Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[C:9][CH2:10][OH:11])=[N:6][C:5]([S:12][CH3:13])=[CH:4][N:3]=1.O>CN(C)C=O.[Cu]I>[CH3:13][S:12][C:5]1[N:6]=[C:7]2[CH:8]=[C:9]([CH2:10][OH:11])[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: CSc1cnc(N)c(C#CCO)n1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: O
Product: CSc1cnc2[nH]c(CO)cc2n1
Temperature: 150 °C
Reaction time: 2 h
Yield: 40.7 %

Procedure:
To a solution of the compound obtained in Example 34 (3) (381 mg) in N,N-dimethylformamide (10 ml), copper(I) iodide (111 mg) was added and the mixture was stirred at 150° C. for 2 hours. The reaction solution was poured into water, and the mixture was extracted with chloroform, washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was separated using silica gel preparative thin-layer chromatography (chloroform:methanol=20:1) to obtain 155 mg (40.7%) of the desired product as a yellow powder.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:35])[C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[NH:24][C:25]([C:27]2[S:28][CH:29]=[C:30]([CH2:33]Cl)[C:31]=2[Cl:32])=[O:26])=[CH:11][CH:10]=1>CN(C=O)C>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:35])[C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[NH:24][C:25]([C:27]2[S:28][CH:29]=[C:30]([CH2:33][N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)[C:31]=2[Cl:32])=[O:26])=[CH:13][CH:14]=1
Reactant: O=C(Nc1ccc(Cl)cc1)c1cc(Cl)ccc1NC(=O)c1scc(CCl)c1Cl
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Cl)cc1)c1cc(Cl)ccc1NC(=O)c1scc(Cn2cncn2)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 102.8 %

Procedure:
To a solution of 1,2,4-triazole (0.40 g, 5.7 mmol) in DMF (10 mL) was added NaH (60% dispersion in mineral oil, 0.23 g, 5.7 mmol) and the mixture stirred at ambient temperature. After 10 min, N-(4-chlorophenyl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide (0.90 g, 1.9 mmol) in DMF (5 mL) was added and stirring continued. After 18 hours, the mixture was poured onto water and extracted with methylene chloride. The organic layer was dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 0.99 g (77% yield) of N-(4-chlorophenyl)-2-[((3-chloro-4-((1,2,4-triazol-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide; as a white solid; NMR (DMSO-d6/TFA) 11.2 (s, 1), 10.7 (s, 1), 9.3 (s, 1), 8.5 (s, 1), 8.3 (d, 1), 8.0 (s, 1), 7.9 (d, 1), 7.7 (d, 2), 7.6 (dd, 1), 7.4 (d, 2), 5.5 (s, 2) ppm.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:5])[CH3:4].F[C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH3:25])[CH:19]=1)=[N:10][CH:11]=[N:12]2>>[NH2:1][CH2:2][C@@H:3]([CH3:4])[O:5][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH3:25])[CH:19]=1)=[N:10][CH:11]=[N:12]2
Reactant: Cc1cc(Nc2ncnc3cccc(F)c23)ccc1O
Reactant: C[C@@H](O)CN
Product: Cc1cc(Nc2ncnc3cccc(O[C@H](C)CN)c23)ccc1O
Yield: 65 %

Procedure:
The procedure described in Example 3 (preparation of starting materials) was repeated using (R)-(−)-1-amino-propan-2-ol and 4-[(5-fluoroquinazolin-4-yl)amino]-2-methylphenol (obtained as described in Example 3, preparation of starting materials) to give 4-({5-[(1R)-2-amino-1-methylethoxy]quinazolin-4-yl}amino)-2-methylphenol as a brown solid in 65% yield; NMR spectrum (DMSO-d6) 1.39 (d, 3H), 2.16 (s, 3H), 2.96 (m, 2H), 3.30 (s, 2H), 4.96 (m, 1H), 6.77 (d, 1H), 7.14 (d, 1H), 7.25 (d, 1H), 7.44 (dd, 1H), 7.51 (d, 1H), 7.67 (t, 1H), 8.39 (s, 1H), 9.16 (s, 1H), 10.50 (s, 1H); Mass spectrum MH+ 325.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13](=[O:15])[CH3:14])=[CH:8][C:7]=1[CH:16]([CH3:18])[CH3:17].[OH:19][C:20]1[C:21]([CH3:32])=[C:22]([C:25]([O:30][CH3:31])=[C:26]([CH3:29])[C:27]=1[CH3:28])[CH2:23]Cl.C(N(CC)CC)C>CN(C)C=O>[OH:19][C:20]1[C:21]([CH3:32])=[C:22]([C:25]([O:30][CH3:31])=[C:26]([CH3:29])[C:27]=1[CH3:28])[CH2:23][N:2]([CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13](=[O:15])[CH3:14])=[CH:8][C:7]=1[CH:16]([CH3:18])[CH3:17])[CH3:1]
Reactant: CNCCOc1cc(C)c(C(C)=O)cc1C(C)C
Reactant: COc1c(C)c(C)c(O)c(C)c1CCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1c(C)c(C)c(O)c(C)c1CN(C)CCOc1cc(C)c(C(C)=O)cc1C(C)C
Temperature: 25 °C
Yield: 95.1 %

Procedure:
N-Methyl-2-(4-acetyl-2-isopropyl-5-methylphenoxy)ethylamine (6.75 g) and 3-hydroxy-6-methoxy-2,4,5-trimethylbenzyl chloride (5.48 g) were dissolved in N,N-dimethylformamide (80 ml), and triethylamine (2.58 g) was added dropwise while stirring the mixture at room temperature. The mixture was stirred at room temperature for 16.5 hours. After the reaction, the solvent was distilled off, and water was added. The mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained liquid was purified by silica gel chromatography (eluent; ethyl acetate/benzene=1/1) to give 10.38 g of a pale-yellow solid. The obtained solid was recrystallized from isopropyl alcohol to give 7.22 g of the title compound (colorless crystals).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6](/[CH:7]=[CH:8]/[S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[S:15]([NH2:25])(=[O:24])([C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1)=[O:16]>>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6](/[CH:7]=[CH:8]/[S:9]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([S:15](=[O:24])(=[O:16])[NH2:25])=[CH:18][CH:19]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(/C=C/S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Product: COc1ccc(/C=C/S(=O)(=O)Nc2ccc(S(N)(=O)=O)cc2)cc1
Yield: 46.2 %

Procedure:
A solution of (E)-4-methoxystyrylsulfonyl chloride (10 mmol) and sulfanilamide (10 mmol) was subjected to General Procedure 1, part B. The title compound, melting point 181-183° C., was obtained in 46.2% yield.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](SC)=[CH:11][N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1.[CH3:17][NH2:18]>CCO>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([NH:18][CH3:17])=[CH:11][N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1
Reactant: CSC(=C[N+](=O)[O-])NCc1ccc(Cl)nc1
Reactant: CN
Solvent: CCO
Product: CNC(=C[N+](=O)[O-])NCc1ccc(Cl)nc1
Yield: 53.8 %

Procedure:
In 100 ml of EtOH was dissolved 1.2 g (4.6×10-3 mole) of 1-(6-chloro-3-pyridylmethyl)amino-1-methylthio-2-nitroethylene and on reflux, a solution of 0.84 g of 40% aqueous methylamine in 30 ml EtOH was added dropwise over 1 hour. After cooling, the reaction mixture was concentrated under reduced pressure to about 50 ml and the resulting crystals were collected by filtration and dried to give 0.6 g of the title compound as pale yellow needles.
Reaction SMILES: [NH:1]([C:3](=[O:32])[CH2:4][CH2:5][N:6]1[C:19](=[O:20])[C:9]2([CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[O:8][C:7]21[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[NH2:2].[CH3:33][CH:34]1[CH2:44][CH2:43][CH:37]2[C:38]([O:40][C:41](=O)[CH:36]2[CH2:35]1)=[O:39].O.CCCCC>C1(C)C(C)=CC=CC=1>[CH3:33][CH:34]1[CH2:44][CH2:43][CH:37]2[C:38]([N:2]([NH:1][C:3](=[O:32])[CH2:4][CH2:5][N:6]3[C:19](=[O:20])[C:9]4([CH2:14][C:13]([CH3:15])([CH3:16])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]4)[O:8][C:7]43[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]4)[C:41](=[O:40])[CH:36]2[CH2:35]1)=[O:39]
Reactant: CC1CCC2C(=O)OC(=O)C2C1
Reactant: CC1(C)CC2(CC(C)(C)N1)OC1(CCCCCCCCCCC1)N(CCC(=O)NN)C2=O
Solvent: CCCCC
Solvent: Cc1ccccc1C
Solvent: O
Product: CC1CCC2C(=O)N(NC(=O)CCN3C(=O)C4(CC(C)(C)NC(C)(C)C4)OC34CCCCCCCCCCC4)C(=O)C2C1

Procedure:
The hydrazide of Example 1, 13.5 g (0.03 mole), was added to 225 ml xylene at 75° C. Added dropwise to this was 4-methylhexahydrophthalic anhydride, 5.1 g (0.03 mole) in 25 ml xylene. The apparatus was fitted with a Dean Stark water separation assembly and the reaction mixture was heated to reflux for 4 hours with azeotropic removal of water as it formed. The xylenes were stripped using aspirator vacuum and the residual sticky solid was slurried with 300 ml pentane. The solid was filtered and dried for 2 hours on the filter funnel. The white solid product weighed 11.7 g and had a melting range of 210°-212° C. The infrared spectrum (mull) showed two carbonyl bands at 1690 and 1730 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].C(Cl)(=O)C([Cl:17])=O>CN(C)C=O>[CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([Cl:17])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cccc(C(=O)O)c1OC
Solvent: CN(C)C=O
Product: COc1cccc(C(=O)Cl)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,3-Dimethoxybenzoic acid (182 mg, 1 mmol) was treated with a solution of oxalyl chloride (1.5 mL of 2 M in dichloromethane, 3 mmol) and a catalytic amount of N,N-dimethylformamide. The reaction was stirred at ambient temperature for 2 hours. The excess oxalyl chloride was removed in vacuo to afford 2,3-dimethoxybenzoyl chloride.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].C([O:8][C:9]1[CH:18]=[C:17]([O:19][CH:20]([CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH3:21])[CH:16]=[C:15]2[C:10]=1[CH:11]([CH2:35][CH2:36][C:37]#[N:38])[CH2:12][CH:13]1[CH2:34][CH2:33][CH2:32][CH2:31][N:14]12)(=O)C.Cl.CN1CCCCC1>CN1CCCCC1.C(O)C>[OH:8][C:9]1[CH:18]=[C:17]([O:19][CH:20]([CH2:22][CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH3:21])[CH:16]=[C:15]2[C:10]=1[CH:11]([CH2:35][CH2:36][C:37]1[NH:38][N:3]=[N:2][N:1]=1)[CH2:12][CH:13]1[CH2:34][CH2:33][CH2:32][CH2:31][N:14]12
Reactant: CC(=O)Oc1cc(OC(C)CCCc2ccccc2)cc2c1C(CCC#N)CC1CCCCN21
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCCC1
Solvent: CCO
Product: CC(CCCc1ccccc1)Oc1cc(O)c2c(c1)N1CCCCC1CC2CCc1nnn[nH]1
Reaction time: 8 h

Procedure:
Finely ground sodium azide (325 mg., 5 mmole) is added to a solution of 7-acetoxy-6-(2-cyanoethyl)-9-(5-phenyl-2-pentyloxy)-2,3,4,4a,5,6-hexahydro-1H-pyrido-[1,2-a]quinoline (506 mg., 1 mmole) in 5 ml. of ethanol-free chloroform containing 271 mg. (2 mmole) N-methyl-piperidine hydrochloride and 5 drops of N-methylpiperidine. The mixture is heated at reflux for one hour, another 2 mmole of N-methylpiperidine hydrochloride is added, refluxing continued for another hour and allowed to stand overnight at room temperature. The mixture is partitioned between chloroform and aqueous sodium carbonate solution. The aqueous layer is adjusted to pH 5, extracted again with chloroform and the combined organic layers washed with water and the chloroform is dried (MgSO4) Evaporation of solvent under reduced pressure affords the title compound.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:23])[S:4]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[C:10](Cl)=[O:11])(=[O:6])=[O:5].[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25]>O1CCCC1>[CH2:24]([N:26]([CH2:27][CH3:28])[C:10](=[O:11])[C:9]1[CH:13]=[CH:14][C:15]([N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[C:7]([S:4](=[O:6])(=[O:5])[N:3]([CH3:23])[CH3:2])[CH:8]=1)[CH3:25]
Reactant: CN1CCN(c2ccc(C(=O)Cl)cc2S(=O)(=O)N(C)C)CC1
Reactant: CCNCC
Agent: Cl
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc(N2CCN(C)CC2)c(S(=O)(=O)N(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
40 Grams of 3-dimethylsulfamoyl-4-(4-methylpiperazine-1-yl)-benzoylchloride-hydrochloride (0.1 mole) were introduced portionwise, while stirring at room temperature, into a solution of 20 g of diethylamine in 0.4 l of tetrahydrofurane. After the addition had been completed, the mixture was stirred for another 30 minutes at room temperature, and subsequently the tetrahydrofurane was completely eliminated in vacuo. The evaporation residue crystallized when triturated with 0.2 l of water, and, after having been suction-filtered and dried, it was recrystallized from butylacetate.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[Cl:30])[CH:16]=2)[CH2:10][C@@H:9]1[CH3:32])=O)(C)(C)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[Cl-].[NH4+]>C1(C)C=CC=CC=1.CO>[ClH:30].[Cl:30][C:24]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=1[C:22]([NH:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([NH:14][C@H:11]2[CH2:12][CH2:13][NH:8][C@@H:9]([CH3:32])[CH2:10]2)[CH:16]=1)=[O:31]
Reactant: C[C@H]1C[C@@H](Nc2cccc(NC(=O)c3ccc(F)cc3Cl)c2)CCN1C(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: Cc1ccccc1
Product: C[C@H]1C[C@@H](Nc2cccc(NC(=O)c3ccc(F)cc3Cl)c2)CCN1
Product: Cl
Temperature: 25 °C
Yield: 127.2 %

Procedure:
Dissolve (2S,4S)-4-(3-(2-chloro-4-fluoro-benzoylamino)-phenylamino)-2-methyl-piperidine-1-carboxylic acid tert-butyl ester (Preparation 58, 137 mg, 0.296 mmol) in toluene (10 mL). Add p-toluenesulfonyl chloride (152 mg, 0.798 mmol) and heat to 100° C. for 2 hr. Cool to room temperature and load onto an SCX column with methanol. Wash the column with methanol, flush with 2M ammonia in methanol, and concentrate in vacuo. Purify by column chromatography (0%-15% 2 M NH3 in methanol/CH2Cl2) to yield an oil. Make the hydrochloride salt by sonication with one equivalent of ammonium chloride dissolved in methanol to yield 75 mg (64%) of the title compound. Mass spectrum (ion spray): m/z=362.1 (M+1), 1H NMR δ (D2O/DCl, ppm) 7.78 (s, 1H), 7.49 (m, 3H), 7.21 (t, J=9 Hz, 18 Hz, 2H), 7.07 (t, J=9.0 Hz, 18.0 Hz, 1H), 3.83 (m, 1H), 3.45 (m, 1H), 3.20 (m, 1H), 2.95 (m, 1H), 2.18 (m, 2H), 1.80 (m, 1H), 1.65 (m, 1H), 1.20 (d, J=6.6 Hz, 3H); mp 202° C. (dec.).
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1.[CH3:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][N:13]1[C:18](=[O:21])[CH2:19][OH:20].[OH-].[K+].C(O)(C)C>O>[CH3:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][N:13]1[C:18](=[O:21])[CH2:19][O:20][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1
Reactant: CC1CCCCN1C(=O)CO
Reactant: Clc1nc(C(Cl)(Cl)Cl)ns1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC1CCCCN1C(=O)COc1nc(C(Cl)(Cl)Cl)ns1
Temperature: -10 °C
Reaction time: 20 h
Yield: 71.7 %

Procedure:
17 g (0.07 mol) of 5-chloro-3-trichloromethyl-1,2,4-thiadiazole are added to a stirred mixture which comprises 11 g (0.07 mol) of hydroxyacetic acid 2-methylpiperidide, 4.5 g (0.07 mol) of potassium hydroxide powder and 100 ml of isopropanol and has been cooled to -10° C. The reaction mixture is stirred for 20 hours at -10° C. and then poured into water, and the product is filtered off under suction and washed with water. 18 g (72% of theory) of (3-trichloromethyl-1,2,4-thiadiazol-5-yl)-oxyacetic acid 2-methyl-piperidide are obtained in the form of a white powder of melting point 88° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][NH2:5].[CH3:6][CH:7]([CH3:21])[C:8](=O)[CH2:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=S.C(N(CC)CC)C.O>C(#N)C>[CH2:13]([O:12][C:10]1[CH:9]=[C:8]([CH:7]([CH3:21])[CH3:6])[N:4]([CH2:3][CH2:2][OH:1])[N:5]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)C(=O)CC(=S)OCc1ccccc1
Reactant: NNCCO
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: CC(C)c1cc(OCc2ccccc2)nn1CCO
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.8 %

Procedure:
2-Hydroxyethylhydrazine (1.90 g) was added to a solution of O-Benzyl 4-methyl-3-oxothiopentanoate (5.90 g) and triethylamine (5.05 g) in acetonitrile (60 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water, and the mixture was extracted with diethyl ether. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=1/1) to give the title compound (5.90 g).
Reaction SMILES: [CH3:1][C:2]1([C:5](Cl)=[O:6])[CH2:4][CH2:3]1.[F:8][C:9]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH2:18])[CH:13]=1.CCN(CC)CC.CCOC(C)=O>C(Cl)Cl>[F:8][C:9]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:5]([C:2]2([CH3:1])[CH2:4][CH2:3]2)=[O:6])[CH:13]=1
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ccn1
Reactant: CC1(C(=O)Cl)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC1(C(=O)Nc2cc(Oc3ccc([N+](=O)[O-])cc3F)ccn2)CC1
Yield: 24 %

Procedure:
Add the solution of the above 1-methylcyclopropanecarbonyl chloride in DCM slowly to a solution of 4-(2-fluoro-4-nitro-phenoxy)pyridin-2-amine (500 mg, 2.0 mmol) and Et3N (505 mg, 5.0 mmol) in DCM (15 mL) at 0° C. Stir the reaction at room temperature for 15 hrs. TLC (EtOAc:PE=1:1) shows the reaction is complete. Concentrate the mixture to give the crude product. Purification by chromatography (silica gel, EtOAc:PE=1:1) affords the target compound (160 mg, 24%). MS: (M+1): 332.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:32]=[C:33]([F:35])[CH:34]=1)[O:5][CH2:6][CH2:7][N:8]1[CH:12]=[C:11](/[CH:13]=[CH:14]/[C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH:24]C(=O)OC(C)(C)C)=[O:16])[CH:10]=[N:9]1.Cl>O1CCOCC1.C(OC(=O)C)C>[NH2:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[NH:17][C:15](=[O:16])/[CH:14]=[CH:13]/[C:11]1[CH:10]=[N:9][N:8]([CH2:7][CH2:6][O:5][C:4]2[CH:32]=[C:33]([F:35])[CH:34]=[C:2]([F:1])[CH:3]=2)[CH:12]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/c1cnn(CCOc2cc(F)cc(F)c2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Nc1ccccc1NC(=O)/C=C/c1cnn(CCOc2cc(F)cc(F)c2)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of (E)-tert-butyl (2-(3-(1-(2-(3,5-difluorophenoxy)ethyl)-1H-pyrazol-4-yl)acrylamido)phenyl)carbamate (113 mg, 0.23 mmol) in dioxane (3 mL) was mixed with a 4 M solution of HCl in dioxane (2 mL). The mixture was stirred for 6 h at room temperature under a nitrogen atmosphere. The reaction mixture was then diluted with ethylaceate (15 mL). The salt was filtered, washed with EtOAc and dried overnight to 92 mg of the hydrochloric acid salt of (E)-N-(2-aminophenyl)-3-(1-(2-(3,5-difluorophenoxy)ethyl)-1H-pyrazol-4-yl)acrylamide as an off-white solid. MS: 1H NMR (CD3OD) δ: 8.07 (s, 1H), 7.86 (s, 1H), 7.70 (d, J=15.4 Hz, 1H), 7.28-7.54 (m, 4H), 6.62 (d, J=15.7 Hz, 1H), 6.45-6.57 (m, 3H), 4.55 (t, J=5.2 Hz, 2H), 4.37 (t, J=5.2 Hz, 2H) ES+(M+Na)+: 407
Reaction SMILES: C1(=O)N([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[C:16](=[O:17])[CH:15]=[CH:14][C:13]2=[O:18])C(=O)C=C1>CN(C)C=O.O>[C:13]1(=[O:18])[N:12]([CH:11]([N:12]2[C:13](=[O:18])[CH:14]=[CH:15][C:16]2=[O:17])[CH2:10][CH2:9][CH2:8][CH2:7][CH3:6])[C:16](=[O:17])[CH:15]=[CH:14]1
Reactant: O=C1C=CC(=O)N1CCCCCCN1C(=O)C=CC1=O
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCC(N1C(=O)C=CC1=O)N1C(=O)C=CC1=O

Procedure:
The experiment was repeated using 1,6-bismaleimidohexane in dry dimethylformamide in place of the lysine bismaleimide in water to yield antibody material cross-linked with bismaleimidohexane.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(N(CC)CC)C.[CH2:27]([S:29](Cl)(=[O:31])=[O:30])[CH3:28]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH:14]1[CH2:15][CH2:16][N:17]([S:29]([CH2:27][CH3:28])(=[O:31])=[O:30])[CH2:18][CH2:19]1
Reactant: CCS(=O)(=O)Cl
Reactant: NC(=O)c1cc(Br)cc2c(C3CCNCC3)n[nH]c12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reaction time: 2 h
Yield: 31.5 %

Procedure:
The crude 5-bromo-3-(4-piperidinyl)-1H-indazole-7-carboxamide (Intermediate 6) (1.23 mmol) was suspended in dichloromethane (20 mL) and treated with triethyl amine (0.856 mL, 6.15 mmols), and ethane sulfonyl chloride (0.175 mL, 1.85 mmols) at 0° C. After 2 hrs, the mixture was concentrated to dryness in vacuo at ambient temperature, treated with water (25 mL), and extracted with dichloromethane (100 mL). The organic phase was washed with water, dried over MgSO4, filtered, and concentrated to give a light brown solid. This was purified by combiflash (column 10 g, eluting with 100% dichloromethane, 5% ethyl acetate/dichloromethane, 30% ethyl acetate/dichloromethane) to give the title compound (0.161 g, 32%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([Br:11])[CH:3]=1.[CH:12]1[CH:13]=[CH:14][N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[NH:18][CH2:17][C:16]=12.C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:18]2[C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[CH2:21][N:15]3[CH:14]=[CH:13][CH:12]=[C:16]3[CH2:17]2)=[O:7])=[C:4]([Br:11])[CH:3]=1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: O=C(Cl)c1ccc(F)cc1Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(F)cc1Br)N1Cc2cccn2Cc2ccccc21
Reaction time: 16 h
Yield: 96.1 %

Procedure:
Step b) (4-Fluoro-2-bromophenyl)-(5H,11H-pyrrolo[2,1-c][1,4]benzo-diazepin-10-yl)-methanone: A solution of 4-fluoro-2-bromobenzoyl chloride (5.32 g) from step a), in dichloromethane (35 ml), was added dropwise to a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]-benzodiazepine (3.44 g) and triethylamine (2.27 g) in dichloromethane (80 ml) and cooled in an ice bath. The cooling bath was removed and after stirring for 16 hours, the reaction mixture was washed sequentially with water, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The dichloromethane solution was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give a pale purple foam. Purification by flash chromatography on silica gel eluting with hexane-ethyl acetate (1:1) resulted in the intermediate (4-fluoro-2-bromophenyl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone as a tan foam (6.91 g), MS m/z: 384 (M)+. This material was used without further purification in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.C1([C:12](=[CH:14][CH:15]=[CH:16][CH:17]=1)O)O.[CH3:18]C(C)=O>II>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6]([C:14]([CH3:12])=[CH:15][C:16]([CH3:17])([CH3:18])[NH:9]2)=[CH:7][CH:8]=1
Reactant: CC(C)=O
Reactant: COc1cccc(N)c1
Reactant: Oc1ccccc1O
Agent: II
Product: COc1ccc2c(c1)NC(C)(C)C=C2C
Yield: 35 %

Procedure:
To a solution of m-anisidine (400 g) in acetone (7.21) were added catechol (33 g) and iodine (27 g), and the mixture was heated under reflux for 4 days. The reaction mixture filtered through silica gel and the solvent was evaporated under reduced pressure. The residue was subjected to normal phase chromatography (elution solvent hexane-ethyl acetate=10:1→5:1) to give the title compound (234 g, 35%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH:7]2[C:13]3=[CH:14][CH:15]=[CH:16][N:12]3[CH2:11][C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=3[O:8]2)[CH2:3][CH2:2]1.Cl[C:22]1[CH:23]=[C:24]([N:28]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[NH:30][C:29]2=[O:37])C=CC=1.[C:38]([O-])([O-:40])=[O:39].[K+].[K+]>CN(C=O)C>[C:29]([OH:37])(=[O:8])[C:38]([OH:40])=[O:39].[O:37]=[C:29]1[N:28]([CH2:24][CH2:23][CH2:22][N:1]2[CH2:2][CH2:3][CH:4]([CH:7]3[C:13]4=[CH:14][CH:15]=[CH:16][N:12]4[CH2:11][C:10]4[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=4[O:8]3)[CH2:5][CH2:6]2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[NH:30]1
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]c2ccccc2n1-c1cccc(Cl)c1
Reactant: c1ccc2c(c1)Cn1cccc1C(C1CCNCC1)O2
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)C(=O)O
Product: O=c1[nH]c2ccccc2n1CCCN1CCC(C2Oc3ccccc3Cn3cccc32)CC1

Procedure:
To 50 ml dry DMF were added 11-(piperidin-4-yl)-5H,11H-pyrrolo[2,1-c][1,4]benzoxazepine (5.0 g, 0.0186 mole), 1-(3-chlorophenyl)-1,3-dihydro-2H-benzimidazol-2-one (4.0 g 0.019 mole), milled K2CO3 (10 g, 0.07 mole) and KI (0.01 g).