Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:8]([O:10][C:11](=[O:41])[C:12]2[CH:17]=[CH:16][C:15](CC3C4C(=CC=C(NC(=O)CC5CCCC5)C=4)N(CC)C=3)=[C:14]([O:39][CH3:40])[CH:13]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:48]1([CH2:53][C:54]([NH:56][C:57]2[CH:65]=[C:64]3[C:60]([CH:61]=[CH:62][N:63]3[CH2:66]C3C=CC(C(O)=O)=CC=3OC)=[CH:59][CH:58]=2)=[O:55])[CH2:52][CH2:51][CH2:50][CH2:49]1>>[C:1]1([N:7]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:8]([O:10][C:11](=[O:41])[C:12]2[CH:17]=[CH:16][C:15]([CH2:66][N:63]3[C:64]4[C:60](=[CH:59][CH:58]=[C:57]([NH:56][C:54](=[O:55])[CH2:53][CH:48]5[CH2:49][CH2:50][CH2:51][CH2:52]5)[CH:65]=4)[CH:61]=[CH:62]3)=[C:14]([O:39][CH3:40])[CH:13]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cc(C(=O)O)ccc1Cn1ccc2ccc(NC(=O)CC3CCCC3)cc21
Reactant: CCn1cc(Cc2ccc(C(=O)OC(=O)N(c3ccccc3)c3ccccc3)cc2OC)c2cc(NC(=O)CC3CCCC3)ccc21
Product: COc1cc(C(=O)OC(=O)N(c2ccccc2)c2ccccc2)ccc1Cn1ccc2ccc(NC(=O)CC3CCCC3)cc21
Yield: 92 %

Procedure:
Using a procedure similar to part (f) of Example 4, but using 4-[6-(2-cyclopentylacetamido)indol-1-ylmethyl]-3-methoxybenzoic acid (Q) instead of acid (J), there was obtained 4-[6-(2-cyclopentylacetamido)indol-1-ylmethyl]-3-methoxybenzoic N,N-diphenyl carbamic anhydride (O) as an off-white powder (1.4 g, 92%); partial NMR: (80 MHz, DMSO-d6): 3.98(s, 3H, OCH3) 5.30(s, 2H, NCH2Ar), 7.40(s, 10H, NArH), 9.69(s, 1H, CONH).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[N:11]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:14]2[CH2:13][CH2:12][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
A solution of 1-fluoro-4-nitrobenzene (500 mg, 3.54 mmol) and tert-butyl piperazine-1-carboxylate (726 mg, 3.9 mmol) in dimethylformamide was treated with potassium carbonate (735 mg, 5.32 mmol) and the suspension was heated at 55° C. for 4 hours and then stirred overnight at room temperature. The reaction was poured into water and the suspension was filtered with water washes to provide the title compound after vacuum drying.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH2:12]([O:19][C:20](=[O:23])[CH2:21][NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:24]([O:28][C:29]([NH:31][C@H:32]([C:34](O)=[O:35])[CH3:33])=[O:30])([CH3:27])([CH3:26])[CH3:25].ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C.C(N(CC)CC)C>[CH2:12]([O:19][C:20](=[O:23])[CH2:21][NH:22][C:34](=[O:35])[C@H:32]([CH3:33])[NH:31][C:29]([O:28][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:30])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NCC(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 12.9 g of glycine benzyl ester tosylate in 200 ml acetonitrile cooled to 0° C., was added dropwise triethylamine (5.3 ml), followed by addition of 12 g of N-tert-butyloxycarbonylalanine N-hydroxysuccinimide ester (prepared by reaction of N-tert-butyloxycarbonylalanine with N-hydroxysuccinimide in the presence of dicyclohexylcarbodiimide). The resulting solution was stirred at 0° C. for one hour and then at room temperature for 18 hours. At the end of reaction, the solvent was distilled off under reduced pressure, the residue was extracted with ethyl acetate, and the extract was washed with 5% acetic acid, water and saturated aqueous solution of sodium chloride in that order, giving 16 g of crude product. Purification of this crude product by silica gel chromatography (chloroform:methanol=40:1) afforded 12.6 g of pure N-tert-butyloxycarbonyl-L-alanyl-glycine benzyl ester.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:38]([O:55][CH2:56][C@@H:57]1[N:62]([CH2:63][CH2:64][C@@H:65]([NH:74][C:75]2[CH:80]=[CH:79][C:78]([S:81]([NH2:84])(=[O:83])=[O:82])=[CH:77][C:76]=2[S:85]([C:88]([F:91])([F:90])[F:89])(=[O:87])=[O:86])[CH2:66][S:67][C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[CH2:61][CH2:60][O:59][CH2:58]1)([C:51]([CH3:54])([CH3:53])[CH3:52])([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[Si:1]([O:8][C@@H:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:84][S:81]([C:78]3[CH:79]=[CH:80][C:75]([NH:74][C@H:65]([CH2:64][CH2:63][N:62]4[CH2:61][CH2:60][O:59][CH2:58][C@@H:57]4[CH2:56][O:55][Si:38]([C:51]([CH3:52])([CH3:53])[CH3:54])([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH2:66][S:67][C:68]4[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=4)=[C:76]([S:85]([C:88]([F:89])([F:90])[F:91])(=[O:86])=[O:87])[CH:77]=3)(=[O:83])=[O:82])=[O:21])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](OC[C@H]1COCCN1CC[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)O)cc2)CC1
Product: CC(C)(C)[Si](C)(C)O[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)NS(=O)(=O)c3ccc(N[C@H](CCN4CCOC[C@@H]4CO[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)CSc4ccccc4)c(S(=O)(=O)C(F)(F)F)c3)cc2)CC1
Yield: 90.9 %

Procedure:
The title product (134 mg, yield: 77%) was prepared using a procedure similar to the one described for the synthesis of INTERMEDIATE 33. (R)-4-(4-((tert-Butyldimethylsilyloxy)(4′-chlorobiphenyl-2-yl)methyl)piperidin-1-yl)benzoic acid (INTERMEDIATE 13, 67.7 mg, 0.13 mmol) and 4-((R)-4-((R)-3-((tert-butyldiphenylsilyloxy)methyl)morpholino)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (INTERMEDIATE 109, 94.4 mg, 0.11 mmol) were used as starting materials. The resulting product was purified by column chromatography (ISCO, 12 g silica gel column, eluting with 0→30% EtOAc/hexanes), providing the title compound.
Reaction SMILES: B.O1CCCC1.[CH3:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=1)=[O:9]>C1(C)C=CC=CC=1.O1CCCC1>[Cl:16][C:12]1[CH:11]=[C:10]([C@H:8]([OH:9])[CH3:7])[CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)c1cccc(Cl)c1
Agent: B
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C[C@@H](O)c1cccc(Cl)c1
Reaction time: 0.17 h
Yield: 77.4 %

Procedure:
To a solution of borane-tetrahydrofuran (0.647 mL, 0.647 mmol, Aldrich, 1 M solution in THF) and (S)-MeCBS (0.647 mL, 0.647 mmol, Aldrich, 1M solution in toluene) was added simultaneously a solution of 3-chloroacetophenone (1.00 g, 6.47 mmol) in anhydrous tetrahydrofuran (2.42 mL) and a solution of borane-tetrahydrofuran (3.24 mL, 3.24 mmol, Aldrich, 1 M solution in THF) over 30 min at ambient temperature. After complete addition, the reaction mixture was stirred for 10 min, quenched slowly at 0° C. with methanol (0.94 mL) and then saturated HCl in ether (0.12 mL). After stirring at 0° C. for 5 min and ambient temperature for 30 min, the solution was concentrated in vacuo to an oil. The oil was twice diluted with benzene and concentrated in vacuo, diluted with ether, and concentrated in vacuo to an oil. The oil was purified by flash chromatography (silica gel, 20% EA in hexane) to give (R)-1-(3-chlorophenyl)ethanol as a clear colorless oil (0.784 g, 78%). Optical rotation in CHCl3 at 20° C. at concentration 0.220 was +40.90 (Literature, Bull. Chem. Soc. Jpn. 1996, 69(4), 1079-1085, optical rotation in CHCl3 at 21° C. at concentration 0.220 was +44°).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[F:21][C:22]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[CH:25][C:23]=1[NH2:24]>>[NH2:24][C:23]1[CH:25]=[CH:26][C:27]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])=[CH:28][C:22]=1[F:21]
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: CC1(C)OB(c2ccc(N)c(F)c2)OC1(C)C
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(N)c(F)c3)ccn2c1=O
Yield: 76.7 %

Procedure:
Methyl 8-(4-amino-3-fluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (200 mg, 0.68 mmol) and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (195 mg, 0.82 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (191 mg, 76%).
Reaction SMILES: C[O:2][C:3](=[O:39])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[N:23]([C:30]4[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:37])[N:24]=[CH:25][C:26]=3[CH:27]([CH3:29])[CH3:28])=[CH:16][C:15]=2[CH3:38])([CH3:13])[CH3:12])[CH:5]=1.[OH-].[Li+]>O1CCOCC1>[Cl:36][C:35]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:37])[C:30]=1[N:23]1[C:22]([CH2:21][O:20][C:17]2[CH:18]=[CH:19][C:14]([C:11]([S:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:39])=[O:2])([CH3:13])[CH3:12])=[C:15]([CH3:38])[CH:16]=2)=[C:26]([CH:27]([CH3:29])[CH3:28])[CH:25]=[N:24]1
Reactant: COC(=O)c1cccc(SC(C)(C)c2ccc(OCc3c(C(C)C)cnn3-c3c(Cl)cccc3Cl)cc2C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)ccc1C(C)(C)Sc1cccc(C(=O)O)c1
Temperature: 50 °C
Yield: 94.5 %

Procedure:
To an ambient temperature solution of 3-(1-{4-[2-(2,6-Dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-1-methyl-ethylsulfanyl)-benzoic acid methyl ester (91 mg, 0.156 mmol) in dioxane (2 mL) is added a solution of lithium hydroxide (234 μL, 0.468 mmol, 2.0N in water). The reaction mixture is heated to 50° C. The reaction mixture is concentrated and the residue is partitioned between Et2O and water. The aqueous layer pH is adjusted to approximately 4 and is extracted with a second portion of Et2O. The combined organic layers are washed with water, dried (MgSO4), filtered, and concentrated to yield the title compound (84 mg, 95%). ES/MS m/e (35Cl) 569.0 (M+1)
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[CH3:24][O:25][CH2:26][C:27](Cl)=[O:28]>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:27](=[O:28])[CH2:26][O:25][CH3:24])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: COCC(=O)Cl
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)COC)nc3cc21

Procedure:
N-[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-2-methoxy-acetamide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and methoxyacetyl chloride (81 μl, 0.89 mmol). The title compound was obtained as light brown powder (171 mg, 55%).
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH:15]([CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:14][CH2:13][O:12]2)=[CH:6][C:5]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30].[OH-].[Na+].C(O)C.P(=O)(O)(O)O>O>[CH:18]1([O:17][CH2:16][CH:15]2[CH2:14][CH2:13][O:12][N:11]2[CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:31])=[O:2])=[C:5]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])[CH:6]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COC(=O)c1ccc(CN2OCCC2COC2CCCCC2)cc1-c1ccccc1C
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccccc1-c1cc(CN2OCCC2COC2CCCCC2)ccc1C(=O)O
Temperature: 25 °C
Yield: 78.5 %

Procedure:
A mixture of example 1130C (355 mg, 0.84 mmol) and sodium hydroxide (1 mL of a 4N aqueous solution, 4 mmol) in 4 mnL of ethanol was heated to reflux for 6 hours and then cooled to room temperature. The mixture was diluted with water and the pH adjusted to 5 with aqueuos phosphoric acid. The mixture was extracted with 3 portions of ethyl acetate and the combined organic fractions were washed with water and brine, dried, filtered and concentrated to provide 270 mg (78%) of the title compound. MS (ESI+): 410 (MH+).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19](=[O:21])[CH3:20])#[CH:11]>>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:11]1[N:18]([C:19](=[O:21])[CH3:20])[C:13]2[C:12]([CH:10]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: COc1ccccc1I
Reactant: C#Cc1ccccc1NC(C)=O
Product: COc1ccccc1-c1cc2ccccc2n1C(C)=O
Yield: 83 %

Procedure:
The general procedure was used to convert 1-iodo-2-methoxybenzene and N-(2-ethynylphenyl)acetamide to the title product. Purification by flash chromatography gave the analytically pure product as a slightly yellow solid, 83% yield. 1H NMR (300 MHz, CDCl3) δ 8.40-8.36 (m, 1H), 7.57-7.53 (m, 1H), 7.45-7.41 (m, 2H), 7.36-7.22 (m, 2H), 7.09-7.04 (m, 1H) 6.95-6.92 (m, 1H), 6.54 (s, 1H), 3.76 (s, 3H), 2.10 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 171.26, 156.93, 137.29, 136.39, 130.66, 130.55, 129.06, 124.76, 123.43, 123.16, 121.04, 120.21, 116.07, 111.30, 110.65, 55.38, 25.80.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[C:5]([CH3:7])[CH3:6].[Mg].[C:9]1([C:15]2([CH2:20][CH2:21][CH2:22][C:23](=[O:25])[CH3:24])[O:19][CH2:18][CH2:17][O:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH4+].[Cl-]>CCOCC.CCCCCCC.CCOCC>[CH3:24][C:23]([OH:25])([CH2:2][CH2:3][CH:4]=[C:5]([CH3:7])[CH3:6])[CH2:22][CH2:21][CH2:20][C:15]1([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[O:19][CH2:18][CH2:17][O:16]1
Reactant: CC(C)=CCCBr
Reactant: CC(=O)CCCC1(c2ccccc2)OCCO1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCCCC
Product: CC(C)=CCCC(C)(O)CCCC1(c2ccccc2)OCCO1
Reaction time: 0.75 h
Yield: 37.8 %

Procedure:
A Grignard reagent of 3.50 g (0.021 mol) of 5-bromo-2-methyl-2-pentene in 13 ml of ether and 0.62 g (0.026 mol) of magnesium turnings in 14 ml of ether was added slowly at −25° under N2 to a stirred solution of 5.54 g (0.024 mol) of 5-(2-phenyl-1,3-dioxolan-2-yl)-2-pentanone obtained under b) in 20 ml of ether. During the introduction, the temperature was left rising up to −5° C. and the reaction mixture left stirring for 45 min. Then a saturated solution of NH4Cl was added and the formation of a white precipitate was observed. Extraction with ether (2×), washing with water (3×), drying (Na2SO4) and concentrating gave 6.24 g of the crude product. Column chromatography (SiO2, heptane/ether 7:3) gave 2.53 g (38%) of a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[N:7]([CH2:11][CH3:12])[C:6](=[O:13])[C:5]2(Br)Br>C(O)(=O)C.[Zn]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[N:7]([CH2:11][CH3:12])[C:6](=[O:13])[CH2:5]2
Reactant: CCN1C(=O)C(Br)(Br)c2cc(Cl)cnc21
Agent: [Zn]
Solvent: CC(=O)O
Product: CCN1C(=O)Cc2cc(Cl)cnc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-chloro-3,3-dibromo-1-ethyl-7-azaoxindole (4.60 g, 13.0 mmol) in glacial acetic acid (75 mL) was added, in portions, zinc powder (2.5 g, 39 mmol). An exothermic reaction took place immediately, however, stirring at room temperature was continued for 1 hour. The mixture was poured into ice/water and then extracted with ethyl acetate. The organic extract was washed with water, dried over magnesium sulfate and evaporated to leave an oil which was chromatographed on a column of silica gel eluting with chloroform. Fractions containing the desired product were combined and concentrated in vacuo to afford an off-white solid, 1.70 g (68%). M.p. 78°-82° C.
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]2(O)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.CCN(S(F)(F)[F:21])CC>C(Cl)Cl>[F:1][C:2]1[C:3]([C:8]2([F:21])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: OC1(c2nccnc2F)CCOCC1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: Fc1nccnc1C1(F)CCOCC1
Reaction time: 2 h

Procedure:
To a solution of 4-(3-fluoropyrazin-2-yl)tetrahydro-2H-pyran-4-ol (0.123 g, 0.621 mmol) in DCM (2 mL) cooled to 0° C. was added dropwise dast (0.164 mL, 1.241 mmol). The resulting mixture was stirred for 2 hr. Reaction was quenched with dropwise addition of saturated NaHCO3 solution and back extracted with DCM to produce product.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([OH:14])=[CH:8][C:3]=1[C:4](OC)=[O:5].CC(O)=O.O.[CH:20]([NH2:22])=O>>[OH:14][C:9]1[CH:8]=[C:3]2[C:2](=[CH:11][C:10]=1[O:12][CH3:13])[N:1]=[CH:20][NH:22][C:4]2=[O:5]
Reactant: COC(=O)c1cc(O)c(OC)cc1N
Reactant: NC=O
Solvent: O
Solvent: CC(=O)O
Product: COc1cc2nc[nH]c(=O)c2cc1O
Temperature: 140 °C
Yield: 89 %

Procedure:
A mixture of methyl 2-amino-5-hydroxy-4-methoxybenzoate (3.1 g, 15.7 mmol) and AcOH (7.1 mL) in formamide (15.5 mL) was heated at 140° C. overnight. To it was added water (20 mL) and filtered to afford 6-hydroxy-7-methoxyquinazoline-4(3H)-one as a solid (2.7 g, 89%). 1H NMR (300 MHz, DMSO-d6) δ 9.82 (s, 1H), 7.9 (s, 1H), 7.4 (s, 1H), 7.1 (s, 1H), 3.9 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][OH:25])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.Br[C:28]1[CH:33]=[CH:32][N:31]=[C:30]([OH:34])[CH:29]=1>>[OH:25][CH2:24][CH2:23][CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:26])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([OH:34])[CH:29]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: Oc1cc(Br)ccn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccnc(O)c2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one following procedures analogous to those described in Example 313 Steps 3 and 4 using 4-bromo-2-hydroxypyridine in Step 4. LC-MS Method 2 tR=1.019, m/z=865.4; 1H NMR (CDCl3) 1.29-1.40 (m, 1H), 1.49 (d, 3H), 1.60-1.72 (m, 1H), 1.83-2.01 (m, 3H), 2.18 (m, 1H), 2.21-2.37 (m, 2H), 2.88 (m, 1H), 3.51 (m, 2H), 5.63 (m, 1H), 6.41 (d, 1H), 6.68 (s, 1H), 6.90 (d, 2H), 7.21-7.33 (m, 7H), 7.39 (d, 1H).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:23])=[C:11]([N:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)[C:12]=3[CH2:14][OH:15])[C:7](=[O:24])[C:6]([C:25]([O:27][CH2:28]C)=[O:26])=[CH:5]2)[CH2:3][CH2:2]1.S(=O)(=O)(O)O.[C:35](=O)([O-])O.[Na+]>CO>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:23])=[C:11]([N:16]4[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]4)[C:12]=3[CH2:14][O:15][CH3:35])[C:7](=[O:24])[C:6]([C:25]([O:27][CH3:28])=[O:26])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(CO)c(N3CCN(C)CC3)c(F)cc2c1=O
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COCc1c(N2CCN(C)CC2)c(F)cc2c(=O)c(C(=O)OC)cn(C3CC3)c12

Procedure:
To a solution of ethyl 1-cyclopropyl-7-(4-methyl-1-piperazinyl)-6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (160 mg) in methanol (10 ml) is added conc. sulfuric acid (2 ml), and the mixture is refluxed for 6.5 hours. The reaction mixture is adjusted to below pH 8 with aqueous saturated sodium hydrogen carbonate and extracted with dichloromethane. The extract is washed with aqueous saturated sodium chloride and then dried over magnesium sulfate and the solvent is distilled off. The residue is crystallized by adding thereto diethyl ether to give methyl 1-cyclopropyl-7-(4-methyl-1-piperazinyl)-6-fluoro-8-methoxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (125 mg), as pale yellow powder, m.p. 200°-204° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[N:10]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][O:21]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31](Cl)=[O:32].C(N(CC)CC)C>O1CCCC1>[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[N:10]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][O:21]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1)=[O:32]
Reactant: O=C(Cl)c1ccco1
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NC(=O)c1ccc2c(c1)c(-c1cccc(NC(=O)c3ccco3)c1)nn2C1CCCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (0.200 g, 0.59 mmol) in 6 mL of tetrahydrofuran was added 2-furanoic acid chloride (0.064 mL, 0.65 mmol), followed by triethyl amine (0.091 mL, 0.65 mmol). The reaction was stirred at room temperature overnight. The crude mixture was partitioned between water and ethyl acetate. The extracts were concentrated to dryness. The crude was not purified (yield not calculated). ES-MS (m/z) 431 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=1[N:18]=[C:19]=[S:20]>CC(=O)OCC>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[NH:9][C:19]([NH:18][C:12]1[C:13]([Cl:17])=[CH:14][CH:15]=[CH:16][C:11]=1[Cl:10])=[S:20]
Reactant: Nc1ccc(F)cc1N
Reactant: S=C=Nc1c(Cl)cccc1Cl
Solvent: CCOC(C)=O
Product: Nc1ccc(F)cc1NC(=S)Nc1c(Cl)cccc1Cl
Yield: 77.9 %

Procedure:
A mixture of 4.37 g (0.0346 mol) of 4-fluoro-1,2-diaminobenzene and 7.07 g (0.0346 mol) of 2,6-dichlorophenyl isothiocyanate in 150 ml of EA was boiled under reflux for 3 hours. After distilling off the solvent, the residue was dissolved in methanol, treated with activated carbon, ⅔ of the solvent volume was distilled off, and the thiourea was allowed to crystallize in an ice bath for a number of hours. 8.9 g of the desired product was obtained. Colorless crystals, 1st m.p.: 175-178° C.; 2nd m.p.: 294-296° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1.C(=O)(O)[O-].[Na+].[N+]([O-])(O)=O.CC1C=C(C)[N:35]([C:39](N)=[NH:40])N=1>C(O)C>[NH:1]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1)[C:39]([NH2:40])=[NH:35]
Reactant: Cc1cc(C)n(C(=N)N)n1
Reactant: Nc1ccc2c(c1)C(=Cc1ccnc3ccccc13)C(=O)N2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O=[N+]([O-])O
Product: N=C(N)Nc1ccc2c(c1)C(=Cc1ccnc3ccccc13)C(=O)N2
Yield: 50 %

Procedure:
A mixture of 5-amino-3-(quinol-4-ylmethylene)-2-oxindole (2.873 g, 10 mmol) and sodium bicarbonate (0.168 g, 2 mmol) in refluxing ethanol (100 ml) was treated with 3,5-dimethylpyrazole-1-carboxamidine nitrate (3.018 g, 15 mmol) for 20 h. The solvent was removed from the cooled solution, and the residue was chromatographed on silica gel with gradient elution (1 to 5% EtOH in CHCl3) to afford pure title compound in about 50% yield.