Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([C:14]([C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20](Cl)=[O:21])([CH3:16])[CH3:15])#[N:13].Cl>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:12]([C:14]([C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)=[O:21])([CH3:16])[CH3:15])#[N:13]
Reactant: CC(C)(C#N)c1cccc(C(=O)Cl)c1
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a suspension of 3-(1-cyano-1-methylethyl)benzoic acid (9.87 g, 52.2 mmol) in toluene (150 mL) was added thionyl chloride (25.3 g, 213 mmol), and the mixture was stirred at 120° C. for 2 hr. The reaction mixture was concentrated under reduced pressure to give 3-(1-cyano-1-methylethyl)benzoyl chloride as a colorless oil. To a solution of 4-methyl-3-nitroaniline (7.63 g, 50.2 mmol) in pyridine (150 mL) were added N,N-dimethylpyridine-4-amine (122 mg, 1.00 mmol) and 3-(1-cyano-1-methylethyl)benzoyl chloride, and the mixture was stirred at room temperature for 14 hr. To the reaction mixture was added 1N hydrochloric acid (200 mL), and the mixture was extracted with ethyl acetate (150 mL, 100 mL). The combined organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (150 mL), and dried over anhydrous magnesium sulfate. After filtration through a silica gel pad, the filtrate was concentrated under reduced pressure to give 3-(1-cyano-1-methylethyl)-N-(4-methyl-3-nitrophenyl)benzamide as a yellow oil. The obtained compound was used for the next reaction without further purification.
Reaction SMILES: C([BH3-])#N.[Na+].[N:5]1([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH3:19])=[CH:13][C:12]=2[S:20]([OH:23])(=[O:22])=[O:21])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[CH3:24][O:25][C:26]1[C:33]([O:34][CH3:35])=[C:32]([O:36][CH3:37])[CH:31]=[CH:30][C:27]=1[CH:28]=O>CO.[Cl-].[Zn+2].[Cl-]>[CH3:24][O:25][C:26]1[C:33]([O:34][CH3:35])=[C:32]([O:36][CH3:37])[CH:31]=[CH:30][C:27]=1[CH2:28][N:8]1[CH2:9][CH2:10][N:5]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH3:19])=[CH:13][C:12]=2[S:20]([OH:23])(=[O:21])=[O:22])[CH2:6][CH2:7]1
Reactant: COc1ccc(C=O)c(OC)c1OC
Reactant: CCCc1ccc(N2CCNCC2)c(S(=O)(=O)O)c1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CCCc1ccc(N2CCN(Cc3ccc(OC)c(OC)c3OC)CC2)c(S(=O)(=O)O)c1
Reaction time: 0.08 h
Yield: 59.7 %

Procedure:
Into a solution of 0.10 g of sodium cyanoborohydride dissolved in 2 ml of a methanol solution was added 0.10 g of zinc chloride, and the mixture was stirred for 5 minutes. Then, 0.40 g of 2-(1-piperazinyl)-5-n-propylbenzenesulfonic acid and 0.58 g of 2,3,4-trimethoxybenzaldehyde were added to carry out the reaction at room temperature for 2 hours. The organic layer was extracted by addition of an aqueous sodium chloride and tetrahydrofuran, and after evaporation of tetrahydrofuran under reduced pressure from the extract, the residue was purified by silicagel column chromatography (eluant:chloroform: methanol:acetic acid=500:100:6) to give 0.39 g (yield: 58.5%) of the above title product as a glassy solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]2[C:13]1[CH:22]=[CH:21][C:20]2[CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16][C:15]=2[N:14]=1)#[N:2]>Cl.O1CCOCC1>[O:12]=[C:7]1[CH:6]([C:13]2[CH:22]=[CH:21][C:20]3[CH2:19][NH:18][CH2:17][CH2:16][C:15]=3[N:14]=2)[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[CH:4]=2)[NH:8]1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(C3C(=O)Nc4ccc(C#N)cc43)ccc2C1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1ccc2c(c1)C(c1ccc3c(n1)CCNC3)C(=O)N2

Procedure:
A solution of tert-butyl 2-(5-cyano-2-oxoindolin-3-yl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (73 mg, 0.187 mmol) in 4N HCl in dioxane (5 mL) was stirred at RT for 3 h. After this period all volatiles were removed in vacuo. The residue was dissolved in water and washed with ethyl acetate. The aqueous layer was neutralized with saturated solution of sodium bicarbonate and extracted with ethyl acetate. The latter extracts were dried over sodium sulfate, filtered, and evaporated to dryness. Quant. yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:22])=[C:6]([C:8]2[CH2:12][CH2:11][CH2:10][C:9]=2[C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=[O:17])[CH:7]=1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[OH-].[K+]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:6]([C:8]2[CH2:12][CH2:11][CH2:10][C:9]=2[C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=[O:17])[CH:7]=1
Reactant: O=C(O)c1cccc(C2=C(c3cc(Br)ccc3O)CCC2)c1
Reactant: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=C(O)c1cccc(C2=C(c3cc(Br)ccc3OCc3ccccc3)CCC2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
3-{2-[5-Bromo-2-(hydroxy)-phenyl]-cyclopent-1-enyl}-benzoic acid (0.04 g, 0.12 mmol), benzyl bromide (0.038 g, 0.22 moles), potassium hydroxide (˜0.15 g), in dimethyl sulphoxide (1.5 mL) were stirred at room temperature over 8 hrs under nitrogen. The reaction mixture was then quenched with ice/water (10/10 mL), stirred at room temperature for ˜1.5 hrs, acidified with 2N hydrochloric acid to pH˜3 and extracted with dichloromethane. The organic extract was then dried (magnesium sulphate) and concentrated down to an oil and was then chromatographed on Waters sep-pak cartridge (10 g) giving (0.028 g, 54%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([OH:9])=[O:8])[O:5][CH:6]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C>[C:10]1([C:2]2[CH:3]=[C:4]([C:7]([OH:9])=[O:8])[O:5][CH:6]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)c1cc(Br)co1
Reactant: OB(O)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1cc(-c2ccccc2)co1
Temperature: 150 °C
Yield: 50.5 %

Procedure:
A solution of 4-bromofuran-2-carboxylic acid (380 mg, 2 mmol), phenylboronic acid (488 mg, 4 mmol) in DMF (3 ml) was place in a microwave reaction tube and treated with a 2 M K3PO4(aq) (2 ml, 4 mmol). The solution was purged with nitrogen for 10 minutes before adding Pd(PPh3)4 (1.5 mg) catalyst. The mixture was again purged with nitrogen for 5 minutes before the reaction tube was sealed. The mixture was heated in a microwave oven at 150° C. for 30 minutes. The reaction mixture was filtered and the filtrate poured into 1N HCl (100 ml) with stirring. The precipitate was filtered and air-dried to give 190 mg of 4-phenylfuran-2-carboxylic acid. MS (ES−) found: (M−H)−=187.07.
Reaction SMILES: C(N1C(C)CCOCC1)C1C=CC=CC=1.[CH2:16]([N:23]1[CH:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:28][CH2:27][O:26][CH2:25][C:24]1=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([N:23]1[CH:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1COCCC(c2ccccc2)N1Cc1ccccc1
Agent: CC1CCOCCN1Cc1ccccc1
Product: c1ccc(CN2CCOCCC2c2ccccc2)cc1

Procedure:
4-Benzyl-5-phenyl-[1,4]oxazepane was prepared by the same procedure as that of 4-benzyl-5-methyl-[1,4]oxazepane except for utilizing 4-benzyl-5-phenyl-[1,4]oxazepan-3-one instead of 4-benzyl-5-methyl-[1,4]oxazepan-3-one. 4-Benzyl-5-phenyl-[1,4]oxazepane was obtained as colorless oil (0.28 g, 1.0 mmol, 39%).
Reaction SMILES: [CH3:1][C:2]1[C:9]([C:10]2[S:11][C:12]([C:21]([NH2:23])=O)=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)=[C:5]2[S:6][CH:7]=[CH:8][N:4]2[N:3]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:1][C:2]1[C:9]([C:10]2[S:11][C:12]([C:21]#[N:23])=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)=[C:5]2[S:6][CH:7]=[CH:8][N:4]2[N:3]=1
Reactant: Cc1nn2ccsc2c1-c1nc(-c2ccccc2)c(C(N)=O)s1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nn2ccsc2c1-c1nc(-c2ccccc2)c(C#N)s1
Reaction time: 0.5 h
Yield: 42.6 %

Procedure:
To a suspension of 2-(6-methylpyrazolo[5,1-b][1,3]thiazol-7-yl)-4-phenyl-1,3-thiazole-5-carboxamide (270 mg, 0.80 mmol) produced in the same manner as in Example 35-B (ix) in tetrahydrofuran (20 mL) was added Burgess reagent (230 mg, 0.96 mmol), and the mixture was stirred for 30 min. The reaction solution was added to ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate solution (100 mL). The resulting solid was collected by filtration, washed with water and dried to give the title compound (110 mg, 42%) as a colorless solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:23]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[C:15]([NH:24]C(=O)C(Cl)(Cl)Cl)[C:14]=2[N:13]=[C:12]1[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C[O-].[Na+]>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:23]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[C:15]([NH2:24])[C:14]=2[N:13]=[C:12]1[CH3:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc2c(NC(=O)C(Cl)(Cl)Cl)nc3ccccc3c2n1CCOCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Product: Cc1nc2c(N)nc3ccccc3c2n1CCOCc1ccccc1
Yield: 14.2 %

Procedure:
Using the general method of example 1 Part D, N-{1-[2-(benzyloxy)ethyl]-2-methyl-1H-imidazo[4,5-c]quinolin-4-yl}-2,2,2-trichloroacetamide (10.46 g, 21.89 mmol) was hydrolyzed with sodium methoxide (20 mL of 25% in methanol). The resulting brown solid was purified by chromatography over silica gel (98/2 dichloromethane/methanol) and dried under vacuum at 60° C. for 18 hours to provide 1.036 g of 1-[2-(benzyloxy)ethyl]-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, m.p. 159-160° C.
Reaction SMILES: C([Li:5])CCC.[CH3:6][C:7]1[CH2:11][C:10]([CH3:12])=[C:9]([CH3:13])[C:8]=1[CH3:14]>C1COCC1>[CH3:6][C:7]1[CH:11]([Li:5])[C:10]([CH3:12])=[C:9]([CH3:13])[C:8]=1[CH3:14]
Reactant: [Li]CCCC
Reactant: CC1=C(C)C(C)=C(C)C1
Solvent: C1CCOC1
Product: [Li]C1C(C)=C(C)C(C)=C1C
Reaction time: 2 h
Yield: 76 %

Procedure:
Meanwhile, n-butyl lithium (26 ml, 0.042 mol) was slowly added to a solution of 1,2,3,4-tetramethylcyclopentadiene (5 g, 0.041 mol) in 100 ml of THF at −78° C. and the mixture was stirred for 2 hours. Then, the solvent was removed and the resultant product was washed with hexane and dried to obtain tetramethylcyclopentadienyl lithium (yield 76%).
Reaction SMILES: [CH3:1][N:2]1[C:7]2[S:8][CH:9]=[C:10]([CH3:11])[C:6]=2[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[N:4][C:3]1=[O:19].S(Cl)([Cl:23])(=O)=O.N>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:7]2[S:8][C:9]([Cl:23])=[C:10]([CH3:11])[C:6]=2[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[N:4][C:3]1=[O:19]
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1csc2c1c(-c1ccccc1Cl)nc(=O)n2C
Agent: N
Solvent: ClC(Cl)Cl
Product: Cc1c(Cl)sc2c1c(-c1ccccc1Cl)nc(=O)n2C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.5 g of 1-methyl-4-(o-chlorophenyl)-5-methyl-1,2-dihydrothieno[2,3-d]pyrimidin-2-one in 30 ml of chloroform is added dropwise 1.62 g of sulfuryl chloride in 6 ml of chloroform. After stirring the reaction mixture for 2 hours at room temperature, the reaction mixture is neutralized with aqueous ammonia, then extracted with chloroform. The chloroform extracts are washed with water, dried, evaporated under reduced pressure to a residue to give crystals of 1-methyl-4-(o-chlorophenyl)-5-methyl-6-chloro-1,2-dihydrothieno[2,3-d]pyrimidin-2-one, which are recrystallized from ethanol to give 1.252 g of crystals having a melting point of 199.5° - 200.5°C; yield 74.5 %.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:14][CH:13]([C:15]2[NH:16][CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[C:27][C:28]4[CH:33]=[CH:32][C:31]([C:34]5[N:35]=[C:36]([CH:39]6[CH2:43][CH2:42][CH2:41][N:40]6[C:44](=[O:54])[CH:45]([NH:49][C:50]([O:52][CH3:53])=[O:51])[CH:46]([CH3:48])[CH3:47])[NH:37][CH:38]=5)=[CH:30][CH:29]=4)=[CH:22][CH:21]=3)[N:19]=2)[N:12]([C:55](=[O:65])[CH:56]([NH:60][C:61]([O:63][CH3:64])=[O:62])[CH:57]([CH3:59])[CH3:58])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:66][Si:67]([CH3:74])([CH3:73])[CH2:68][CH2:69][O:70][CH2:71]Cl>CN(C)C=O>[C:3]([O:7][C:8]([N:10]1[CH2:14][CH:13]([C:15]2[N:16]([CH2:71][O:70][CH2:69][CH2:68][Si:67]([CH3:74])([CH3:73])[CH3:66])[CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[C:27][C:28]4[CH:33]=[CH:32][C:31]([C:34]5[N:35]=[C:36]([CH:39]6[CH2:43][CH2:42][CH2:41][N:40]6[C:44](=[O:54])[CH:45]([NH:49][C:50]([O:52][CH3:53])=[O:51])[CH:46]([CH3:48])[CH3:47])[N:37]([CH2:71][O:70][CH2:69][CH2:68][Si:67]([CH3:74])([CH3:73])[CH3:66])[CH:38]=5)=[CH:30][CH:29]=4)=[CH:22][CH:21]=3)[N:19]=2)[N:12]([C:55](=[O:65])[CH:56]([NH:60][C:61]([O:63][CH3:64])=[O:62])[CH:57]([CH3:58])[CH3:59])[CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: C[Si](C)(C)CCOCCl
Reactant: COC(=O)NC(C(=O)N1CCCC1c1nc(-c2ccc(C#Cc3ccc(-c4c[nH]c(C5CN(C(=O)OC(C)(C)C)CN5C(=O)C(NC(=O)OC)C(C)C)n4)cc3)cc2)c[nH]1)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)NC(C(=O)N1CCCC1c1nc(-c2ccc(C#Cc3ccc(-c4cn(COCC[Si](C)(C)C)c(C5CN(C(=O)OC(C)(C)C)CN5C(=O)C(NC(=O)OC)C(C)C)n4)cc3)cc2)cn1COCC[Si](C)(C)C)C(C)C
Temperature: 25 °C
Yield: 156.5 %

Procedure:
Sodium hydride (60% in mineral oil, 27 mg, 0.55 mmol) was added to a solution of 3′-(2-methoxycarbonylamino-3-methyl-butyryl)-4-[4-(4-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-phenylethynyl)-phenyl]-2′,3′,4′,5′-tetrahydro-1H-[2,4′]biimidazolyl-1′-carboxylic acid tert-butyl ester (248 mg, 0.23 mmol) in dimethylformamide (8 mL) under an atmosphere of nitrogen at 0° C. After 15 minutes 2-(trimethylsilyl)ethoxymethyl chloride (107.5 μL, 0.48 mmol) was added and the reaction was allowed to warm to ambient temperature. After 2 hours the solvent was removed under reduced pressure. The residue was taken up in dichloromethane (50 mL) washed with water (20 mL), and dried over sodium sulfate and filtered. The solvent was removed under reduced pressure. The residue was subjected to flash chromatography with eluent of (10% methanol in ethyl acetate) and hexane. The product-containing fractions were combined and the solvent was removed under reduced pressure to yield 3′-(2-methoxycarbonylamino-3-methyl-butyryl)-4-[4-(4-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl}-phenylethynyl)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-2′,3′,4′,5′-tetrahydro-1H-[2,4]biimidazolyl-1′-carboxylic acid tert-butyl ester (410 mg, 0.36 mmol). C58H85N9O10Si2 calculated 1123.6 observed [M+1]+1124.7; rt=3.10 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[C:11]([C:17]([F:20])([F:19])[F:18])[N:10]([CH3:21])[N:9]=2)=[CH:4][C:3]=1[N+:22]([O-])=O.C(O)(=O)C.O.C(OCC)(=O)C>CO.[Fe]>[NH2:22][C:3]1[CH:4]=[C:5]([C:8]2[C:12]([C:13]([F:14])([F:15])[F:16])=[C:11]([C:17]([F:20])([F:19])[F:18])[N:10]([CH3:21])[N:9]=2)[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: Cn1nc(-c2ccc(Cl)c([N+](=O)[O-])c2)c(C(F)(F)F)c1C(F)(F)F
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: Cn1nc(-c2ccc(Cl)c(N)c2)c(C(F)(F)F)c1C(F)(F)F
Reaction time: 3 h

Procedure:
A solution of 10 g (26 mmol) of 3-(4-chloro-3-nitrophenyl)-1-methyl-4,5-di(trifluoromethyl)-1H-pyrazole in 50 ml of methanol was added dropwise to a mixture, heated at reflux temperature, of 4.5 g (80 mmol) of iron powder and 30 ml of glacial acetic acid. After the mixture had been stirred for 3 hours it was poured into 100 ml of water. Then, 100 ml of ethyl acetate were added to the mixture. The solids were subsequently separated off from the mixture and washed with ethyl acetate. The organic phase was separated off from the combined filtrates, washed with water, dried over magnesium sulfate and finally concentrated.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Br:5][CH2:6][C:7](Br)=[O:8].[F:10][C:11]([F:29])([F:28])[C:12]([N:14]1[CH2:27][CH2:26][C:18]2=[CH:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[N:17]2[CH2:16][CH2:15]1)=[O:13].C([O-])(O)=O.[Na+]>ClCCl>[Br:5][CH2:6][C:7]([C:19]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=2[N:17]2[CH2:16][CH2:15][N:14]([C:12](=[O:13])[C:11]([F:29])([F:28])[F:10])[CH2:27][CH2:26][C:18]=12)=[O:8]
Reactant: O=C(N1CCc2cc3ccccc3n2CC1)C(F)(F)F
Reactant: O=C(Br)CBr
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CBr)c1c2n(c3ccccc13)CCN(C(=O)C(F)(F)F)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
(Chart E, Step 1): A dry round bottom flask is charged with AlCl3 (66.7 mg, 0.5 mmol) and dichloromethane (4 mL) to make a heterogeneous solution. Dropwise addition of bromo-acetylbromide (0.044 mL, 0.5 mmol) turns the reaction into a homogeneous orange solution. After 30 minutes of stirring at ambient temperature, a solution of 2,2,2-trifluoro-1-(1,2,4,5-tetrahydro-3H-[1,4]diazepino[1,7-a]indol-3-yl)-1-ethanone (141.1 mg, 0.5 mmol) in dichloromethane (2 mL) is added dropwise and stirred for three days. The reaction turns dark purple within the first 4 hours of stirring. The reaction is poured in a sat. aq. NaHCO3 solution and extracted three times with dichloromethane. The combined organics are combined, dried with MgSO4, filtered and concentrated to 192 mg of a purple foam. The crude is purified by LC (230-400 silica gel) eluting with 10% ethyl acetate and 20% dichloromethane in heptane to afford 120 mg of 1-[11-(2-bromoacetyl)-1,2,4,5-tetrahydro-3H-[1,4]diazepino[1,7-a]indol-3-yl]-2,2,2-trifluoro-1-ethanone as a white foam.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:14][C:15]1[CH:16]=[CH:17][C:18]([Sn](CCCC)(CCCC)CCCC)=[N:19][CH:20]=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>[CH3:13][O:12][C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([C:18]2[CH:17]=[CH:16][C:15]([CH3:14])=[CH:20][N:19]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C)cn1
Reactant: COC(=O)c1cc(Br)cc(OC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(OC)cc(-c2ccc(C)cn2)c1
Temperature: 25 °C

Procedure:
A mixture of methyl 3-bromo-5-methoxybenzoate (0.1 g, 0.4 mmol), 5-methyl-2-(tributylstannyl)pyridine (0.1 mL, 0.3 mmol), tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.02 mmol) and toluene (4 mL) under argon was subjected to microwave irradiation at 120° C. for 2 hours. The mixture was cooled to room temperature and purified via flash chromatography to afford the desired product as a light yellow oil. LC-MS: 257.9 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH2:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][C:14]1[N:19]=[C:18](Br)[CH:17]=[CH:16][CH:15]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH:12][C:18]3[CH:17]=[CH:16][CH:15]=[C:14]([CH3:13])[N:19]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cccc(Br)n1
Reactant: Cc1ccc2cccc(N)c2n1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cccc(Nc2cccc3ccc(C)nc23)n1
Yield: 68 %

Procedure:
To a flask were added 4.2 g of 2-methylquinolin-8-amine, 4.6 g of 6-methyl-2-bromopyridine, 3.3 g of sodium tert-butoxide, and 75 ml toluene. The mixture was purged thoroughly with nitrogen and 44 mg of 1,1′-bis(diphenylphosphino)ferrocene and 18 mg of palladium acetate were added. The reaction mixture was heated to 80 C for 16 hours, and then cooled to 22 C. After quenching with 100 ml of water, the product was extracted with 75 ml ethyl acetate. The product was extracted with 120 ml of 1M hydrochloric acid, and then basified with 3M sodium hydroxide. Following extraction with 75 ml of ethyl acetate and washing with 30 ml of water, the solvent was removed. The product was purified by dissolving in a hot mixture of 20 ml of 2-propanol and 5 ml of water, and after cooling to 5 C, the product was filtered, washed with 50% 2-propanol, and dried, resulting in 4.5 g of a tan solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C:41]([CH3:53])([CH3:52])[C@H:42]([N:46]1[CH2:50][CH2:49][NH:48][C:47]1=[O:51])[C:43](O)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH3:40][C:41]([CH3:53])([CH3:52])[C@H:42]([N:46]1[CH2:50][CH2:49][NH:48][C:47]1=[O:51])[C:43]([NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)=[O:44]
Reactant: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: CC(C)(C)[C@@H](C(=O)O)N1CCNC1=O
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCNC1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.6 %

Procedure:
A solution of the product of Example 1H (0.020 g, 0.038 mmol) in tetrahydrofuran (0.40 mL) was treated with the product from Example 160B (0.0075 g, 0.038 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine (0.035 mL, 0.201 mmol), stirred at 25° C. for 12 hours and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic layer was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with a gradient starting with dichloromethane and ending with 50% acetone in dichloromethane to give the title compound (0.020 g, 74% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.80 (s, 9 H), 0.86 (s, 9 H), 1.33-1.56 (m, 2 H), 2.55-2.72 (m, 4 H), 2.82 (dd, J=5.9, 12.9 Hz, 1 H), 2.89-2.56 (m, 1 H), 3.08 (q, J=8.8 Hz, 1 H), 3.24-3.28 (m, 1 H), 3.50-3.57 (m, 4 H), 3.83 (d, J=9.6 Hz, 1 H), 3.87-3.94 (m, 1 H), 3.97 (s, 1 H), 4.14-4.20 (m, 1H), 4.42 (d, J=7.4 Hz, 1 H), 6.29 (s, 1 H), 6.88 (d, J=9.6 Hz, 1 H), 7.09-7.25 (m, 7 H), 7.30-7.34 (m, 1 H), 7.44 (d, J=9.6 Hz, 1 H), 7.83-7.97 (m, 5 H), 8.62 (m, 1 H).
Reaction SMILES: [OH-].[Na+].O[C:4]1[C:9](C(CC)(C)C)=[CH:8][C:7](C(CC)(C)C)=[CH:6][C:5]=1[N:20]=[N:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N+:28]([O-:30])=[O:29]>>[N+:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[N:21]=[N:20][C:5]1[CH:4]=[CH:9][CH:8]=[CH:7][CH:6]=1)([O-:30])=[O:29]
Reactant: CCC(C)(C)c1cc(N=Nc2ccccc2[N+](=O)[O-])c(O)c(C(C)(C)CC)c1
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1ccccc1N=Nc1ccccc1

Procedure:
The same procedure as described in Example 1 was carried out except that the 27.4 grams of 50% sodium hydroxide was used with 155 grams of 2'-hydroxy-3',5'-di-tert-amyl-2-nitroazobenzene to give a ratio of moles of alkali to moles of o-nitroazobenzene intermediate of 0.848/1 compared to the ratio of 0.42/1 employed in Example 1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[C@@H:7]([NH:16][C:17]([O:19][CH2:20][CH:21]1[C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:35]1[CH:40]=[CH:39][C:38]([CH2:41]O)=[CH:37][CH:36]=1>>[C:1]([O:5][C:6](=[O:34])[C@@H:7]([NH:16][C:17]([O:19][CH2:20][CH:21]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=2[C:28]2[C:33]1=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:18])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:41][C:38]2[CH:39]=[CH:40][N:35]=[CH:36][CH:37]=2)=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OCc1ccncc1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCc2ccncc2)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21

Procedure:
In a manner similar to that described in Example H, the product from Example G (0.5 g, 1.08 mmol) and 4-pyridylcarbinol (0.12 mL, 1.26 mmol) were converted to the title compound.