Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][C:14]#[N:15])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(O)C.Cl.[F:20][C:21]1[C:22](N)=[C:23]([NH2:27])[CH:24]=[CH:25][CH:26]=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([CH:6]1[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][C:14]2[NH:27][C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([F:20])[C:22]=3[N:15]=2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: Nc1cccc(F)c1N
Reactant: CCOC(=O)C1CCN(CCC#N)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1CCN(CCc2nc3c(F)cccc3[nH]2)CC1
Reaction time: 20 h
Yield: 54.3 %

Procedure:
A solution of (a) (6.4 g, 30 mmol) and ethanol (2.1 ml, 40 mmol) in chloroform (60 ml) was saturated with gaseous hydrochloric acid at 0° C. for 0.5 hours. The mixture was left 20 hours at 4° C. then concentrated in vacuo to afford a white foam. This was suspended in chloroform (60 ml), treated with 3-fluorophenylenediamine (3.8 g, 30 mmol) and heated under reflux for 1 hour. The mixture was poured onto water. The aqueous phase was then basified with sodium bicarbonate and extracted three times with dichloromethane. The organic extract was washed with water, brine, dried over magnesium sulfate and evaporated. The resulting residue was triturated with ethyl acetate, then diethyl ether to give a white solid (5.2 g, 55%).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([NH:22][CH2:23][CH2:24][NH2:25])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[C:26](=O)([O:32]C(C)(C)C)[O:27][C:28]([CH3:31])([CH3:30])[CH3:29]>ClCCl>[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([NH:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: NCCNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.1 %

Procedure:
Triethylamine (3.12 mL, 22.4 mmol) was added to a slurry of N-(2-chloro-3-nitroquinolin-4-yl)ethane-1,2-diamine (3.00 g, 11.2 mmol) in dichloromethane (80 mL). A solution of di-tert-butyl carbonate (2.95 g, 13.5 mmol) in dichloromethane (20 mL) was added over 5 minutes to the slurry. The solution was stirred at room temperature for three hours and then was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The aqueous layer was extracted with dichloromethane. The organic layers were combined and washed with brine, dried over magnesium sulfate, filtered, and concentrated to an orange solid. The crude product was purified by flash chromatography (silica gel, 3:1 hexanes/ethyl acetate as the eluent) to afford tert-butyl 2-[(2-chloro-3-nitroquinolin-4-yl)amino]ethylcarbamate (3.70 g) as a bright yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C:3]1=O.C[N:9](C1C=CC=CC=1)[S:10]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]2[CH:33]=[CH:32][C:21]3=[N:22][CH:23]=[C:24]([C:26]4[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=4)[CH:25]=[C:20]3[C:19](=[O:34])[C:18]=2[CH:35]=1)(=[O:12])=[O:11].N1C=CC=C(N)C=1>CS(C)=O.O>[CH3:31][N:29]1[CH:30]=[C:26]([C:24]2[CH:25]=[C:20]3[C:19](=[O:34])[C:18]4[CH:35]=[C:14]([CH2:13][S:10]([NH:9][C:3]5[CH:1]=[N:2][CH:6]=[CH:5][CH:4]=5)(=[O:12])=[O:11])[CH:15]=[CH:16][C:17]=4[CH:33]=[CH:32][C:21]3=[N:22][CH:23]=2)[CH:27]=[N:28]1
Reactant: CN1CCCC1=O
Reactant: CN(c1ccccc1)S(=O)(=O)Cc1ccc2ccc3ncc(-c4cnn(C)c4)cc3c(=O)c2c1
Agent: Nc1cccnc1
Solvent: O
Solvent: CS(C)=O
Product: Cn1cc(-c2cnc3ccc4ccc(CS(=O)(=O)Nc5cccnc5)cc4c(=O)c3c2)cn1
Temperature: 180 °C
Reaction time: 2.25 h

Procedure:
N-Methyl-2-pyrrolidinone (3 ml) was added to N-methyl-1-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-phenylmethanesulfonamide (150 mg, 0.319 mmol) and pyridin-3-amine (150 mg, 1.594 mmol) in a vial. The vial was sealed and the resulting solution was heated to 180° C. with stirring. After 2.25 h., the reaction was cooled to room temperature and diluted in DMSO and water. The resulting solution was filtered and purified by preparative HPLC Reverse phase (C-18), eluting with Acetonitrile/Water+0.05% TFA, to afford the title compound as a brown solid. 1H NMR (600 MHz, DMSO-D6) δ 9.21 (d, 1H); 8.52 (d, 1H); 8.48 (s, 1H); 8.33 (d, 1H); 8.16 (d, 1H); 8.15 (s, 1H); 8.07 (s, 1H); 7.77 (d, 1H); 7.68 (dd, 1H); 7.52 (m, 1H); 7.35 (d, 1H); 7.32 (d, 1H); 7.25 (m, 1H); 4.77 (s, 2H); 3.89 (s, 3H). LRMS (APCI) calculated for C24H19N5O3S [M+H]+, 458.1. found 458.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:23]#[N:24])=[N:9]2)=[CH:4][CH:3]=1.CI.[C:27](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:27][NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:23]#[N:24])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CS(=O)(=O)c1ccc(-c2cc(C#N)nn2-c2ccc(N)cc2)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CNc1ccc(-n2nc(C#N)cc2-c2ccc(S(C)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.8 %

Procedure:
A mixture of 1-(4-aminophenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole-3-carbonitrile (1 g), methyl iodide (0.42 g) and potassium carbonate (0.6 g) in N,N-dimethylformamide (10 ml) was stirred at ambient temperature for 1 hour. The mixture was poured into water and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated. The residue (1.2 g) was purified by column chromatography on silica gel (20 g) eluting with chloroform to give crystals of 1-[4-(methylamino)phenyl]-5-[4-(methylsulfonyl)phenyl]pyrazole-3 -carbonitrile (0.31 g).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9]C(C)=O)[C:5]([CH3:13])=[C:4]2[CH2:14][CH2:15][C@:16]([CH2:19][CH2:20][CH2:21][C@@H:22]([CH2:24][CH2:25][CH2:26][C@@H:27]([CH2:29][CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[CH3:28])[CH3:23])([CH3:18])[O:17][C:3]=12.S(=O)(=O)(O)O>C(O)C>[CH3:8][C:7]1[C:2]([CH3:1])=[C:3]2[C:4]([CH2:14][CH2:15][C@:16]([CH2:19][CH2:20][CH2:21][C@@H:22]([CH2:24][CH2:25][CH2:26][C@@H:27]([CH2:29][CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[CH3:28])[CH3:23])([CH3:18])[O:17]2)=[C:5]([CH3:13])[C:6]=1[OH:9]
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Agent: O=S(=O)(O)O
Solvent: CCO
Product: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2

Procedure:
D-α-tocopherol acetate (produced by Amakasu Chemical Co. of Japan) is heated in a mixed solution of 50% aqueous sulfuric acid and ethyl alcohol (the ratio of about 1:5) to conduct hydrolysis. With the use of D-α-tocopherol thus obtained, treatment is carried out in the same manner as in Example 1.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15]([Br:24])=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[CH:18]=3)[C:3]=12.[OH-].[Na+].C(O)=O>CS(C)=O.O>[NH2:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15]([Br:24])=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[CH:18]=3)[C:3]=12
Reactant: CCOC(=O)c1c(C)nc2sc(Br)c(-c3cccc(Br)c3)c2c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O=CO
Solvent: O
Product: Cc1nc2sc(Br)c(-c3cccc(Br)c3)c2c(N)c1C(=O)O
Temperature: 150 °C
Yield: 77.1 %

Procedure:
To a solution of ethyl 4-amino-2-bromo-3-(3-bromophenyl)-6-methylthieno[2,3-b]pyridine-5-carboxylate (Description 47) (2.566 g, 5.46 mmol) in DMSO (25 mL) was added aqueous NaOH (2M) (13.64 mL, 27.3 mmol). The mixture was then heated at 150° C. for 1 h. After cooling to RT, the solution was diluted with water (40 mL) and acidified (ca. pH 4-5) with formic acid. The aqueous layer was then extracted with ethyl acetate (50 mL×3), and the combined organic layers were dried and concentrated. Water (excess) was then added to the residue, and a white precipitate crashed-out. The solution was filtered and the precipitate was collected and left to dry overnight in the vacuum oven, to give the title compound (1.861 g). LCMS (A) m/z: 443 [M+1]+, Rt 1.10 min (acidic).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:18][CH3:19])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]2=[N:20][CH:21]=[C:22]([C:23]#[N:24])[N:4]2[N:3]=1.[NH2:25][C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([CH2:35][CH2:36][CH2:37][N:38]2[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]2)[C:33]=1[Cl:34])[C:29]#[N:30]>>[Cl:34][C:33]1[C:32]([CH2:35][CH2:36][CH2:37][N:38]2[CH2:39][CH2:40][N:41]([CH3:44])[CH2:42][CH2:43]2)=[CH:31][C:28]([C:29]#[N:30])=[CH:27][C:26]=1[NH:25][C:2]1[N:7]=[C:6]([N:8]([CH2:18][CH3:19])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]2=[N:20][CH:21]=[C:22]([C:23]#[N:24])[N:4]2[N:3]=1
Reactant: CN1CCN(CCCc2cc(C#N)cc(N)c2Cl)CC1
Reactant: CCN(Cc1ccc(OC)cc1)c1nc(Cl)nn2c(C#N)cnc12
Product: CCN(Cc1ccc(OC)cc1)c1nc(Nc2cc(C#N)cc(CCCN3CCN(C)CC3)c2Cl)nn2c(C#N)cnc12

Procedure:
2-((2-chloro-5-cyano-3-(3-(4-methylpiperazin-1-yl)propyl)phenyl)amino)-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile was prepared from 2-chloro-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile and 3-amino-4-chloro-5-(3-(4-methylpiperazin-1-yl)propyl)benzonitrile using the procedure described in Example 577D.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[C:14]([C:33]4[CH:48]=[CH:47][C:36]([C:37]([O:39][CH2:40][C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)=[O:38])=[CH:35][CH:34]=4)[N:15]3[CH2:18][CH2:19][CH2:20][CH2:21][N:22]3[C:30](=[O:31])[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]3=[O:32])=[CH:11][CH:10]=2)=[O:8])=[CH:4][C:3]=1[CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51].[F-].[Cs+].[OH:57][C:58]1[CH:59]=[C:60](B(O)O)[CH:61]=[CH:62][CH:63]=1.O>COCCOC.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:31]=[C:30]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](=[O:32])[N:22]1[CH2:21][CH2:20][CH2:19][CH2:18][N:15]1[C:16]2[C:12](=[CH:11][CH:10]=[C:9]([C:7]([C:5]3[S:6][C:2]([C:62]4[CH:61]=[CH:60][CH:59]=[C:58]([OH:57])[CH:63]=4)=[C:3]([CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])[CH:4]=3)=[O:8])[CH:17]=2)[CH:13]=[C:14]1[C:33]1[CH:48]=[CH:47][C:36]([C:37]([O:39][CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)=[O:38])=[CH:35][CH:34]=1
Reactant: OB(O)c1cccc(O)c1
Reactant: CCOC(=O)Cc1cc(C(=O)c2ccc3cc(-c4ccc(C(=O)OCc5ccccc5)cc4)n(CCCCN4C(=O)c5ccccc5C4=O)c3c2)sc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)Cc1cc(C(=O)c2ccc3cc(-c4ccc(C(=O)OCc5ccccc5)cc4)n(CCCCN4C(=O)c5ccccc5C4=O)c3c2)sc1-c1cccc(O)c1
Yield: 81.6 %

Procedure:
A mixture of 5 (60 mg, 0.075 mmol), Pd(PPh3)4 (17 mg, 0.015 mmol), CsF (34 mg, 0.22 mmol), 3-hydroxyphenylboronic acid (16 mg, 0.12 mmol), and H2O (80 μL) in DME (8 mL) was degassed with N2 for 10 minutes and then refluxed. When the reaction was over by TLC monitoring, the mixture was poured into H2O (10 mL) and then extracted with 70 mL Et2O. The organic layer was washed with brine (2×10 mL), dried over MgSO4, and then concentrated in vacuo. MPLC purification (Hex:EtOAc/5:1) of the residue gave 6 as a yellow amorphous solid (50 mg, 82%). 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J=8.0 Hz, 2H), 8.04 (s, 1H), 7.74-7.61 (m, 7H), 7.56 (d, J=8.0 Hz, 2H), 7.49-7.26 (m, 6H), 7.13 (s, 1H), 7.03 (d, J=7.6 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 6.63 (s, 1H), 5.40 (s, 2H), 4.32 (t, J=7.2 Hz, 2H), 4.16-4.06 (m, 2H), 3.72 (s, 2H), 3.51 (t, J=6.8 Hz, 2H), 1.72-1.69 (m, 2H), 1.49-1.46 (m, 2H), and 1.26 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 188.62, 171.45, 168.65, 166.21, 157.16, 149.47, 143.69, 141.59, 138.00, 137.26, 137.23, 136.09, 134.28, 131.99, 131.82, 130.66, 130.37, 130.33, 130.12, 129.33, 128.90, 128.62, 128.53, 123.49, 121.88, 121.13, 120.87, 116.54, 116.46, 112.82, 104.20, 67.20, 61.46, 43.92, 37.36, 34.81, 27.45, 25.84, and 14.42.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][C:6](=[O:12])[CH:5]2[C:13](=[O:19])[C:14]1[S:18][CH:17]=[CH:16][CH:15]=1.[C:20](=[O:26])=[N:21]S(Cl)(=O)=O.ClS(NC=O)(=O)=O>CS(C)=O>[Cl:1][C:2]1[N:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[N:7]([C:20]([NH2:21])=[O:26])[C:6](=[O:12])[CH:5]2[C:13](=[O:19])[C:14]1[S:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: O=C1Nc2cc(Cl)c(Cl)nc2C1C(=O)c1cccs1
Agent: O=CNS(=O)(=O)Cl
Solvent: CS(C)=O
Product: NC(=O)N1C(=O)C(C(=O)c2cccs2)c2nc(Cl)c(Cl)cc21

Procedure:
The title compound was prepared from 5,6-dichloro-3-(2-thenoyl)-4-azaoxindole (Example 6B) according to the procedure of Example 2C, using 5,6-dichloro-3-(2-thenoyl)-4-azaoxindole (194 mg, 0.62 mmol), N-chlorosulfonyl isocyanate (81 L, 0.93 mmol) acetonitrile (10 mL), and a temperature of 50° C. The crude N-chlorosulfonyl carboxamide was hydrolysed by stirring in DMSO in a flask open to the air. After dilution with water, the solid was collected by filtration and recrystallized from acetic acid. Yield: 129 mg (58%).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH:21][C:22](=[O:30])OC3C=CC=CC=3)=[CH:15][CH:14]=2)[CH:5]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)[N:7]=1)[CH3:2].[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([S:38]([NH2:41])(=[O:40])=[O:39])=[CH:34][CH:33]=1>>[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([S:38]([NH:41][C:22]([NH:21][CH2:20][CH2:19][C:16]2[CH:17]=[CH:18][C:13]([N:4]3[CH:5]=[C:6]([C:8]4[S:9][CH:10]=[CH:11][N:12]=4)[N:7]=[C:3]3[CH2:1][CH3:2])=[CH:14][CH:15]=2)=[O:30])(=[O:39])=[O:40])=[CH:36][CH:37]=1
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Reactant: CCc1nc(-c2nccs2)cn1-c1ccc(CCNC(=O)Oc2ccccc2)cc1
Product: CCc1nc(-c2nccs2)cn1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 18 from phenyl 2-{4-[2-ethyl-4-(1,3-thiazol-2-yl)-1H-imidazol-1-yl]phenyl}ethylcarbamate and 4-chlorobenzenesulfonamide. MS (ESI) m/z 516 [M+H]+, 514 [M−H]−, 1H-NMR (CDCl3)δ1.22 (3H, t, J=7.5 Hz), 2.69 (2H, q, J=7.5 Hz), 2.88 (2H, t, J=6.8 Hz), 3.49-3.56 (2H, m), 6.64 (1H, br), 7.21-7.30 (4H, m), 7.48 (2H, d, J=8.8 Hz), 7.58 (1H, s), 7.77 (2H, d, J=3.3 Hz), 7.80 (2H, d, J=8.8 Hz)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]O)=[CH:4][CH:3]=1.[BrH:11]>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][Br:11])=[CH:4][CH:3]=1
Reactant: OCCc1ccc(O)cc1
Reactant: Br
Product: Oc1ccc(CCBr)cc1
Temperature: 20 °C
Yield: 96.2 %

Procedure:
500 g 2-(4-hydroxyphenyl) ethanol was placed in a 5 L round bottom flask, to which 2960 g of 48% aq. HBr was added with stirring. The reaction mixture was placed in a bath at 75° C. After 2.5 h agitation 5 g of A11 seed crystals was added. The reaction mixture was stirred at this temperature for another 24 h. The reaction mixture was slowly cooled to 20° C. The precipitate was isolated by filtration and washed with 10% aq. sodium bicarbonate solution to give 700 g (96% yield) of the title product. 1H NMR (CDCl3); δ 3.10 (2H, t, J=7.8 Hz), 3.53 (2H, t, J=7.5 Hz), 6.80 (2H, d, J=8.4 Hz), 7.09 (2H, d, J=8.4 Hz).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].C[Si]([C:23]#[C:24][C:25]1[N:30]2[N:31]=[C:32]([NH:34][C:35]([CH:37]3[CH2:39][CH2:38]3)=[O:36])[N:33]=[C:29]2[CH:28]=[CH:27][CH:26]=1)(C)C>C1COCC1.C(#N)C>[C:24]([C:25]1[N:30]2[N:31]=[C:32]([NH:34][C:35]([CH:37]3[CH2:38][CH2:39]3)=[O:36])[N:33]=[C:29]2[CH:28]=[CH:27][CH:26]=1)#[CH:23]
Reactant: C[Si](C)(C)C#Cc1cccc2nc(NC(=O)C3CC3)nn12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC#N
Product: C#Cc1cccc2nc(NC(=O)C3CC3)nn12
Temperature: 25 °C
Yield: 96.7 %

Procedure:
TBAF (0.4 mmol) 1M solution in THF is added to a solution of cyclopropanecarboxylic acid(5-trimethylsilanylethynyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amide (0.32 mmol) in acetonitrile (4 mL) at room temperature. The reaction mixture is stirred at room temperature until all the starting material disappears by LCMS. The solvent of the reaction is removed under vacuum, and the mixture is redissolved in ethyl acetate. The organic phase is washed with water. The organic layer is dried over MgSO4, filtered and the solvent is removed under vacuum to afford the pure product (70 mg, 97% yield). No further purification is carried out on the product.
Reaction SMILES: [Br-:1].[NH2:2][CH2:3][CH2:4][N+:5]([CH2:8][CH2:9][NH:10][C:11]([C:13]1[C:18]([NH2:19])=[N:17][C:16]([NH2:20])=[C:15]([Cl:21])[N:14]=1)=[O:12])([CH3:7])[CH3:6].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][S:30](Cl)(=[O:32])=[O:31])=[CH:25][CH:24]=1.CN1CCOCC1>CN(C=O)C>[Br-:1].[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29][S:30]([NH:2][CH2:3][CH2:4][N+:5]([CH2:8][CH2:9][NH:10][C:11]([C:13]2[C:18]([NH2:19])=[N:17][C:16]([NH2:20])=[C:15]([Cl:21])[N:14]=2)=[O:12])([CH3:6])[CH3:7])(=[O:32])=[O:31])=[CH:27][CH:28]=1
Reactant: C[N+](C)(CCN)CCNC(=O)c1nc(Cl)c(N)nc1N
Reactant: O=S(=O)(Cl)Cc1ccc(Cl)cc1
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C[N+](C)(CCNC(=O)c1nc(Cl)c(N)nc1N)CCNS(=O)(=O)Cc1ccc(Cl)cc1

Procedure:
A solution of (2-amino-ethyl)-{2-[(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-amino]-ethyl}-dimethyl-ammonium bromide (Intermediate K) (0.3 g, 0.78 mmol), (4-chloro-phenyl)-methanesulfonyl chloride (0.18 g, 0.78 mmol) and N-methylmorpholine (0.35 mL, 3.18 mmol) in DMF (5 mL) is shaken at RT for 16 h. After this time the solvent is removed in vacuo and the residue is subjected to chromatography (basic alumina, 0-15% methanol in DCM) to yield the title compound. M+ 490.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2
Reactant: O=C1Cc2cc([N+](=O)[O-])ccc2N1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)CC(=O)N2
Yield: 57.3 %

Procedure:
5-Nitro-1,3-dihydro-indol-2-one (6.3 g) was hydrogenated in methanol over 10% palladium on carbon to give 3.0 g (60% yield) of 5-amino-1,3-dihydro-indol-2-one as a white solid.
Reaction SMILES: [C:1]([N:4]1[CH2:8][C@H:7]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=[C:23]([CH3:31])[CH:22]=3)=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C@H:6]([C:32]([OH:34])=O)[CH2:5]1)(=[O:3])[CH3:2].[NH2:35][OH:36]>>[C:1]([N:4]1[CH2:8][C@H:7]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=[C:23]([CH3:31])[CH:22]=3)=[CH:15][CH:14]=2)(=[O:11])=[O:12])[C@H:6]([C:32]([NH:35][OH:36])=[O:34])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1C[C@H](NS(=O)(=O)c2ccc(OCc3cc(C)nc4ccccc34)cc2)[C@H](C(=O)O)C1
Reactant: NO
Product: CC(=O)N1C[C@H](NS(=O)(=O)c2ccc(OCc3cc(C)nc4ccccc34)cc2)[C@H](C(=O)NO)C1
Yield: 41 %

Procedure:
According to the procedure of example 17, Step 5, the reaction of 113.5 mg of cis-1-acetyl-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]pyrrolidine-3-carboxylic acid with hydroxylamine provided 39 mg (41% yield) of cis-1-acetyl-N-hydroxy-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]pyrrolidine-3-carboxamide. MS: 499.2 (M+H)+
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:17]2[S:21][C:20]([C:22]([O:24][CH3:25])=[O:23])=[CH:19][CH:18]=2)[CH:6]=[CH:7][C:8]=1OS(C(F)(F)F)(=O)=O)#[N:2].C(=O)([O-])[O-].[K+].[K+].O.[NH2:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1>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.C1(C)C=CC=CC=1>[NH2:33][C:34]1[CH:39]=[C:38]([C:8]2[CH:7]=[CH:6][C:5]([C:17]3[S:21][C:20]([C:22]([O:24][CH3:25])=[O:23])=[CH:19][CH:18]=3)=[CH:4][C:3]=2[C:1]#[N:2])[CH:37]=[CH:36][CH:35]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: COC(=O)c1ccc(-c2ccc(OS(=O)(=O)C(F)(F)F)c(C#N)c2)s1
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: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(-c3cccc(N)c3)c(C#N)c2)s1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A toluene (0.5 ml) suspension of 20 mg of methyl 5-(3-cyano-4-{[(trifluoromethyl)sulfonyl]oxy}phenyl)thiophene-2-carboxylate and 10 mg of potassium carbonate was added to 15 mg of 3-aminobenzeneboronic acid monohydrate, and in an argon atmosphere, 8 mg of tetrakis(triphenylphosphine)palladium was added thereto. The mixture was stirred overnight at 100° C., then cooled to room temperature, and filtered through Celite. The solvent was evaporated under reduced pressure to obtain methyl 5-(3′-amino-2-cyanobiphenyl-4-yl)thiophene-2-carboxylate. (2) 0.2 ml of aqueous 1 M sodium hydroxide solution was added to a methanol (0.25 ml)/tetrahydrofuran (0.25 ml) solution of methyl 5-(3′-amino-2-cyanobiphenyl-4-yl)thiophene-2-carboxylate, followed by stirring overnight at 60° C. 1 M hydrochloric acid was added to the reaction liquid to make it acidic, and the solvent was evaporated under reduced pressure. The residue was purified by HPLC [elution through column: SunFire (registered trademark) C18 5 μm, 19 mm×100 mm, solvent: MeOH/aqueous 0.1% formic acid solution=10/90 for 1 minute, ratio change to 95/5, taking 8 minutes, and further elution with 95/5 for 3 minutes, flow rate: 25 mL/min), thereby obtaining 2.5 mg of 5-(3′-amino-2-cyanobiphenyl-4-yl)thiophene-2-carboxylic acid.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([CH3:3])[CH3:2].[Br:11]Br>ClCCl>[Br:11][C:9]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:10]=1
Reactant: BrBr
Reactant: CC(C)c1ccccc1N
Solvent: ClCCl
Product: CC(C)c1cc(Br)ccc1N
Yield: 135.3 %

Procedure:
To a cooled solution of 2-iso-propyl aniline (714 mg, 5.28 mmol) in dichloromethane (20 mL) at −50° C. in a dry ice/acetone bath was added a solution of bromine (269 μl, 5.28 mmol) in dichloromethane (5 mL) over 20 min. After completion of the addition, the reaction mixture was stirred for an additional hour. Purification by column chromatography (silica gel, hexane/ethyl acetate) gave 4-bromo-2-iso-propyl-phenylamine as a brown oil (1.53 g, 57%); 1H NMR (300 MHz, DMSO-d6): δ 7.01 (m, 2H), 6.55 (d, 1H, J=13 Hz), 5.05 (bs, 2H), 2.92 (m, 1H), 1.11 (d, 6H, J=7 Hz); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=Hexane/ethyl acetate [10:1]; Rf=0.11
Reaction SMILES: [CH3:1][C:2](=[O:7])[C:3]([CH3:6])([CH3:5])[CH3:4].[CH:8](OC)=[O:9]>C(OCC)C>[CH3:4][C:3]([CH3:6])([CH3:5])[C:2](=[O:7])[CH:1]=[CH:8][OH:9]
Reactant: COC=O
Reactant: CC(=O)C(C)(C)C
Solvent: CCOCC
Product: CC(C)(C)C(=O)C=CO
Temperature: 30 °C
Reaction time: 12 h
Yield: 97.2 %

Procedure:
56.0 g (0.5 mole) of potassium tert.-butylate are added to a mixture of 50.0 g (0.5 mole) of pinacolone and 42.0 g (0.5 mole) of methyl formate at 15° to 20° C., with cooling. The reaction mixture is subsequently stirred at 30° C. for 12 hours. For working up, 400 ml of diethyl ether are added and the product precipitated is filtered off with suction and dried. 62.3 g (75% of theory) of 4,4-dimethyl-1-hydroxy-1-penten-3-one, as the potassium salt, are obtained in the form of a light yellow powder.