Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:11]([O:16][CH3:17])(=[O:15])[C:12]([CH3:14])=O.N1CCCCC1>CO>[CH3:17][O:16][C:11]([C:12]1[CH:14]=[CH:4][C:3]2[C:2](=[CH:9][C:8]([NH2:10])=[CH:7][CH:6]=2)[N:1]=1)=[O:15]
Reactant: COC(=O)C(C)=O
Reactant: Nc1ccc(C=O)c(N)c1
Solvent: CO
Solvent: C1CCNCC1
Product: COC(=O)c1ccc2ccc(N)cc2n1

Procedure:
For example, 2,4-diaminobenzaldehyde 53.7 (Apin Chemicals) is reacted with one molar equivalent of methyl pyruvate 53.2 in methanol, in the presence if a base such as piperidine, to afford methyl-7-aminoquinoline-2-carboxylate 53.8. Basic hydrolysis of the product, employing one molar equivalent of lithium hydroxide in aqueous methanol, then yields the carboxylic acid 53.9. The amino-substituted carboxylic acid is then converted into the diazonium tetrafluoborate 53.10 by reaction with sodium nitrite and tetrafluoboric acid. The diazonium salt is heated in aqueous solution to afford the 7-hydroxyquinoline-2-carboxylic acid, 53.11, Z=OH. Alternatively, the diazonium tetrafluoborate is heated in aqueous organic solution with one molar equivalent of cuprous bromide and lithium bromide, to afford 7-bromoquinoline-2-carboxylic acid 53.11, X═Br. Alternatively, the diazonium tetrafluoborate 53.10 is reacted in acetonitrile solution with the sulfhydryl form of an ion exchange resin, as described in Sulfur Lett., 2000, 24, 123, to prepare 7-mercaptoquinoline-2-carboxylic acid 53.11, Z=SH.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([CH2:9]Cl)[CH:3]=1.[Cl-].[Li+].C([Mg]Cl)(C)C.[C:18]([N:25]1[CH2:28][C:27](=[O:29])[CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[C:27]1([CH2:26][N:25]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:28]1)[O:29][CH2:9]2
Reactant: ClCc1cc(Br)ccc1I
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(Br)ccc12
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
To a solution of 4-bromo-2-(chloromethyl)-1-iodobenzene (2.0 g, 6.04 mmol, 1 eq) in THF (16 mL), isopropylmagnesium chloride lithium chloride complex (5.11 mL, 1.3M in THF, 1.1 eq) was added over about 5 min while the internal temperature didn't exceed −15° C. Reaction is stirred at −15° C. for 30 min. Then a solution of 1-Boc-3-azetidinone (1.24 g, 1.2 eq) in THF (4 mL) was added dropwise; internal temperature at −30° C. The reaction is stirred at room temperature overnight. Reaction was quenched with a solution of citric acid (14 mL of 1M). This was extracted with MTBE and organic layer was washed with aqueous NaHCO3 and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude yellow oil is submitted to silica gel column chromatography (0 to 50% ethyl acetate in heptane). 1.6 g of tert-butyl 5′-bromo-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-carboxylate was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1.Cl.[NH2:18][OH:19]>>[Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][C:8](=[N:18][OH:19])[CH2:7][CH2:6]1
Reactant: NO
Reactant: O=C1CCN(Cc2c(Cl)cccc2Cl)CC1
Agent: Cl
Product: ON=C1CCN(Cc2c(Cl)cccc2Cl)CC1

Procedure:
1-(2,6-Dichlorobenzyl)-4-piperidone oxime is prepared from 1-(2,6-dichlorobenzyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [C:1]([C:3]1[C:4]([O:30][CH:31]([CH3:33])[CH3:32])=[CH:5][C:6]([NH:9][C:10]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([CH2:27][NH:28][CH3:29])=[C:19]([CH:22]([O:25][CH3:26])[O:23][CH3:24])[N:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1)#[N:2].CCN(CC)CC.[CH3:41][N:42]([CH3:47])[CH2:43][C:44](Cl)=[O:45]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:1]([C:3]1[C:4]([O:30][CH:31]([CH3:33])[CH3:32])=[CH:5][C:6]([NH:9][C:10]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([CH2:27][N:28]([CH3:29])[C:44](=[O:45])[CH2:43][N:42]([CH3:47])[CH3:41])=[C:19]([CH:22]([O:25][CH3:26])[O:23][CH3:24])[N:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1)#[N:2]
Reactant: CN(C)CC(=O)Cl
Reactant: CNCc1cc2c(nc1C(OC)OC)N(C(=O)Nc1cc(OC(C)C)c(C#N)cn1)CCC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(OC)c1nc2c(cc1CN(C)C(=O)CN(C)C)CCCN2C(=O)Nc1cc(OC(C)C)c(C#N)cn1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
To a solution of N-(5-cyano-4-isopropoxypyridin-2-yl)-7-(dimethoxymethyl)-6-((methylamino)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 191, 212 mg, 0.466 mmol) in DCM (4 ml) at 0° C. was added NEt3 (0.103 ml, 0.746 mmol) and 2-(dimethylamino)acetyl chloride (91 mg, 0.49 mmol) and the reaction mixture was stirred for 75 min. Additional NEt3 (0.103 ml, 0.746 mmol) was added and the reaction was continued to stir at 0° C. for 30 min. The reaction mixture was allowed to warm to room temperature and a total of NEt3 (0.206 ml, 1.486 mmol) and 2-(dimethylamino)acetyl chloride (273 mg, 1.469 mmol) and DCM (2 ml) were added stepwise during the next 22 h. The reaction mixture was diluted with saturated aqueous NaHCO3 and DCM. Phases were separated and the water phase was extracted with DCM (2×), organic phases were combined and dried using Na2SO4, filtered and concentrated. The crude product was purified using silica gel column chromatography eluting with a gradient of MeOH (3-10%) in DCM. Fractions containing the product were combined and evaporated to yield the title compound as a brown solid. (UPLC-MS 3) tR 0.90 min, ESI-MS 540.3 [M+H]+. 1H NMR (600 MHz, CDCl3) (indicates an overlapping mixture of rotamers of the title compound in an approximate mixture of 0.6:0.4) δ 13.92 (s, 0.6H), 13.83 (s, 0.4H), 8.31-8.26 (m, 1H), 7.90-7.85 (m, 1H), 7.38 (s, 0.6H), 7.23 (s, 0.4H), 5.38 (s, 0.6H), 5.33 (s, 0.4H), 4.83-4.72 (m, 3H), 4.02-3.93 (m, 2H), 3.44 (s, 2.4H), 3.42 (s, 3.6H), 3.18 (s, 1.2H), 3.08 (s, 0.8H), 2.92 (s, 1.8H), 2.87 (s, 1.2H), 2.79-2.72 (m, 2H), 2.34 (s, 3.6H), 2.26 (s, 2.4H), 1.98-1.88 (m, 2H), 1.41-1.34 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[Cl:11][CH2:12][C:13](=O)[CH2:14][C:15](OCC)=[O:16].C1(COC2C(OC)=CC=CC=2/C=C/C2N=C3SC=CN3C(=O)C=2I)CC1>>[Cl:11][CH2:12][C:13]1[N:1]=[C:2]2[S:3][CH:4]=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]2[C:15](=[O:16])[CH:14]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Nc1nc(C(F)(F)F)cs1
Agent: COc1cccc(/C=C/c2nc3sccn3c(=O)c2I)c1OCC1CC1
Product: O=c1cc(CCl)nc2scc(C(F)(F)F)n12

Procedure:
This compound was synthesized from 2-amino-4-trifluoromethylthiazole, Step 1 intermediate (3.70 g, 22.541 mmol) and ethyl chloroacetoacetate (5.194 g, 31.558 mmol) in polyphosphoric acid (30.0 g) according to the procedure described in Step 1, Intermediate 2 to afford 4.0 g of the desired compound: 1H NMR (300 MHz, DMSO-d6) δ 2.28 (s, 3H), 2.60 (s, 3H), 4.52 (s, 1H), 6.25 (s, 1H); ESI-MS (m/z) 269.22 (M+H)+.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].[NH2:32][C:33]1[CH:34]=[CH:35][C:36]([CH3:40])=[C:37]([OH:39])[CH:38]=1>C1COCC1>[OH:39][C:37]1[CH:38]=[C:33]([NH:32][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[C:16]([NH:20][C:21]([C:23]5[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=5)=[O:22])[CH:17]=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:31])[CH:34]=[CH:35][C:36]=1[CH3:40]
Reactant: Cc1ccc(N)cc1O
Reactant: CCn1nc(C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Solvent: C1CCOC1
Product: CCn1nc(C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2ccc(C)c(O)c2)c1
Temperature: 65 °C
Reaction time: 24 h
Yield: 65.8 %

Procedure:
A small screw cap test tube was charged with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 69, 100 mg, 0.240 mmol) and THF (2 mL). To the resulting solution was added 5-amino-2-methylphenol (36.76 mg, 0.264 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was dissolved in EtOAc. The resulting solution was diluted with Hexanes to initiate the precipitation of the product. The solid precipitate that formed was filtered then washed with ˜1 mL of i-prOH yielding 66% (85 g, 0.158 mmol) of the title compound.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19](=[O:29])[CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[C:32]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1>>[C:32]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:33]=[CH:34][C:35]([NH:38][C:3]([C:5]2[N:14]3[C:8]([CH2:9][N:10]([C:19](=[O:29])[CH2:20][O:21][C:22]4[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=4)[C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[CH2:13]3)=[CH:7][CH:6]=2)=[O:4])=[CH:36][CH:37]=1
Reactant: O=C(COc1ccc(Cl)cc1)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Reactant: Nc1ccc(-c2ccccc2)cc1
Product: O=C(Nc1ccc(-c2ccccc2)cc1)c1ccc2n1Cc1ccccc1N(C(=O)COc1ccc(Cl)cc1)C2

Procedure:
The title compound was synthesized from 2,2,2-trichloro-1-{10-[(4-chlorophenoxy)acetyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 67 (0.3 mmol) and biphenyl-4-ylamine (2.2 eq.) in the manner of Example 68, m.p. 201-202° C. MS [(+)ESI, m/z]: 548 [M+H]+
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:4]=1[O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][CH2:16][OH:17])[N:10]=[CH:9]2.[C:23]([C:27]1[CH:31]=[C:30]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[N:29]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)[N:28]=1)([CH3:26])([CH3:25])[CH3:24]>>[C:23]([C:27]1[CH:31]=[C:30]([NH:32][C:33]([NH:1][CH2:2][C:3]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:4]=2[O:5][C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[N:11]([CH2:15][CH2:16][OH:17])[N:10]=[CH:9]3)=[O:34])[N:29]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)[N:28]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: NCc1cc(F)ccc1Oc1ccc2c(cnn2CCO)c1
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)cc1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)NCc2cc(F)ccc2Oc2ccc3c(cnn3CCO)c2)cc1

Procedure:
heating a mixture of 2-(5-(2-(aminomethyl)-4-fluorophenoxy)-1H-indazol-1-yl)ethanol and phenyl 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-ylcarbamate in an organic solvent at 35-40° C. for 5 hours to form 1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(5-fluoro-2-(1-(2-hydroxyethyl)-1H-indazol-5-yloxy)benzyl)urea;
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH:5]=[CH:6][C:7]([NH:9][C:10]1[CH:22]=[CH:21][C:13]([CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:12][CH:11]=1)=[O:8].B([O-])([O-])O[C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:34][C:31]1[CH:32]=[CH:33][C:28]([C:2]2[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=2)[CH:5]=[CH:6][C:7]([NH:9][C:10]2[CH:22]=[CH:21][C:13]([CH2:14][N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:12][CH:11]=2)=[O:8])=[CH:29][CH:30]=1
Reactant: O=C(C=Cc1cccc(Br)c1)Nc1ccc(CN2CCCCC2)cc1
Reactant: [O-]B([O-])Oc1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C(C=Cc1cccc(-c2ccc(F)cc2)c1)Nc1ccc(CN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.8 %

Procedure:
A suspension of 1-(4-(3-bromocinnamoylamino)-benzyl)piperidine (0.4 g), 4-fluorophenyl borate (0.14 g), 1M potassium carbonate (2 ml) and ethanol (1 ml) in toluene (5 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the suspension was added tetrakistriphenylphosphinepalladium (0.05 g), and the mixture was refluxed over night. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column (methanol/triethylamine/ethyl acetate) to give crude crystals, which were recrystallized from ethyl acetate-hexane to give 1-(4-(3-(4-fluoro-phenyl)-cinnamoylamino)benzyl)piperidine (Compound 83) (0.35 g) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[BH4-].[Na+].CC(C)=O>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[OH:9])=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1ccc(Br)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: OC(c1ccccc1)c1ccc(Br)cc1
Reaction time: 0.25 h

Procedure:
To a solution of (4-bromophenyl)(phenyl)methanone (200 g, 0.766 mole) in THF (600 mL) and methanol (400 mL) was added in portions pulverized sodium borohydride (29 g, 0.766 mole) while maintaining the internal temperature between 3° C. and 10° C. After stirring for an additional 15 minutes, acetone (125 mL) was added and the mixture stirred for a subsequent 10 minutes. The solution was concentrated and the residue partitioned between water (250 mL) and ethyl acetate (1.0 L). The organic layer was separated, dried (Na2SO4), filtered and concentrated. The residue was pumped on by high vacuum for 18 hours to give the title compound as an oil.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH3:14][Mg]Br>>[CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])([CH3:14])[CH3:12])=[CH:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)c1ccc(OC(C)C)cc1
Reactant: C[Mg]Br
Product: CC(C)Oc1ccc(C(C)(C)O)cc1

Procedure:
Reaction of 1-isopropoxy-4-acetylbenzene with methyl magnesium bromide afforded 1-isopropoxy-4-(1-hydroxy-1-methylethyl)benzene. A solution of 35 g. of 1-isopropoxy-4-(1-hydroxy-1-methylethyl)benzene in 65 ml. of ethyl alcohol and 300 ml. of liquid ammonia was stirred while 5 g. of Lithium metal in the form of small pieces was added portionwise over thirty minutes. The reaction mixture was stirred for an additional thirty minutes, and then was diluted with 150 ml. of toluene and 35 g. of ammonium chloride. The reaction mixture was stirred at room temperature for twelve hours, and then was further diluted with 200 ml. of water. The aqueous layer was separated and extracted with 100 ml. of fresh toluene. The toluene layers were combined, washed with water, dried, and concentrated by evaporation under reduced pressure. Distillation of the residue provided 22.8 g. of 1-isopropoxy-4-(1-hydroxy-1-methylethyl)-1,4-cyclohexadiene. B.P. 85°-87° C. at 0.02 torr.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:15]3[C:10](=[CH:11][N:12]=[CH:13][CH:14]=3)[CH2:9][O:8][C:6]=2[CH:7]=1.[OH:16][CH2:17][C@@H:18]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH:20]([CH3:22])[CH3:21].C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH:14]1[CH:13]=[N:12][CH:11]=[C:10]2[CH2:9][O:8][C:6]3[CH:7]=[C:2]([O:16][CH2:17][CH:18]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28])[CH2:19][CH:20]([CH3:22])[CH3:21])[CH:3]=[CH:4][C:5]=3[C:15]=12
Reactant: Clc1ccc2c(c1)OCc1cnccc1-2
Reactant: CC(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)CC(COc1ccc2c(c1)OCc1cnccc1-2)NC(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 44.5 %

Procedure:
To 8-chloro-5H-chromeno[3,4-c]pyridine (0.489 g, 2.247 mmol) (prepared as in Example 5, Part D), (S)-tert-butyl (1-hydroxy-4-methylpentan-2-yl)carbamate (1.474 g, 6.79 mmol), di-tert-butyl(2′,4′,6′-triisopropyl-[1′,1′-biphenyl]-2-yl)phosphine (0.572 g, 1.348 mmol), palladium (II) acetate (0.151 g, 0.674 mmol) and cesium carbonate (1.098 g, 3.37 mmol) was added toluene (4 mL). Nitrogen gas was bubbled through the mixture for 5 min and the mixture heated at 80° C. for 15 h. The reaction mixture was cooled to room temperature and filtered through a bed of celite. Water (10 mL) was added to the filtrate and the product was extracted with ethyl acetate (3×15 mL). The combined organic extracts were washed with brine (1×10 mL), dried with sodium sulfate and concentrated under reduced pressure. The residue so obtained was purified by preparative TLC using (50% ethyl acetate in pet ether) to afford tert-butyl (1-((5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (0.4 g, 1.00 mmol, 45% yield) as a semi solid. LCMS (ESI) m/e 399.2 [(M+H)1, calcd for C23H31N2O4 399.5]; LC/MS retention time (Method C): tR=2.16 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]([O:13][CH3:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1.C(OC(=O)[C@@H](OC)CC1C=CC(O[CH2:29][CH2:30][Br:31])=CC=1)C>>[CH3:1][O:2][C:3](=[O:15])[CH:4]([O:13][CH3:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:29][CH2:30][Br:31])[CH:7]=1
Reactant: COC(=O)C(Cc1cccc(O)c1)OC
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Product: COC(=O)C(Cc1cccc(OCCBr)c1)OC

Procedure:
The title compound was prepared from 3-(3-hydroxy-phenyl)-2-methoxy-propionic acid methyl ester (Example 291, Step 4) (4.76 mol, 1000 mg) via the same procedure used for the preparation of (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step 2). MS (ES) for C13H17BrO4 [M+NH4]+: 334:2.
Reaction SMILES: N[C:2]1[N:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.C(ON=O)CC(C)C.[CH2:23]([S:25]SCC)[CH3:24]>>[CH2:23]([S:25][C:2]1[N:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH3:24]
Reactant: Nc1cc2c(cn1)[nH]c1ccccc12
Reactant: CCSSCC
Agent: CC(C)CCON=O
Product: CCSc1cc2c(cn1)[nH]c1ccccc12
Temperature: 80 °C

Procedure:
732 mg of 3-amino-β-carboline in 7 ml of diethyldisulfide are heated to 80° C. and mixed with 1 ml of isoamylnitrite. After 0.5 hours of heating to 80° C., it is again mixed with 1 ml of isoamylnitrite and heated to 80° C. for 1.5 hours. After distilling off, the residue is chromatographed twice on silica gel with ethyl acetate/cyclohexane as eluant. After absorptive precipitation of the corresponding evaporated fraction with cyclohexane/diisopropyl ether, 206 mg of 3-ethylthio-β-carboline with a 132°-133° C. melting point are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[CH:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:21]=3)[CH2:16][CH:15]2[C:34](O)=[O:35])=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2].CCN(C(C)C)C(C)C.Cl.[CH3:47][NH:48][CH:49]=[CH:50][CH2:51][CH2:52][CH2:53][CH3:54].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[CH:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:21]=3)[CH2:16][CH:15]2[C:34](=[O:35])[N:48]([CH2:49][CH2:50][CH2:51][CH2:52][CH:53]=[CH2:54])[CH3:47])=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2]
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(OC)nc(-c3ccccc3)n2)CC1C(=O)O)C(=O)OCC
Reactant: CCCCC=CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCCCN(C)C(=O)C1CC(Oc2cc(OC)nc(-c3ccccc3)n2)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Temperature: 25 °C

Procedure:
Compound 7b (1.32 g, 2.67 mmol) was dissolved in 30 ml dry DMF. DIEA (2.1 ml, 12.0 mmol), N-methylhexeneamine HCl (440 mg, 3.9 mmol) and HATU (1.48 g, 3.9 mmol) were added at 0° C., and the reaction mixture was stirred at RT over night. The DMF was evaporated and the residue was dissolved in EtOAc, washed with sat. NaHCO3(aq), H2O and brine. The organic layer was dried (MgSO4), filtered and evaporated, followed by column chromatography (Heptane/EtOAc), giving the title compound. (1.1 g, 70%), MS (M+H)+591.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9](Br)[CH:10]=2)[S:5][C:4](=[O:13])[CH2:3]1.[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17]>C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15])[CH:10]=2)[S:5][C:4](=[O:13])[CH2:3]1
Reactant: C#C[Si](C)(C)C
Reactant: CC1(C)CC(=O)Sc2ccc(Br)cc21
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC1(C)CC(=O)Sc2ccc(C#C[Si](C)(C)C)cc21
Temperature: 55 °C
Reaction time: 24 h

Procedure:
A solution of 1.0 g (3.7 mmol) of 4,4-dimethyl-6-bromo-2-oxo-thiochroman in 1 ml of triethylamine was placed in a heavy-walled tube and degassed and then treated under argon with 2.0 g (2.75 ml, 20.0 mmol) of trimethylsilylacetylene and a powdered mixture of 0.038 g of cuprous iodide and 0.084 g of bis(triphenylphosphine) palladium (II) chloride. The reaction mixture was degassed again, then placed under argon and the tube was sealed. The mixture was heated at 55 degrees C. for 24 hours, allowed to cool to room temperature and taken up with methylene chloride and silica. Solvent was removed in-vacuo and the resulting residual material on silica was purified using flash chromatography (SiO2 ; 2% ethyl acetate in hexanes) to give the title compound as a yellow oil.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH2:9]([C:16]1[CH:37]=[C:36]([O:38][CH3:39])[C:19]2[N:20]([CH2:32][CH2:33][O:34][CH3:35])[C:21]([C:23]3[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=3)=[N:22][C:18]=2[CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(#N)C>[CH2:9]([C:16]1[CH:37]=[C:36]([O:38][CH3:39])[C:19]2[N:20]([CH2:32][CH2:33][O:34][CH3:35])[C:21]([C:23]3[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=3)=[N:22][C:18]=2[C:17]=1[I:1])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(Cc3ccccc3)cc(OC)c21
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(I)c(Cc3ccccc3)cc(OC)c21
Yield: 66.5 %

Procedure:
417 mg (1.78 mmol) N-iodo-succinimide are added to a solution of 670 mg (1.62 mmol) 5-benzyl-2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazole in 25 ml acetonitrile. The reaction mixture is stirred at reflux temperature for 3 h. The reaction mixture is poured on water and extracted (3×) with ethyl acetate. The combined organic layers are washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=4:1) to afford 582 mg of the title compound as a white crystalline solid.