)=[CH:51][CH:50]=3)[CH2:45][CH2:44]2)(=[O:42])=[O:41])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)=[O:32]
Reactant: O=C(NO)C1(CS(=O)(=O)N2CCN(c3ccc(Br)cc3)CC2)CCOCC1
Reactant: CC(C)C(CS(=O)(=O)N1CCN(c2ccc(-c3ccco3)cc2)CC1)C(=O)O
Agent: OB(O)c1ccco1
Product: O=C(NO)C1(CS(=O)(=O)N2CCN(c3ccc(-c4ccco4)cc3)CC2)CCOCC1
Yield: 14 %

Procedure:
Prepared according to the method for the preparation 2-[4-(4-Furan-2-yl-phenyl)piperazine-1-sulfonylmethyl]-3-methylbutyric acid, from 4-[4-(4-bromophenyl)piperazine-1-sulfonylmethyl]tetrahydropyran-4-carboxylic acid hydroxyamide (0.249 g) and furan-2-boronic acid (0.066 g), to give the title compound as a cream solid (0.034 g, 14%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[N:6]=[C:5]2[NH:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=1.[N:27]1([CH2:32][CH2:33][CH2:34][NH2:35])[CH2:31][CH2:30][CH2:29][CH2:28]1.N1CCC[C@H]1C(O)=O.C(=O)([O-])[O-].[K+].[K+]>[Cu]I.O>[Cl:26][C:21]1[CH:20]=[C:19]([NH:18][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:35][CH2:34][CH2:33][CH2:32][N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH:3]=3)[N:8]=[C:7]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:6]=2)[CH:24]=[CH:23][C:22]=1[F:25]
Reactant: NCCCN1CCCC1
Reactant: Fc1ccc(Nc2nc(-c3cccnc3)nc3ccc(Br)cc23)cc1Cl
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: O
Product: Fc1ccc(Nc2nc(-c3cccnc3)nc3ccc(NCCCN4CCCC4)cc23)cc1Cl
Temperature: 100 °C
Yield: 15.5 %

Procedure:
A 2.0 dram reaction vial was charged with 6-bromo-N-(3-chloro-4-fluorophenyl)-2-(pyridin-3-yl)quinazolin-4-amine (synthesized as described in Scheme 1 and 4, substituting 5-bromo-2-nitrobenzoic acid for 2-nitro-5-propoxy-benzoic acid and 3-chloro-4-fluoroaniline for 2-aminobenzamide) (100 mg, 0.233 mmol, 1.0 equiv), 3-(pyrrolidin-1-yl)propan-1-amine (40 mg, 0.345 mmol, 1.5 equiv), copper(I) iodide (4.4 mg, 0.023 mmol, 0.1 equiv), L-proline (5.3 mg, 0.046 nm tool, 0.2 equiv), and potassium carbonate (96 mg, 0.69 mmol, 3.0 equiv) in 1DMF (3 mL). The reaction mixture was heated at 100° C. overnight. After cooling, water was added to the reaction mixture, and the resultant precipitate was collected by filtration. The crude product was purified via prep-TLC (silica, 2000 micron plate, 95% dichloromethane-5% methanol-0.1% NH4OH) to yield the desired compound as a brown solid (17.2 mg, 15%). LCMS m/z=477.4 (M+1) (Method C) (retention time=1.68 min). 1H NMR (300 MHz, DMSO) δ 9.68 (s, 1H), 9.46 (s, 1H), 8.59 (d, J=9.4 Hz, 2H), 8.25 (dd, J=6.8, 2.6 Hz, 1H), 7.93 (dd, J=8.3, 3.5 Hz, 1H), 7.69-7.59 (m, 1H), 7.52 (dd, J=11.0, 7.1 Hz, 2H), 7.36-7.19 (m, 2H), 6.41 (s, 1H), 3.34 (m, 2H) 2.69 (m, 6H), 2.02-1.82 (m, 2H), 1.75 (bs, 4H).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH:16][C:17](=[O:23])[CH2:18][CH2:19][CH2:20][CH2:21]Br)=[N:13][C:12]=1[CH3:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(NC(C1SC(NC(=O)CCCBr)=NC=1C)=O)C1C=CC=CC=1>>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2=[O:23])=[N:13][C:12]=1[CH3:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(NC(=O)CCCCBr)sc1C(=O)NCc1ccccc1
Agent: Cc1nc(NC(=O)CCCBr)sc1C(=O)NCc1ccccc1
Product: Cc1nc(N2CCCCC2=O)sc1C(=O)NCc1ccccc1
Yield: 35 %

Procedure:
Following the procedure as described in Example 1, making variations as required to use N-benzyl-2-(5-bromopentanamido)-4-methylthiazole-5-carboxamide in replace of N-benzyl-2-(4-bromobutanamido)-4-methylthiazole-5-carboxamide, the title compound was obtained as a white solid in 35% yield: mp 175-176° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.33-7.25 (m, 5H), 5.96 (s, 1H), 4.57 (d, J=5.6 Hz, 2H), 4.13 (t, J=6.0 Hz, 2H), 2.66 (t, J=6.8 Hz, 2H), 2.64 (s, 3H), 2.02-1.87 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 169.8, 162.7, 156.9, 152.0, 138.0, 128.8, 127.9, 127.6, 119.4, 48.0, 44.0, 32.7, 22.5, 20.2, 17.4; MS (ES+) m/z 330.6 (M+1).