Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[O:9][C:4]=2[CH:3]=1.Br[C:16]1[CH:17]=[CH:18][C:19]([Cl:23])=[C:20]([CH3:22])[CH:21]=1.C(=O)([O-])[O-].[K+].[K+].CNCCNC>[Cu]I.O.C1(C)C=CC=CC=1>[NH2:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]([C:16]3[CH:17]=[CH:18][C:19]([Cl:23])=[C:20]([CH3:22])[CH:21]=3)[C:7](=[O:12])[C:8]([CH3:10])([CH3:11])[O:9][C:4]=2[CH:3]=1
Reactant: Cc1cc(Br)ccc1Cl
Reactant: CC1(C)Oc2cc(N)ccc2NC1=O
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(N2C(=O)C(C)(C)Oc3cc(N)ccc32)ccc1Cl
Temperature: 110 °C
Yield: 39.6 %

Procedure:
A mixture of 7-amino-2,2-dimethyl-2H-1,4-benzoxazin-3(4H)-one (compound obtained in Reference Example 3(1); 150 mg), 5-bromo-2-chlorotoluene (321 mg), copper(I) iodide (37 mg), potassium carbonate (216 mg), N,N′-dimethylethylenediamine (40 μL) and toluene (8 mL) was heated at 110° C. overnight under argon atmosphere. After cooling, to the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (solvent; n-hexane/ethyl acetate=4/1→1/1) to give 7-amino-4-(4-chloro-3-methylphenyl)-2,2-dimethyl-2H-1,4-benzoxazin-3(4H)-one (98 mg) as a pale orange powder.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([CH:13]2[NH:18][CH2:17][CH2:16][NH:15][C:14]2=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CCOCC>[C:7]1([CH:13]2[CH2:14][NH:15][CH2:16][CH2:17][NH:18]2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C1NCCNC1c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: c1ccc(C2CNCCN2)cc1
Temperature: 0 °C
Yield: 83.4 %

Procedure:
To an ice-cooled stirred suspension of 25. g (0.66 mol) of lithium aluminum hydride in 2.6 liters of anhydrous ether was added in portions over 0.5 hour 30 g (0.17 mol) of 3-phenyl-2-piperazinone. The resulting mixture was heated at reflux for 20 hours and then cooled to 0° C. Isolation of the product by standard methods gave 23 g (83%) of 2-phenylpiperazine as an off-white solid (mp. 83°-85° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:28][CH2:29][N:30]([CH3:32])[CH3:31]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])=[CH:4][CH:3]=1
Reactant: CN(C)CCCl
Reactant: COc1ccccc1N1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Product: COc1ccccc1N1CCN(C(=O)c2cn(CCN(C)C)c3cc(Cl)ccc23)CC1

Procedure:
Analogous to general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperazin-1-yl]-methanone (prepared herein) with (commercially available) (2-chloro-ethyl)-dimethyl-amine gave the title compound.
Reaction SMILES: [C@@H:1]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.C(Cl)(Cl)Cl.C[Si]([Br:18])(C)C.C1C=C(NS(C2C=CC(N/N=C3/C=CC(C(C(O)=O)=C/3)=O)=CC=2)(=O)=O)N=CC=1>CS(C)=O>[Br:18][C@@H:4]1[C@H:5]2[CH2:6][C@H:1]([C:7](=[O:9])[O:8]2)[CH2:2][CH2:3]1
Reactant: O=C(O)[C@H]1CC=CCC1
Reactant: C[Si](C)(C)Br
Agent: O=C(O)C1=C/C(=N\Nc2ccc(S(=O)(=O)Nc3ccccn3)cc2)C=CC1=O
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: O=C1O[C@@H]2C[C@H]1CC[C@@H]2Br

Procedure:
(R)-Cyclohex-3-enecarboxylic acid (2.30 g, 18.2 mmol) ([α]D=+83.8° (c=1, CHCl3)=88.2% e.e., resolved by the method of Schwartz et al, J. Am. Chem. Soc., 100, 5199, (1978)) was reacted with trimethylsilyl bromide and DMSO (by the method of Iwata et al, Heterocycles., 31, 987 (1990)) to give a white solid, (2.13 g, 10.4 mmol, 57%);
Reaction SMILES: [I:1]Cl.[NH2:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[C:6]#[N:7].O>CC(O)=O>[NH2:3][C:4]1[CH:11]=[CH:10][C:9]([I:1])=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: ClI
Reactant: N#Cc1ccccc1N
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1cc(I)ccc1N
Reaction time: 3 h

Procedure:
A solution of iodine monochloride (16.7 g, 0.1 mol) in glacial AcOH (30 mL) as added dropwise over 15 min to a stirred solution of 2-aminobenzonitrile (11.8 g, 0.1 mol) in glacial AcOH (125 mL) at room temperature. The mixture was stirred for 3 h and then poured into H2O (1000 mL). The resulting pinkish-brown solid was filtered, washed with H2O, and dried in vacuo. Crystallization from cyclohexane-toluene (9:1) gave 2-amino-5-iodobenzonitrile (9) as translucent plates (14.9 g, 64%): mp 85-86° C. (lit. 85-86° C.); 1H NMR (CDCl3) δ 7.60 (d, J=1.6 Hz, 1H, H-6), 7.57 (dd, J=9.2 Hz, 1.6 Hz, 1H, H-4), 6.53 (d, J=9.2 Hz, 1H, H-3), 4.45 (br s; 2H, NH2). The product was used directly in the next reaction (Step 2).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7]([N+]([O-])=O)[CH:6]=1)(=[O:4])=[O:3].[CH3:17][O-:18].[Na+].O>CO>[CH3:1][S:2]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7]([O:18][CH3:17])[CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc([N+](=O)[O-])cc(S(C)(=O)=O)c1
Yield: 70.3 %

Procedure:
To a solution of 1-methylsulfonyl-3,5-dinitro-benzene (2.0 g; 8 mmol) in methanol (15 ml) a solution of sodium methoxide (0.5 g; 10 mmol) in methanol (5 ml) was added. The mixture was refluxed for 2 hours. Water was added and the precipitate washed with a diisopropylether/ethanol mixture. 1.3 g (5.62 mmol; 70% yield) of 1-methylsulfonyl-3-methoxy-5-nitro-benzene were obtained as a yellow solid.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=O)[CH2:5][CH2:4]1)[CH3:2].S(Cl)([Cl:14])=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([Cl:14])=[O:11])[CH2:5][CH2:4]1)[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC[C@H]1CC[C@H](C(=O)O)CC1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC[C@H]1CC[C@H](C(=O)Cl)CC1

Procedure:
First, 1.0 g (6.1 nmmol) of trans-4-ethylcyclohexane carboxylic acid was mixed with 1.1 g (9.2 mmol) of thionyl chloride, 0.1 ml of pyridine, and 3 ml of toluene, and reacted at 60° C. for hours. Excess amount of thionyl chloride and toluene were distilled off at a reduced pressure to obtain a crude trans-4-ethylcyclohexylcarbonylchloride.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=2)[CH:7]=[C:8]2[C:16]=1[NH:15][C:14]1[CH:13]=[C:12]([C:17]([O-:19])=O)[CH:11]=[CH:10][C:9]2=1)(=[O:3])[NH2:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:53]1[CH2:58][CH2:57][S:56](=[O:60])(=[O:59])[CH2:55][CH2:54]1>CN(C1C=CN=CC=1)C.CN(C=O)C>[F:28][C:22]1[CH:21]=[C:20]([C:6]2[CH:5]=[C:4]([C:1]([NH2:2])=[O:3])[C:16]3[NH:15][C:14]4[C:9]([C:8]=3[CH:7]=2)=[CH:10][CH:11]=[C:12]([C:17]([N:53]2[CH2:58][CH2:57][S:56](=[O:60])(=[O:59])[CH2:55][CH2:54]2)=[O:19])[CH:13]=4)[CH:25]=[CH:24][C:23]=1[O:26][CH3:27]
Reactant: COc1ccc(-c2cc(C(N)=O)c3[nH]c4cc(C(=O)[O-])ccc4c3c2)cc1F
Reactant: O=S1(=O)CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc(C(N)=O)c3[nH]c4cc(C(=O)N5CCS(=O)(=O)CC5)ccc4c3c2)cc1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 63.9 %

Procedure:
8-Carbamoyl-6-(3-fluoro-4-methoxyphenyl)-9H-carbazole-2-carboxylic acid (Example 395, 35 mg, 0.083 mmol), HATU (150 mg, 0.394 mmol), DMAP (50 mg, 0.409 mmol), Thiomorpholine-1,1-dioxide (90 mg, 0.666 mmol) and DMF (2 ml) were combined and stirred at room temperature for 3 days. The reaction mixture was filtered through a 0.45 um Nylon filter and purify by preparative HPLC. Product containing fractions were evaporated to give 26.3 mg 3-(3-fluoro-4-methoxyphenyl)-7-(1,1-dioxo-thiomorpholine-4-carbonyl)-9H-carbazole-1-carboxamide. MS (ESI) m/e+=496, m/e−=494, consistent with [M+H]+and [M−H]− resp. HPLC retention time 9.61 min. (Sunfire C18 3.5 μm, 4.6×150 mm column, 15 min gradient, 10-100% B, 1 mL/min. Solvent A: 5% CH3CN—95% H2O—0.1% TFA; Solvent B: 95% CH3CN—5% H2O—0.1% TFA). 1H NMR (DMSO-d6) δ ppm 11.60 (s, 1H), 8.73 (d, 1H, J=1.6), 8.39 (b, 1H), 8.34-8.30 (m, 2H), 7.86 (d, 1H, J=0.7), 7.81 (dd, 1H, J=13.3, 2.3), 7.71 (dd, 1H, J=8.5, 1.2), 7.60 (b, 1H), 7.35 (dd, 1H, J=8.1, 1.4), 7.31 (t, 1H, J=9.0), 3.92 (s, 3H), 4.2-3.7 (b, 4H), 3.35-3.25 (b, 4H).
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][C:7]1[NH:8][CH:9]=[CH:10][N:11]=1.[C:12]([C:15](=[CH:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[C:16]([O:18][CH3:19])=[O:17])(=O)[CH3:13]>>[CH:21]1([CH:20]2[N:8]3[CH:9]=[CH:10][N:11]=[C:7]3[NH:6][C:12]([CH3:13])=[C:15]2[C:16]([O:18][CH3:19])=[O:17])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COC(=O)C(=CC1CCCCC1)C(C)=O
Reactant: Nc1ncc[nH]1
Agent: O=S(=O)(O)O
Product: COC(=O)C1=C(C)Nc2nccn2C1C1CCCCC1

Procedure:
Crystals are obtained by reacting 6.8 of 2-aminoimidazole sulfate with 10.5 g of methyl 2-acetyl-3-cyclohexylacrylate in a similar manner as described in Example 13. Recrystallization from methanol gives 4.8 g of 5-cyclohexyl-6-methoxycarbonyl-7-methyl-5,8-dihydroimidazo[1,2-a]pyrimidine, melting at 178° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:19][C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=1[N:29]1[CH2:34][CH2:33][CH:32]([CH2:35][CH2:36][OH:37])[CH2:31][CH2:30]1.O>CN(C)C1C=CN=CC=1.ClCCl>[F:19][C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=1[N:29]1[CH2:30][CH2:31][CH:32]([CH2:35][CH2:36][O:37][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:33][CH2:34]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=[N+]([O-])c1ccc(N2CCC(CCO)CC2)c(F)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCC2CCN(c3ccc([N+](=O)[O-])cc3F)CC2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 52.2 %

Procedure:
p-Toluenesulfonyl chloride (0.858 g, 4.50 mmol), triethylamine (0.820 ml, 6.00 mmol) and 4-dimethylaminopyridine (0.0366 g, 0.300 mmol) were added to a solution of 2-[1-(2-fluoro-4-nitrophenyl)piperidin-4-yl]ethanol (compound of Reference Example 25; 0.804 g, 3.00 mmol) in anhydrous dichloromethane (5 ml), and the mixture was stirred at room temperature for 17 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=2:1) to give the title compound (0.661 g, 52%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][C:13]([OH:15])=O)(=[O:11])=[O:10])=[CH:4][C:3]=1[C:16]([F:19])([F:18])[F:17].Cl.[CH2:21]([O:23][C:24](=[O:27])[CH2:25][NH2:26])[CH3:22].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH2:21]([O:23][C:24](=[O:27])[CH2:25][NH:26][C:13](=[O:15])[CH2:12][S:9](=[O:10])(=[O:11])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:16]([F:19])([F:18])[F:17])[CH:4]=1)[CH3:22]
Reactant: CCOC(=O)CN
Reactant: O=C(O)CS(=O)(=O)Nc1ccc(F)c(C(F)(F)F)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CNC(=O)CS(=O)(=O)Nc1ccc(F)c(C(F)(F)F)c1
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
Under nitrogen, 1.81 g (6 mmol) of 2-[2-[N-(4-fluoro-3-trifluoromethylphenyl)sulfamoyl]acetic acid, 0.845 g (6 mmol) of glycine ethyl ester hydrochloride (98%), and 0.919 g (6 mmol) of hydroxybenzotriazole, hydrate, are added to 100 ml of dimethylformamide and the mixture is cooled to -10° C. under agitation. Then 0.607 g (6 mmol) of triethylamine is added thereto, the mixture is agitated for 10 minutes and combined with 1.24 g (6 mmol) of dicyclohexylcarbodiimide. The mixture is stirred for another hour at the low temperature and then overnight without cooling. The mixture is suctioned off from the solid matter, the solution is concentrated to dryness under vacuum, and the residue is distributed between sodium bicarbonate solution and ethyl acetate. The ethyl acetate solution is washed with water, dried over sodium sulfate, and concentrated to dryness under vacuum. The residue is crystallized from ethyl acetate/hexane, thus obtaining 1.72 g (74.1% of theory) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:10]1[CH:11]=[C:12]([CH:27]=[CH:28][CH:29]=1)[O:13][CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:10]1[CH:11]=[C:12]([CH:27]=[CH:28][CH:29]=1)[O:13][CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(COc2cccc([C@@H](NC(=O)OC(C)(C)C)c3ccccc3)c2)cc1OC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(COc2cccc([C@@H](NC(=O)OC(C)(C)C)c3ccccc3)c2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.6 %

Procedure:
To a solution of (S)-methyl 4-((3-(((tert-butoxycarbonyl)amino)(phenyl)-methyl)phenoxy)methyl)-2-methoxybenzoate (0.90 g, 1.89 mmol) in a mixture of THF (9 mL) and methanol (9 mL) was added aqueous 2 M sodium hydroxide (9 mL). The reaction mixture was stirred at RT for 18 hours. 10% aqueous citric acid was added to the reaction mixture to pH 3. The mixture was extracted with ethyl acetate (×2). The combined organic phases were washed with brine, dried (magnesium sulfate), filtered and the solvent evaporated at reduced pressure to afford the title compound (0.82 g, 87%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:44])[CH2:10][CH2:11][CH2:12][N:13]2[CH2:43][CH2:42][C:16]3([N:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:19][N:18]([CH2:27][C:28]4[CH:29]=[C:30]([CH:38]=[CH:39][CH:40]=4)[C:31]([O:33]C(C)(C)C)=[O:32])[C:17]3=[O:41])[CH2:15][CH2:14]2)=[CH:5][CH:4]=1>Cl.O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:44])[CH2:10][CH2:11][CH2:12][N:13]2[CH2:43][CH2:42][C:16]3([N:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:19][N:18]([CH2:27][C:28]4[CH:29]=[C:30]([CH:38]=[CH:39][CH:40]=4)[C:31]([OH:33])=[O:32])[C:17]3=[O:41])[CH2:15][CH2:14]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)CCCN2CCC3(CC2)C(=O)N(Cc2cccc(C(=O)OC(C)(C)C)c2)CN3c2ccccc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(C(=O)CCCN2CCC3(CC2)C(=O)N(Cc2cccc(C(=O)O)c2)CN3c2ccccc2)cc1
Yield: 24.9 %

Procedure:
A solution of tert-butyl 3-((8-(4-(4-methoxyphenyl)-4-oxobutyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (100 mg, 0.496 mmol, 1 equiv) in 4M hydrogen chloride solution in dioxane was stirred at ambient temperature for 4 h. The mixture was concentrated in vacuo and the crude residue was purified using preparatory high performance liquid chromatography to afford the acetate salt of the title compound as a white solid (67 mg, 74%); 1H NMR (400 MHz, DMSO-d6): δ 1.78 (bs, 2H); 1.95 (bs, 2H); 2.52-2.54 (m, 3H); 2.76 (bs, 4H); 3.08 (bs, 3H); 3.84 (s, 3H); 4.62 (s, 2H); 4.63 (s, 2H); 6.78 (d, 1H, J=7.2 Hz); 6.93 (bs, 2H); 7.05 (d, 2H, J=9.2 Hz); 7.20 (t, 2H, J=7.6 and 7.2 Hz); 7.49-7.57 (m, 2H); 7.87-7.89 (m, 2H); 7.96-7.98 (m, 2H); 12.45 (s, 1H); MS for C32H35N3O5 m/z 542.02 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.[H-].[Na+].[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[C:16]1([S:22]([N:7]2[C:8]3[C:4](=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1ccc2[nH]ccc2c1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1OC
Temperature: 25 °C
Yield: 85.5 %

Procedure:
To 4,5-dimethoxyindole (241 mg, 1.36 mmol) in 5 mL THF at 0° C. was added 82 mg (2.04 mmol, 1.5 eq) of sodium hydride, followed by benzenesulfonyl chloride (260 μL, 2.04 mmol, 1.5 eq). The reaction was warmed to room temperature over 5 h then quenched with H2O and concentrated. The residue was dissolved in CH2Cl2 and extracted with NaHCO3, H2O, aqueous NaCl, dried (Na2SO4), and concentrated. The product was purified by silica gel column chromatography (7/3 hexanes/EtOAc) to give 369 mg of 1-benzenesulfonyl-4,5-dimethoxy-1H-indole (86%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14][C:15]1([CH3:24])[CH2:20][CH2:19][C:18](B(O)O)=[CH:17][CH2:16]1>CCOC(C)=O.CCCCCC>[CH3:14][C:15]1([CH3:24])[CH2:20][CH2:19][C:18]([C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=2[N+:11]([O-:13])=[O:12])=[CH:17][CH2:16]1
Reactant: CC(=O)c1ccc(Br)c([N+](=O)[O-])c1
Reactant: CC1(C)CC=C(B(O)O)CC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)c1ccc(C2=CCC(C)(C)CC2)c([N+](=O)[O-])c1
Yield: 99.2 %

Procedure:
The title compound was prepared by the Suzuki coupling procedure of Example 11, step (e) using 1-(4-bromo-3-nitro-phenyl)-ethanone (347 mg, 1.42 mmol), and 4,4-dimethylcyclohexen-1-ylboronic acid (254 mg, 1.65 mmol). Silica gel chromatography (5-15% EtOAc/hexane) afforded the title compound (385 mg, 99%) as a faint green oil. Mass spectrum (APCI, m/z): Calcd. for C16H19NO3, 274.1 (M+H), found 274.0.
Reaction SMILES: [CH2:1]([O:4][NH2:5])[CH2:2][CH3:3].C(Cl)CCl.C(=O)([O-])[O-].[K+].[K+].Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>O>[CH2:1]([O:4][NH:5][C:17](=[O:18])[O:19][CH2:20][CH3:21])[CH2:2][CH3:3]
Reactant: CCCON
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCCl
Product: CCCONC(=O)OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.6 %

Procedure:
22 g (197 mmol) of n-propoxyamine hydroxhloride was dissolved in 100 ml of water, and 200 ml of ethylene dichloride was added thereto. Then, 27.2 g (197 mmol) of potassium carbonate was added in several times under cooling, and then 21.3 g (196 mmol) of ethyl chloroformate was dropwise added thereto at a temperature of not higher than 10° C. After raising the temperature to room temperature, the mixture was further stirred at the same temperature for 4 hours. The ethylene dichloride layer was separated, and then the aqueous layer was extracted twice with 100 ml of chloroform. The ethylene dichloride layer and the chloroform layer were put together, and washed with a saturated sodium chloride aqueous solution, and then dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure. 27 g of ethyl N-n-propoxycarbamate was obtained by distillation under reduced pressure. Boiling point: 88° C./2.5 mmHg
Reaction SMILES: C(OC([NH:11][CH:12]1[N:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]2[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=2[N:14]([CH2:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:13]1=[O:38])=O)C1C=CC=CC=1>C(Cl)Cl>[NH2:11][CH:12]1[N:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]2[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=2[N:14]([CH2:29][C:30](=[O:37])[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:13]1=[O:38]
Reactant: O=C(NC1N=C(c2ccccc2)c2ccccc2N(CC(=O)c2ccccc2)C1=O)OCc1ccccc1
Solvent: ClCCl
Product: NC1N=C(c2ccccc2)c2ccccc2N(CC(=O)c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
A solution of 3-(Benzoxycarbonyl)amino-2,3-dihydro-1-(2-oxo-2-phenylethyl)-5-phenyl-1H-1,4-benzodiazepin-2-one (3.7 g, 7.36 mmol) in 100 mL of anhydrous methylene chloride was cooled to 0° C. under nitrogen. A stream of anhydrous HBr gas was then bubbled through this solution for 1 h. The bubbler was removed and the reaction was warmed to room temperature under nitrogen. After stirring 1 h the reaction was concentrated under vacuum and the residue was redissolved in 20 mL of methylene chloride. The crude HBr salt of the product was precipitated from solution using 300 mL of anhydrous ether and collected by filtration as a light yellow solid. After washing with ether, the solid was dissolved in methylene chloride and saturated sodium bicarbonate. The layers were separated and the organic layer was extracted with saturated sodium bicarbonate. The combined aqueous layers were then back extracted twice with methylene chloride. The combined organic layers were extracted once with water and dried over sodium sulfate. After concentration under vacuum, 2.27 g of the product was obtained as an orange foam which was carried on without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19]Cl)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[OH:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][CH:28]=[CH:27]2>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19][O:23][C:24]4[CH:25]=[C:26]5[C:30](=[CH:31][CH:32]=4)[NH:29][CH:28]=[CH:27]5)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1
Reactant: CCN1c2ncc(CCl)cc2C(=O)N(C)c2ccc(Cl)nc21
Reactant: Oc1ccc2[nH]ccc2c1
Product: CCN1c2ncc(COc3ccc4[nH]ccc4c3)cc2C(=O)N(C)c2ccc(Cl)nc21
Yield: 22 %

Procedure:
Using a procedure analogous to that described in Example 98, the title compound, m.p. 176°-178° C., was prepared from 2-chloro-8-chloromethyl-5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and 5-hydroxyindole. The yield was 22% of theory.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:30]1[S:31][CH:32]=[CH:33][N:34]=1)[S:7]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16]([C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([NH2:24])=O)=[N:15][CH:14]=[C:13]2[F:29])(=[O:9])=[O:8].O=P(Cl)(Cl)Cl.C(O)(C(F)(F)F)=O>N1C=CC=CC=1.C(OCC)(=O)C>[C:22]([C:21]1[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=1[C:16]1[C:17]2[C:12](=[CH:11][C:10]([S:7]([NH:6][C:30]3[S:31][CH:32]=[CH:33][N:34]=3)(=[O:8])=[O:9])=[CH:19][CH:18]=2)[C:13]([F:29])=[CH:14][N:15]=1)#[N:24]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccccc4C(N)=O)ncc(F)c3c2)c(OC)c1
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccccc1-c1ncc(F)c2cc(S(=O)(=O)Nc3nccs3)ccc12
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
2-(6-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)-4-fluoroisoquinolin-1-yl)benzamide was dissolved in pyridine (0.6 mL) and cooled to 0° C. POCl3 (0.023 mL, 0.243 mmol) was added. The reaction was stirred for 5 minutes at room temperature. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was dissolved in DCM and TFA (0.1 mL, 1.298 mmol) was added. The reaction was stirred for 30 minutes at room temperature. The reaction was concentrated and purified via column chromatography (RediSep Gold 12 g, gradient elution 0-10% MeOH:DCM) to afford 1-(2-cyanophenyl)-4-fluoro-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=13.02 (br. s., 1H), 8.84 (d, J=1.6 Hz, 1H), 8.57 (d, J=1.3 Hz, 1H), 8.13-8.03 (m, 2H), 7.99-7.86 (m, 2H), 7.83-7.73 (m, 2H), 7.68-7.51 (m, 2H), 7.31 (d, J=4.5 Hz, 1H), 6.90 (d, J=4.6 Hz, 1H). m/z (ESI) 410.9 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:13][S:12][C:11]=2[CH:22]=1.[NH:23]1[CH2:26][CH2:25][CH2:24]1>>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:23]4[CH2:26][CH2:25][CH2:24]4)=[CH:22][C:11]=3[S:12][CH:13]=2)=[CH:16][CH:17]=1
Reactant: Fc1ccc(-c2csc3cc(OCCCCBr)ccc23)cc1
Reactant: C1CNC1
Product: Fc1ccc(-c2csc3cc(OCCCCN4CCC4)ccc23)cc1

Procedure:
In analogy to example 3.1, 6-(4-Bromo-butoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene and azetidine were converted to yield 1-{4-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-azetidine as colorless oil, MS: 356 (MH+).