Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:23][CH3:24])[S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][C:15](=[O:22])[C:16](=[CH:20][CH:21]=2)[C:17](O)=O)=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:2].C(Cl)[Cl:26].C[Si](Cl)(C)C.S(Cl)(Cl)=O>C(N(CC)CC)C>[CH2:1]([N:3]([CH2:23][CH3:24])[S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][C:15](=[O:22])[C:16](=[CH:20][CH:21]=2)[CH2:17][Cl:26])=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:2]
Reactant: ClCCl
Reactant: CCN(CC)S(=O)(=O)c1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CCN(CC)S(=O)(=O)c1ccc(-c2ccc(CCl)c(=O)[nH]2)cc1

Procedure:
From 6.0 g. of 6-[4-(diethylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinic acid in 175 ml. of methylene chloride, 2.4 ml. of triethylamine, 2.2 ml. of trimethylsilyl chloride and 2.5 ml. of thionyl chloride, following the procedure of a) above, there is obtained 6-[4-(diethylaminosulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl chloride.
Reaction SMILES: [Si]([O:8][C@H:9]([CH3:39])[C@@H:10]([NH:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[C:29]([C:35]([F:38])([F:37])[F:36])[CH:28]=1)[C:11]1[O:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[N:14][N:15]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:8][C@H:9]([CH3:39])[C@@H:10]([NH:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[C:29]([C:35]([F:36])([F:37])[F:38])[CH:28]=1)[C:11]1[O:12][C:13]([C:16]2[CH:17]=[CH:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)=[N:14][N:15]=1
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](Nc1ccc(C#N)c(C(F)(F)F)c1)c1nnc(-c2ccc(S(C)(=O)=O)cc2)o1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@@H](Nc1ccc(C#N)c(C(F)(F)F)c1)c1nnc(-c2ccc(S(C)(=O)=O)cc2)o1

Procedure:
To a pre-cooled (−70° C.) solution of 4-((1R,2R)-2-(tert-butyldimethylsilyloxy)-1-(5-(4-(methylsulfonyl)phenyl)-1,3,4-oxadiazol-2-yl)propylamino)-2-(trifluoromethyl)benzonitrile (1 g, 1.83 mmol) in THF (200 mL) was added TBAF (1.83 mL, 1.83 mmol, 1 M solution in THF) dropwise over 10 minutes. Upon complete addition the reaction mixture was concentrated under reduced pressure. The resulting residue was taken up in EtOAc (100 mL) and washed with H2O (80 mL). The biphasic mixture was separated and the aqueous layer extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine (1×70 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide a yellow oil, which was purified by flash chromatography over silica gel (50% EtOAc in hexanes then 100% EtOAc) to provide the title compound as an off-white solid. The resulting solid was diluted with CH2Cl2 (90 mL) and hexanes (70 mL) was added. Upon concentration of the suspension a white solid was provided (329 mg, 39%). 1H NMR (400 MHz, acetone-d6, δ in ppm) 8.24 (d, J=8.8 Hz, 2H), 8.16 (d, J=9 Hz, 2H), 7.74 (d, J=9 Hz, 1H), 7.38 (s, 1H), 7.19 (d, J=9 Hz, 1H), 7.01 (d, J=8 Hz, 1H), 5.19 (dd, J=6, 8 Hz, 1H), 4.59 (d, J=6 Hz, 1H), 4.49-4.42 (m, 1H), 3.2 (s, 3H) and 1.42 (d, J=7 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:3][CH:4]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)c1ccc(Br)cc1
Product: COC(=O)c1ccc(Nc2ccccc2)cc1

Procedure:
Reaction of methyl 4-bromobenzoate with aniline according to general procedure A provided methyl ester of Compound 4 as a yellow oil (84% yield). 1H NMR (CDCl3, 500 MHz): δ=7.92 (d, J=8.8 Hz, 2H), 7.32-7.38 (m, 2H), 7.18 (d, J=7.5 Hz, 2H), 7.09 (m, 1H), 6.99 (d, J=8.8 Hz, 2H), 6.02 (s, 1H), 3.89 (s, 3H). 13C NMR (CDCl3, 125 MHz): δ=167.2, 148.3, 141.1, 131.7, 129.7, 123.4, 121.5, 120.7, 114.9, 51.9.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[C:12]([CH3:25])=[N:13][N:14]([CH3:24])[C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[F:23])=[O:10].[BH4-].[Na+]>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:11]1[C:12]([CH3:25])=[N:13][N:14]([CH3:24])[C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[F:23])[OH:10]
Reactant: Cc1nn(C)c(-c2ccc(F)cc2F)c1C(=O)c1ccc(F)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1nn(C)c(-c2ccc(F)cc2F)c1C(O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of (2,4-difluorophenyl)-[5-(2,4-difluorophenyl)-1,3-dimethyl-1H-pyrazol-4-yl]methanone (i.e. the product of Example 7) (80 mg, 0.23 mmol) in ethanol (3 mL) at about 0° C. was added sodium borohydride (38 mg, 0.92 mmol). The reaction mixture was stirred at room temperature for 2 h, and then diluted with ice/hydrochloric acid (about 1 mL). The resulting mixture was poured onto a solid phase extraction tube (Varian Chem Elute®, prepacked with diatomaceous earth) eluting with ethyl acetate (75 mL). The ethyl acetate eluant was concentrated under reduced pressure and the resulting material was purified by MPLC (20 to 70% gradient of ethyl acetate in hexanes as eluant) to provide the title compound, a compound of the present invention, as a solid (63 mg).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[CH2:10]=O>O.[Pd]>[CH3:10][N:5]1[CH2:6][C@H:2]([OH:1])[CH2:3][C@H:4]1[C:7]([OH:9])=[O:8]
Reactant: C=O
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Agent: [Pd]
Solvent: O
Product: CN1C[C@H](O)C[C@H]1C(=O)O
Reaction time: 24 h
Yield: 98.3 %

Procedure:
To 40 g (305 mmol) of trans-4-hydroxy-L-proline in 80 ml of water was added 80 ml of 30% aqueous formaldehyde solution and 7.0 g of 5% palladium on carbon catalyst (50 % wet), and the mixture was hydrogenated at 50 psig using a Parr Shaker. After 24 hours, the catalyst was recovered by filtration over diatomaceous earth and the filtrate evaporated under reduced pressure to provide 43.5 g (98.3%) of title product; mp 140°-142° C. (decomposition); 1H-NMR (D2O): 4.65 (m, 1H), 4.20 (dd, 1H), 3.97 (dd, 1H), 3.2 (dm, 1H), 2.50 (m, 1H), 2.25 (m, 1H); [alpha]D =-54.8° (c=1.18, H2O).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([OH:14])=[O:13].[Br:15]Br>C(Cl)(Cl)Cl>[Br:15][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([OH:1])=[C:3]([C:12]([OH:14])=[O:13])[CH:4]=1
Reactant: O=C(O)c1ccc2ccccc2c1O
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: O=C(O)c1cc(Br)c2ccccc2c1O

Procedure:
To a solution of 2.50 g 1-hydroxy-2-naphthoic acid in 50 ml chloroform a solution of 0.68 ml bromine in 5 ml chloroform was added dropwise. After 16 h the reaction was concentrated to yield 3.40 g 4-bromo-1-hydroxy-naphthalene-2-carboxylic acid.
Reaction SMILES: Br[CH:2]([CH2:8][CH3:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1>>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([S:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=1)[CH2:8][CH3:9])[CH3:7]
Reactant: CCOC(=O)C(Br)CC
Reactant: COc1ccc(S)cc1
Product: CCOC(=O)C(CC)Sc1ccc(OC)cc1

Procedure:
2-(4-Methoxy-phenylsulfanyl)-butyric acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from ethyl 2-bromobutyrate (10.71 g, 55 mmol) and 4-methoxythiophenol (7 g, 50 mmol), 5.19 g (40%); clear oil; MS: 255.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9]1[CH:13]=[C:12]([C:14]2[N:15]=[C:16]3[C:22]([C:23]([OH:25])=O)=[CH:21][N:20]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:17]3=[N:18][CH:19]=2)[N:11]=[CH:10]1.[NH2:34][C@H:35]([CH:44]1[CH2:46][CH2:45]1)[C:36]([N:38]1[CH2:41][CH:40]([C:42]#[N:43])[CH2:39]1)=[O:37].C(Cl)CCl>CN(C1C=CN=CC=1)C.ClCCl>[C:42]([CH:40]1[CH2:41][N:38]([C:36](=[O:37])[C@H:35]([NH:34][C:23]([C:22]2[C:16]3[C:17](=[N:18][CH:19]=[C:14]([C:12]4[N:11]=[CH:10][N:9]([C:3]5[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=5[F:1])[CH:13]=4)[N:15]=3)[N:20]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:33])[CH3:32])[CH:21]=2)=[O:25])[CH:44]2[CH2:45][CH2:46]2)[CH2:39]1)#[N:43]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(-c3cn(-c4cc(F)ccc4F)cn3)cnc21
Reactant: N#CC1CN(C(=O)[C@H](N)C2CC2)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CC(C#N)C2)C2CC2)c2nc(-c3cn(-c4cc(F)ccc4F)cn3)cnc21
Yield: 49.7 %

Procedure:
A solution of 2-[1-(2,5-difluoro-phenyl)-1H-imidazol-4-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.067 g, 0.14 mmol), (R)-1-(2-amino-2-cyclopropylacetyl)azetidine-3-carbonitrile (0.038 g, 0.21 mmol), DMAP (0.021 g, 0.17 mmol) and EDC (0.036 g, 0.19 mmol) in 2 mL dichloromethane was stirred for 13.5 h. Dichloromethane (10 mL) was added, and the solution was sequentially washed with 10 mL of a 1 M citric acid solution, 10 mL of water, and 10 mL of a sat. aq. NaCl solution then dried over Na2SO4, filtered and concentrated. The residue was purified using column chromatography (80% EtOAc/hexanes) to afford 0.044 g (48%) of 2-[1-(2,5-difluoro-phenyl)-1H-imidazol-4-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide as a foamy pale yellow solid. MS: (M+Na)+=655.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:8][CH2:7][C@@H:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:5][CH2:4]1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl>[CH3:17][S:18]([O:1][CH2:2][CH:3]1[CH2:4][CH2:5][C@H:6]([NH:9][C:10]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:16])[CH2:7][O:8]1)(=[O:20])=[O:19]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC(CO)OC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCC(COS(C)(=O)=O)OC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
tert-Butyl [(3S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]carbamate (331 mg, 1.43 mmol) in dichloromethane (5 mL) was treated with methanesulfonyl chloride (0.222 mL, 2.87 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h, then concentrated and partitioned between ethyl acetate and water. The organic phase was concentrated and purified on silica gel (eluting with a gradient of 0 to 50% ethyl acetate in hexanes) to give the desired product (0.38 g, 86%). LCMS calculated for C8H16NO6S (M-t-Bu+H)+: m/z=254.1. Found: 254.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[O:8][C:9](I)=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:3]=12.[F:18][C:19]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[CH:30][C:20]=1[O:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[Na+].[Na+].C(#N)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.O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[O:8][C:9]([C:32]3[CH:31]=[CH:30][C:20]([O:21][CH2:22][CH2:23][N:24]4[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]4)=[C:19]([F:18])[CH:33]=3)=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:3]=12
Reactant: CC1(C)OB(c2ccc(OCCN3CCCCC3)c(F)c2)OC1(C)C
Reactant: Clc1ccnc2oc(I)c(-c3ccccc3)c12
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: [Na+]
Solvent: CC#N
Solvent: O
Product: Fc1cc(-c2oc3nccc(Cl)c3c2-c2ccccc2)ccc1OCCN1CCCCC1
Temperature: 80 °C
Reaction time: 23 h

Procedure:
A resealable tube was charged with 4-chloro-2-iodo-3-phenylfuro[2,3-b]pyridine 6d (0.100 g, 0.281 mmol), 1-(2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)piperidine 201 (0.200 g, 0.576 mmol), sodium carbonate (0.074 g, 0.703 mmol), acetonitrile (4 mL), and water (1 mL). Tetrakis(triphenylphosphine)palladium (0) (0.032 g, 0.028 mmol) was added and the system was purged with argon. The tube was sealed and the mixture stirred at 80° C. for 23 h. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The aqueous phase was separated and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a brown oil. Purification via preparative thin layer chromatography (eluting with 95:5:0.5 dichloromethane/methanol/ammonium hydroxide) afforded 4-chloro-2-(3-fluoro-4-(2-(piperidin-1-yl)ethoxy)phenyl)-3-phenylfuro[2,3-b]pyridine 6f as a yellow orange oil. MS (MH+) 451.1; Calculated 450 for C26H24ClFN2O2.
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[N:5]=[CH:6][C:7]([O:10][C@H:11]2[CH2:26][N:14]3[CH2:15][CH2:16][N:17](C(OC(C)(C)C)=O)[CH2:18][C@@H:13]3[CH2:12]2)=[N:8][CH:9]=1)[CH3:3]>Cl.O1CCOCC1>[CH2:1]=[C:2]([C:4]1[N:5]=[CH:6][C:7]([O:10][C@H:11]2[CH2:26][N:14]3[CH2:15][CH2:16][NH:17][CH2:18][C@@H:13]3[CH2:12]2)=[N:8][CH:9]=1)[CH3:3]
Reactant: C=C(C)c1cnc(O[C@@H]2C[C@H]3CN(C(=O)OC(C)(C)C)CCN3C2)cn1
Agent: Cl
Solvent: C1COCCO1
Product: C=C(C)c1cnc(O[C@@H]2C[C@H]3CNCCN3C2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
The product from Example 152B (157 mg, 0.436 mmol) was dissolved in 2 mL of 4 M HCl-dioxane and stirred at room temperature for 30 minutes. The mixture was concentrated under a stream of nitrogen and the residue was purified by chromatography on a 12 g silica gel column, eluting with 2.5% methanol (containing 2 N ammonia) in dichloromethane for 3 minutes followed by a gradient to 10% methanol (2 N ammonia) in dichloromethane to afford the title compound as a colorless glass (102 mg, 90%). 1H NMR (300 MHz, CDCl3) δ ppm 8.24-8.20 (m, 1H), 8.15 (d, J=1.4 Hz, 1H), 5.80 (t, J=2.6 Hz, 1H), 5.43-5.32 (m, 1H), 5.22 (p, J=1.4 Hz, 1H), 3.77-3.68 (m, 1H), 3.12 (ddd, J=7.2, 5.3, 1.8 Hz, 1H), 3.03-2.93 (m, 2H), 2.84 (ddt, J=7.3, 5.8, 2.9 Hz, 1H), 2.55-2.44 (m, 1H), 2.37-2.21 (m, 4H), 2.20-2.15 (m, 3H), 2.00-1.83 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21]C(C(F)(F)F)=O)=[CH:17][C:16]=2[N+:28]([O-:30])=[O:29])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+]>CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[N+:28]([O-:30])=[O:29])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC(=O)C(F)(F)F)cc2[N+](=O)[O-])CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2[N+](=O)[O-])CC1
Temperature: 50 °C

Procedure:
To 4-(N′-(t-butoxycarbonyl)piperidin-4-yl)oxy-3-nitro-N-(trifluoromethylcarbonyl)benzenamine in methanol (150 mL) and water (150 mL) was added K2CO3 (6.0 g) and the reaction was heated to 50° C. for overnight. The reaction was extracted with ethyl acetate. The extract was dried, concentrated and purified on silica gel column (ethyl acetate/hexane) to afford 4-(N′-(t-butoxycarbonyl)piperidin-4-yl)oxy-3-nitrobenzenamine (11.0 g).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:4]=1[C:5]([OH:7])=[O:6].[C:15](Cl)(Cl)=[O:16]>O.O1CCCC1>[N+:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:3]2[NH:2][C:15](=[O:16])[O:7][C:5](=[O:6])[C:4]=12)([O-:14])=[O:13]
Reactant: O=C(Cl)Cl
Reactant: Nc1cccc([N+](=O)[O-])c1C(=O)O
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=c1[nH]c2cccc([N+](=O)[O-])c2c(=O)o1
Reaction time: 3 h

Procedure:
A solution of 56.5 g of 2-amino-6-nitrobenzoic acid hydrochloride in 200 ml of demineralized water and 200 ml of tetrahydrofuran is cooled to 10° while stirring and treated with phosgene at 10°-30° for 1 hour, a precipitate resulting. The mixture is subsequently diluted with 300 ml of demineralized water and air is conducted through the suspension vigorously for about 3 hours (until the sample is negative for phosgene). The precipitate is filtered off, washed with water and dried in vacuo over phosphorus pentoxide. There is obtained 6-nitroisatoic acid anhydride as beige crystals of m.p. 220°-222° (decomposition).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:14][O:15][C:16]2[CH:37]=[CH:36][C:19]([CH2:20][N:21]3[CH:25]=[C:24]([CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])[C:23]([O:33][CH2:34][CH3:35])=[N:22]3)=[CH:18][CH:17]=2)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[Cl:1][C:2]1[C:3]([CH2:14][O:15][C:16]2[CH:37]=[CH:36][C:19]([CH2:20][N:21]3[CH:25]=[C:24]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])[C:23]([O:33][CH2:34][CH3:35])=[N:22]3)=[CH:18][CH:17]=2)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)ccc3Cl)cc2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1nn(Cc2ccc(OCc3nc(-c4ccccc4)ccc3Cl)cc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.8 %

Procedure:
After a mixture of ethyl 3-[1-[4-(3-chloro-6-phenyl-2-pyridylmethoxy)benzyl]-3-ethoxy-1H-pyrazol-4-yl]propionate (738 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 3 hours, 1 N hydrochloric acid (3 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[1-[4-(3-chloro-6-phenyl-2-pyridylmethoxy)benzyl]-3-ethoxy-1H-pyrazol-4-yl]propionic acid (669 mg, yield: 96%). This was recrystallized from ethyl acetate-hexane. Melting point: 120–121° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:13][CH3:14])[CH2:4][C:5]1[N:12]=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]#[N:8].C([O-])([O-])=[O:16].[Na+].[Na+].OO>CC(C)=O>[CH3:14][O:13][CH:3]([O:2][CH3:1])[CH2:4][C:5]1[N:12]=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]([NH2:8])=[O:16]
Reactant: O=C([O-])[O-]
Reactant: COC(Cc1ncccc1C#N)OC
Agent: OO
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(Cc1ncccc1C(N)=O)OC
Temperature: 25 °C
Reaction time: 14 h
Yield: 78 %

Procedure:
A mixture of 2-(2,2-dimethoxyethyl)nicotinonitrile (7 g, 36.42 mmol), aqueous Na2CO3 (3 N, 145 mL), H2O2 (15%, 145 mL) in acetone (73 mL) was stirred at room temperature for 14 h. After removal of acetone, the residue was diluted with water and extracted with DCM (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (eluting with PE/EtOAc v/v 1:1 and with EtOAc) to yield 2-(2,2-dimethoxyethyl)nicotinamide as a solid (6 g, yield 78%). ESI MS: m/z 211 [M+H]+, 233 [M+Na]+.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([NH:10][C:11]3[O:12][CH2:13][C:14]4[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30](O)=[O:31])[CH2:25][CH2:24]1>>[CH:1]1([C:4]2[CH:5]=[C:6]([NH:10][C:11]3[O:12][CH2:13][C:14]4[CH:20]=[C:19]([NH:21][C:30](=[O:31])[CH2:29][N:26]5[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]5)[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: CN1CCN(CC(=O)O)CC1
Reactant: Nc1ccc2c(c1)COC(Nc1cccc(C3CC3)c1)=N2
Product: CN1CCN(CC(=O)Nc2ccc3c(c2)COC(Nc2cccc(C4CC4)c2)=N3)CC1
Yield: 25.1 %

Procedure:
Prepared from N2-(3-cyclopropyl-phenyl)-4H-benzo[d][1,3]oxazine-2,6-diamine (160 mg, 0.57 mmol) and and 4-methylpiperazin-1-acetic acid (109 mg, 0.69 mmol) according to the procedure described for example 93. Obtained the title compound as an off-white solid (60 mg, 25%), MS (ISP) m/e=420.3 [(M+H)+].
Reaction SMILES: [CH:1]1[C:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11](O)=[CH:12][CH:13]=2)=[CH:5][CH:4]=[C:3](O)[CH:2]=1.CC1C([N:26]2[C:30](=[O:31])[CH:29]=[CH:28][C:27]2=[O:32])=C(C=CC=1)C(Cl)=O>C(N(CC)CC)C.ClCCCl>[CH:1]1[C:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([N:26]3[C:30](=[O:31])[CH:29]=[CH:28][C:27]3=[O:32])=[CH:12][CH:13]=2)=[CH:5][CH:4]=[C:3]([N:26]2[C:27](=[O:32])[CH:28]=[CH:29][C:30]2=[O:31])[CH:2]=1
Reactant: Oc1ccc(Cc2ccc(O)cc2)cc1
Reactant: Cc1cccc(C(=O)Cl)c1N1C(=O)C=CC1=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C1C=CC(=O)N1c1ccc(Cc2ccc(N3C(=O)C=CC3=O)cc2)cc1

Procedure:
A 6.0 g quantity of 4,4′-dihydroxydiphenylmethane is dissolved in a solution of 12.6 ml of triethylamine in 50 ml of 1,2-dichloroethane in a 250 ml flask. To the solution is slowly added a solution of 15.5 g of methyl maleimidobenzoyl chloride in 50 ml of 1,2-dichloroethane. The mixture is allowed to react at room temperature for 16 hr. The reaction mixture is precipitated in water, filtered under reduced pressure, washed sequentially with water and ethanol, and dried at 60° C. under vacuum for 48 hr, yielding the bismaleimide compound of Formula 20m.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:8]=1)[C:4]([OH:6])=[O:5].[Cl:19][CH:20]([Cl:24])[C:21](Cl)=[O:22]>>[Cl:19][CH:20]([Cl:24])[C:21]([O:1][N:2]=[C:3]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:8]=1)[C:4]([OH:6])=[O:5])=[O:22]
Reactant: CS(=O)(=O)Nc1cc(C(=NO)C(=O)O)ccc1O
Reactant: O=C(Cl)C(Cl)Cl
Product: CS(=O)(=O)Nc1cc(C(=NOC(=O)C(Cl)Cl)C(=O)O)ccc1O
Yield: 98.7 %

Procedure:
2-Hydroxyimino-2-(3-mesylamino-4-hydroxyphenyl)acetic acid (syn isomer) (1.37 g.) and dichloroacetyl chloride (0.9 g.) were treated according to similar manners to those of Preparation 5(1) to 5(3) to give 2-dichloroacetoxyimino-2-(3-mesylamino-4-hydroxyphenyl)acetic acid (syn isomer) (1.9 g.), which was used as a starting material for the following acylating reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[NH:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:8]=2[N:9]=1.C([O-])(=O)C.[Na+].[I:22]Cl.O>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:16])[NH:4][C:5]1[S:6][C:7]2[C:13]([I:22])=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:8]=2[N:9]=1
Reactant: COC(=O)Nc1nc2c(OC)cccc2s1
Reactant: ClI
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)Nc1nc2c(OC)ccc(I)c2s1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
(4-Methoxy-benzothiazol-2-yl)-carbamic acid methyl ester (31.0 g, 130 mmol) and sodium acetate (32.3 g, 394 mmol) are dissolved in 400 ml of glacial acetic acid and slowly treated with iodine monochloride (13.5 ml, 264 mmol) at 0° C. The reaction mixture is then slowly warmed to room temperature and stirred for 15 hours. After addition of water (1.3 l), the formed precipitate is filtered off and washed with water. The filter cake is then dissolved in a minimal amount of tetrahydrofurane (about 150 ml) and decolorized with 1M aqueous sodium thiosulfate. The product is precipitated by the addition of water (about 2.0 l), filtered off and dried at 60° C. for 12 hours. 42.3 g (89%) white solid. MS: m/e=364 (M+).
Reaction SMILES: [CH2:1]([C:4]1[C:5](=[O:18])[C:6]2[CH:17]=[CH:16][CH:15]=[CH:14][C:7]=2[NH:8][C:9](=[O:13])[C:10]=1[O:11]C)[CH:2]=[CH2:3].B(Br)(Br)Br>ClCCl.O>[CH2:1]([C:4]1[C:5](=[O:18])[C:6]2[CH:17]=[CH:16][CH:15]=[CH:14][C:7]=2[NH:8][C:9](=[O:13])[C:10]=1[OH:11])[CH:2]=[CH2:3]
Reactant: C=CCc1c(OC)c(=O)[nH]c2ccccc2c1=O
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: C=CCc1c(O)c(=O)[nH]c2ccccc2c1=O
Yield: 74.3 %

Procedure:
To a solution of 4-allyl-3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (0.2 g) in dichloromethane was added boron tribromide (1M in dichloromethane, 3 mL). The precipitate that formed was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried and evaporated using toluene to azeotrope the water. The solid was recrystallized from hot toluene to give the title compound (0.14 g); mp 174°-175° C.; NMR: 5.80 (m,1); 5.03 (s,1); 4.98 (d,1); 3.38 (d,2); MS: m/z=229(M+1). Analysis for C13 H11NO3.0.1 H2O: Calculated: C, 67.58; H, 4.89; N, 6.06; Found: C, 67.63; H, 4.88; N, 5.95.