Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]([CH3:18])([CH3:17])[CH3:16])[O:11][C:10]([CH3:30])([CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=1)[CH:9]=[CH:8]2)(=[O:3])[CH3:2].[H][H]>C1C=CC=CC=1.C(O)(=O)C.[Pd]>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]([CH3:18])([CH3:16])[CH3:17])[O:11][C:10]([CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([NH2:27])=[CH:25][CH:26]=1)([CH3:30])[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc2c(cc1C(C)(C)C)OC(C)(COc1ccc([N+](=O)[O-])cc1)C=C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CC(=O)Oc1cc2c(cc1C(C)(C)C)OC(C)(COc1ccc(N)cc1)CC2

Procedure:
2.1 g of 6-acetoxy-7-t-butyl-2-methyl-2-(4-nitrophenoxymethyl)-2H-chromene (prepared as described in Preparation 57) were dissolved in a mixture of 20 ml of benzene and 2 ml of acetic acid, and the compound was reduced for 10 hours at room temperature, in the presence of 0.1 g of 10% w/w palladium-on-carbon, and under about 1 atmosphere (about 1 bar) pressure of hydrogen. The catalyst was filtered off, and the reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and then with water, after which it was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography, eluted with benzene, to give the title compound as a slightly brown oil.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8](F)=[CH:7][CH:6]=1)=[O:4].C(N(CC)CC)C.[CH2:21]([NH2:24])[C:22]#[CH:23]>C(#N)C>[F:1][C:2]([F:13])([F:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:24][CH2:21][C:22]#[CH:23])=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C(c1ccc(F)cc1)C(F)(F)F
Reactant: C#CCN
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C#CCNc1ccc(C(=O)C(F)(F)F)cc1
Yield: 100.1 %

Procedure:
To a solution of 8.64 g (45 mmol) of 2,2,2-trifluoro-1-(4-fluorophenyl)ethanone (Journal of Organic Chemistry, Vol. 32, pp. 1311-1318 (1967)) and 7.53 ml (54 mmol) of triethylamine in 150 ml of acetonitrile, cooled in an ice-bath, is added 31.13 ml (0.45 mol) of 2-propynylamine. The ice-bath is removed and the solution is heated under reflux for eighteen hours. The reaction solution is cooled and concentrated to give a solid, which is partitioned between ethyl acetate and water. The ethyl acetate layer is separated, dried (magnesium sulfate), and concentrated to give 10.23 g of a red-brown oil. This is applied to a column of 250 g of flash silica gel packed in n-heptane-dichloromethane (2:1). Elution with the same solvent gives 4.05 g (39.6%) of the product as a fluffy white solid; mp 96°-98° C.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[NH:12][C:11]2=[O:23])=[CH:6][CH:5]=1.ClCCl.[I:29]Cl>O>[F:25][C:2]([F:1])([F:24])[O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:15](=[O:16])[C:14]([I:29])=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[NH:12][C:11]2=[O:23])=[CH:8][CH:9]=1
Reactant: ClI
Reactant: O=c1cc(-c2ccccn2)[nH]c(=O)n1-c1ccc(OC(F)(F)F)cc1
Solvent: O
Solvent: ClCCl
Product: O=c1[nH]c(-c2ccccn2)c(I)c(=O)n1-c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Yield: 44.1 %

Procedure:
1.0 g of the obtained 3-(4-trifluoromethoxyphenyl)-6-(2-pyridyl)-2,4(1H,3H)-pyrimidinedione was added to 20 ml of dichloromethane, and 0.7 g of iodine monochloride was added thereto with stirring at room temperature. The resulting solution was further stirred at room temperature for 3 hours, then poured into 100 ml of water and extracted with 100 ml of ethyl acetate. The obtained organic layer was washed with a sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Then the solvent was distilled away under reduced pressure to obtain 0.60 g of the objective compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH2:17]([C:21]1[NH:25][C:24]([CH:26]=[O:27])=[C:23]([Cl:28])[N:22]=1)[CH2:18][CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>CCOC(C)=O>[C:13]([NH:12][S:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:25]2[C:24]([CH:26]=[O:27])=[C:23]([Cl:28])[N:22]=[C:21]2[CH2:17][CH2:18][CH2:19][CH3:20])=[CH:4][CH:5]=1)(=[O:11])=[O:10])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(CBr)cc1
Reactant: CCCCc1nc(Cl)c(C=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(S(=O)(=O)NC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.1 %

Procedure:
Intermediate (2a) (13.6 g, 45 mmol, 1.0 eq), 2-butyl-5-chloro-3H-imidazole-4-carbaldehyde (8.4 g, 45 mmol, 1.0 eq) and potassium carbonate (12.4 g, 90 mmol, 2.0 eq) were added to 90 mL of DMF. The mixture was stirred at room temperature for 16 hours. The mixture was then diluted with 300 mL EtOAc and extracted with 100 mL 10% aq. LiCl, 2×200 mL water, 100 mL saturated aqueous NaCl, dried over MgSO4, and filtered. The filtrate was evaporated and purified by flash chromatography (40% EtOAc:hexanes) to yield intermediate (2b) (13.0 g). MS m/z: [M+H+] calcd for C19H26ClN3O3S, 412.1; found 412.4.
Reaction SMILES: [C:1]([OH:12])(=O)[CH2:2][CH:3]=[CH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].S(Cl)([Cl:15])=O>>[C:1]([Cl:15])(=[O:12])[CH2:2][CH:3]=[CH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCC=CCC(=O)O
Product: CCCCCCC=CCC(=O)Cl

Procedure:
The 3-decenoic acid was converted to its corresponding acyl chloride (3-decenoyl chloride) by reaction with thionyl chloride.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15](O)=[O:16])[N:12]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]2=[O:24])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:25][C:26]1[C:27]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[N:28][C:29]([CH3:32])=[CH:30][N:31]=1>>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]([N:36]3[CH2:37][CH2:38][N:33]([C:27]4[C:26]([CH3:25])=[N:31][CH:30]=[C:29]([CH3:32])[N:28]=4)[CH2:34][CH2:35]3)=[O:16])[N:12]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]2=[O:24])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1cnc(C)c(N2CCNCC2)n1
Reactant: O=C(O)C1CN(S(=O)(=O)c2ccccc2)C(=O)N1C1CCCCC1
Product: Cc1cnc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4ccccc4)C(=O)N3C3CCCCC3)CC2)n1

Procedure:
In analogy to example 1, (RS)-1-benzenesulfonyl-3-cyclohexyl-2-oxo-imidazolidine-4-carboxylic acid (example 39, step 4) was coupled with 3′,6′-dimethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (CAS 59215-42-8) to give the title compound as a colorless solid. MS: 526.8 ([M+H]+)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[CH:3]=1.[Li]CCCC.CCCCCC.CON(C)[C:23]([C@@H:25]1[O:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]1)=[O:24]>C1COCC1>[Cl:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:23]([C@@H:25]1[O:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]1)=[O:24]
Reactant: Clc1cccc(Br)c1
Reactant: CON(C)C(=O)[C@H]1CN(C(=O)OC(C)(C)C)CCO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCO[C@@H](C(=O)c2cccc(Cl)c2)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
To a solution of 1-bromo-3-chlorobenzene (5 g, 18.2 mmol) in anhydrous THF (25 mL) at −78° C. under nitrogen was added dropwise a solution of 2.5 M n-BuLi in hexane (18.2 mmol). After stirring for 1 h at −78° C., a solution of (R)-tert-butyl 2-(methoxy(methyl)carbamoyl)morpholine-4-carboxylate (3.47 g, 18.2 mmol) in anhydrous THF (10 mL) was added dropwise. After addition, the reaction mixture was allowed to warm to rt and stirred for 2 h. Tlc indicated the reaction was complete. The mixture was quenched with satd aq NH4Cl (50 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude product (5.5 g, 93%), which was used immediately for next step without purification.
Reaction SMILES: [CH:1]12[C:9](=[C:10]([C:18]3[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=3)[C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][CH2:2]2.[C:25]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:28])[CH:26]=[CH2:27].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC>CC([O-])=O.CC([O-])=O.[Pd+2].CC#N>[CH:1]12[C:9](=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[C:18]3[CH:23]=[CH:22][C:21](/[CH:27]=[CH:26]/[C:25]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:20][CH:19]=3)[CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][CH2:2]2
Reactant: C=CC(=O)OC(C)(C)C
Reactant: Oc1ccc(C(=C2C3CCCC2CCC3)c2ccc(Br)cc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2C3CCCC2CCC3)c2ccc(O)cc2)cc1
Temperature: 85 °C
Yield: 91.9 %

Procedure:
Compound 43 (0.32 g, 0.834 mmol), t-butyl acrylate (0.734 mL, 5.01 mmol), P(o-tolyl)3 (0.11 g, 0.359 mmol), Pd(OAc)2 (0.0394 g, 0.175 mmol) and Et3N (0.7 mL, 5.01 mmol) were added to a flask containing CH3CN (13 mL) and the stirred reaction mixture was heated at 85° C. for 24 h under a nitrogen atmosphere. The reaction mixture was allowed to cool at RT and then partitioned between water and EtOAc. The layers were separated, and the organic phase was washed with brine, dried (MgSO4), filtered, and the filtrate was concentrated to give an oily residue. The crude oil was adsorbed onto silica and purified by flash column chromatography on silica gel with a hexanes:EtOAc gradient (100:0 to 50:50) to give compound 44 as a yellow foam (0.33 g, 92%). 1H NMR (400 MHz, DMSO-d6): δ 1.45-1.53 (m, 10H), 1.72-1.73 (m, 7H), 1.96-2.01 (m, 2H), 2.53-2.64 (m, 4H), 6.42 (d, J=16.1 Hz, 1H), 6.66 (d, J=8.5 Hz, 2H), 6.87 (d, J=8.3 Hz, 2H), 7.08 (d, J=8.1 Hz, 2H), 7.48 (d, J=16.1 Hz, 1H), 7.57 (d, J=8.1 Hz, 2H), 9.30 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.[CH3:28][O:29][C:30]([CH:32]1[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]1)=[O:31]>>[CH3:28][O:29][C:30]([C:32]1([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH2:33][CH2:34][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:36][CH2:37]1)=[O:31]
Reactant: Clc1ncnc2ccc(I)cc12
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(c2ncnc3ccc(I)cc23)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Prepared essentially as described in Example 1c using 4-chloro-6-iodo-quinazoline, as prepared in the preceding step, 1.1 eq LiHMDS/THF and 1.1 eq piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester, as prepared in Example 1b, and stirring at rt for 14 h following enolate formation at −78° C. The homogeneous brown solution was worked up as described in Example 1c to provide the impure crude title compound as a very dark brown thick oil (14.97 g). 1H-NMR (300 MHz, CDCl3) δ 9.28 (s, 1H), 8.41 (d, 1H), 8.10 (dd, 1H), 7.80 (d, 1H), 3.8-3.5 (m, 4H), 3.66 (s, 3H), 2.45-2.35 (m, 4H), 1.46 (s, 9H). LC/MS (ESI): calcd mass 497.1, found 398.0 (MH-Boc)+.
Reaction SMILES: [NH:1]([C:8](=[O:28])[CH:9]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][N:20]=1)[C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.[CH:40]1[CH:41]=[CH:42][C:43]2[N:48](O)N=[N:46][C:44]=2[CH:45]=1.C1(N)C=CC=CC=1N>CN(C=O)C>[NH2:46][C:44]1[CH:45]=[CH:40][CH:41]=[CH:42][C:43]=1[NH:48][C:23]([C:22]1[CH:26]=[CH:27][C:19]([CH:9]([C:8]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:28])[C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])=[N:20][CH:21]=1)=[O:25]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1ccc(C(C(=O)Nc2ccccc2)C(=O)Nc2ccccc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Nc1ccccc1N
Solvent: CN(C)C=O
Product: Nc1ccccc1NC(=O)c1ccc(C(C(=O)Nc2ccccc2)C(=O)Nc2ccccc2)nc1
Reaction time: 0.5 h
Yield: 37 %

Procedure:
To a solution of 6-[2-anilino-1-(anilinocarbonyl)-2-oxoethyl]nicotinic acid (35 mg, 0.093 mmol) in DMF (1 mL) at room temperature was added EDCI (22 mg, 0.11 mmol) and HOBT (14 mg, 0.10 mmol). The solution was stirred for 30 min and 1,2-phenylenediamine (34 mg, 0.31 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 18 h and purified by reverse phase HPLC (5% to 80% MeCN in water) to give 2-(5-{[(2-aminophenyl)amino]carbonyl}pyridin-2-yl)-N,N′-diphenylmalonamide (16 mg, TFA salt, 21% from methyl 6-[2-anilino-1-(anilinocarbonyl)-2-oxoethyl]nicotinate) as a white solid: ESIMS calcd 466.2 (M++H), found 466.1 (M++H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O.C(Cl)(Cl)(Cl)Cl>>[Br:18][CH2:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc2c1ncn2C(=O)OC(C)(C)C
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)n1cnc2c(CBr)cccc21
Yield: 42.4 %

Procedure:
A mixture of 4-methylbenzimidazole-1-carboxylic acid, 1,1-dimethylethyl ester (6.50 g, 28.0 mmol) and N-bromosuccinimide (5.50 g, 30.9 mmol) in carbon tetrachloride (75 mmol) was stirred and irradiated with a 250 W flood lamp for 1 h. The reaction mixture was allowed to cool and the solid was filtered off and discarded. The filtrate was evaporated and purified by HPLC (20% ethyl acetate/hexanes) to give 4-(bromomethyl)benzimidazole-1-carboxylic acid, 1,1-dimethylethyl ester (3.69 g, 42%).
Reaction SMILES: [C:1]1([CH:7]2[NH:11][N:10]=[C:9]3[C:12](=[CH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][S:14](=[O:17])(=[O:16])[CH2:15][CH:8]23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[C:26](OC(=O)C)(=[O:28])[CH3:27]>C(O)(=O)C>[C:26]([N:11]1[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]2[CH2:15][S:14](=[O:16])(=[O:17])[CH2:13][C:12](=[CH:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:9]2=[N:10]1)(=[O:28])[CH3:27]
Reactant: O=S1(=O)CC(=Cc2ccccc2)C2=NNC(c3ccccc3)C2C1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)N1N=C2C(=Cc3ccccc3)CS(=O)(=O)CC2C1c1ccccc1
Temperature: 25 °C

Procedure:
A suspension of 1.6g of 2,3,3a,4,6,7-hexahydro-3-phenyl-7-(phenylmethylene)thiopyrano[4,3-c]pyrazole-5,5-dioxide in 2ml of acetic anhydride and 30ml of acetic acid is heated on a steam bath for 15 minutes. Hot water (50ml) is added with stirring and the solution is allowed to cool to room temperature. The solids are collected and washed well with water and dried in vacuo over phosphorus pentoxide at 50°C to yield 1.65g of the title compound, melting point 218°-219.5°C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[NH2:9][NH:10][C:11]([NH2:13])=[S:12].O>C(O)C.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[N:9][NH:10][C:11]([NH2:13])=[S:12]
Reactant: NNC(N)=S
Reactant: O=Cc1ccccn1
Solvent: O
Solvent: CCO
Product: NC(=S)NN=Cc1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The corresponding pyridine-2-formaldehyde (23, 23a or 28a-k, 10 mmol) was dissolved in ethanol-water (2:1 v/v, 150 mL). To the solution was added thiosemicarbazide (11 mmol). The solution was stirred for 30 min at ambient temperature. After addition of water (50 mL), the reaction mixture was stirred vigorously for 2 h at room temperature. The yellow precipitate was collected by filtration, washed with ethanol-water (1:4 v/v) and dried in vacuum to afford the corresponding pyridine-2-carboxaldehyde thiosemicarbazone (24, 24a, 29a-k).
Reaction SMILES: [CH2:1]=O.[NH2:3][C@H:4]([C:15]([OH:17])=[O:16])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1.[OH-].[Na+].Cl>O>[CH2:1]1[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][C@@H:4]([C:15]([OH:17])=[O:16])[NH:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: C=O
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)[C@@H]1Cc2c([nH]c3ccccc23)CN1
Temperature: 50 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
Formaldehyde (37% aq. solution, 39.7 mL, 490 mmol) was added to a stirred solution of L-tryptophan (100.0 g, 490 mmol) in aqueous sodium hydroxide solution (19.6 g in 200 mL of H2O, 490 mmol) and stirred for 2 hr. The mixture was heated to reflux and stirred for 3.5 hr. The mixture was cooled to 50° C. and carefully acidified to pH 5-6 with 6.0 M HCl(aq) solution. The mixture was diluted with water (200 mL). The flask was removed from heat and cooled to room temperature. The precipitates filtered off and washed with water. The solids were resuspended in THF (800 mL), stirred at RT for 1 hr, and filtered to afford compound 1 (101.3 g, 95%) as beige solid. 1H NMR (300 MHz, DMSO-d6): δ 10.93 (s, 1H), 8.88 (br s, 1H), 7.43 (d, 1H), 7.31 (d, 1H), 7.02 (t, 1H), 6.97 (t, 1H), 4.18 (q, 2H), 3.61-3.56 (m, 1H), 3.12 (dd, 1H), 2.83-2.75 (m, 1H); LC-MS [M+H+ 217].
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].O.[NH2:17][NH2:18]>C(O)C>[Cl:1][C:2]1[C:3]([NH:17][NH2:18])=[N:4][CH:5]=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: NN
Reactant: CC(C)(C)OC(=O)c1cnc(Cl)c(Cl)c1
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)c1cnc(NN)c(Cl)c1
Temperature: 75 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl 5,6-dichloronicotinate (2.0 g, 8.1 mmol)) in ethanol (40.3 mL) was added hydrazine hydrate (1.18 mL, 24.2 mmol). The mixture was heated 75° C. After 18 h, the mixture was cooled to ambient temperature. The mixture was concentrated to dryness: LC-MS [M+1]=244.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][CH:7]=1.C1COCC1.[NH2:15][C:16]1[C:17]([C:38](N(OC)C)=[O:39])=[N:18][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([NH:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:29])[CH:23]=2)=[CH:20][N:21]=1>O>[NH2:15][C:16]1[N:21]=[CH:20][C:19]([C:22]2[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=2)[C:28]([NH:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:29])=[N:18][C:17]=1[C:38]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)=[O:39]
Reactant: CON(C)C(=O)c1nc(-c2cccc(C(=O)NCc3ccccc3)c2)cnc1N
Reactant: Fc1cccc([Mg]Br)c1
Solvent: O
Solvent: C1CCOC1
Product: Nc1ncc(-c2cccc(C(=O)NCc3ccccc3)c2)nc1C(=O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 4 %

Procedure:
3-Fluorophenylmagnesium bromide (1.5 mL of a 0.5 M solution in TBF, 0.75 mmol) was added dropwise to a THF (10 mL) solution of 3-amino-6-{3-[(benzylamino)carbonyl]phenyl}-N-methoxy-N-methylpyrazine-2-carboxamide (0.10 g, 0.25 mmol) at 0° C. under N2. The reaction mixture was warmed to room temperature and stirred for 2 h. The mixture was diluted with water and extracted 3× with ethyl acetate. The combined organic layers were dried with magnesium sulfate, filtered, and concentrated under reduced pressure to give a yellow oil. The crude product was separated by preparative HPLC and lyophilized to give a yellow solid (4 mg, 4% yield). 1H NMR (400 MHz, d6-DMSO): δ 9.10 (t, 1H), 9.05 (s, 1H), 8.42 (bs, 1H), 8.01 (m, 2H), 7.86-7.80 (m, 2H), 7.74 (d, 1H), 7.57-7.51 (m, 2H), 7.47-7.43 (m, 2H), 7.38-7.32 (m, 2H), 7.28-7.24 (m, 2H), 6.47-6.59 (m, 1H), 4.50 (d, 2H). MS (EI) for C25H19FN4O2: 427 (MH+).
Reaction SMILES: [N+:1]([CH2:4][C:5]([CH3:9])=[CH:6][CH:7]=[O:8])([O-:3])=[O:2].[CH2:10](O)[CH2:11][OH:12].O>C1C=CC=CC=1>[N+:1]([CH2:4][C:5]([CH3:9])=[CH:6][CH:7]1[O:12][CH2:11][CH2:10][O:8]1)([O-:3])=[O:2]
Reactant: OCCO
Reactant: CC(=CC=O)C[N+](=O)[O-]
Solvent: O
Solvent: c1ccccc1
Product: CC(=CC1OCCO1)C[N+](=O)[O-]

Procedure:
0.1 Mol of 4-nitro-3-methyl-2-butenal and 0.1 Mol of ethyleneglycol is benzene were refluxed for 1 hour, collecting 0.1 Mol of water in a Dean Stark trap. After cooling the reaction mixture it was quenched in a solution of sat. Sodiumbicarbonate and extracted several times with benzene. The reaction product was purified by Kugelrohr distillation followed by chromotography over silica gel. The product was obtained as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:21][CH2:20][C:11]3[NH:12][C:13]4[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][C:18]=4[C:10]=3[CH2:9]2)=[CH:4][CH:3]=1.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]=[CH2:30])=[CH:25][N:24]=1.[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:21][CH2:20][C:11]3[N:12]([CH2:30][CH2:29][C:26]4[CH:25]=[N:24][C:23]([CH3:22])=[CH:28][CH:27]=4)[C:13]4[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][C:18]=4[C:10]=3[CH2:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(c1ccc(Cl)cc1)CC3
Reactant: C=Cc1ccc(C)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CCN(c2ccc(Cl)cc2)C1

Procedure:
The title compound is prepared from a mixture of 2-(4-chlorophenyl)-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole, 2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15]Cl)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][O-:18].[Na+].[Na]>CO.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][O:18][CH3:17])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccc(OCc2ccccc2)cn1
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CO
Product: COCc1ccc(OCc2ccccc2)cn1
Yield: 94 %

Procedure:
50 g (0.21 mol) of 5-benzyloxy-2-chloromethylpyridine (CAS 127590-90-3; D. I. Scopes, N. F. Norman, D. E. Bays, D. Belton, J. Brain et al., J. Med. Chem., 1992, 35, 490-501) in solution in 150 ml of methanol are added to the solution of sodium methoxide prepared by adding 6.4 g (0.28 mol) of sodium to 150 ml of methanol. After refluxing for 3 hours under nitrogen, the solution is concentrated to dryness. The oil obtained is taken up in ethyl acetate. The solution is washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulphate and then concentrated to dryness. 46 g (94%) of a brown oil are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:11])[CH3:10])=[CH:5][CH:4]=1.CC(C1C=CC(OC)=CC=1)=O.COC1C=CC([C@@H](O)C)=CC=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([OH:11])[CH3:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(C)O)cc1
Agent: COc1ccc(C(C)=O)cc1
Agent: COc1ccc([C@H](C)O)cc1
Product: COc1ccc([C@@H](C)O)cc1
Reaction time: 144 h
Yield: 56 %

Procedure:
As shown here, the biochemical conversion reaction of immobilized buckwheat protein for the substrate (±)-1-(4-methoxyphenyl)ethanol (200 mg) requires 6 days by going through bioconversion to 4-methoxyacetophenone accompanying sterically selective oxidation of (S)-1-(4-methoxyphenyl)ethanol to obtain 112 mg of (R)-1-(4-methoxyphenyl)ethanol at a yield of 46%. Optical purity was obtained at 99% e.e.