Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:11][CH2:12][CH3:13])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:18]([CH3:30])[CH:17]=1.Cl>O1CCCC1>[C:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH:5]([C:4](=[O:3])[CH2:11][CH2:12][CH3:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:17][C:18]=1[CH3:30])#[N:29]
Reactant: CCCC(=O)CC(=O)OCC
Reactant: Cc1cc(CBr)ccc1-c1ccccc1C#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)c(C)c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
To a solution (15 mL) of 4′-(hydroxymethyl)-2′-methylbiphenyl-2-carbonitrile (4.12 g) in toluene was added phosphine tribromide (6.00 g) at room temperature, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate. The obtained ethyl acetate solution was washed with saturated aqueous sodium hydrogen carbonate and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow oil (5.08 g, 96%). To a mixture of 60% sodium hydride in oil (1.10 g) and tetrahydrofuran (20 mL) was added dropwise a mixture of ethyl 3-oxohexanoate (5.62 g) in tetrahydrofuran (20 mL) at 0° C., and the mixture was stirred at room temperature for 30 min. Then, 4′-(bromomethyl)-2′-methylbiphenyl-2-carbonitrile (5.08 g) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 1 M hydrochloric acid (50 mL), and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless oil (4.53 g, 70%).
Reaction SMILES: Cl.N(OC(C)(C)C)=O.[NH:9]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C@H:10]([C:17]([NH:19][C@H:20]([C:27]([NH:29]N)=[O:28])[CH2:21][O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:18])[CH2:11][O:12][C:13]([CH3:16])([CH3:15])[CH3:14].N[C@H:42]([C:47]([NH:49][C@H:50]([C:52]([O:54][CH3:55])=[O:53])[CH3:51])=[O:48])[CH2:43][C:44](=[O:46])[NH2:45].C(N1CCOCC1)C>C(OCC)(=O)C.CN(C)C=O>[NH:9]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C@H:10]([C:17]([NH:19][C@H:20]([C:27]([NH:29][C@H:42]([C:47]([NH:49][C@H:50]([C:52]([O:54][CH3:55])=[O:53])[CH3:51])=[O:48])[CH2:43][C:44](=[O:46])[NH2:45])=[O:28])[CH2:21][O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:18])[CH2:11][O:12][C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: COC(=O)[C@H](C)NC(=O)[C@@H](N)CC(N)=O
Reactant: CC(C)(C)OC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](COC(C)(C)C)C(=O)NN
Agent: CC(C)(C)ON=O
Agent: CCN1CCOCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](COC(C)(C)C)NC(=O)[C@H](COC(C)(C)C)NC(=O)OCc1ccccc1
Reaction time: 15 h

Procedure:
61.8 ml of 2.32 N-hydrochloric acid in ethyl acetate and 7.3 ml of tert.butyl nitrite are added to 25.95 g of Z-Ser(But)-Ser(But)-NH-NH2 in 200 ml of dimethylformamide at -10°. After 10 minutes a solution of 14.8 g of HCl.H-Asn-Ala-OMe and 36.16 ml of N-ethyl morpholine in 150 ml of dimethylformamide is added dropwise and the mixture is then kept for one hour at -10° and 15 hours at 0°. The solution is freed from the solvent by evaporation, the residue is taken up in chloroform and washed with sodium bicarbonate, dilute hydrochloric acid and with water. The Z-Ser(But)-Ser(But)-Asn-Ala-OCH3 obtained after evaporation of the solvent is reprecipitated from chloroform-petroleum ether. The Rf-value on silicagel in the system chloroform-methanol 9:1 is 0.35.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20](O)[CH:21]([CH3:23])[CH3:22])=[CH:16][CH:15]=1.B(F)(F)F.CCOCC>O1CCOCC1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([C:3]2[C:4](=[O:12])[O:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:21]([CH3:23])[CH3:22])=[CH:16][CH:15]=1
Reactant: O=c1cc(O)c2ccccc2o1
Reactant: CC(C)C(O)c1ccc(Br)cc1
Agent: FB(F)F
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)C(c1ccc(Br)cc1)c1c(O)c2ccccc2oc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 3.8 %

Procedure:
To a flame-dried flask containing a near-solution of 324 mg of 4-hydroxycoumarin and 573 mg of 1-(4-bromophenyl)-2-methylpropan-1-ol of Preparation 14 in 10 mL of dioxane under an argon atmosphere is added 1.2 mL of boron trifluoride etherate. The resulting yellow solution is left to stir at room temperature overnight. The volatiles are removed and the residue is partioned between diethyl ether and 1N sodium hydroxide. The basic aqueous phase is washed with diethyl ether and acidified to pH=1 with 6N hydrochloric acid. The resulting precipitant is repeatedly extracted with dichloromethane (methanol-chloroform co-solvents). The combined dichloromethane extracts are washed once with dilute sodium bicarbonate to remove most of the unreacted 4-hydroxycoumarin, then brine, dried (magnesium sulfate), and finally concentrated under reduced pressure. The residue is adsorbed onto silica and flash column chromatographed with 50% to 60% ethyl acetate in hexanes to yield 28 mg of the title product as a tan solid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[SH:10][CH2:11][CH2:12][OH:13]>>[OH:13][CH2:12][CH2:11][S:10][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: OCCS
Product: N#Cc1ccc(SCCO)cc1

Procedure:
5 g of 4-fluorobenzonitrile was used in Procedure Q with 2-mercaptoethanol to afford 4-(2-hydroxyethylthio)benzonitrile. 900 mg of 4-(2-hydroxyethylthio)benzonitrile was reacted via Procedure T to give 4-(2-hydroxyethylthio)benzoic acid. 1.0 g of 4-(2-hydroxyethylthio)benzoic acid was reacted via Procedure R to give 4-(2-hydroxyethylsulfonyl)benzoic acid. 80 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(2-hydroxyethylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxyethylsulfonyl)benzamide. MS (Q1) 417.0 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[CH2:10]([N:17]1[CH2:22][C:21](OC)=[CH:20][C:19](=[O:25])[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>CCOCC.C1COCC1>[CH2:10]([N:17]1[CH2:22][C:21]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:20][C:19](=[O:25])[CH2:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: COC1=CC(=O)CN(Cc2ccccc2)C1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C1C=C(c2ccc(Cl)cc2)CN(Cc2ccccc2)C1
Reaction time: 1 h

Procedure:
A solution of p-chlorophenyl magnesium bromide (0.17 M) in ether (100 ml) was treated with a solution of 1-benzyl-1,6-dihydro-5-methoxy-3-[2H]pyridone (32.5 g, 0.25 M) in THF (150 ml). The reaction was stirred 1 hour, poured onto cold 2 N hydrochloric acid (250 ml) and stirred 30 min. Removal of the resulting precipitate by filtration, followed by air-drying and recrystallisation from methanol gave the title compound as the hydrochloride hydrate (24.1 g) m.p. 166°-8°.
Reaction SMILES: [OH-].[Na+].C([NH:11][C:12]([NH:14][C:15]1[CH:20]=[C:19]([I:21])[CH:18]=[C:17]([I:22])[CH:16]=1)=[S:13])(=O)C1C=CC=CC=1>O.C1COCC1>[I:21][C:19]1[CH:20]=[C:15]([NH:14][C:12]([NH2:11])=[S:13])[CH:16]=[C:17]([I:22])[CH:18]=1
Reactant: O=C(NC(=S)Nc1cc(I)cc(I)c1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NC(=S)Nc1cc(I)cc(I)c1
Temperature: 70 °C
Reaction time: 12 h
Yield: 76.2 %

Procedure:
A solution of NaOH (1.30 g, 0.033 mol) dissolved in 35 mL of H2O was added to a solution of 1-benzoyl-3-(3,5-diiodo-phenyl)-thiourea (6.30 g, 0.013 mol) in 75 mL of THF. The resulting reaction mixture was stirred at 70° C. for 12 hours. THF was distilled off and extracted with ethyl acetate (×3). The combined organic layer was dried over Na2SO4, filtered and distilled off to get the crude residue that was washed with hexane to obtain the desired compound (4.0 g, 75%).
Reaction SMILES: C(C1N(CC2C=CC=CC=2Cl)C([C:10]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]([O:18]CC)=[O:17])[C:11]([O:13]CC)=[O:12])=CN=1)CCC.[OH-].[K+]>C(O)C.O>[CH2:21]([CH:10]([C:11]([OH:13])=[O:12])[C:16]([OH:18])=[O:17])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCCCc1ncc(C(Cc2ccccc2)(C(=O)OCC)C(=O)OCC)n1Cc1ccccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C(Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of diethyl [2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-benzyl-malonate [Example 8(iii)] (5.54 g, 0.0108 mol) in ethanol (75 mL) was treated all at once with a solution of potassium hydroxide (3.65 g, 0.065 mol) in water (50 mL). The resulting mixture was stirred at room temperature for 24 hours, then refluxed for 3 hours. The ethanol was evaporated, water was added to the aqueous product, and the basic solution was extracted with diethyl ether. The aqueous layer was acidified to pH 4 with hydrochloric acid and the product was extracted into ethyl acetate. The dried, concentrated product was crystallized twice from ethyl acetate to give 0.6 g of 2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-benzyl-malonic acid; mp 165°-166° C.(d). The filtrates from the crystallizations (4.9 g) consisted of additional malonic acid, the propanoic acid derivative and the mono ethyl ester malonate derivative. These are converted to [ 2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-benzylpropanoic acid by the method described previously.
Reaction SMILES: [CH3:1][C:2]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[N:16]([CH3:40])[C:17]3[C:22]([N:23]=2)=[C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:20]=[C:19]([N:30]2[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[N:32]=[C:31]2[CH3:39])[N:18]=3)[CH2:10][CH2:9]1)([CH3:7])[C:3](OC)=[O:4].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:7][C:2]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[N:16]([CH3:40])[C:17]3[C:22]([N:23]=2)=[C:21]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[N:20]=[C:19]([N:30]2[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[N:32]=[C:31]2[CH3:39])[N:18]=3)[CH2:10][CH2:9]1)([CH3:1])[CH2:3][OH:4]
Reactant: COC(=O)C(C)(C)N1CCC(Cc2nc3c(N4CCOCC4)nc(-n4c(C)nc5ccccc54)nc3n2C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCN(C(C)(C)CO)CC3)n(C)c2n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 2-methyl-2-(4-((9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-morpholino-9H-purin-8-yl)methyl)piperidin-1-yl)propanoate 507 (0.10 g, 0.183 mmol) in THF (10 mL) was added a 1.0 M solution of lithium aluminum hydride in THF (0.18 mL, 0.18 mmol) at 0° C. The reaction was stirred at 0° C. for 1 hour. The reaction was then quenched by adding 2 mL of sat. NH4Cl solution. The cloudy mixture was then loaded onto an ISOLUTE® SCX-2 column. The column was first washed with MeOH prior to eluting the product by adding 2M NH3 in MeOH. The crude product was then concentrated and purified by RP-HPLC to give 509. LCMS m/z: 519.3 (MH+)
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][C:13](=[O:17])[NH:14]2)=[CH:9][CH:8]=1)(=O)=O.[CH3:20][N:21](C=O)C>[C-]#N.[C-]#N.[Zn+2].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:17]=[C:13]1[CH2:12][CH2:11][C:10]2[C:15](=[CH:16][C:7]([C:20]#[N:21])=[CH:8][CH:9]=2)[NH:14]1
Reactant: O=C1CCc2ccc(OS(=O)(=O)C(F)(F)F)cc2N1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc2c(c1)NC(=O)CC2
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Step R1-2: The mixture of 2-oxo-1,2,3,4-tetrahydroquinolin-7-yl trifluoromethanesulfonate (338 g), Zn(CN)2 (134 g) and Pd(PPh3)4 (33.5 g) in DMF (3.0 L) was heated at 100° C. for 4 hours and cooled to room temperature. To the mixture, Zn(CN)2 (134 g) and Pd(PPh3)4 (12.7 g) were added and the mixture was stirred at 100° C. for 2 hours. After cooling to 60° C., the reaction mixture was filtrated through a pad of Celite. The filtrate was concentrated to obtain a solid. The solid was washed with EtOAc twice to obtain 2-oxo-1,2,3,4-tetrahydroquinoline-7-carbonitrile as a pale yellow solid (165 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[CH:6][C:7]=1[F:8].C([O-])([O-])=O.[K+].[K+].[CH2:16](I)[CH3:17]>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([S:9][CH2:16][CH3:17])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(S)cc1Br
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCSc1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.5 %

Procedure:
To a mixture of 3-bromo-4-fluorobenzenethiol (2.07 g, 10 mmol) and K2CO3 (4.14 g, 30 mmol) in acetone (20 mL) was added EtI (3.12 g, 20 mmol). The mixture was stirred at room temperature for 12 h, filtered, and the volatile components were removed under vacuum to give the title compound (2.34 g) as light yellow oil which was carried on without purification. 1H NMR (CDCl3, 400 MHz): d 7.54 (dd, J1=6.4 Hz, J2=2.4 Hz, 1H), 7.26-7.25 (m, 1H), 7.05 (t, J=8.4 Hz, 1H), 2.91 (q, J=7.6 Hz, 2H), 1.30 (t, J=7.6 Hz, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[N:19]1([C:24](Cl)=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][N:13]([C:24]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:25])[CH2:12][CH:11]([C:15]([O:17][CH3:18])=[O:16])[CH2:10]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: O=C(Cl)N1CCCC1
Reactant: CCc1ccc(C2CNCC(C(=O)OC)C2)cc1
Product: CCc1ccc(C2CC(C(=O)OC)CN(C(=O)N3CCCC3)C2)cc1

Procedure:
6.7 g (24.1 mmol) of methyl 5-(4-ethylphenyl)piperidine-3-carboxylate and 4.2 g (31.4 mmol, 1.3 eq.) of pyrrolidine-1-carbonyl chloride were reacted according to General Method 3A. Yield: 7.6 g (91% of theory)
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[N:7][N:6]2[C:13]=1[S:14]([NH2:17])(=[O:16])=[O:15])[CH3:2].ClC1C=CC=C(C(OO)=O)C=1.[OH2:29].[OH2:30].N>CN(C=O)C>[CH2:1]([C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][C:8]([S:11]([CH3:12])(=[O:30])=[O:29])=[N:7][N:6]2[C:13]=1[S:14]([NH2:17])(=[O:15])=[O:16])[CH3:2]
Reactant: CCc1nc2ccc(SC)nn2c1S(N)(=O)=O
Reactant: O
Agent: N
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CN(C)C=O
Product: CCc1nc2ccc(S(C)(=O)=O)nn2c1S(N)(=O)=O

Procedure:
2-Ethyl-6-methylthioimidazo[1,2-b]pyridazin-3-ylsulfonamide (1.10 g, 4.04 mmol) was dissolved in DMF (10.0 ml) and stirred under ice-cooling, during which m-chloro-perbenzoic acid (abbreviated into mCPBA) (70%, 2.48 g, 10.1 mmol) was added thereto. The mixture was stirred under ice-cooling for 1 hour and at TOM temperature for 3 hours, and then the reaction solution was poured into water (50.0 ml), and 25% ammonia water (1.0 ml) was added thereto. After the reaction solution was stirred for 5 minutes, the precipitated crystals were filtered and washed with water, to give the title compound as colorless crystals. The yield was 1.04 g (84.5%).
Reaction SMILES: [C:1]1([C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:18][N:17]([C:19]([C:21]4[CH:32]=[CH:31][C:24]([O:25][C@H:26]5[CH2:30][CH2:29][NH:28][CH2:27]5)=[CH:23][CH:22]=4)=[O:20])[CH2:16]3)[CH2:11][CH2:10]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.[CH3:40][N:41]([CH3:46])[S:42](Cl)(=[O:44])=[O:43]>C(Cl)Cl>[CH3:40][N:41]([CH3:46])[S:42]([N:28]1[CH2:29][CH2:30][C@H:26]([O:25][C:24]2[CH:31]=[CH:32][C:21]([C:19]([N:17]3[CH2:16][CH:15]([N:12]4[CH2:11][CH2:10][N:9]([C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)=[O:8])[CH2:14][CH2:13]4)[CH2:18]3)=[O:20])=[CH:22][CH:23]=2)[CH2:27]1)(=[O:44])=[O:43]
Reactant: O=C(c1ccccc1)N1CCN(C2CN(C(=O)c3ccc(O[C@H]4CCNC4)cc3)C2)CC1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)S(=O)(=O)N1CC[C@H](Oc2ccc(C(=O)N3CC(N4CCN(C(=O)c5ccccc5)CC4)C3)cc2)C1
Reaction time: 3 h
Yield: 58 %

Procedure:
A solution of compound 33a (0.164 mmol) and Et3N (0.5 mL) in CH2Cl2 (2 mL) was treated with N,N-dimethylsulfamoyl chloride (26 μL, 0.246 mmol) at room temperature. The resulting mixture was stirred for 3 h, and the solvent was then removed under reduced pressure. The resultant residue was directly loaded onto a silica gel column and was purified by silica gel flash column chromatography, eluting with 5% MeOH/CH2Cl2 to give compound 439 (51.5 mg). 1H NMR (CDCl3): δ 7.61 (d, J=8.21 Hz, 2H), 7.36-7.46 (m, 5H), 6.86 (d, J=8.6 Hz, 2H), 4.98 (m, 1H), 4.31 (br. s., 1H), 4.11-4.26 (m, 2H), 4.05 (br. s., 1H), 3.87-3.96 (m, 1H), 3.84 (m, 1H), 3.70-3.79 (m, 1H), 3.66 (dd, J=11.4, 4.8 Hz, 1H), 3.39-3.58 (m, 4H), 3.21-3.26 (m, 1H), 2.82 (s, 6H), 2.42 (br. s., 4H), 2.19-2.29 (m, 2H); MS m/z (M+H+) 542.0.
Reaction SMILES: [OH-].[Na+].[CH:3]1([C:9]2[C:10]3[CH:11]=[CH:12][C:13]([C:28]([O:30]C)=[O:29])=[CH:14][C:15]=3[N:16]3[CH2:22][C:21](=[O:23])[CH2:20][C:19]4[CH:24]=[CH:25][CH:26]=[CH:27][C:18]=4[C:17]=23)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl>CO.O1CCCC1>[CH:3]1([C:9]2[C:10]3[CH:11]=[CH:12][C:13]([C:28]([OH:30])=[O:29])=[CH:14][C:15]=3[N:16]3[CH2:22][C:21](=[O:23])[CH2:20][C:19]4[CH:24]=[CH:25][CH:26]=[CH:27][C:18]=4[C:17]=23)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(=O)Cc1ccccc1-3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C1Cc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1
Temperature: 90 °C
Yield: 92.7 %

Procedure:
Sodium hydroxide (0.2 mL of 1 N, 0.2 mmol) was added to a solution of the Methyl 13-cyclohexyl-6,7-dihydro-6-oxo -5H-indolo[2,1-a][2]benzazepine-10-carboxylate (20 mg, 0.052 mmol) in methanol (0.5 mL) and tetrahydrofuran (0.5 mL) in a microwave vial. The vial was sealed and the contents heated at 90° C. for 5 min in a microwave apparatus. The solution was acidified with dilute hydrochloric acid to precipitate the crude acid. The solid was collected and purified on the Shimadzu preparative liquid chromatograph. The product containing fraction was concentrated on a Speed Vac® to leave the titled compound as a white solid (18 mg, 92%). ESI-MS m/z 374 (MH+); 1H NMR (500 MHz, ACETONE-D6) δ 1.22–1.35 (m, 1 H) 1.41–1.58 (m, 2 H) 1.59–1.70 (m, 1 H) 1.73–1.85 (m, 2 H) 1.92–2.00 (m, 1 H) 2.11–2.26 (m, 3 H) 3.04 (m, 1 H) 3.60 (d, J=14.04 Hz, 1 H) 3.97 (d, J=13.73 Hz, 1 H) 4.56 (d, J=18.31 Hz, 1 H) 5.19 (d, J=18.31 Hz, 1 H) 7.51 (m, 2 H) 7.57 (t, J=7.32 Hz, 1 H) 7.66 (d, J=7.63 Hz, 1 H) 7.81 (dd, J=8.39, 1.37 Hz, 1 H) 8.03 (d, J=8.24 Hz, 1 H) 8.23 (s, 3 H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11]([NH2:14])(=[O:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:15]1OCOCO1.FC(F)(F)S(O)(=O)=O.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>ClCCCl.ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH2:10][S:11](=[O:12])(=[O:13])[NH:14][CH2:15][C:8]=2[CH:9]=1)([O-:3])=[O:2]
Reactant: NS(=O)(=O)Cc1ccc([N+](=O)[O-])cc1
Reactant: C1OCOCO1
Agent: O=S(=O)(O)C(F)(F)F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: ClCCCl
Product: O=[N+]([O-])c1ccc2c(c1)CNS(=O)(=O)C2
Temperature: 35 °C
Reaction time: 2 h
Yield: 23 %

Procedure:
To a mixture of (4-nitrophenyl)methanesulfonamide (864 mg, 4.0 mmol) and s-trioxane (120 mg, 4.0 mmol) in 1,2-dichoroethane (10 mL) was added trifluoromethanesulfonic acid (1.5 mL), followed by the addition of trifluoromethanesulfonic anhydride (1.5 mL, 4.0 mmol). The reaction mixture was stirred at 35° C. for 2 hours and refluxed overnight. The mixture was then diluted with dichloromethane (100 mL) and washed with water (100 mL) and brine (50 mL). The solvents were evaporated and the residue was purified by Prep-HPLC to give 6-nitro-3,4-dihydro-1H-benzo[d][1,2]thiazine 2,2-dioxide (210 mg, 23%) as a gray solid. MS (ES+) C8H8N2O4S requires: 228, found: 229 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>ClCCl>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: C1CCNCC1
Solvent: ClCCl
Product: O=C(c1ccc(I)cc1)N1CCCCC1
Temperature: 25 °C
Yield: 100.1 %

Procedure:
To a suspension of 4-iodo-benzoyl chloride (2.00 g, 7.51 mmol) in dichloromethane (25 mL) was added piperidine (1.85 mL, 18.76 mmol). The reaction mixture was heated at reflux for 1.5 hour and then cooled to room temperature. The organic layer was washed with an aqueous 1M HCl solution, brine, dried (Na2SO4), filtered, concentrated under vacuum to give the title compound (2.37 g, 100%) as a white solid.
Reaction SMILES: [CH2:1]([C:3]1([CH2:30][CH3:31])[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18](F)[CH:17]=3)[N:13]=[C:12]3[NH:24][N:25]=[C:26]([CH3:27])[C:11]=23)[C:6]([CH3:29])([CH3:28])[CH2:5][NH:4]1)[CH3:2].[Cl:32]C1C=C(O)C=CC=1B1OCC(C)(C)CO1>>[Cl:32][C:17]1[CH:18]=[C:19]([OH:22])[CH:20]=[CH:21][C:16]=1[C:14]1[N:13]=[C:12]2[NH:24][N:25]=[C:26]([CH3:27])[C:11]2=[C:10]([CH2:9][N:7]2[CH2:8][C:3]([CH2:30][CH3:31])([CH2:1][CH3:2])[NH:4][CH2:5][C:6]2([CH3:29])[CH3:28])[CH:15]=1
Reactant: CCC1(CC)CN(Cc2cc(-c3ccc(O)c(F)c3)nc3[nH]nc(C)c23)C(C)(C)CN1
Reactant: CC1(C)COB(c2ccc(O)cc2Cl)OC1
Product: CCC1(CC)CN(Cc2cc(-c3ccc(O)cc3Cl)nc3[nH]nc(C)c23)C(C)(C)CN1

Procedure:
The title compound was synthesized in a similar manner as Example 58 (4-[4-(5,5-Diethyl-2,2-dimethyl-piperazin-1-ylmethyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl]-2-fluoro-phenol) employing 3-chloro-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenol in step (b).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([O:19][CH3:20])[C:13]=3[C:12](I)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Mg]Cl)(C)C.[C:27]([O:31][C:32](=[O:51])[N:33]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[Cl:50])[C:34]1[CH:39]=[CH:38][C:37]([CH:40]=[O:41])=[C:36]([F:42])[N:35]=1)([CH3:30])([CH3:29])[CH3:28].O>O1CCCC1>[C:27]([O:31][C:32](=[O:51])[N:33]([C:34]1[CH:39]=[CH:38][C:37]([CH:40]([C:12]2[C:13]3[C:18]([O:19][CH3:20])=[N:17][CH:16]=[N:15][C:14]=3[N:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[CH:11]=2)[OH:41])=[C:36]([F:42])[N:35]=1)[CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[Cl:50])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1Cl)c1ccc(C=O)c(F)n1
Reactant: COc1ncnc2c1c(I)cn2S(=O)(=O)c1ccccc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1ncnc2c1c(C(O)c1ccc(N(Cc3ccccc3Cl)C(=O)OC(C)(C)C)nc1F)cn2S(=O)(=O)c1ccccc1
Temperature: 5 °C
Yield: 92.9 %

Procedure:
To a solution of 7-benzenesulfonyl-5-iodo-4-methoxy-7H-pyrrolo[2,3-d]pyrimidine (42, 0.408 g, 0.983 mmol) in 4.0 mL of tetrahydrofuran at −50° C. under an atmosphere of nitrogen, isopropylmagnesium chloride (0.500 mL, 2.00 M in tetrahydrofuran, 1.00 mmol) was added slowly. The reaction was allowed to warm to 5° C. over 70 minutes, cooled to −45° C. and (2-chloro-benzyl)-(6-fluoro-5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester (19, 0.240 g, 0.658 mmol) in 2.0 mL of tetrahydrofuran was added. The reaction was allowed to warm to room temperature over an hour, then poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel chromatography eluting with 20-100% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (44, 0.400 g).