Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]3[CH2:15][CH2:14][S:13][C:9]=3[C:10](=[O:12])[O:11][C:6]=2[CH:5]=[C:4]([CH:16]([CH:18]([CH3:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:17])[CH:3]=1.O=[C:26]1CCSCC1C(OCC)=O.Cl>C(O)C>[OH:1][C:2]1[C:7]2[C:8]3[CH2:15][CH2:14][S:13][CH2:26][C:9]=3[C:10](=[O:12])[O:11][C:6]=2[CH:5]=[C:4]([CH:16]([CH:18]([CH3:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:17])[CH:3]=1
Reactant: CCOC(=O)C1CSCCC1=O
Reactant: CCCCCC(C)C(C)c1cc(O)c2c3c(c(=O)oc2c1)SCC3
Agent: Cl
Solvent: CCO
Product: CCCCCC(C)C(C)c1cc(O)c2c3c(c(=O)oc2c1)CSCC3
Reaction time: 120 h
Yield: 68 %

Procedure:
A solution of 6.4 g. (0.027 mole) of 5-(3-methyl-2-octyl-resorcinol of Example 1 and 5.0 g. (0.0266 mole) of ethyl 4-oxo-1,3,5,6-tetrahydro-4H-thiopyran-3-carboxylate [prepared according to the method of Bennett and Scorah, J. Chem. Soc., 194 (1927)] in 35 ml. of absolute ethanol was cooled in an ice bath while it was saturated with hydrogen chloride. The resulting deep red solution was tightly stoppered and allowed to stand at room temperature for 120 hours. After one day yellow crystalline material had collected on the bottom of the flask. The reaction mixture was warmed gently on the steam bath for 15 minutes, cooled and poured onto a water-ice mixture. The gum-like material that precipitated was extracted with several portions of chloroform. The chloroform solution was washed with aqueous potassium bicarbonate and with water and dried over sodium sulfate. Evaporation of the solvent left 7.5 g. of a light-colored solid. This material was triturated several times with boiling petroleum ether to remove unreacted keto ester. The residue was recrystallized from an ethyl acetate-petroleum ether mixture to give 6.5 g. (68%) of the desired compound, m.p. 153°-155°C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:13]([CH2:14]O)=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:20])=O>C(Cl)CCl>[ClH:20].[N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:13]([CH2:14][Cl:20])=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCc1ccc(OCCN2CCCCC2)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Product: Cl
Product: ClCc1ccc(OCCN2CCCCC2)cc1

Procedure:
The solution of 4-(2-piperidinylethoxy)benzyl alcohol in ethylene dichloride can be combined with thionyl chloride and heated until the reaction is complete. Upon cooling, the mixture can be concentrated, followed by addition of 1,2-dimethoxyethane and additional concentration. The precipitate can be collected and dried to yield intermediate 4-(2-piperidinylethoxy)benzylchloride hydrochloride, as shown in Scheme IX.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C@@H:4]([C:5]#[C:6][C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].N1C2C(=CC=CC=2)C=CC=1>C(OCC)(=O)C.[OH-].[Pd+2].[OH-]>[CH3:1][C:2]1([CH3:17])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: CC(C)(C)OC(=O)[C@@H]1[C@H](C#CC(=O)O)C1(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: c1ccc2ncccc2c1
Product: CC(C)(C)OC(=O)[C@@H]1[C@H](/C=C\C(=O)O)C1(C)C
Yield: 99.2 %

Procedure:
2 g of 1,1-dimethylethyl (1R,cis) 2,2-dimethyl-3[2-carboxyethynyl]-cyclopropane-carboxylate in 41 ml of ethyl acetate were hydrogenated in the presence of 0.38 g of 10% palladium hydroxide on barium sulfate and 0.4 ml of quinoline and the mixture was filtered. The filfrate was washed with 0.5N hydrochloric acid, then with water until neutral, dried and evaporated to dryness under reduced pressure to obtain 2 g of 1,1-dimethylethyl (1R,cis) 2,2-dimethyl-3-[(Z) 2-carboxyethenyl]-cyclopropane-carboxylate melting at 94° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+]>CC(O)=O.CCOC(C)=O.O.[Fe]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(Sc2ccccn2)cc1
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ccc(Sc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.3 %

Procedure:
To a solution of 4-(2-pyridinylthio)-1-nitrobenzene (Menai ST 3355A; 0.220 g, 0.95 mmol) and H2O (0.5 mL) in AcOH (5 mL) was added iron powder (0.317 g, 5.68 mmol) and the resulting slurry stirred for 16 h at room temp. The reaction mixture was diluted with EtOAc (75 mL) and H2O (50 mL), basified to pH 10 by adding solid K2CO3 in portions (Caution: foaming). The organic layer was washed with a saturated NaCl solution, dried (MgSO4), concentrated in vacuo. The residual solid was purified by MPLC (30% EtOAc/70% hexane) to give the desired product as a thick oil (0.135 g, 70%): TLC (30% EtOAc/70% hexanes) Rf 0.20. A3a. General Method for Substituted Aniline Formation Via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction
Reaction SMILES: [OH-].[Na+].[NH2:3][C@H:4]([C:8]([OH:10])=[O:9])[C@@H:5]([CH3:7])[OH:6].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:18]([O:20][CH3:21])=[O:19]>>[OH:6][C@H:5]([CH3:7])[C@H:4]([NH:3][C:18]([O:20][CH3:21])=[O:19])[C:8]([OH:10])=[O:9]
Reactant: COC(=O)Cl
Reactant: C[C@@H](O)[C@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)N[C@H](C(=O)O)[C@@H](C)O
Temperature: 0 °C
Reaction time: 15 h
Yield: 538.6 %

Procedure:
An aqueous NaOH (1 M, 167 mL) solution is added, while stirring, to L-Threonine (20 g, 30.5 mmol) in a round bottom flask (1 L). To this solution was added sodium carbonate (9.8 g, 92.3 mmol). The flask is cooled to 0° C. in an ice-water bath. Methyl chloroformate (14.3 mL, 184.7 mmol) is added drop wise and the reaction mixture is allowed to stir for 15 hours and reach room temperature. The reaction mixture is washed with CH2Cl2 (3×50 mL), and the aqueous layer is contained in a round bottom flask and cooled over an ice-water bath. Concentrated HCl (aq) is added drop wise until pH 2. The aqueous solution is brought to room temperature and the water is removed in vacuum. The residue was taken up in a 2:1 mixture of MeOH/CH2Cl2 (150 mL, filtered and washed with 2:1 mixture of MeOH/CH2Cl2 (50 mL). The filtrate was concentrated and dried in vacuum at 40° C., resulting in white foam (29.1 g, 98%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[CH2:18]=O>C(O)C>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:18][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: C1COCCN1
Reactant: C=O
Reactant: O=C1COc2cc(O)ccc21
Solvent: CCO
Product: O=C1COc2c1ccc(O)c2CN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.6 %

Procedure:
A solution of 6-hydroxybenzofuran-3(2H)-one (1.50 g, 10.0 mmol) in ethanol (10 mL) was added with morpholine (0.871 g, 10.0 mmol), and 37% aqueous formaldehyde (0.812 g, 10.0 mmol) at room temperature. The mixture was stirred overnight at room temperature, and then the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the objective 6-hydroxy-7-(morpholinomethyl)benzofuran-3(2H)-one (0.987 g, 40%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=2)=[N:24][CH:25]=1.O.O.O.Cl([O-])(=O)(=O)=O.[Li+]>C(#N)C>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH2:27][CH2:28][N:29]([C@H:11]([CH3:12])[C@:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])([OH:10])[CH2:13][N:14]3[CH:18]=[N:17][CH:16]=[N:15]3)[CH2:30][CH:31]=2)=[N:24][CH:25]=1
Reactant: Clc1ccc(C2=CCNCC2)nc1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: C[C@@H](N1CC=C(c2ccc(Cl)cn2)CC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 63.8 %

Procedure:
(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)oxirane (0.76 g, 3.0 mmol) and 5-chloro-1′,2′,3′,6′-tetrahydro-2,4′-bipyridine (1.31 g, 6.7 mmol) were dissolved in acetonitrile (20 ml), and lithium perchlorate trihydrate (1.50 g, 9.3 mmol) was added thereto and refluxed for 40 hours. The solvent was evaporated under a reduced pressure, and the thus obtained residue was dissolved in ethyl acetate and washed with water. The solvent was again evaporated under a reduced pressure, and the residue was purified using a silica gel column to obtain 0.88 g of the intended substance (yield 63.8%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[C:13]2[CH:19]=[CH:18][NH:17][C:14]2=[CH:15][N:16]=1)[CH3:2].[H-].[Na+].Br[CH:23]([CH2:27][CH2:28][CH3:29])[CH2:24][CH2:25][CH3:26].O>CN(C=O)C.CCOC(C)=O>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[C:13]2[CH:19]=[CH:18][N:17]([CH:23]([CH2:27][CH2:28][CH3:29])[CH2:24][CH2:25][CH3:26])[C:14]2=[CH:15][N:16]=1)[CH3:2]
Reactant: CCc1cccc(CC)c1-c1cc2cc[nH]c2cn1
Reactant: CCCC(Br)CCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(CCC)n1ccc2cc(-c3c(CC)cccc3CC)ncc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-(2,6-diethyl-phenyl)-1H-pyrrolo[2,3-c]pyridine (32 mg, 0.13 mmol) in DMF (0.5 mL) is added NaH (95%, 6 mg). The reaction mixture is stirred at room temperature for 30 minutes, and 4-bromo-heptane (137 mg, 0.77 mmol) is added. The mixture is heated at 60° C. for three hours and cooled. To the mixture, water (2 mL) and EtOAc (2 mL) are added. The organic layer is separated, washed with water once and concentrated under reduced pressure. The residue is purified by PTLC (Hexane/EtOAc 4:1) to give the titled compound. 1H NMR: (CDCl3) 8.82 (s, 1H), 7.43 (s, 1H), 7.32 (d, 1H), 7.31 (t, 1H), 7.16 (d, 2H), 6.87 (s, 1H), 6.53 (d, 1H), 4.42 (m, 1H), 2.32-2.40 (m, 4H), 1.86-1.95 (m, 4H), 1.15-1.32 (m, 4H), 1.03 (t, 6H), 0.84 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]([CH2:21][CH2:22][CH2:23][N:24]2[CH2:31][CH:30]3[CH:26]([CH2:27][NH:28][CH2:29]3)[CH2:25]2)[C:10]([CH:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:20])[CH3:19])[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8].CCN(C(C)C)C(C)C.[Cl:41][C:42]1[CH:47]=[C:46]([F:48])[CH:45]=[CH:44][C:43]=1[S:49](Cl)(=[O:51])=[O:50]>C(Cl)Cl>[Cl:41][C:42]1[CH:47]=[C:46]([F:48])[CH:45]=[CH:44][C:43]=1[S:49]([N:28]1[CH2:29][CH:30]2[CH2:31][N:24]([CH2:23][CH2:22][CH2:21][N:9]([C:4]3[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([Cl:1])[CH:3]=3)[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:20])[CH3:19])[CH2:14][CH2:13]3)=[O:11])[CH2:25][CH:26]2[CH2:27]1)(=[O:51])=[O:50]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Cl
Reactant: CC(=O)N1CCC(C(=O)N(CCCN2CC3CNCC3C2)c2ccc(C)c(Cl)c2)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC(C(=O)N(CCCN2CC3CN(S(=O)(=O)c4ccc(F)cc4Cl)CC3C2)c2ccc(C)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 42b (0.016 g, 0.035 mmol) and DIPEA (0.02 mL, 0.105 mmol) in DCM (1 mL) at RT was added 2-chloro-4-fluorobenzenesulfonyl chloride (104, 0.016 g, 0.07 mmol) and the mixture shaken overnight at rt. The reaction mixture was concentrated in vacuo and purified by reverse phase HPLC to afford II-296: ms (ES+) m/z 639 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:30])([CH3:29])[C@H:3]([NH:8][C:9]([N:11]1[C:19]2[CH2:18][CH2:17][NH:16][CH2:15][C:14]=2[C:13]([C:20]2[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=2[F:28])=[N:12]1)=[O:10])[C:4]([NH:6][CH3:7])=[O:5].CCN(C(C)C)C(C)C.Br[CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43]>C(#N)C>[CH3:1][C:2]([CH3:30])([CH3:29])[C@H:3]([NH:8][C:9]([N:11]1[C:19]2[CH2:18][CH2:17][N:16]([CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:15][C:14]=2[C:13]([C:20]2[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=2[F:28])=[N:12]1)=[O:10])[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CNC(=O)[C@@H](NC(=O)n1nc(-c2cc(F)c(F)cc2F)c2c1CCNC2)C(C)(C)C
Reactant: CCOC(=O)CBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN1CCc2c(c(-c3cc(F)c(F)cc3F)nn2C(=O)N[C@H](C(=O)NC)C(C)(C)C)C1
Temperature: 60 °C
Yield: 57 %

Procedure:
A mixture of intermediate 84 (0.39 g), DIEA (0.35 mL) and ethyl bromoacetate (0.22 mL) in acetonitrile was heated at 60° C. for 1.5 h. After evaporation of MeCN, the residue was extracted between EtOAc and saturated sodium bicarbonate. The organic phase was dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography with 70% to 90% EtOAc/Hex to give compound 83 (0.27 g, 57%). LCMS (+ESI) m/z=510.3 [M+H]+.
Reaction SMILES: [CH:1]1[C:6]2[C:7]([NH:9][C:10](=[O:11])[C:5]=2[CH:4]=[N:3][CH:2]=1)=[O:8].[H-].[Na+].CI.[C:16](OCC)(=O)C>CN(C)C=O>[CH3:16][N:9]1[C:7](=[O:8])[C:6]2[CH:1]=[CH:2][N:3]=[CH:4][C:5]=2[C:10]1=[O:11]
Reactant: O=C1NC(=O)c2cnccc21
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1C(=O)c2ccncc2C1=O
Reaction time: 0.5 h

Procedure:
To a stirred solution of 3,4-pyridinedicarboximide (10.0 g, 6.75 nmol) in N, N-dimethylformamide was added sodium hydride (1.55 g, =b 60=l % dispersion in mineral oil, 67.5 mmol) at room temperature. The mixture was stirred for about 30 minutes, then methyl iodide (9.58 g, 67.5 mmol) was added, and the reaction was stirred overnight. Ethyl acetate was added to the reaction mixture, and the mixture was extracted once with water, twice with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo (azeotroping excess N,N-dimethylformamide with heptanes) to give crude product. Purification by silica gel chromatography using 0-5% methanol/dichloromethane as eluent afforded the title compound of part 11-A as an off-white solid (5 g, 46%): PB MS (M+1)+ 163; 1H NMR=250 MHz (CDCl3) δ: 9.11 (arom, s, 1 H), 9.08 (arom, d, 1 H), 7.75 (arom, d, 1 H), 3.20 (Me, s, 3 H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[C:10]([N+:18]([O-:20])=[O:19])=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O.[CH2:21]([O:23][CH:24]([O:27][CH2:28][CH3:29])[CH2:25][NH2:26])[CH3:22].C(N(CC)CC)C>ClCCl.CN(C)C=O>[CH2:21]([O:23][CH:24]([O:27][CH2:28][CH3:29])[CH2:25][NH:26][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][CH:17]=[C:9]([O:8][CH3:7])[C:10]=1[N+:18]([O-:20])=[O:19])[CH3:22]
Reactant: COc1cccc(C(=O)O)c1[N+](=O)[O-]
Reactant: CCOC(CN)OCC
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(CNC(=O)c1cccc(OC)c1[N+](=O)[O-])OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
Oxalyl chloride (34 mL, 0.395 mol) was added to a solution of 3-methoxy-2-nitrobenzoic acid (60 g, 0.305 mol) in dry dichloromethane (600 mL), followed by N,N-dimethylformamide (0.6 mL, 7.8 mmol), which initiates mild gas evolution. The mixture was stirred at room temperature for two hours, then concentrated under vacuum to remove volatiles. The crude acid chloride was dissolved in dry dichloromethane (150 mL) then added dropwise to a cooled (5° C.) solution of aminoacetaldehyde diethylacetal (48 mL, 0.33 mol) and triethylamine (52 mL, 0.374 mol) in dry dichloromethane (250 mL). The mixture was stirred at room temperature for two hours, then washed with saturated aqueous sodium bicarbonate (2×100 mL) and brine (100 mL). The organics were dried over sodium sulfate and concentrated to give N-(2,2-diethoxyethyl)-3-methoxy-2-nitrobenzamide (296a, 92 g, 97% yield) as a yellow solid. MS: 335 [M+1].
Reaction SMILES: [NH:1]1[C:9]2[C:4](=CC=C[CH:8]=2)[CH:3]=[CH:2]1.C([N:17]1[C:29]2[C:28]([OH:30])=[C:27]3[N:31](C(OC(C)(C)C)=O)[C:32]4[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][C:37]=4[C:26]3=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[C:21]([Cl:46])[CH:22]=2)(OC(C)(C)C)=O.C(OC(N1CCC[C@H]1CO)=O)(C)(C)C>>[Cl:38][C:35]1[CH:36]=[C:37]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:27]1[C:28]([O:30][CH2:8][C@@H:9]3[CH2:4][CH2:3][CH2:2][NH:1]3)=[C:29]3[NH:17][C:18]4[CH:19]=[CH:20][C:21]([Cl:46])=[CH:22][C:23]=4[C:24]3=[CH:25][C:26]2=1
Reactant: CC(C)(C)OC(=O)n1c2ccc(Cl)cc2c2cc3c4cc(Cl)ccc4n(C(=O)OC(C)(C)C)c3c(O)c21
Reactant: c1ccc2[nH]ccc2c1
Agent: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Product: Clc1ccc2[nH]c3c(OC[C@@H]4CCCN4)c4[nH]c5ccc(Cl)cc5c4cc3c2c1

Procedure:
The title compound was prepared in a manner analogous to Example 28 except the starting indole is 5,7-diBOC-2,10-dichloro-6-hydroxyindolo[2,3-b]carbazole and the reagent is (S)-(+)-1-(tert-butoxycarbonyl)-2-pyrrolidinemethanol. 1H-NMR (400 MHz, CD3OD) δ ppm 8.46 (s, 1H), 8.11 (d, J=2.4 Hz, 2H), 7.41 (d, J=8.4 Hz, 2H), 7.30 (dd, J=8.4, 2.4 Hz, 2H), 4.33 (dd, J=10.0, 3.2 Hz, 1H), 4.11 (dd, J=10.0, 8.4 Hz, 1H), 3.91-3.82 (m, 1H), 3.16 (t, J=7.2 Hz, 2H), 2.16-2.05 (m, 1H), 2.03-1.84 (m, 2H), 1.72-1.62 (m, 1H); MS (ESI) m/z 422.2 (M−H)−; MS (ESI) m/z 424.0 (M+H)+
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH:10]=[CH:9][C:8](O)=[C:7]([C:12]#[N:13])[C:6]2=[O:14])[CH2:3][CH2:2]1.P(Br)(Br)([Br:17])=O>CN(C=O)C>[Br:17][C:8]1[CH:9]=[CH:10][N:5]([CH2:4][CH:1]2[CH2:3][CH2:2]2)[C:6](=[O:14])[C:7]=1[C:12]#[N:13]
Reactant: O=P(Br)(Br)Br
Reactant: N#Cc1c(O)ccn(CC2CC2)c1=O
Solvent: CN(C)C=O
Product: N#Cc1c(Br)ccn(CC2CC2)c1=O
Temperature: 110 °C
Yield: 63.8 %

Procedure:
To a solution of intermediate 3 (10.4 g, 54.67 mmol) in DMF (250 ml) was added phosphoric tribromide (31.3 g, 109.3 mmol) and the mixture was heated at 110° C. for 1.5 hours. After cooling in an ice bath the solution was partitioned between water and EtOAc. After three extractions with EtOAc the combined organic fractions were washed with brine, dried over MgSO4 and the solvent evaporated in vacuo. The crude product was purified by column chromatography (silica gel; DCM as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate 5 (8.83 g, 64%).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:33])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25](=[O:31])(=[O:30])[NH:26][CH2:27][CH2:28][OH:29])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:32])[CH:14]=2)[CH:9]=1.C1COCC1.O>CCCCCC>[Cl:32][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:7][C:6]([OH:33])=[O:5])[C:17]([CH3:18])=[C:16]2[C:19]1[CH:24]=[CH:23][C:22]([S:25](=[O:30])(=[O:31])[NH:26][CH2:27][CH2:28][OH:29])=[CH:21][CH:20]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(S(=O)(=O)NCCO)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CC(=O)O)cc2ccc(Cl)cc2c1-c1ccc(S(=O)(=O)NCCO)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.9 %

Procedure:
Lithium hydroxide monohydrate (0.019 g, 0.45 mmol) was added to a solution of {6-chloro-4-[4-(2-hydroxyethylsulfamoyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.05 g, 0.11 mmol) in a 3:1 mixture of THF—H2O mixture (5 mL). The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated to remove the THF, and the crude material was diluted with water, acidified [pH˜2] with a 6 N aqueous solution of hydrochloric acid. The mixture was extracted twice with ethyl acetate. The collected organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. Trituration with hexane gave {6-chloro-4-[4-(2-hydroxyethylsulfamoyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid (0.03 g, 62%) as a solid. 1H NMR (DMSO-d6) δ: 12.48 (br. s, 1H), 7.98 (d, J=7.8 Hz, 3H), 7.91 (s, 1H), 7.73 (t, J=5.6 Hz, 1H), 7.49 (d, J=7.8 Hz, 3H), 7.03 (s, 1H), 4.73 (br. s, 1H), 3.86 (s, 2H), 3.44 (d, J=5.4 Hz, 2H), 2.93 (q, J=5.9 Hz, 2H), 2.08 (s, 3H). MS calcd. for C21H21ClNO5S [(M+H)+] 434, obsd. 434.2.
Reaction SMILES: [O:1]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[NH:5][CH3:6])[CH3:2].CO[C:13](=[O:35])[C:14]1[CH:19]=[C:18]([C:20]2[CH:21]=[N:22][C:23]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:25]=2[C:26]#[N:27])[C:17]([Cl:32])=[CH:16][C:15]=1[O:33][CH3:34]>C1(C)C=CC=CC=1.ClCCCl.N#N>[Cl:32][C:17]1[C:18]([C:20]2[CH:21]=[N:22][C:23]([C:28]([F:31])([F:29])[F:30])=[CH:24][C:25]=2[C:26]#[N:27])=[CH:19][C:14]([C:13]([N:5]([C:4]2[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=2[O:1][CH3:2])[CH3:6])=[O:35])=[C:15]([O:33][CH3:34])[CH:16]=1
Reactant: CNc1ccccc1OC
Reactant: COC(=O)c1cc(-c2cnc(C(F)(F)F)cc2C#N)c(Cl)cc1OC
Agent: N#N
Solvent: Cc1ccccc1
Solvent: ClCCCl
Product: COc1cc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)cc1C(=O)N(C)c1ccccc1OC
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 7.4 %

Procedure:
To a mixture of 2-methoxyl-N-methylaniline (27.7 mg, 0.2 mmol) and Et3AI (196 μL, 1.9 M in toluene, 0.2 mmol) in 1,2-dichloroethane (1 mL) which was preheated at 50° C. for 10 min under N2 atmosphere, was added 4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-methoxy-benzoic acid methyl ester (50 mg, 0.14 mmol). The mixture was sealed in N2 atmosphere and heated at 80° C. for 16 hrs. Upon cooling to rt, the mixture was quenched with 2 N HCl (5 mL) and diluted with 1,2-dichloroethane. The organic layer was separated and concentrated. The residue was purified via reverse phase preparative LCMS to yield 4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-methoxy-N-(2-methoxy-phenyl)-N-methyl-benzamide 38-1 (4.9 mg). MS [M+H]+ 475.9; tR=5.91 min (method 3)
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([C:14]1[S:15][CH:16]=[CH:17][C:18]=1[CH3:19])[N:10]([CH:12]=[O:13])[CH3:11].[CH2:20]=O.[C:22]([BH3-])#[N:23].[Na+]>C(#N)C>[CH3:20][N:23]([CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([C:14]1[S:15][CH:16]=[CH:17][C:18]=1[CH3:19])[N:10]([CH:12]=[O:13])[CH3:11]
Reactant: [BH3-]C#N
Reactant: C=O
Reactant: Cc1ccsc1C(Cc1ccccc1N)N(C)C=O
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccsc1C(Cc1ccccc1N(C)C)N(C)C=O
Reaction time: 1.5 h

Procedure:
A solution of 5.0 g of 2-amino-N-formyl-N-methyl-α-(3-methyl-2-thienyl)benzeneethanamine in 48 ml of acetonitrile was treated with 6.5 ml of a 37% formaldehyde solution and 1.9 g of sodium cyanoborohydride. The mixture was stirred for 1.5 hr and then concentrated. The residue was dissolved in 75 ml of ether and washed with 1N potassium hydroxide solution and with saturated brine. The ether solution was dried over anhydrous potassium carbonate and concentrated. The residue was purified by Preparative HPLC (Waters Associates Prep LC/System 500, silica gel, eluted with ethyl acetate 200 ml/min, Glo-Mac Model 80-800 UV detector). The appropriate fractions were collected and concentrated to give 3.8 g of product, as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:8]([C:10]1[CH:11]=[CH:12][C:13]2[S:17][C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)=[N:15][C:14]=2[CH:28]=1)=[O:9].[ClH:35].C(O)C.C(=O)([O-])[O-].[NH4+:43].[NH4+]>C(O)(=O)C.C(Cl)Cl.C(O)C>[ClH:35].[ClH:35].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:8]([C:10]1[CH:11]=[CH:12][C:13]2[S:17][C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:43])[NH2:27])=[CH:22][CH:21]=3)=[N:15][C:14]=2[CH:28]=1)=[O:9]
Reactant: CCOC(=O)CN(C(=O)c1ccc2sc(CNc3ccc(C#N)cc3)nc2c1)c1ccccn1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)CN(C(=O)c1ccc2sc(CNc3ccc(C(=N)N)cc3)nc2c1)c1ccccn1
Yield: 68 %

Procedure:
Prepared analogously to Example 9 from 2-[N-(4-cyanophenyl)aminomethyl]benzothiazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(ethoxycarbonylmethyl)amide, ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 68% of theory, C25H24N6O3S (488.57); Rf value: 0.14 (silica gel; methylene chloride/ethanol=4:1+a few drops of acetic acid); EKA mass spectrum: (M+H)+=489.