Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(S[C:9]1[N:13]=[C:12]([CH3:14])[N:11]([C:15]2[N:20]=[C:19]([O:21][CH3:22])[N:18]=[C:17]([O:23][CH3:24])[N:16]=2)[N:10]=1)C1C=CC=CC=1.O.[S:26]([Cl:30])(Cl)(=[O:28])=[O:27]>ClCCl>[CH3:22][O:21][C:19]1[N:18]=[C:17]([O:23][CH3:24])[N:16]=[C:15]([N:11]2[C:12]([CH3:14])=[N:13][C:9]([S:26]([Cl:30])(=[O:28])=[O:27])=[N:10]2)[N:20]=1
Reactant: COc1nc(OC)nc(-n2nc(SCc3ccccc3)nc2C)n1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: COc1nc(OC)nc(-n2nc(S(=O)(=O)Cl)nc2C)n1
Temperature: 5 °C

Procedure:
A solution of 3-benzylthio-1-(4,6-dimethoxy-1,3,5-triazin-2-yl)-5-methyl-1,2,4-triazole (6 g) in dichloromethane (60 ml) was treated with silica gel (14 g) 60-120 mesh and water (2.8 g). Sulphuryl chloride (10.6 ml) in dichloromethane (12 ml) was added dropwise with stirring whilst maintaining a temperature of 5° C. for 2 hours. The silica gel was filtered off, washed with dichloromethane (150 ml) and ethyl acetate (100 ml), and the combined washings were extracted with water and aqueous sodium bicarbonate. The organic layer was dried and evaporated at 40° C. in vacuo. The residue was triturated with ether and filtered to give 3 g of the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]3[CH2:21][CH2:20][CH2:19][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([NH2:18])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.CO[C:25](OC)([N:27]([CH3:29])[CH3:28])[CH3:26]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]3[CH2:21][CH2:20][CH2:19][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([N:18]=[C:25]([N:27]([CH3:29])[CH3:28])[CH3:26])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COC(C)(OC)N(C)C
Reactant: NC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Solvent: CN(C)C=O
Product: CC(=NC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2)N(C)C
Reaction time: 2.5 h

Procedure:
19 g (60 mmol) of (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxamide are suspended in 110 ml of N,N-dimethylformamide, whereupon the suspension is treated with 17 ml (116 mmol) of N,N-dimethylacetamide dimethyl acetal and the mixture is stirred at 115° for 2.5 hours. The mixture is then cooled to 0°, the product is filtered off under suction, rinsed with N,N-dimethylformamide and diethyl ether and dried at 80° in a high vacuum. There is obtained (S)-8-chloro-N-[1-(dimethylamino)ethylidene]-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxamide of decomposition point 289°-291°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][N:5]([CH3:27])[C:6]2[C:7]=1[CH:8]=[CH:9][C:10]1[N:19]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:18][CH:17]=[C:12]3[NH:13][C:14](=[O:16])[C:15]=2[C:11]=13.C(N(CC)C(C)C)(C)C.[C:37]1([S:43](Cl)(=[O:45])=[O:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>ClCCl>[F:26][C:23]1[CH:22]=[CH:21][C:20]([N:19]2[C:10]3=[C:11]4[C:15](=[C:6]5[N:5]([CH3:27])[CH:4]=[CH:3][C:2]([NH:1][S:43]([C:37]6[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=6)(=[O:45])=[O:44])=[C:7]5[CH:8]=[CH:9]3)[C:14](=[O:16])[NH:13][C:12]4=[CH:17][CH2:18]2)=[CH:25][CH:24]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CN1C=CC(N)=c2ccc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1C=CC(NS(=O)(=O)c2ccccc2)=c2ccc3c4c([nH]c(=O)c-4c21)=CCN3c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stock solution of Example 23e and N,N-diisopropylethylamine (0.08 M and 0.16 M in dichloromethane, respectively, 500 μL, 0.042 mmol Example 23e and 0.083 mmol N,N-diisopropylethylamine), and benzenesulfonyl chloride (0.40 M in dichloromethane, 239 μL, 0.096 mmol) were mixed and stirred at ambient temperature overnight. The reaction mixture was concentrated, dissolved in methanol (1 mL) and injected on the reverse phase HPLC(C8, acetonitrile/water (0.1% TFA), 5-100%) to yield the title compound as an impure mixture.
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17]CC2C=CC=CC=2)=[CH:13][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].[H][H]>[Pd].O1CCCC1>[CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)OCC
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Yield: 97 %

Procedure:
A mixture of racemic ethyl 2-ethoxy-3-(4-benzyloxyphenyl)propionate of the formula (12a) (40 g) obtained according to the procedure described in step (iv) above, 5% Pd/C catalyst (8 g) and tetrahydrofuran (120 ml) was subjected to hydrogenation at room temperature and 50–60 psi of hydrogen pressure for a period of 8–12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the catalyst was filtered off and the solvent was removed under reduced pressure to afford the title compound of the formula (13a) (28–29 g, 97–98%).
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:8]2[N:9]=[C:10]([C:13]#[N:14])[N:11]=[CH:12][C:7]=2[CH:6]=[C:5]1[CH2:15][N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1.N1C=CC=CC=1.[OH:31][NH2:32]>C(Cl)Cl>[CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:8]2[N:9]=[C:10]([C:13]#[N:14])[N:11]=[CH:12][C:7]=2[CH:6]=[C:5]1[CH2:15][N:16]1[CH2:21][CH2:20][C:19](=[N:32][OH:31])[CH2:18][CH2:17]1
Reactant: NO
Reactant: CC(C)(C)Cn1c(CN2CCC(=O)CC2)cc2cnc(C#N)nc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)Cn1c(CN2CCC(=NO)CC2)cc2cnc(C#N)nc21
Reaction time: 24 h
Yield: 97.9 %

Procedure:
To a solution of 100 mg (0.30 mmoles) of 7-(2,2-dimethyl-propyl)-6-(4-oxo-piperidin-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile and 0.047 ml (0.75 mmoles) of pyridine in 5 ml of CH2Cl2, 52 mg (0.75 mmoles) of hydroxyl amine is added at ambient temperature. After being stirred for 24 hours, the reaction mixture is quenched with H2O and extracted with CH2Cl2. The combined extracts are washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to give 100 mg of desired 7-(2,2-dimethyl-propyl)-6-(4-hydroxyimino-piperidin-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 98% yield.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]3=2)[CH2:4][CH2:3][C@@H:2]1[CH2:15][OH:16].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:16][CH2:15][C@H:2]2[CH2:3][CH2:4][C:5]3[C:10](=[C:9]4[CH:11]=[CH:12][CH:13]=[CH:14][C:8]4=[CH:7][CH:6]=3)[O:1]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: OC[C@H]1CCc2ccc3ccccc3c2O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCc3ccc4ccccc4c3O2)cc1
Temperature: 50 °C
Yield: 77.2 %

Procedure:
To a solution of (2R)-3,4-dihydro-2H-benzo[h]chromen-2-ylmethanol (0.90 g, 4.22 mmol) in dichloromethane (50 mL) is added p-toluenesulfonyl chloride (1.61 g, 8.44 mmol), 4-(dimethylamino)pyridine (0.10 g, 0.84 mmol), and N,N-diisopropylethylamine (1.20 g, 9.28 mmol) and the reaction mixture is heated to 50° C. for 12 h. The reaction mixture is quenched by the addition of water (100 mL). The aqueous layer is separated and extracted with dichloromethane (100 mL). The combined organic extracts are washed with aqueous hydrogen chloride (1.0 M, 100 mL), water (100 mL), aqueous sodium chloride (100 mL), dried (magnesium sulfate), and the solvent is removed in vacuo to provide a crude solid. Purification by flash column chromatography (silica, ethyl acetate:hexanes 2:3) provides 1.20 g (77%, 50% ee) of (2R)-3,4-dihydro-2H-benzo[h]chromen-2-ylmethyl 4-methylbenzenesulfonate as a white solid. [α]D25=−10.23 (c 10.16 in chloroform, 50% ee); Rf=0.68 (silica, ethyl acetate:hexanes 2:3); mp 107-111° C.; Anal. Calcd. for C21H20O4S: C, 68.46; H, 5.47. Found: C, 68.10; H, 5.27.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[F:25][C:4]1[C:5]([CH3:24])=[C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:30]4[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]4)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: CN1CCNCC1
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Product: Cc1c(-c2cnn(-c3ccc(C(=O)N4CCN(C)CC4)cn3)c2O)ccc(C#N)c1F

Procedure:
The title compound was prepared in a manner similar to Example 301 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 1-methylpiperazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.33 (d, J=2.53 Hz, 3H) 2.84 (s, 3H) 3.17 (s, 8H) 7.63 (d, J=7.58 Hz, 1H) 7.70-7.79 (m, 1H) 8.04-8.57 (m, 3H) 8.59 (d, J=1.52 Hz, 1H). ESI-MS m/z [M+H]+ 421.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([CH2:30][CH2:31][OH:32])[CH:29]=1)[CH2:5][N:6]1[CH2:26][CH2:25][C:9]2([O:14][CH2:13][CH2:12][N:11]([C:15]([C:17]3[N:18]=[C:19]([CH:22]([CH3:24])[CH3:23])[S:20][CH:21]=3)=[O:16])[CH2:10]2)[CH2:8][CH2:7]1.FC(F)(F)C(O)=O.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:29]=[C:28]([CH2:30][CH:31]=[O:32])[CH:27]=[C:4]([CH2:5][N:6]2[CH2:26][CH2:25][C:9]3([O:14][CH2:13][CH2:12][N:11]([C:15]([C:17]4[N:18]=[C:19]([CH:22]([CH3:23])[CH3:24])[S:20][CH:21]=4)=[O:16])[CH2:10]3)[CH2:8][CH2:7]2)[CH:3]=1
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cc(Cl)cc(CCO)c4)CC3)C2)cs1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cc(Cl)cc(CC=O)c4)CC3)C2)cs1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of (9-(3-chloro-5-(2-hydroxyethyl)benzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-isopropylthiazol-4-yl)methanone (example 52, step c) (0.242 g) in DCM (5 mL) was cooled in ice-water, treated with trifluoroacetic acid (0.059 mL) and stirred for 5 minutes. Dess-Martin periodinane (0.323 g) was added, then the mixture was removed from the cooling bath and stirred at room temperature for 30 minutes. The solution was diluted with saturated sodium thiosulphate solution (5 mL), saturated sodium bicarbonate solution (5 mL) and ethyl acetate (5 mL) and the resulting mixture was stirred vigorously for 10 minutes. The mixture was then extracted twice with ethyl acetate, the combined organic phases were washed with brine, acidified with acetic acid (0.1 mL), dried over anhydrous magnesium sulphate and concentrated in vacuo to give the crude subtitled compound as a yellow foam. Yield 0.297 g. ink 476 (M+H)+ (APCI)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[S:11](Cl)(=[O:13])=[O:12].[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[S:11]([NH:8][C:4]1[CH:3]=[CH:2][CH:1]=[C:19]2[C:20]=1[N:15]=[CH:16][CH:17]=[CH:18]2)(=[O:13])=[O:12]
Reactant: c1ccncc1
Reactant: Cc1cccc([N+](=O)[O-])c1S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1cccc([N+](=O)[O-])c1S(=O)(=O)Nc1cccc2cccnc12
Yield: 39 %

Procedure:
In a similar fashion using route 14 general procedure 27, 8-aminoqunoline (1.6 g, 11.1 mmol), 2-methyl-6-nitro-benzenesulfonyl chloride (Intermediate 451) (3.5 g, 14.4 mmol), pyridine (10 ml), DMAP (cat.) and DCM (5 ml) gave the title compound (1.5 g, 39%) after purification by column chromatography with n-hexane/EtOAc (85:15) as the eluent.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=2)=[N:6][CH:7]=1.[C:18]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:21])[CH:19]=[CH2:20].CCN(C(C)C)C(C)C>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:17][O:16][C:10]1[CH:9]=[C:8]([C:5]2[N:6]=[CH:7][C:2](/[CH:20]=[CH:19]/[C:18]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:3][CH:4]=2)[CH:13]=[CH:12][C:11]=1[O:14][CH3:15]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: COc1ccc(-c2ccc(Br)cn2)cc1OC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc(/C=C/C(=O)OC(C)(C)C)cn2)cc1OC
Reaction time: 18 h
Yield: 82.4 %

Procedure:
To a degassed solution of bromide 37 (0.47 g, 1.6 mmol), tert-butyl acrylate 38 (1.12 mL, 7.7 mmol), POT (0.34 g, 1.1 mmol) and Hunig's base (1.11 mL, 6.4 mmol) in DMF (8 mL) was added tris(dibenzylideneacetone)dipalladium (0) (0.124 g, 0.16 mmol). The solution was placed in a preheated oil bath at 120° C., stirred for 18 h and concentrated. Flash chromatography purification of the residue (eluent: 3:1 hexane:AcOEt) afforded title compound 39 (0.45 g, 83% yield).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].P(Cl)(Cl)[Cl:12]>ClCCCl.ClC(Cl)C>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:12])=[O:5]
Reactant: ClP(Cl)Cl
Reactant: O=C(O)c1ccccc1Br
Solvent: CC(Cl)Cl
Solvent: ClCCCl
Product: O=C(Cl)c1ccccc1Br

Procedure:
To a mixture of 50.2 g (0.25 mole) of 2-bromobenzoic acid in 200 ml of 1,2-dichloroethane was added 13.7 g (0.10 mole) of phosphorous trichloride in 100 ml of dichloroethane. The mixture was heated at reflux for 4 hours to provide 2-bromobenzoyl chloride.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:4][CH:5]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]=1[N+:8]([O-:10])=[O:9].[OH:17]O>C(O)(=O)C>[CH3:1][S:2]([C:3]1[NH:4][CH:5]=[C:6]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:7]=1[N+:8]([O-:10])=[O:9])=[O:17]
Reactant: CSc1[nH]cc(-c2ccccc2)c1[N+](=O)[O-]
Reactant: OO
Solvent: CC(=O)O
Product: CS(=O)c1[nH]cc(-c2ccccc2)c1[N+](=O)[O-]
Reaction time: 5 h
Yield: 77.5 %

Procedure:
2-Methylthio-3-nitro-4-phenylpyrrole (3.00 g, 0.013 mol) was suspended in glacial acetic acid (200 ml), and 30% hydrogen peroxide (1,45 g, 0.013 mol) was added. The mixture was stirred at 80° for five hours, after which the mixture was evaporated to dryness and the solid residue was recrystallised from isopropanol to give 2-methylsulphinyl-3-nitro-4-phenyl pyrrole (2.52 g), m.p. 197° dec.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:38])[CH:11]([O:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([C:31]3[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=3)(=[O:30])=[O:29])=[CH:24][CH:23]=2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:5][C:4]=1[N+:39]([O-:41])=[O:40])[NH2:2].Cl.[CH2:43]([O:45][C:46]([CH2:48][C:49](=N)[O:50]CC)=O)[CH3:44]>>[N+:39]([C:4]1[CH:5]=[C:6]([NH:9][C:10](=[O:38])[CH:11]([O:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([C:31]3[CH:32]=[CH:33][C:34]([OH:37])=[CH:35][CH:36]=3)(=[O:29])=[O:30])=[CH:24][CH:23]=2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:7]=[CH:8][C:3]=1[N:1]1[C:49](=[O:50])[CH:48]=[C:46]([O:45][CH2:43][CH3:44])[NH:2]1)([O-:41])=[O:40]
Reactant: CCOC(=N)CC(=O)OCC
Reactant: CCCCCCCCCC(Oc1ccc(S(=O)(=O)c2ccc(O)cc2)cc1)C(=O)Nc1ccc(NN)c([N+](=O)[O-])c1
Agent: Cl
Product: CCCCCCCCCC(Oc1ccc(S(=O)(=O)c2ccc(O)cc2)cc1)C(=O)Nc1ccc(-n2[nH]c(OCC)cc2=O)c([N+](=O)[O-])c1
Yield: 29 %

Procedure:
N-[3-nitro-4-(3-ethoxy-5-pyrazolon-1-yl)phenyl]2- [4-(4-hydroxyphenylsulphonyl)phenoxy]undecylamide was prepared by the method in (2b) from N-(4-hydrazino-3-nitrophenyl)- 2-[4-(4-hydroxyphenylsulphonyl)phenoxy]undecylamide (3b) and O-ethyl 2-ethoxycarbonylacetimidate hydrochloride (prepared from ethyl cyanoacetate and ethanol as in method (2a)). The crude product was partially purified by column chromatography using 63-200 mesh silica gel and ethyl acetate/60°-80° C. petroleum ether (1:1) as the eluent. The yield was 29% over the two stages (3a) to (3c).
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[C:15]([C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([NH:25][C:26](=[O:29])[CH2:27]Cl)=[C:20]([Cl:30])[CH:19]=1)(=[O:17])[CH3:16].C(N(CC)CC)C>CN(C)C=O>[C:15]([C:18]1[CH:19]=[C:20]([Cl:30])[C:21]([NH:25][C:26](=[O:29])[CH2:27][N:7]2[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3][CH:2]2[CH3:1])=[C:22]([Cl:24])[CH:23]=1)(=[O:17])[CH3:16]
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Reactant: CC(=O)c1cc(Cl)c(NC(=O)CCl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)c1cc(Cl)c(NC(=O)CN2CCN(C(=O)OC(C)(C)C)CC2C)c(Cl)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 12 parts of (1,1-dimethylethyl) 3-methyl-1-piperazinecarboxylate, 18.7 parts of N-(4-acetyl-2,6-dichlorophenyl)-2-chloroacetamide, 11.8 parts of N,N-diethylethanamine and 230 parts of N,N-dimethylformamide was stirred first for 8 hours at 70° C. and then over weekend at room temperature. The reaction mixture was evaporated and the residue was taken up in water. The product was extracted twice with dichloromethane. The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using trichloromethane as eluent. The desired fraction was collected and the eluent was evaporated, yielding 27 parts (100%) of (1,1-dimethylethyl) 4-[2-[(4-acetyl-2,6-dichlorophenyl)amino]-2-oxoethyl]-3-methyl-1-piperazinecarboxylate as a residue (int. 21).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl>CN(C)C=O>[CH2:3]([O:10][C:11]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:19]=1)=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(Nc1ccc(O)cc1)OCc1ccccc1
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(NC(=O)OCc2ccccc2)cc1
Reaction time: 0.08 h
Yield: 86.4 %

Procedure:
1.89 g (45.2 mmol) of sodium hydride (as a 55% w/w dispersion in mineral oil) were added, whilst ice-cooling, to a solution of 10.0 g (41.1 mmol) of 4-(benzyloxycarbonylamino)phenol [prepared as described in step (a) above] in 100 ml of dimethylformamide, and the mixture was stirred for 5 minutes. 5.01 ml (45.2 mmol) of ethyl bromoacetate were then added to the resulting mixture, after which the mixture was stirred at room temperature for 3 hours. At the end of this time, the reaction mixture was neutralized with 1N aqueous hydrochloric acid, and the solvent was removed by distillation under reduced pressure. The residue was mixed with ethyl acetate, and the resulting organic solution was washed with a 5% w/v aqueous solution of citric acid, with a 5% w/v aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order. The reaction mixture was then dried over anhydrous sodium sulfate, and the organic solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate in ratios ranging from 10:1 to 6:1 by volume as the eluent, to give 11.7 g of the title compound as colorless crystals, melting at 85°-86° C.
Reaction SMILES: C1(C(=[N:14][C:15]([CH3:21])([CH2:18][CH2:19][F:20])[C:16]#[N:17])C2C=CC=CC=2)C=CC=CC=1.[ClH:22]>O1CCCC1.O>[ClH:22].[NH2:14][C:15]([CH3:21])([CH2:18][CH2:19][F:20])[C:16]#[N:17]
Reactant: CC(C#N)(CCF)N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(N)(C#N)CCF
Temperature: 25 °C
Reaction time: 8 h

Procedure:
17.45 g (50.45 mmol; 81% purity) of rac-2-[(diphenylmethylene)amino]-4-fluoro-2-methylbutanonitrile from Example 69A were dissolved in 235.6 ml of tetrahydrofuran and 9.1 ml of water, 111 ml (55.46 mmol) of hydrogen chloride solution (0.5 N in diethyl ether) were added and the mixture was stirred at room temperature overnight. The slightly turbid reaction solution was admixed with 25.21 ml (50.42 mmol) of hydrogen chloride solution (2 N in diethyl ether) and concentrated by rotary evaporation. The isolated crude product was reacted further directly without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:12]2[CH:13]=[N:14][N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:25])[CH3:24])[CH2:19][CH2:18]3)[CH:16]=2)=[C:6]2[CH:10]=[C:9](Cl)[O:8][C:7]=12.[O:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[N:32]1[C:40]2[C:35](=[CH:36][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:38][CH:39]=2)[C:34]([C:50]#[N:51])=[N:33]1>>[C:23]([N:20]1[CH2:21][CH2:22][CH:17]([N:15]2[CH:16]=[C:12]([C:5]3[CH:4]=[N:3][C:2]([NH2:1])=[C:7]4[O:8][C:9]([C:37]5[CH:36]=[C:35]6[C:40](=[CH:39][CH:38]=5)[N:32]([CH:27]5[CH2:28][CH2:29][CH2:30][CH2:31][O:26]5)[N:33]=[C:34]6[C:50]#[N:51])=[CH:10][C:6]=34)[CH:13]=[N:14]2)[CH2:18][CH2:19]1)(=[O:25])[CH3:24]
Reactant: CC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(Cl)cc34)cn2)CC1
Reactant: CC1(C)OB(c2ccc3c(c2)c(C#N)nn3C2CCCCO2)OC1(C)C
Product: CC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(-c5ccc6c(c5)c(C#N)nn6C5CCCCO5)cc34)cn2)CC1
Yield: 65 %

Procedure:
The title compound was prepared in 65% yield from 1-{4-[4-(7-amino-2-chlorofuro[2,3-c]pyridin-4-yl)-1H-pyrazol-1-yl]piperidin-1-yl}ethanone and 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-3-carbonitrile by a procedure analogous to Example 87. 1H NMR (400 MHz, CDCl3): δ 8.39 (s, 1 H), 8.07-7.92 (m, 2 H), 7.90-7.80 (m, 2 H), 7.72 (s, 1 H), 7.19 (s, 1 H), 5.87 (dd, J=2.9, 8.2 Hz, 1 H), 4.97 (s, 2 H), 4.87-4.68 (m, 1 H), 4.60-4.28 (m, 1 H), 4.11-3.87 (m, 2 H), 3.88-3.68 (m, 1 H), 3.39-3.16 (m, 1 H), 2.95-2.69 (m, 1 H), 2.61-2.43 (m, 1 H), 2.31 (br. s, 2 H), 2.23-2.12 (m, 4 H), 2.12-1.96 (m, 2 H), 1.93-1.62 (m, 4 H); MS (ESI): 551.19 [M+H]+; HPLC tR=2.62 min (ZQ3, polar—4 min).
Reaction SMILES: Cl[C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][N:10]=2)=[O:7])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].[C:21]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:24]([O:23][C:21](=[O:22])[NH:28][C:29]1[CH:30]=[CH:31][C:32]([O:35][C:2]2[CH:17]=[CH:16][C:5]([C:6](=[O:7])[NH:8][C:9]3[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][N:10]=3)=[CH:4][C:3]=2[N+:18]([O-:20])=[O:19])=[CH:33][CH:34]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: O=C(Nc1ccc(Cl)cn1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc(C(=O)Nc3ccc(Cl)cn3)cc2[N+](=O)[O-])cc1
Temperature: 80 °C
Yield: 60.9 %

Procedure:
A solution of the product of Example 199A (300 mg, 0.9612 mmol) in anhydrous N,N-dimethylformamide (5 mL) was treated with N-Boc-4-hydroxyaniline (201 mg, 0.9612 mmol) and potassium carbonate (266 mg, 1.922 mmol) at room temperature, then heated at 80° C. under a nitrogen atmosphere for 5 hours. The reaction was cooled to room temperature and the solvent removed by rotary evaporation in vacuo. The residue was taken up in ethyl acetate (100 mL) and washed with water (4×50 mL) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation in vacuo. Trituration with 5% ethyl acetate gave the title compound (284 mg, 61%).
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[CH2:5][O:6][CH3:7].C([O-])([O-])=O.[K+].[K+]>CO>[C:9]([NH:8][CH:4]([CH2:5][O:6][CH3:7])[C:3]([OH:19])=[O:2])([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]
Reactant: COCC(NC(=O)OCc1ccccc1)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COCC(NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.6 %

Procedure:
Compound 10 (0.58 g) was dissolved in 80% aqueous methanol (3.0 mL). To this solution was added anhydrous K2CO3 (0.5 g) and the reaction mixture was stirred at room temperature (8 hours). The methanol was evaporated in vacuo and the residue suspended in water (50 mL). The aqueous suspension was washed with ethyl ether (2×25 mL) and then acidified to pH 3.0 using 5N HCl. The acidified aqueous phase was extracted with ethyl acetate (3×25 mL). The ethyl acetate extracts were combined, dried (Na2SO4), filtered, and evaporated in vacuo to obtain pure 11 as a clear viscous oil (0.52 g, 95%): Rf0.30 (10% MeOH/CHCl3).