Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](=[O:15])[NH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([NH:23][C:24]([C:26]1[S:30][C:29](Br)=[N:28][C:27]=1[CH3:32])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([NH:23][C:24]([C:26]1[S:30][C:29]([N:13]2[CH:14]=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:10]=[CH:11][C:12]2=[O:15])=[N:28][C:27]=1[CH3:32])=[O:25])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1nc(Br)sc1C(=O)NCc1ccccc1
Reactant: O=c1ccc(OCc2ccccc2)c[nH]1
Product: Cc1nc(-n2cc(OCc3ccccc3)ccc2=O)sc1C(=O)NCc1ccccc1
Yield: 32 %

Procedure:
Following the procedure as described in Example 3, making variations only as required to use 5-(benzyloxy)pyridin-2(1H)-one in place of 4-aminopyridin-2(1H)-one to react with N-benzyl-2-bromo-4-methylthiazole-5-carboxamide, the title compound was obtained as a white solid in 32% yield: mp 166-167° C.; 1H NMR (300 MHz, CDCl3) δ 8.36 (d, J=2.7 Hz, 1H), 7.48-7.22 (m, 11H), 6.61 (d, J=9.9 Hz, 1H), 6.45 (t, J=5.4 Hz, 1H), 4.98 (s, 2H), 4.56 (d, J=5.4 Hz, 2H), 2.70 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.2, 158.7, 153.3, 152.1, 143.3, 137.8, 136.1, 135.5, 128.7, 128.6, 127.9, 127.8, 127.6, 121.7, 112.0, 71.3, 44.0, 17.3; MS (ES+) m/z 432.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:11])[N:7]=[C:8]([NH2:10])[CH:9]=1)=[O:4].[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:11])[N:7]=[C:8]([NH:10][CH2:16][C:15]2[CH:18]=[CH:19][CH:20]=[C:13]([Cl:12])[CH:14]=2)[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(N)nn1C
Reactant: O=Cc1cccc(Cl)c1
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(NCc2cccc(Cl)c2)nn1C

Procedure:
5-Amino-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (644, 1.3 g, 8.0 mmol) was combined with 3-chlorobenzaldehyde (645, 0.95 mL, 8.4 mmol) and acetonitrile (40 mL). Trifluoroacetic acid (3.2 mL, 42.0 mmol) was added followed by triethylsilane (6.7 mL, 42.0 mmol). The reaction was heated to reflux overnight and then concentrated. Ethyl acetate was added and the solution was washed with 1N potassium carbonate. The organic portion was dried over anhydrous sodium sulfate, filtered and concentrated. The compound (646, 0.944 g, 42%) was crystallized from a mixture of ethyl acetate:hexane.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([F:13])[CH:6]=[C:7]([F:12])[CH:8]=2)[N:3]=1.[N:14]1[N:15]=[CH:16][N:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=12.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:14]1[N:15]=[C:16]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[C:5]([F:13])[CH:6]=[C:7]([F:12])[CH:8]=3)[N:3]=2)[N:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=12
Reactant: Fc1cc(F)c2nc(Cl)ccc2c1
Reactant: c1ccn2cnnc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Fc1cc(F)c2nc(-c3nnc4ccccn34)ccc2c1
Yield: 59.5 %

Procedure:
2-Chloro-6,8-difluoroquinoline (0.025 g, 0.125 mmol) was combined with [1,2,4]triazolo[4,3-a]pyridine (0.016 g, 0.14 mmol), micronized Cs2CO3 (0.082 g, 0.25 mmol), and PdCl2(PPh3)2 (0.0088 g, 0.013 mmol), and the solids were slurried in dioxane (1.25 mL). The reaction was degassed with argon (bubbled through the solution) then heated to reflux for 20 hours. The crude reaction mixture was chromatographed without workup on SiO2 eluting with a gradient of 6% NH4OH in MeOH/ethyl acetate to provide the desired product as an orange solid (21 mg).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:10]=1[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.[NH3:24]>O1CCCC1>[Cl:23][C:20]1[CH:21]=[CH:22][C:9]2[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[CH2:2][N:24]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10]=2[CH:19]=1
Reactant: N
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1-c1ccccc1CBr
Solvent: C1CCOC1
Product: Clc1ccc2c(c1)C(c1ccccc1)=NCc1ccccc1-2
Reaction time: 48 h

Procedure:
The solution of 2.8 g of 2-(o-bromomethylphenyl)-5-chlorobenzophenone in 20 ml of tetrahydrofuran is added dropwise to the solution of 130 ml of saturated ethanolic ammonia while stirring. After 2 days' standing at room temperature the mixture is evaporated, the residue taken up in methylene chloride, the solution washed with aqueous sodium carbonate, dried, evaporated and the residue crystallized from methanol to give the 9-chloro-7-phenyl-5H-dibenz[c,e]azepine melting at 118°-119°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:14][NH:15][C:16]([CH:18]3[O:23][CH2:22][CH2:21][NH:20][CH2:19]3)=[O:17])=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.I[C:25]1[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=1[C:27]([O:29][CH3:30])=[O:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([CH2:14][NH:15][C:16]([CH:18]3[O:23][CH2:22][CH2:21][N:20]([C:25]4[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=4[C:27]([O:29][CH3:30])=[O:28])[CH2:19]3)=[O:17])=[C:11]([CH3:13])[N:12]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccccc1I
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1CNC(=O)C1CNCCO1
Product: COC(=O)c1ccccc1N1CCOC(C(=O)NCc2sc(-c3ccc(Cl)cc3)nc2C)C1
Yield: 85.6 %

Procedure:
Using N-[[2-(4-chlorophenyl)-4-methylthiazol-5-yl]methyl]morpholine-2-carboxamide (54.4 mg, 0.155 mmol) and methyl 2-iodobenzoate (40.6 mg, 0.155 mmol), the same procedure was followed as in Example 58 to give 64.5 mg (86%) of the desired compound as a colorless powder.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:12][C@H:11]([S:13][C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][C@H:9]2[CH2:33][O:34][CH2:35][C:36]2[CH:41]=[C:40]([F:42])[C:39]([F:43])=[CH:38][C:37]=2[F:44])=[N:6][CH:7]=1.[C:45]1(B(O)O)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.CCO.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>[C:45]1([C:2]2[CH:3]=[N:4][C:5]([N:8]3[CH2:12][C@H:11]([S:13][C:14]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:10][C@H:9]3[CH2:33][O:34][CH2:35][C:36]3[CH:41]=[C:40]([F:42])[C:39]([F:43])=[CH:38][C:37]=3[F:44])=[N:6][CH:7]=2)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: Fc1cc(F)c(COC[C@@H]2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2c2ncc(Br)cn2)cc1F
Reactant: OB(O)c1ccccc1
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: COCCOC
Solvent: CCO
Product: Fc1cc(F)c(COC[C@@H]2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2c2ncc(-c3ccccc3)cn2)cc1F
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 35.6 %

Procedure:
A solution of 1.35 g (2 mmol) (2S,4R)-5-Bromo-2-[2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidin-1-yl]-pyrimidine in 12 ml dimethoxyethane were added to a suspension of 0.116 g (0.1 mmol) tetrakis(triphenylphosphine)palladium in 1.4 ml dimethoxyethane and stirred for 15 min. 0.29 g (2.4 mmol) Phenylboronic acid in 3.4 ml EtOH was then added and after 10 min, 8.8 ml of a aqueous 2 M Na2CO3 solution. The reaction was heated for 2 h at 90° C., evaporated and extracted wit H2O/Et2O (3×). The organic phases were washed with aqueous 10% NaCl, dried (Na2SO4) and evaporated. Purification by flash-chromatography on silica gel (toluene) gave 0.48 g (36%) (2S,4R)-5-Phenyl-2-[2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidin-1-yl]-pyrimidine, MS: 674 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([CH3:23])([CH3:22])[C:10](=[O:21])[C:11]([N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)=[CH:12]N(C)C)=[CH:4][CH:3]=1.[CH2:24]([Mg]Br)[CH2:25][CH3:26].Cl>CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([CH3:22])([CH3:23])[C:10](=[O:21])[C:11]([N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)=[CH:12][CH2:24][CH2:25][CH3:26])=[CH:6][CH:7]=1
Reactant: CN(C)C=C(C(=O)C(C)(C)Cc1ccc(Cl)cc1)n1cncn1
Reactant: CCC[Mg]Br
Agent: Cl
Solvent: CCOCC
Product: CCCC=C(C(=O)C(C)(C)Cc1ccc(Cl)cc1)n1cncn1
Reaction time: 1.5 h
Yield: 60.5 %

Procedure:
49.9 g (0.15 mol) of 1-(4-chlorophenyl)-2,2-dimethyl-5-dimethylamino-4-(1,2,4-triazol-1-yl)-4-penten-3-one are dissolved in 750 ml of ether, and a solution of 33.9 g (0.23 mol) of n-propyl-magnesium bromide in 100 ml of ether is added dropwise at -20° C. The reaction mixture is subsequently stirred for 1.5 hours, during which it warms to room temperature. The reaction mixture is adjusted to a pH value of 7 to 8 with dilute hydrochloric acid. The organic phase is then separated off, washed with water, dried over sodium sulphate and concentrated. The residue is purified by column chromatography (silica gel; ethyl acetate/cyclohexane=3:1). 30.1 g (60.5% of theory) of 1-(4-chlorophenyl)-2,2-dimethyl-4-(1,2,4-triazol-1-yl)-4-octen-3-one of refractive index nD20 1.5429 are obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][N:3]=1.[NH2:19][NH2:20]>C1COCC1>[NH:19]([C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][N:3]=1)[NH2:20]
Reactant: CCOC(=O)c1cnc(Cl)nc1-c1ccccc1
Reactant: NN
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(NN)nc1-c1ccccc1
Yield: 91 %

Procedure:
The title compound was prepared as described in Example 18, but employing a solution of ethyl 2-chloro-4-phenylpyrimidine-5-carboxylate (0.09 g, 0.34 mmol) and hydrazine (0.06 g, 1.7 mmol) in THF resulting in a 91% yield (0.08 g); m.p. 74-75° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8]1[C:9]([OH:20])=[C:10]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:11]([O:13][CH3:14])=[O:12].C(N(CC)CC)C>ClCCl>[CH3:6][O:7][C:8]1[C:9]([O:20][S:2]([CH3:1])(=[O:4])=[O:3])=[C:10]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1ccc(OC)c(OC)c1O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(OC)c(OC)c1OS(C)(=O)=O
Temperature: 25 °C

Procedure:
Methanesulfonyl chloride (634 μl, 0.008 mol) was added dropwise to an ice-cooled solution of methyl 3,4-dimethoxy-2-hydroxybenzoate (1.58 g, 0.0075 mol) and triethylamine (1.27 ml, 0.009 mol) in dichloromethane (30 ml) and the reaction then allowed to warm to room temperature, with stirring. The reaction mixture was washed with water (2×25 ml) and the organic layer dried (MgSO4), filtered and evaporated under reduced pressure. The crude product was purified on silica gel eluting with a solvent gradient of diethyl ether:hexane (60:40 to 100:0, v/v) to give the subtitle compound as a colourless oil that crystallised on standing (1.94 g, 90%). MS m/z 308 (MNH4)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[CH:12][C:11]=1[NH:19][C:20]([C:22]1([CH3:25])[CH2:24][O:23]1)=[O:21]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:25][C:22]([OH:23])([CH3:24])[C:20]([NH:19][C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([N+:16]([O-:18])=[O:17])[C:10]=2[CH3:9])=[O:21])=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: Cc1c(NC(=O)C2(C)CO2)cccc1[N+](=O)[O-]
Product: Cc1c(NC(=O)C(C)(O)COc2ccc(F)cc2)cccc1[N+](=O)[O-]

Procedure:
3-(4-Fluorophenoxy)-2-hydroxy-2-methyl-N-(2-methyl-3-nitrophenyl)propionamide was prepared as described in Example 1c starting from 4-fluorophenol and 2-methyloxirane-2-carboxylic acid (2-methyl-3-nitrophenyl)amide. The crude product was purified by flash chromatography (dichloromethane-1% methanol). 1H NMR (400 MHz, DMSO-d6): 1.44 (3H, s), 2.28 (3H, s), 3.96 (1H, d, J=9.5 Hz), 4.17 (1H, d, J=9.5 Hz), 6.14 (1H, s), 6.93-6.97 (2H, m), 7.08-7.13 (2H, m), 7.41-7.45 (1H, m), 7.66-7.68 (1H, m), 7.72-7.75 (1H, m), 9.72 (1H, s).
Reaction SMILES: [Br: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=O.[N+:13]([C:16]1[CH:25]=[CH:24][C:19]([C:20]([NH:22][NH2:23])=[O:21])=[CH:18][CH:17]=1)([O-:15])=[O:14]>C(O)(=O)C>[N+:13]([C:16]1[CH:25]=[CH:24][C:19]([C:20]([NH:22][N:23]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=3)[NH:7][C:6]2=[O:11])=[O:21])=[CH:18][CH:17]=1)([O-:15])=[O:14]
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Reactant: NNC(=O)c1ccc([N+](=O)[O-])cc1
Solvent: CC(=O)O
Product: O=C1Nc2ccc(Br)cc2C1=NNC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 85 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-bromo-1H-indole-2,3-dione in acetic acid was added 4-nitrobenzohydrazide. After stirring at 100° C. the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 165 mg of the title compound (85%) as a orange solid in 95.3% purity by HPLC (Rt: 4.80, 5.53, gradient of 10 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:13]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[CH:22][S:23][C:16]=34)[CH:11]=[CH:10][C:5]=2[C:6]=1[C:7](Cl)=[O:8].[N:24]1([CH2:30][CH2:31][CH2:32][NH2:33])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[N:24]1([CH2:30][CH2:31][CH2:32][NH:33][C:7]([C:6]2[C:5]3[CH:10]=[CH:11][C:12]([O:14][C:15]4[CH:20]=[CH:19][N:18]=[C:17]5[CH:21]=[CH:22][S:23][C:16]=45)=[CH:13][C:4]=3[O:3][C:2]=2[CH3:1])=[O:8])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: NCCCN1CCOCC1
Reactant: Cc1oc2cc(Oc3ccnc4ccsc34)ccc2c1C(=O)Cl
Product: Cc1oc2cc(Oc3ccnc4ccsc34)ccc2c1C(=O)NCCCN1CCOCC1

Procedure:
This material was prepared from 2-methyl-6-[thieno[3,2-b]pyridin-7-yloxy]benzofuran-3-carbonyl chloride 101 and 3-(morpholin-4-yl)propylamine in a similar manner as that described for example 108. 1H NMR (DMSO-d6) δ 8.50 (1H, d, J=5.6 Hz), 8.14 (1H, d, J=5.6 Hz), 8.07 (1H, bm), 7.80 (1H, d, J=8.6 Hz), 7.64 (1H, d, J=2.0 Hz), 7.59 (1H, d, J=5.6 Hz), 7.24 (1H, dd, J=8.3, 2.0 Hz), 6.61 (1H, d, J=5.6 Hz), 3.56 (4H, bm), 3.35–3.27 (4H, m), 2.63 (3H, s), 2.36 (4H, bm), 1.73 (2H, bm).
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:12][NH:13][OH:14].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:14][N:13]([CH3:12])[C:8](=[O:9])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CNO
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(O)C(=O)Cc1ccccc1

Procedure:
At 0° C. phenyl-acetyl chloride (11.2 mL) is added drop wise to a solution of N-methyl-hydroxylamine hydrochloride (7.07 g) and triethylamine (59 mL) in DCM (300 mL). After stirring for 90 min a sat. aqueous NaHCO3 solution is added, the layers are separated and the aqueous layer is extracted twice with DCM (2×200 mL). The solvents are removed in vacuo and the residue is purified by flash chromatography (EA/heptane 1/1) to give the desired N-hydroxy-acetamide as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16](F)=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:24]#[N:25])[CH:5]=[CH:6][C:7]=1[F:8].[OH:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:26][C:27]4[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=4)=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:24]#[N:25])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N#Cc1cnc2cc(F)c([N+](=O)[O-])cc2c1Nc1ccc(F)c(Cl)c1
Reactant: Oc1ccncc1
Product: N#Cc1cnc2cc(Oc3ccncc3)c([N+](=O)[O-])cc2c1Nc1ccc(F)c(Cl)c1

Procedure:
The compound was prepared according to the process of Preparation 2 and with 4-(3-chloro-4-fluorophenylamino)-7-fluoro-6-nitroquinoline-3-carbonitrile and 4-hydroxypyridine as starting materials.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][N:5]([CH2:7][CH3:8])[CH:6]=1.S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:18]=[C:19]([CH:32]=[CH:33][CH:34]=1)[C:20]([C:22]1[CH:30]=[C:29]2[C:25]([CH2:26][C:27](=[O:31])[NH:28]2)=[CH:24][CH:23]=1)=[O:21]>C1COCC1>[O:31]=[C:27]1[CH2:26][C:25]2[C:29](=[CH:30][C:22]([C:20]([C:19]3[CH:18]=[C:17]([NH:16][C:9]([C:3]4[C:2]([Cl:1])=[CH:6][N:5]([CH2:7][CH3:8])[N:4]=4)=[O:11])[CH:34]=[CH:33][CH:32]=3)=[O:21])=[CH:23][CH:24]=2)[NH:28]1
Reactant: CCn1cc(Cl)c(C(=O)O)n1
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCn1cc(Cl)c(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4)c2)n1
Temperature: 79 °C
Reaction time: 3 h
Yield: 54.4 %

Procedure:
A dry flask was charged with 4-Chloro-1-ethyl-1H-pyrazole-3-carboxylic acid (0.179 g, 1.03 mmol) and thionyl chloride (5 mL) and allowed to stir at 79° C. for 3 h. The thionyl chloride was then removed by concentration in vacuo. The crude acid chloride was cooled to room temperature, and then dissolved in THF (10 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 0.260 g, 1.03 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux overnight. The reaction mixture was then allowed to cool to room temperature and subsequently vacuum filtered. The solid was washed with 0° C. THF (˜5 mL) and collected to afford the 4-Chloro-1-ethyl-1H-pyrazole-3-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide as a solid (0.227 g, 0.560 mmol, 54%).
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH:13][C:14]([O:16][CH3:17])=[O:15])=[S:12])=[C:6]([N+:18]([O-])=O)[CH:5]=1)[CH3:2].O>CO>[NH2:18][C:6]1[CH:5]=[C:4]([S:3][CH2:1][CH3:2])[CH:9]=[CH:8][C:7]=1[NH:10][C:11]([NH:13][C:14]([O:16][CH3:17])=[O:15])=[S:12]
Reactant: CCSc1ccc(NC(=S)NC(=O)OC)c([N+](=O)[O-])c1
Solvent: CO
Solvent: O
Product: CCSc1ccc(NC(=S)NC(=O)OC)c(N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
A mixture of 4-ethylthio-1-(3-methoxycarbonyl-2-thioureido)-2-nitrobenzene (14.0 g), ferrous chloride tetrahydrate (3.04 g), methanol (235 ml) and water (50 ml) was heated to reflux and treated with reduced iron powder (15.5 g) portionwise during 5 minutes. The mixture was heated at reflux with stirring for one hour. Methanol (250 ml) was added and the mixture was again heated to reflux. The hot mixture was filtered and the filtrate was allowed to cool to room temperature. The solid which crystallised on cooling was filtered off to give 2-amino-4-ethylthio-1-(3-methoxycarbonyl-2-thioureido)benzene (7.5 g), m.p. 168° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH2:20][CH2:21][NH2:22])=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:34])[CH:31]([CH3:33])[CH3:32]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:32][CH:31]([CH3:33])[C:30]([NH:22][CH2:21][CH2:20][O:19][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[N:10]([S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:9])=[O:8])[CH:11]=[CH:12]2)=[O:34]
Reactant: NCCOc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Reactant: CC(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)NCCOc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 264.7 %

Procedure:
2-{[1-(Phenylsulfonyl)-1H-indol-5-yl]oxy}ethanamine (Intermediate 24, 0.20 g, 0.63 mmol) in DCM (100 mL) was treated with triethylamine (0.27 mL, 1.9 mmol) and 4-dimethylaminopyridine (39 mg, 0.32 mmol). The solution was cooled to 0° C. and was treated with isobutyryl chloride (0.14 g, 0.13 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was washed with saturated aqueous NaHCO3 (50 mL) and 1 M HCl (2×40 mL). The organic phase was dried (MgSO4) and concentrated in vacuo to give the title compound (133 mg). MS m/z 387 [M+H]+.
Reaction SMILES: [OH-:1].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:11]([NH:12][C@@H:13]3[CH2:17][N:16]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:19])[CH2:15][C@@:14]3([F:29])[CH3:28])=[C:10]([C:30]#[N:31])[CH:9]=[N:8][N:7]2[CH:32]=1.OO>CS(C)=O.CO>[Br:3][C:4]1[CH:5]=[C:6]2[C:11]([NH:12][C@@H:13]3[CH2:17][N:16]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:19])[CH2:15][C@@:14]3([F:29])[CH3:28])=[C:10]([C:30](=[O:1])[NH2:31])[CH:9]=[N:8][N:7]2[CH:32]=1
Reactant: C[C@]1(F)CN(C(=O)OCc2ccccc2)C[C@H]1Nc1c(C#N)cnn2cc(Br)cc12
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: C[C@]1(F)CN(C(=O)OCc2ccccc2)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Reaction time: 1 h
Yield: 92.3 %

Procedure:
A 2.0 M aqueous NaOH (0.6 mL, 1.200 mmol) was added dropwise to a solution of (3S,4R)-benzyl 4-((6-bromo-3-cyanopyrrolo[1,2-b]pyridazin-4-yl)amino)-3-fluoro-3-methylpyrrolidine-1-carboxylate (120 mg, 0.254 mmol) in methyl sulfoxide (2 mL), methanol (2 mL) and hydrogen peroxide (0.3 mL, 2.94 mmol) at 0° C. After 1 h at 0° C., the mixture was quenched with saturated NaHCO3 (5 mL), diluted with ethyl acetate (80 mL), washed with water, brine, dried (MgSO4) and concentrated. The residue was purified by silica gel chromatography, eluting with 20 to 80% ethyl acetate in hexanes, to give (3S,4R)-benzyl 4-((6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-3-fluoro-3-methylpyrrolidine-1-carboxylate (115 mg, 92% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 10.71 (d, J=8.4 Hz, 1H), 7.98-7.85 (m, 1H), 7.73-7.59 (m, 1H), 7.51-7.30 (m, 5H), 6.79 (d, J=7.5 Hz, 1H), 5.79-5.54 (m, 2H), 4.69-4.33 (m, 1H), 4.32-4.08 (m, 1H), 4.00-3.74 (m, 1H), 3.59-3.42 (m, 2H), 1.61-1.43 (m, 3H); MS (ES+) m/z: 490.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:24])[NH:10][N:11]=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.Br[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[C:28]([Cl:33])[CH:27]=1.N>>[Cl:33][C:28]1[CH:27]=[C:26]([N:10]2[C:9](=[O:24])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=3)[CH:12]=[N:11]2)[CH:31]=[CH:30][C:29]=1[F:32]
Reactant: CS(=O)(=O)c1ccc(-c2cn[nH]c(=O)c2-c2ccc(Cl)cc2)cc1
Reactant: Fc1ccc(Br)cc1Cl
Agent: N
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(Cl)c3)c(=O)c2-c2ccc(Cl)cc2)cc1

Procedure:
The title compound was prepared according to Example 93, starting with 4-(4-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (described in Example 99) in place of 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 1-bromo-3-chloro-4-fluorobenzene in place of 4-bromothioanisole (yield: 330 mg, 58.8%). mp 205° C. 1H NMR (300 MHz, CDCl3) δ 3.10 (s, 3H), 7.17 (d, J=9 Hz, 2H), 7.23-7.31 (m, 1H), 7.28 (d, J=9 Hz, 2H), 7.41 (d, J=9 Hz, 2H), 7.65 (ddd, J=9 Hz, 3 Hz, 1.5 Hz, 1H), 7.85 (dd, J=9 Hz, 3 Hz, 1H), 7.93 (d, J=9 Hz, 2H), 8.01 (s, 1H). MS (DCI/NH3) m/z 489 (M+H)+, 508 (M+NH4)+. Anal. calc. for C23H15Cl2N2O3S: C, 56.44; H, 3.17; N, 5.73. Found: C, 56.37; H, 3.19; N, 5.64.