Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[N:13]([CH3:14])[C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)=[C:4]([F:17])[CH:3]=1.[CH:18]([S:21](Cl)(=[O:23])=[O:22])([CH3:20])[CH3:19].N1C=CC=CC=1>O>[C:15]([C:12]1[N:13]([CH3:14])[C:9]([C:5]2[C:4]([F:17])=[CH:3][C:2]([NH:1][S:21]([CH:18]([CH3:20])[CH3:19])(=[O:23])=[O:22])=[C:7]([F:8])[CH:6]=2)=[CH:10][CH:11]=1)#[N:16]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: Cn1c(C#N)ccc1-c1cc(F)c(N)cc1F
Solvent: O
Solvent: c1ccncc1
Product: CC(C)S(=O)(=O)Nc1cc(F)c(-c2ccc(C#N)n2C)cc1F
Temperature: 100 °C
Yield: 12 %

Procedure:
5-(4-amino-2,5-difluorophenyl)-1-methyl-1H-pyrrole-2-carbonitrile (150 mg, 0.64 mmol) was dissolved in isopropyl sulfonyl chloride (1.0 mL, 9.0 mmol), pyridine (0.2 mL) was added and the mixture was heated to 100° C. for 6 hours. The mixture was then cooled, diluted with water and extracted with ethyl acetate. The organics were combined, washed with water, brine, dried over MgSO4, and concentrated. Flash chromatography (0%-100% ethyl acetate in hexane) afforded N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2,5-difluorophenyl]propane-2-sulfonamide (26 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([CH2:16][CH2:17][CH3:18])[C:13](O)=[S:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:22][CH:21]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([CH2:16][CH2:17][CH3:18])[C:13]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:24][CH:25]=2)=[S:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: CCC[C@@H](NS(=O)(=O)c1ccc(Cl)cc1)C(O)=S
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCC[C@@H](NS(=O)(=O)c1ccc(Cl)cc1)C(=S)Nc1ccc(CC(=O)OCC)cc1
Yield: 2.1 %

Procedure:
The procedure described in Example 180 was repeated, except that (R)-2-(4-chlorobenzenesulfonylamino)-4-methylthiobutanoic acid (715 mg) and ethyl 4-aminophenylacetate (430 mg) were condensed in dichloromethane (15 ml) in the presence of N,N'-dicyclohexylcarbodiimide (546 mg). The reaction mixture was filtered, and the filtrate was concentrated. The resulting crude product was recrystallized from hexanechloroform to obtain (R)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-methylthiobutanamide (22.9 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:10])=[C:7]([OH:9])[CH:8]=1.[CH2:11]([O:13][C:14](=[O:25])[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=1[CH3:24])[CH3:12].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[CH2:11]([O:13][C:14](=[O:25])[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][C:20]([O:9][C:7]2[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[CH3:10])=[CH:19][C:18]=1[CH3:24])[CH3:12]
Reactant: CCOC(=O)C=Cc1ccc(F)cc1C
Reactant: COc1ccc(C)c(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)C=Cc1ccc(Oc2cc(OC)ccc2C)cc1C
Temperature: 140 °C
Reaction time: 8 h
Yield: 47.2 %

Procedure:
The compounds of 5-methoxy-2-methyl-phenol (1.46 g, 9.60 mmol), 3-(4-fluoro-2-methyl-phenyl)-acrylic acid ethyl ester (1.00 g, 4.80 mmol), potassium carbonate (1.33 g, 9.60 mmol) are dissolved in dimethylsulfoxide (12 mL) under nitrogen, and the mixture is stirred overnight at 140° C. HCl 10% is added, and the mixture is extracted with diethyl ether. The organic layer is washed with water, dried (Na2SO4) and filtered, and then the solvent is evaporated in vacuo. Purification by flash chromatography by eluting with hexane:ethyl acetate 10:1 to afford the title compound (0.74 g, 47%). Rf=0.44 (hexane:ethyl acetate 5:1). 1H NMR (300 MHz, CDCl3): δ1.34 (t, 3H, J=7.3 Hz), 2.13 (s, 3H), 2.40 (s, 3H), 3.74 (s, 3H), 4.26 (q, 2H, J=7.1 Hz), 6.28 (d, 1H, J=15.9 Hz), 6.53 (d, 1H, J=2.4 Hz), 6.66-6.73 (m, 3H), 7.15 (d, 1H, J=8.3 Hz), 7.51 (d, 1H, J=8.3 Hz), 7.93 (d, 1H, J=16.0 Hz).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[O:4][C:3]=1[CH2:13][OH:14].[F:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:15][C:16]1[CH:21]=[C:20]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:12])[O:4][C:3]=2[CH2:13][OH:14])[CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: O=c1oc(CO)c(Br)c2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=c1oc(CO)c(-c2cccc(F)c2)c2ccccc12
Yield: 39.6 %

Procedure:
The title compound was made in a similar way as that of the intermediate B2 using 4-bromo-3-(hydroxymethyl)-1H-isochromen-1-one (Intermediate A1, 0.5 g, 1.960 mmol), 3-fluorophenylboronic acid (0.4 g, 2.86 mmol), Pd(PPh3)4 (0.136 g, 0.118 mmol) and Cs2CO3 (0.96 g, 2.94 mmol) to afford the title compound (0.21 g, 40%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Br[C:14]1[CH:15]=[N:16][CH:17]=[C:18]([CH:23]=1)[C:19]([O:21][CH3:22])=[O:20].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:22][O:21][C:19](=[O:20])[C:18]1[CH:23]=[C:14]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[CH:3]=2)[CH:15]=[N:16][CH:17]=1
Reactant: COC(=O)c1cncc(Br)c1
Reactant: COc1ccc(B(O)O)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cncc(-c2ccc(OC)c(Cl)c2)c1
Yield: 37.3 %

Procedure:
6.5 g of 3-chloro-4-methoxyphenylboronic acid, 5.0 g of methyl 5-bromonicotinate, 1.3 g of tetrakis(triphenylphosphine)palladium(0), and 22.6 g of Cs2CO3 were stirred in 325 ml of DMF and 65 ml of water for 3 h at 45° C. The reaction mixture was then poured into 750 ml of water and extracted three times using 300 ml of EA each. The combined organic layers were then washed twice using 150 ml of water each. The organic layer was then dried using MgSO4 and evaporated. Chromatography on silica gel using EA/HEP (gradient) yielded 2.4 g of the title compound, colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.N1(C(N2C=CN=C2)=O)C=CN=C1.[CH2:31]([O:33][C:34](=[O:39])[C:35]([NH:37]O)=[NH:36])[CH3:32]>CN(C=O)C.O>[CH2:31]([O:33][C:34]([C:35]1[N:37]=[C:12]([C:11]2[CH:15]=[CH:16][N:17]=[CH:18][C:10]=2[NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])[O:14][N:36]=1)=[O:39])[CH3:32]
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: CCOC(=O)C(=N)NO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1noc(-c2ccncc2Nc2ccc(I)cc2F)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.9 %

Procedure:
A reaction mixture of 3-(2-Fluoro-4-iodo-phenylamino)-isonicotinic acid (1000 mg, 2.79 mmol, 1.00 eq), and Di-imidazol-1-yl-methanone ((543 mg, 3.35 mmol, 1.20 eq) in DMF was stirred for 4 hrs at RT under argon. Then hydroxyamino-imino-acetic acid ethyl ester (612 mg, 4.19 mmol, 1.5 eq.) was added and the reaction mixture was stirred overnight, and then diluted with water. A yellow precipitate was formed that was filtered to afford the product (785 mg). [5.46 min; 455 (M+1)]
Reaction SMILES: [OH:1][C@@H:2]([C@@H:8]([CH3:11])[CH2:9][CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])O.[Na+]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)C>[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[O:1][C@@H:2]([C@@H:8]([CH3:11])[CH2:9][CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: C1=COCCC1
Reactant: CCOC(=O)[C@@H](O)[C@@H](C)CC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)[C@@H](OC1CCCCO1)[C@@H](C)CC
Yield: 40.3 %

Procedure:
In a 200 ml flask were charged 10 g of ethyl (2S,3S)-2-hydroxy-3-methylvalerate, 10.5 g of 3,4-dihydro-2H-pyran, 0.24 g of p-toluenesulfonic acid, and 100 ml of diethyl ether, and the mixture was allowed to react at room temperature overnight. The reaction mixture was neutralized with a sodium hydrogencarbonate aqueous solution, and diethyl ether was removed by distillation to obtain 6.15 g (49.7%) of a crude product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)[CH:13]=2)=[O:11])=[CH:4][C:3]=1[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][N:33]2[CH2:38][CH2:37][N:36](C(OCC3C=CC=CC=3)=O)[C@@H:35]([CH3:49])[CH2:34]2)[CH:27]=1.[H][H]>CO.[Pd]>[F:1][C:2]1[C:3]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][N:33]3[CH2:38][CH2:37][NH:36][C@@H:35]([CH3:49])[CH2:34]3)[CH:27]=2)=[CH:4][C:5]([CH2:8][NH:9][C:10](=[O:11])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH:19]3[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]3)[CH:13]=2)=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: C[C@H]1CN(Cc2cccc(-c3cc(CNC(=O)c4cccc(CC5CCN(C)CC5)c4)ccc3F)c2)CCN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: C[C@H]1CN(Cc2cccc(-c3cc(CNC(=O)c4cccc(CC5CCN(C)CC5)c4)ccc3F)c2)CCN1
Yield: 68.3 %

Procedure:
To a solution of phenylmethyl (2S)-4-[(2′-fluoro-5′-{[({3-[(1-methyl-4-piperidinyl)methyl]phenyl}carbonyl)amino]methyl)-3-biphenylyl)methyl]-2-methyl-1-piperazinecarboxylate (120 mg, 0.18 mmol) in 5 mL of MeOH, was added 10% Pd/C (60 mg). The mixture was hydrogenated using a hydrogen balloon for 12 hours. After flittering off the catalyst, the mixture was concentrated and the residue was purified by Gilson reverse phase HPLC, eluting with acetonitrile/water/0.1% TFA (10/90 to 70/30, v/v, over 12 min), to give the title compound (65 mg, 41%). LC/MS: m/z, 529 (M+H), 1.29 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12](=[O:17])[C:13](Br)([F:15])[F:14])[CH3:10]>[Cu].CS(C)=O>[CH2:9]([O:11][C:12](=[O:17])[C:13]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)([F:15])[F:14])[CH3:10]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: Brc1ccc(I)cc1
Agent: [Cu]
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)c1ccc(Br)cc1
Temperature: 55 °C
Reaction time: 24 h

Procedure:
According to the Kumadaki method (supra) and the above-described scheme, 4-bromoiodobenzene (848.7 mg, 3.0 mmol), bromodifluoroacetic acid ethyl ester (Compound 1f; 608.9 mg, 3.0 mmol), copper powder (381 mg, 6.0 mmol) and DMSO (6.0 mL) were put into a two-neck reaction tube, and the mixture was stirred under argon atmosphere at 55° C. for 24 hours. The reaction mixture was extracted with ethyl acetate and washed with water, and an organic layer was dried with anhydrous sodium sulfate. Ethyl acetate was distilled away under reduced pressure, and by carrying out purification by silica gel column chromatography, 2-(4-bromophenyl)-2,2-difluoroacetic acid ethyl ester (Compound 2f) was obtained with a yield of 69%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)=[C:15]3[N:10]([N:11]=[C:12]([OH:27])[CH:13]=[CH:14]3)[N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH:31]([F:33])[F:32].O>CN(C)C=O>[F:32][CH:31]([F:33])[O:27][C:12]1[CH:13]=[CH:14][C:15]2[N:10]([N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:19][CH:18]=2)[N:11]=1
Reactant: CS(=O)(=O)c1ccc(-c2c(-c3ccc(F)cc3)nn3nc(O)ccc23)cc1
Reactant: FC(F)Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-c2c(-c3ccc(F)cc3)nn3nc(OC(F)F)ccc23)cc1
Reaction time: 0.5 h

Procedure:
A solution of 2-(4-fluoro-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazin-6-ol (0.2 9) in anhydrous dimethyl formamide (5 ml) was treated with sodium hydride (0.046 g, 60% dispersion in mineral oil), after effervescence ceased a stream of bromodifluoromethane gas was passed through the mixture at ambient temperature for 30 minutes. The reaction mixture was then poured into water (50 ml) and extracted with ethyl acetate (50 ml), the organic extract was washed with water (3×50 ml), dried and concentrated in vacuo. The residue was purified by chromatography to give the title compound as a white solid (0.17 g).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[CH2:6][CH2:7][CH2:8][C:9]3[S:13][C:12]([NH2:14])=[N:11][C:10]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29](Cl)=[O:30]>C1COCC1.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[CH2:6][CH2:7][CH2:8][C:9]3[S:13][C:12]([NH:14][C:29](=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][Br:24])=[N:11][C:10]=3[C:4]=2[CH:3]=1
Reactant: Nc1nc2c(s1)CCCc1ccc(F)cc1-2
Reactant: O=C(Cl)CCCCBr
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCCCBr)Nc1nc2c(s1)CCCc1ccc(F)cc1-2
Temperature: 25 °C
Reaction time: 72 h
Yield: 70.4 %

Procedure:
9-Fluoro-5,6-dihydro-4H-benzo[6,7]cyclohepta[d][1,3]thiazol-2-amine (150 mg, 0.640 mmole) was dissolved in 3 ml of dry THF, mixed with triethylamine (135 μl, 0.970 mmole), cooled in an ice bath and treated with 5-bromovaleryl chloride (90 μl, 0.67 mmole). The mixture was stirred at room temperature for 3 days. TLC analysis of the mixture showed 50% completion. Hence, a catalytic amount of DMAP was added and stirring was continued for 16 hours. There was no change in the TLC of the mixture. 5-Bromovaleryl chloride (90 μl) was added and stirred for 3 days. The reaction mixture was partitioned between ethyl acetate and saturated sodium carbonate and the aqueous phase separated and extracted with 2×3 ml ethyl acetate. The combined ethyl acetate extracts were washed with saturated sodium chloride solution, concentrated and chromatographed (silica, Ethyl acetate/hexanes) to give 179 mg of the desired product as a white foam (70%): 397, 399 (ESMS, MH+).
Reaction SMILES: C(OC([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21]3[NH:25][C:24]4[CH:26]=[CH:27][C:28]([O:30][C:31]5[CH:36]=[CH:35][N:34]=[C:33]([C:37](=[O:40])[NH:38][CH3:39])[CH:32]=5)=[CH:29][C:23]=4[N:22]=3)=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:39][NH:38][C:37]([C:33]1[CH:32]=[C:31]([O:30][C:28]2[CH:27]=[CH:26][C:24]3[NH:25][C:21]([NH:20][C:12]4[CH:11]=[C:10]5[C:15]([C:16]([CH3:19])([CH3:18])[CH2:17][NH:8][CH2:9]5)=[CH:14][CH:13]=4)=[N:22][C:23]=3[CH:29]=2)[CH:36]=[CH:35][N:34]=1)=[O:40]
Reactant: CNC(=O)c1cc(Oc2ccc3[nH]c(Nc4ccc5c(c4)CN(C(=O)OC(C)(C)C)CC5(C)C)nc3c2)ccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1cc(Oc2ccc3[nH]c(Nc4ccc5c(c4)CNCC5(C)C)nc3c2)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-tert-butoxycarbonyl-4,4-dimethyl-7-[5-(2-methylcarbamoyl-pyridin-4-yloxy)-1H-benzimidazol-2-ylamino]-3,4-dihydro-1H-isoquinoline (230 mg) (Example 11) in CH2Cl2 (10 mL) was added TFA (1 mL). The mixture was stirred at RT for 2 h. Solvent was evaporated, aqueous NaHCO3 solution was added, and the mixture was extracted with EtOAc. The organic phase was dried, filtered and evaporated to give the title compound. MS (MH+)=443.2; Calc'd 442.21 for C25H26N6O2.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[O:8][CH2:9][C:10](=[O:12])[NH:11][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.Cl[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]Cl>ClC1C=CC=CC=1>[N:1]1([C:2]2[C:7]3[O:8][CH2:9][C:10](=[O:12])[NH:11][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: Nc1cccc2c1OCC(=O)N2
Reactant: ClCCNCCCl
Agent: Cl
Solvent: Clc1ccccc1
Product: O=C1COc2c(cccc2N2CCNCC2)N1
Reaction time: 2 h
Yield: 64.3 %

Procedure:
To a solution of intermediate 58 (164 mg, 1.0 mmol) in chlorobenzene (5 mL) was added bis(2-chloroethyl)amine hydrochloric acid (285 mg, 1.6 mmol) and the mixture was heated to reflux for 100 h. The reaction mixture was concentrated in vacuo and the residue was stirred in EtOAc for 2 h. The resulting brown solid was filtered and purified by silica gel chromatography to give 8-(piperazin-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (intermediate 59) (150 mg, 64%). HPLC: 99%, RT 1.344 min. MS (ESI) m/z 234.1[M+H]+.
Reaction SMILES: [C:1]1(=[O:19])[N:5]([CH2:6][S:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]12.[CH3:20][NH2:21].CO>C(Cl)(Cl)Cl>[CH3:20][NH:21][C:4]([C:3]1[CH:15]=[CH:16][CH:17]=[CH:18][C:2]=1[C:1]([NH:5][CH2:6][S:7][C:8]1[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=1)=[O:19])=[O:14]
Reactant: CN
Reactant: O=C1c2ccccc2C(=O)N1CSc1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CNC(=O)c1ccccc1C(=O)NCSc1ccncc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.1 %

Procedure:
To a solution of 6.76 g (25.0 mmol) of 4-phthalimidomethylthiopyridine in 100 ml of chloroform, 5 ml of 40% methylamine-methanol solution was added, and the mixture was stirred at room temperature for 3 hours. Additional 5 ml of 40% methylamine-methanol solution was added, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off and the residue was purified by column chromatography (eluent: ethanol/ethyl acetate=1:10), and the resulting crude product was crystallized from methylene chloride-diethylether to give 2.645 g of the desired compound (35.1% yield, yellow crystals), mp. 118°-121° C.
Reaction SMILES: [C:1]([C:4]1[CH:27]=[CH:26][C:7]([C:8]([NH:10][NH:11][C:12]([C:14]2[CH:25]=[CH:24][C:17]([O:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=2)=[O:13])=[O:9])=[CH:6][CH:5]=1)(=[S:3])[NH2:2].I[CH3:29]>CC(C)=O>[CH3:29][S:3][C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][NH:11][C:12]([C:14]2[CH:25]=[CH:24][C:17]([O:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=2)=[O:13])=[O:9])=[CH:26][CH:27]=1)=[NH:2]
Reactant: COC(=O)COc1ccc(C(=O)NNC(=O)c2ccc(C(N)=S)cc2)cc1
Reactant: CI
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(C(=O)NNC(=O)c2ccc(C(=N)SC)cc2)cc1
Reaction time: 4 h

Procedure:
Methyl 4-[3-(4-thiocarbamoylbenzoyl)carbazoyl]phenoxyacetate (10.5 g) was suspended in acetone (1 L) and iodomethane (100 ml) was added. The reaction mixture was heated to 40°-45° C. with stirring for 4 hours and then cooled to ambient temperature before a further aliquot of iodomethane (20 ml) was added. The reaction mixture was stirred at ambient temperature overnight. A further aliquot of iodomethane (20 ml) was added and the reaction mixture was heated again to 40°-45° C. with stirring for 3 hours. Removal of the solvents in vacuo yielded methyl 4-[3-[4-(methylthio)carbonimidoylbenzoyl)carbazoyl]phenoxyacetate as an orange-brown solid which was not purified further. A portion of the residue (10 g) was suspended in a mixture of methanol (300 ml) and dichloromethane (300 ml), and covered with a blanket of argon before a solution of dry ammonium acetate (27 g) in methanol (100 ml) was added. The reaction mixture was stirred under argon for 2-3 days. Removal of the solvents in vacuo yielded a solid residue which was crystallised, with filtration, from boiling methanol to give the title compound (8.57 g) as a pale yellow solid; m.p. 208°-210° C. (decomposes); NMR Spectrum (DMSO-d6) 1.76 (3H, s), 3.72 (3H, s), 4.91 (2H, s), 7.06 (2H, d), 8.05 (2H, d), 7.90 (4H, m); Mass Spectrum m/Z 371 (M+H)+; Elemental Analysis: calculated for C18H18N4O5. 1.0 CH3CO2H. 1.0 CH3OH. 1.0 H2O: C, 52.5%; H, 5.87%; N, 11.7%; found: C, 52.1%; H, 6.0%; N, 11.7%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][C:23]#[CH:24])=[C:10]1[C:25]([O:27][CH2:28][CH3:29])=[O:26].S(=O)(=O)(O)[OH:31]>O.O1CCOCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][C:23]([CH3:24])=[O:31])=[C:10]1[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: C#CCOCC1=C(C(=O)OCC)C(c2cccc(Cl)c2Cl)C(C(=O)OC)=C(C)N1
Reactant: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)C1=C(COCC(C)=O)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl

Procedure:
A solution of 1-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl]methoxy}-2-propyne (1.06 g) [see Preparation 8], mercuric sulphate (0.10 g) and concentrated sulphuric acid (0.2 ml) in a mixture of water (20 ml) and dioxane (20 ml) was heated at 60° for 2 hours and then evaporated. The residue was partitioned between ether and water and the organic layer washed with saturated aqueous sodium chloride solution and water, dried over sodium sulphate and evaporated to give the title compound (0.93 g), m.p. 119°-121°. This material was confirmed spectroscopically to be identical to the product of Preparation 6.
Reaction SMILES: C([CH:3]([C:7]1([CH3:20])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[N+:16]([O-])=O)[NH:9][C:8]1=S)[C:4]([O-:6])=[O:5])C.[BH4-].[Na+].[CH2:23]1COC[CH2:24]1>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[NH2:16][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[C:7]([CH2:3][C:4]([O:6][CH2:23][CH3:24])=[O:5])([CH3:20])[CH2:8][NH:9]2
Reactant: C1CCOC1
Reactant: CCC(C(=O)[O-])C1(C)C(=S)Nc2cccc([N+](=O)[O-])c21
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)CC1(C)CNc2cccc(N)c21
Reaction time: 0.17 h

Procedure:
To a solution of (±)-ethyl (3-methyl-4-nitro-2-thioxo-2,3-dihydro-1H-indol-3-yl)acetate from Step A (3.65 g, 12.4 mmol) and nickel (II) chloride hexahydrate (23.6 g, 99.2 mmol) in MeOH (30 mL) and THF (30 mL), at 0° C., was added NaBH4 (11.3 g, 298 mmol) in portions over 1 h. The resulting mixture was stirred for 10 min, then filtered through a pad of Celite, washing with MeOH, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with CH2Cl2:MeOH—90:10, to give the title compound. MS: m/z=235 (M+1).
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:8]([O:12][CH3:13])(=[O:11])[CH:9]=[CH2:10]>CO>[N:2]1([NH:1][CH2:10][CH2:9][C:8]([O:12][CH3:13])=[O:11])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: NN1CCCCC1
Reactant: C=CC(=O)OC
Solvent: CO
Product: COC(=O)CCNN1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.5 %

Procedure:
To a solution of 1-aminopiperidine (100 g, 1.00 mol) in dry MeOH (1.00 L) at 0° C., methyl acrylate (99 mL, 1.10 mol) was added dropwise over 2 h. The resulting mixture was stirred overnight at rt. The solvents were evaporated, hexane was added to the residue, and white solid (impurity) was precipitated. The solid was removed by filtration, and the filtrate was evaporated to give 94.10 g (50.5%) of the desired material as a yellow oil, which was used without purification in Example 13.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:14]N)[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH:8]=[C:7]2[Cl:13].[F:16][C:17]([F:22])([F:21])[C:18](O)=O>>[Cl:13][C:7]1[C:6]2[C:11](=[C:2]([F:1])[CH:3]=[C:4]3[N:14]([CH2:18][C:17]([F:22])([F:21])[F:16])[CH:11]([CH3:6])[CH:2]([CH3:3])[C:5]3=2)[NH:10][C:9](=[O:12])[CH:8]=1
Reactant: NNc1cc(F)c2[nH]c(=O)cc(Cl)c2c1
Reactant: O=C(O)C(F)(F)F
Product: CC1c2c(cc(F)c3[nH]c(=O)cc(Cl)c23)N(CC(F)(F)F)C1C

Procedure:
This compound was prepared using the method described in Example 23 from 8-fluoro-6-hydrazino-4-chloroquinolin-2(1H)-one and trifluoroacetic acid. Spectral data for compound 151: 1H NMR (500 MHz, acetone-d6) δ 10.36 (s, 1H), 7.06 (d, J=11.5 Hz, 1H), 6.78 (s, 1H), 4.11 (qn, J=6.8 Hz, 1H), 4.08 (dq, J=16.4, 9.9 Hz, 1H), 3.93 (dq, J=16.4, 9.2 Hz, 1H), 3.86 (qn, J=6.6 Hz, 1H), 1.45 (d, J=6.6 Hz, 3H), 1.17 (d, J=6.8 Hz, 3H).