Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:18]=[C:17]([F:19])[S:16][C:15]=2[CH2:20][O:21][C:22]2[C:27]([F:28])=[CH:26][C:25]([CH2:29][CH2:30][C:31](OCC)=[O:32])=[CH:24][C:23]=2[F:36])=[CH:10][CH:9]=1>>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:18]=[C:17]([F:19])[S:16][C:15]=2[CH2:20][O:21][C:22]2[C:27]([F:28])=[CH:26][C:25]([CH2:29][CH2:30][CH2:31][OH:32])=[CH:24][C:23]=2[F:36])=[CH:12][CH:13]=1
Reactant: CCOC(=O)CCc1cc(F)c(OCc2sc(F)cc2-c2ccc(Cl)cc2)c(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCCCc1cc(F)c(OCc2sc(F)cc2-c2ccc(Cl)cc2)c(F)c1

Procedure:
The title compound was prepared according to the procedure described in Example 223 by LAH reduction of ethyl 3-(4-((3-(4-chlorophenyl)-5-fluorothiophen-2-yl)methoxy)-3,5-difluoro phenyl)propanoate to give the desired product as off-white oil. 1H NMR (300 MHz, CD3OD) δ7.40-7.52 (m, 4H), 6.83 (d, J=9.6 Hz, 2H), 6.67 (s, 1H), 5.08 (s, 2H), 3.57 (t, J=6.6 Hz, 2H), 2.659 (t, J=7.5 Hz, 2H), 1.77-1.86 (m, 2H). Mass spectrum (ESI, m/z): Calcd. for: C20H16ClF3O2S, 225.0 (M-C9H9F2O2). found 224.9.
Reaction SMILES: C([Li])CCC.C1(NC2CCCCC2)CCCCC1.[CH3:19][Si:20]([CH3:34])([CH3:33])[CH2:21][CH2:22][O:23][C:24]([CH:26]1[CH2:31][CH2:30][CH2:29][C:28](=[CH2:32])[CH2:27]1)=[O:25].Br[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([CH3:45])([CH3:44])[CH3:43])[CH:37]=1.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].C(OCC)(=O)C>[CH3:19][Si:20]([CH3:33])([CH3:34])[CH2:21][CH2:22][O:23][C:24]([C:26]1([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([CH3:45])([CH3:44])[CH3:43])[CH:37]=2)[CH2:31][CH2:30][CH2:29][C:28](=[CH2:32])[CH2:27]1)=[O:25]
Reactant: CC(C)(C)c1cccc(Br)c1
Reactant: C=C1CCCC(C(=O)OCC[Si](C)(C)C)C1
Agent: [Pd]
Agent: C1CCC(NC2CCCCC2)CC1
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: C=C1CCCC(C(=O)OCC[Si](C)(C)C)(c2cccc(C(C)(C)C)c2)C1
Reaction time: 0.08 h
Yield: 80.3 %

Procedure:
A 1.6 M solution of n-butyllithium (12.0 mL, 19.2 mmol) was added to a solution of dicyclohexylamine (3.7 mL, 18.6 mmol) in toluene (40 mL). After stirring for 5 min, 3-methylene-cyclohexanecarboxylic acid 2-trimethylsilanyl-ethyl ester (3.45 g, 14.4 mmol) was added. After stirring for 30 min, 1-bromo-3-tert-butyl-benzene (3.16 g, 14.8 mmol) was added followed by the simultaneous addition of tri-tert-butylphosphonium tetrafluoroborate (220 mg, 758 mmol) and tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (380 mg, 367 mmol). The solution was placed into a preheated oil bath at 60° C. After stirring for 16 h, the solution was directly flash chromatographed with 99:1, 49:1, 24:1, and 23:2 hexanes:ethyl acetate as the eluant to yield 4.31 g (81% yield) of 1-(3-tert-butyl-phenyl)-3-methylene-cyclohexanecarboxylic acid 2-trimethylsilanyl-ethyl ester as a light yellow oil.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[CH2:9]1)=O)(C)(C)C.Cl>CO.O1CCOCC1>[ClH:28].[Cl:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[CH2:21][O:20][C:14]1[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=1[O:12][CH:10]1[CH2:11][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(F)ccc2OCc2cccc(Cl)c2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Fc1ccc(OCc2cccc(Cl)c2)c(OC2CNC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 209.1 %

Procedure:
The title compound from step C (85 mg) was dissolved in MeOH (5 mL) and 4M HCl in dioxane (3 mL) was added. The mixture was stirred at rt for 18 h. The reaction was concentrated and dried under vacuum to yield the title compound (75 mg). MS (ESI): mass calcd. for C16H15ClFNO2, 307.8; m/z found, 310.2 [M+H]+. 1H NMR (MeOD): 7.46 (s, 1H), 7.37-7.28 (m, 3H), 7.04 (dd, J=9.0 Hz, 5.3, 1H), 6.75-6.61 (m, 2H), 5.09-5.00 (m, 3H), 4.42 (dd, J=12.7, 6.6 Hz, 2H), 4.14 (dd, J=12.7, 4.9 Hz, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:5]=[CH:4][N:3]=1.[C:19]([C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24])#[CH:20].CS(C)=O>C(Cl)Cl>[C:19]([C:21]1[CH:22]=[C:23]([NH:24][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:10]=[N:11][C:12]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:5]=[CH:4][N:3]=2)[CH:25]=[CH:26][CH:27]=1)#[CH:20]
Reactant: C#Cc1cccc(N)c1
Reactant: Clc1nccc(Nc2cnc3ccccc3c2)n1
Solvent: ClCCl
Solvent: CS(C)=O
Product: C#Cc1cccc(Nc2nccc(Nc3cnc4ccccc4c3)n2)c1
Temperature: 100 °C

Procedure:
A mixture of (2-chloro-pyrimidin-4-yl)-quinolin-3-yl-amine (70 mg 0.272 mmol) and 3-ethynylaniline (33 mg, 0.282 mmol) was suspended in a sealed tube with 0.3 mL of DMSO. The resulting mixture was heated at 100° C. for 2 h, cooled to RT, diluted with CH2Cl2. The precipitate was collected by suction filtration then dried under vacuum to give the desired product as an off-white solid. M+H—338; Calc'd for C21H15N5: 337.13.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[C:24]([C:28]1[CH:29]=[C:30]([OH:34])[CH:31]=[CH:32][CH:33]=1)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([C:28]1[CH:29]=[C:30]([CH:31]=[CH:32][CH:33]=1)[O:34][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)c1cccc(O)c1
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc(C(C)(C)C)cc2)cc1
Product: COC(=O)C(Oc1cccc(C(C)(C)C)c1)c1ccc(Oc2ccc(C(C)(C)C)cc2)cc1
Yield: 82.9 %

Procedure:
In a manner similar to Example 16, 7.54 g of methyl α-bromo-α-[p-(p-tert-butylphenoxy)phenyl]acetate was treated with 3.75 g of m-tert-butylphenol to yield 7.4 g of product as a pale yellow glass.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[Cl:20][C:21]1[S:25][C:24]([CH2:26][C:27](O)=[O:28])=[CH:23][CH:22]=1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:27](=[O:28])[CH2:26][C:24]3[S:25][C:21]([Cl:20])=[CH:22][CH:23]=3)[N:11]=2)=[CH:13][CH:14]=1
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Reactant: O=C(O)Cc1ccc(Cl)s1
Product: O=C(Cc1ccc(Cl)s1)Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O

Procedure:
The product of Example 86A and 2-(5-chlorothiophen-2-yl)acetic acid were treated using a method similar to that described in Example 5 to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.77-11.81 (bs, 1H), 8.39-8.42 (m, 1H), 7.84-8.05 (m, 2H), 7.70-7.76 (m, 1H), 7.56-7.68 (m, 4H), 6.99 (d, J=3.8 Hz, 1H), 6.92 (d, J=3.8 Hz, 1H), 3.91-3.92 (bs, 2H); MS (ESI+) M/Z 430 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[CH2:12][C:13]([OH:15])=O.[NH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1[CH:23]=[O:24]>S(Cl)(Cl)=O.ClCCl.CCOC(C)=O>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[CH2:12][C:13]([NH:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1[CH:23]=[O:24])=[O:15]
Reactant: O=C(O)Cc1c(Cl)ccc([N+](=O)[O-])c1Cl
Reactant: Nc1ccncc1C=O
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=Cc1cnccc1NC(=O)Cc1c(Cl)ccc([N+](=O)[O-])c1Cl
Reaction time: 2 h
Yield: 95.2 %

Procedure:
A solution of (2,6-dichloro-3-nitro-phenyl)-acetic acid (15.0 g, 60.0 mmol) in thionyl chloride (60 mL) is refluxed for one hour. The solvent is removed by concentration; dry toluene is added and concentrated to thoroughly remove thionyl chloride. To the solution of acid chloride in dry dichloromethane (200 mL) is added (drop-wise) a solution of 4-amino-pyridine-3-carbaldehyde (6.6 g, 54 mmol) in dichloromethane (50 mL) and DIEDA (10.7 mL, 60 mmol). The mixture is at room temperature for 2 hours. The reaction mixture is diluted with EtOAc (300 ml) and washed with saturated K2CO3 and brine. The organic layer is dried, filtered and concentrated to give crude product. Recrystallization with dichloromethane/hexane results in the titled compound as a solid (18.2 g, 95.2%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:26]2[S:30][C:29]([C:31]3([O:35]COC)[CH2:34][CH2:33][CH2:32]3)=[N:28][CH:27]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[CH2:19][N:20]([CH3:22])[CH3:21])=[C:13]([O:24][CH3:25])[CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.ClC1C(C2SC(C3(OCOC)CCC3)=NC=2)=C2C=C(C3N=C(C4CCCN(C(OC(C)(C)C)=O)C4)ON=3)NC2=NC=1>>[Cl:1][C:2]1[C:3]([C:26]2[S:30][C:29]([C:31]3([OH:35])[CH2:34][CH2:33][CH2:32]3)=[N:28][CH:27]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[CH2:19][N:20]([CH3:21])[CH3:22])=[C:13]([O:24][CH3:25])[CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COCOC1(c2ncc(-c3c(Cl)cnc4[nH]c(-c5ccc(NC(=O)CN(C)C)c(OC)c5)cc34)s2)CCC1
Agent: COCOC1(c2ncc(-c3c(Cl)cnc4[nH]c(-c5noc(C6CCCN(C(=O)OC(C)(C)C)C6)n5)cc34)s2)CCC1
Product: COc1cc(-c2cc3c(-c4cnc(C5(O)CCC5)s4)c(Cl)cnc3[nH]2)ccc1NC(=O)CN(C)C

Procedure:
The title compound was prepared as described in Example 22E, substituting N-(4-(5-chloro-4-(2-(1-(methoxymethoxy)cyclobutyl)thiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-methoxyphenyl)-2-(dimethylamino)acetamide (Example 49C) for 1 tert-butyl 3-(3-(5-chloro-4-(2-(1-(methoxymethoxy)cyclobutyl)thiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate (Example 22D). 1H NMR (500 MHz, DMSO-d6) ppm 12.54 (s, 1H) 9.53 (s, 1H) 8.31 (m, 2H) 8.27 (s, 1H) 7.70 (d, 1H) 7.61 (dd, 1H) 7.08 (s, 1H) 6.68 (s, 1H) 3.99 (s, 3H) 3.10 (s, 2H) 2.63 (m, 2H) 2.42 (m, 2H) 2.32 (s, 6H) 1.99 (m, 2 H); MS ESI(+) m/z 512.1 [M+H]+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][C@@H:9]1[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH3:30])C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].C(O)C>[CH3:30][O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[CH2:22][CH2:21][C@H:9]1[CH2:10][NH:11][CH2:12][CH2:13][NH:8]1
Reactant: COc1ccccc1CC[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COc1ccccc1CC[C@H]1CNCCN1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.6 %

Procedure:
Combine (S)-1,4-dibenzyl-2-(2-(2-methoxy-phenyl)-ethyl)-piperazine (2.10 g, 5.24 mmol), ammonium formate (1.65 g, 26.19 mmol), 5% Pd/C (253.6 mg), and ethanol (100 mL). Stir and heat the mixture at reflux. After 3 hours, cool to ambient temperature and remove the catalyst by vacuum filtration through celite. Reduce the filtrate to residue and purify it on silica gel using dichloromethane/2N ammonia in methanol (80:20) to give (1.00 g, 87%) of the title compound: mass spectrum (ion spray): m/z=221.1 (M+1).
Reaction SMILES: [CH2:1]([C:10]1[CH:18]=[C:14]([C:15]([OH:17])=[O:16])[C:13]([OH:19])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:20]1([CH3:27])[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=1.[CH2:28]1OCOC[O:29]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(=O)C>[CH2:1]([C:10]1[CH:18]=[C:14]([C:15]([OH:17])=[O:16])[C:13]([OH:19])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:20]1([CH3:27])[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=1[CH:28]=[O:29]
Reactant: C1OCOCO1
Reactant: Cc1cccc(C)c1
Agent: CCCCCCCCCc1ccc(O)c(C(=O)O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Product: Cc1cccc(C)c1C=O

Procedure:
To a mixture of 26.4 parts of 5-nonylsalicylic acid, 5.9 parts of m-xylene, 3.4 parts of sym-trioxane and 15 parts of acetic acid was added 4.0 parts of p-toluenesulfonic acid (catalyst). After being heated under reflux for 5 hours, the reaction mixture was washed with water, and unreacted m-xylene and water were removed by vacuum distillation to give 38 parts of 5-nonylsalicylic acid-m-xylene-formaldehyde co-condensation product. To 10 parts of the co-condensation product was added gradually a mixture of 0.9 parts of zinc oxide and 0.5 parts of ammonium hydrogencarbonate at a temperature of 150° C. After the completion of the addition, the reaction was allowed to proceed for an additional hour at 150° C. to give 10.8 parts of zinc salt of 5-nonylsalicylic acid-m-xylene-formaldehyde co-condensation product.
Reaction SMILES: [CH3:1][CH:2]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5](=O)[CH2:4][CH2:3]1.[BH4-].[Na+]>CO>[CH3:1][CH:2]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][CH2:3]1
Reactant: CC1CCC(=O)c2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1CC=Cc2ccccc21
Reaction time: 8 h

Procedure:
1,2-Dihydro-1-methylnaphthalene ((±)-8) was prepared using a similar procedure to that reported in Ferraz et al., Tetrahedron, 57:1709ff (2001) (“Ferraz”), which is hereby incorporated by reference). The scheme is set forth in FIG. 7C. To a stirred solution of commercially available 4-methyl-α-tetralone (0.50 g, 3.12 mmol) in methanol (50 mL) was added NaBH4 (0.35 g, 9.36 mmol) portionwise. The reaction mixture was followed by TLC and, after complete consumption of the starting material (approx. 2 h), was quenched with saturated NaHCO3. The aqueous layer was extracted with diethyl ether, dried with magnesium sulfate (MgSO4), filtered, and the solvent was removed under reduced pressure. The crude alcohol was dissolved in toluene (15 mL), and a few crystals of p-TsOH were added. The reaction mixture was stirred overnight, then neutralized by slow addition of saturated sodium bicarbonate (NaHCO3) and extracted with diethyl ether. The combined organic layers where washed with brine, dried with magnesium sulfate (MgSO4), filtered, and the solvent was removed under reduced pressure. The product was purified by flash chromatography (SiO2, hexanes) to give 1,2-dihydro-1-methylnaphthalene ((±)-8) as a clear oil (0.35 g, 78% yield). The compound is volatile and cannot be dried for long periods (>30 min) under high vacuum. The spectroscopic data are consistent with previously reported data (Ferraz, which is hereby incorporated by reference).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=4)[C:17]4[CH2:23][NH:22][CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>>[CH3:1][C:2]1[N:3]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]3[N:15]=[C:16]([CH2:24][C:25]4[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=4)[C:17]4[CH2:23][N:22]([C:32](=[O:34])[CH3:33])[CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:11][CH:12]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ccc(Cc2nc(Nc3ccc(-n4ccnc4C)cc3)nc3c2CNCC3)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1CCc2nc(Nc3ccc(-n4ccnc4C)cc3)nc(Cc3ccc(C)cc3)c2C1
Yield: 10.6 %

Procedure:
1-(2-(4-(2-Methyl-1H-imidazol-1-yl)phenylamino)-4-(4-methylbenzyl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanone (11.3 mg, 10.6%) was synthesised from N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-4-(4-methylbenzyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (Example 50a) and acetic anhydride according to the general procedure for N-acetylation. MS (ES+) m/z 453.2 (M+H)+
Reaction SMILES: O[CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:13][C:14](=[O:26])[C:15]3[C:20]([CH:21]=2)=[CH:19][C:18]([O:22][CH3:23])=[CH:17][C:16]=3[O:24][CH3:25])=[CH:7][C:6]=1[CH3:27].[C:28]1(=[O:38])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30](=[O:37])[NH:29]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:23][O:22][C:18]1[CH:19]=[C:20]2[C:15](=[C:16]([O:24][CH3:25])[CH:17]=1)[C:14](=[O:26])[NH:13][C:12]([C:8]1[CH:9]=[C:10]([CH3:11])[C:5]([O:4][CH2:3][CH2:2][N:29]3[C:30](=[O:37])[C:31]4[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:28]3=[O:38])=[C:6]([CH3:27])[CH:7]=1)=[CH:21]2
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCO)c(C)c3)cc2c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCN4C(=O)c5ccccc5C4=O)c(C)c3)cc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of 3-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-6,8-dimethoxy-2H-isoquinolin-1-one (0.80 g, 2.16 mmol), isoindole-1,3-dione (0.35 g, 2.38 mmol), and triphenylphosphine (0.85 g, 3.25 mmol) in THF (30 mL), was added diethyl azodicarboxylate (0.56 g, 3.25 mmol) and the reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated in vacuo and the residue was washed with ether to give the title compound as an off-white solid. Yield: 1.11 g (crude). 1H NMR (400 MHz, CDCl3): δ 8.34 (s, 1H), 7.89 (m, 2H), 7.77 (m, 2H), 7.21 (s, 2H), 6.49 (br s, 2H), 6.44 (s, 1H), 4.16 (m, 2H), 4.08 (m, 2H), 3.97 (s, 3H), 3.89 (s, 3H), 2.25 (s, 6H). MS (ES) m/z: 499.06 (M+1) (100%).
Reaction SMILES: CN(C)[CH:3]=[O:4].O=P(Cl)(Cl)Cl.[CH2:11]([N:18]1[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CCOC(C)=O>[CH2:11]([N:18]1[C:19]2[CH:20]=[CH:21][C:22]([CH:3]=[O:4])=[CH:23][C:24]=2[C:25]2[C:30]1=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1ccc(Cn2c3ccccc3c3ccccc32)cc1
Reactant: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc2c(c1)c1ccccc1n2Cc1ccccc1
Temperature: 0 °C
Yield: 36.3 %

Procedure:
A 50-mL 3-necked round-bottomed flask was charged with N,N-dimethylformamide (400 mg, 5.42 mmol, 2.80 equiv, 99%). To this, POCl3 (700 mg, 4.56 mmol, 2.40 equiv, 99%) was added drop wise with stirring at 0° C. and allowed to stir at room temperature for 1 hour. To this mixture was added 9-benzyl-9H-carbazole (500 mg, 1.93 mmol, 1.00 equiv, 99%) in small portions at 45° C. over 5 minutes. Then, the temperature was raised to 95° C. in an oil bath and allowed to stir for 18 hours. The progress was monitored by TLC (EtOAc:PE=1:4). Upon completion, the reaction mixture was cooled down to room temperature and quenched with water (20 mL). The resulting mixture was allowed to stir for an additional 4 hours at room temperature. The solids were collected by filtration and dried to afford 9-benzyl-9H-carbazole-3-carbaldehyde as green solid (200 mg, 36.1%). LCMS: [M+H]+: 286
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([O:15]CC)=[O:14])[S:10][N:9]=2)=[C:4]([O:18][CH3:19])[CH:3]=1.[OH-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[S:10][N:9]=2)=[C:4]([O:18][CH3:19])[CH:3]=1
Reactant: CCOC(=O)c1cc(-c2ccc(Cl)cc2OC)ns1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(Cl)ccc1-c1cc(C(=O)O)sn1
Yield: 42.8 %

Procedure:
Ethyl 3-(4-chloro-2-methoxyphenyl)isothiazole-5-carboxylate (500 mg, 1.68 mmol) prepared in the Step 44-1-2-A was suspended in ethanol (10 ml), and 1 mol/L sodium hydroxide (10 ml) was added thereto. The mixture was heated under reflux for one hour. After being allowed to cool, the mixture was neutralized with hydrochloric acid, and then separated by filtration and washed with water. The washed product was subjected to through circulation drying to give the title compound (194 mg, 43%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([OH:12])=O.C(Cl)(=O)C([Cl:16])=O.CN(C)C=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([Cl:16])=[O:12]
Reactant: O=C(O)CCc1ccccc1Br
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)CCc1ccccc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3-(2-bromophenyl)propanoic acid (prepared in 2 steps from 2-bromobenzyl bromide, 2.0 g, 8.73 mmole), oxalyl chloride (1.14 ml, 13.1 mmole) and methylene chloride (20 ml) was cooled in an ice bath and N,N-dimethylformamide (34 μL, 0.44 mmole) was added dropwise. The mixture was stirred at room temperature for 3 hours. Concentration in vacuo gave 3-(2-bromophenyl)propanoyl chloride which was taken up in methylene chloride and used in the next step as a crude.
Reaction SMILES: COCCN(S(F)(F)[F:11])CCOC.[C@@:14]12([OH:23])[N:21]([CH3:22])[C@@H:18]([CH2:19][CH2:20]1)[CH2:17][CH:16]=[CH:15]2.O[C:25]1([C:38]([O-:40])=[O:39])[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2.O.C([O-])(O)=O.[Na+]>ClCCl>[C@@:14]12([OH:23])[N:21]([CH3:22])[C@@H:18]([CH2:19][CH2:20]1)[CH2:17][CH:16]=[CH:15]2.[F:11][C:25]1([C:38]([O-:40])=[O:39])[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: O=C([O-])C1(O)c2ccccc2-c2ccccc21
Agent: CN1[C@@H]2CC=C[C@@]1(O)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C([O-])C1(F)c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1.66 mL (0.009 mol) of bis-(2-methoxyethyl)aminosulfur trifluoride are placed in 10 mL dichloromethane and within 20 minutes at 15°-20° C., a solution of 2.4 g (0.007 mol) of 4a in 25 mL dichloromethane is added dropwise thereto. The mixture is stirred for 20 hours at ambient temperature, cooled to 0° C., and carefully combined with 80 mL of water with thorough stirring. Then the mixture is carefully adjusted to pH 8 with aqueous NaHCO3 solution, the organic phase is separated off, the aqueous phase is extracted again with dichloromethane, the combined organic phases are washed with water, dried over magnesium sulfate, and evaporated to dryness. The hydrochloride is precipitated and recrystallized from acetonitrile-diethyl ether. Then the free base is liberated again using 10% aqueous sodium carbonate solution. Yield: 1.05 g bright yellow crystals (53% of theoretical yield).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.Cl.N([O-])=O.[Na+].[I-:19].[K+]>>[I:19][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1
Reactant: Nc1ccc(CCCC(=O)O)cc1
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Product: O=C(O)CCCc1ccc(I)cc1
Reaction time: 8 h

Procedure:
A 5 C. mixture of 4-(4-aminophenyl)butyric acid (1.0 eq) and aqueous 6N hydrochloric acid (5.44 eq) was treated with 1.05 eq of a 3N aqueous solution of sodium nitrite, adding slowly so as to keep the temperature below 5 C. A solution of 2.8N aqueous potassium iodide (1.01 eq) was added. The reaction was stirred overnight. The layers were separated. The organic phase was purified by flash chromatography using methanol/methylene chloride as eluant to give 4-(4-iodophenyl)butyric acid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:19])[CH:6]=[C:7]([O:15][CH:16](C)C)[C:8]2=[O:14]>CO>[F:2][C:3]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:19])[CH:6]=[C:7]([O:15][CH3:16])[C:8]2=[O:14]
Reactant: CC(C)OC1=CC(=O)c2c(F)cc(F)cc2C1=O
Agent: Cl
Solvent: CO
Product: COC1=CC(=O)c2c(F)cc(F)cc2C1=O
Temperature: 25 °C
Yield: 83.6 %

Procedure:
A solution of 0.48 g (13.2 mM) of anhydrous hydrogen chloride in 15 mL of methanol was treated with 0.175 g (0.694 mM) of 5,7-difluoro-2-isopropoxy-1,4-naphthoquinone. The mixture was heated to solvent reflux temperature for 0.33 hours, cooled to room temperature and concentrated in vacuo to give 0.13 g of product. 1H NMR (dmso-d6): δ=7.8 (m, 1H), 7.68 (dd, 1H, JH-Fortho =7.5 Hz), 6.31 (s, 1H), 3.86(s, 3H).