Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]3[C:26](=[O:27])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=[CH:18]3)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[CH3:30][O:31]C1C=CC=CC=1N1CCNCC1>>[CH3:30][O:31][C:6]1[CH:7]=[CH:8][CH:3]=[CH:4][C:5]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[CH:18]2)[CH2:11][CH2:10]1
Reactant: O=c1c2ccccc2ncn1CCN1CCN(c2cccc(C(F)(F)F)c2)CC1
Reactant: COc1ccccc1N1CCNCC1
Product: COc1ccccc1N1CCN(CCn2cnc3ccccc3c2=O)CC1

Procedure:
This compound was prepared in compliance with the procedure described in 1c, using 1-(2-methoxyphenyl)piperazine instead of 1-(3-(trifluoromethyl)phenyl)piperazine.
Reaction SMILES: Cl[C:2]1[CH:20]=[N:19][C:5]2[NH:6][C:7]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.ClC1C=NC2NC(N3C=CN=C3)=NS(=O)(=O)C=2C=1.C(N)CCCCC>>[CH2:13]([NH:12][C:7]1[NH:6][C:3]2[CH:2]=[CH:20][N:19]=[CH:5][C:4]=2[S:9](=[O:11])(=[O:10])[N:8]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCNC1=NS(=O)(=O)c2cc(Cl)cnc2N1
Agent: O=S1(=O)N=C(n2ccnc2)Nc2ncc(Cl)cc21
Solvent: CCCCCCN
Product: CCCCCCNC1=NS(=O)(=O)c2cnccc2N1

Procedure:
In a similar manner the following compound was prepared: 7--Chloro-3-hexylamino-4H- pyrido[2,3-e]-1,2,4-thiadiazine 1,1-dioxide; m.p. 176-179° C.; from 7-chloro-3-(imidazol-1-yl)-4H-pyrido[2,3-e]-1,2,4-thiadiazine 1,1-dioxide and hexylamine.(Compound 12).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][Cl:17])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[O:20]([C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl.N1C=CC=CC=1.O>C(OCCO)C>[Cl:17][CH2:16][CH2:15][O:14][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:31][C:30]3[CH:29]=[CH:28][C:27]([O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:33][CH:32]=3)=[C:3]([C:18]#[N:19])[CH:4]=[N:5]2)=[CH:10][C:9]=1[O:12][CH3:13]
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1OCCCl
Agent: Cl
Solvent: CCOCCO
Solvent: O
Solvent: c1ccncc1
Product: COc1cc2c(Nc3ccc(Oc4ccccc4)cc3)c(C#N)cnc2cc1OCCCl
Temperature: 135 °C
Yield: 78 %

Procedure:
Following the procedure of Example 1, a mixture of 3.0 g (0.01 mol) of 4-chloro-7-(2-chloroethoxy)-6-methoxy-3-quinolinecarbonitrile (Boschelli, Diane H.; Ye, Fei; Wang, Yanong D.; Dutia, Minu; Johnson, Steve L.; Wu, Biqi; Miller, Karen; Powell, Dennis W.; Yaczko, Deanna; Young, Mairead; Tischler, Mark; Arndt, Kim; Discafani, Carolyn; Etienne, Carlo; Gibbons, Jay; Grod, Janet; Lucas, Judy; Weber, Jennifer M.; Boschelli, Frank. J. Med. Chem. 2001, 44, 3965-3977), 2.04 g (0.011 mol) of 4-phenoxyaniline and pyridine hydrochloride 1.16 g (0.01 mol) in 100 mL of 2-ethoxyethanol is heated at 135° C. for 2 hours. Water is added to the reaction mixture, and the precipitate is filtered off. After washing with water, ether and ethyl acetate, the solid is dried in vacuo to provide 3.48 g of 7-(2-chloroethoxy)-6-methoxy-4-(4-phenoxyphenylamino)quinoline-3-carbonitrile as a yellow solid, mp 148-151° C.
Reaction SMILES: Br[C:2]1[C:3]([CH3:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C([O-])([O-])=O.[Na+].[Na+].[CH3:19][N:20](C)C(=O)C>[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.O.O.O.[K+].[K+].[K+].[K+].[Fe+2].CC([O-])=O.CC([O-])=O.[Pd+2]>[C:19]([C:2]1[C:3]([CH3:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])#[N:20]
Reactant: COC(=O)c1cccc(Br)c1C
Reactant: CC(=O)N(C)C
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Product: COC(=O)c1cccc(C#N)c1C
Temperature: 120 °C
Yield: 70 %

Procedure:
To a flask was added methyl 3-bromo-2-methylbenzoate (21 g, 91.7 mmol), potassium hexacyanoferrate (II) trihydrate (9.7 g, 22.9 mmol), Na2CO3 (9.7 g, 91.7 mmol) and Pd(OAc)2 (102 mg) in N,N-dimethylacetamide (100 mL). The flask's atmosphere was evacuated and replaced with nitrogen, and the reaction mixture heated at 120° C. for 10 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (150 mL). The resultant slurry was filtered and washed thoroughly with ethyl acetate (2×50 mL). The combined filtrate was washed with brine and water, dried over Na2SO4 and evaporated under reduced pressure. The residue obtained after the concentration was purified using flash chromatography (ethyl acetate-hexanes (1:9) as the eluent) to provide methyl 3-cyano-2-methylbenzoate (11.2 g, 70% yield). 1H NMR spectrum (in DMSO-d6): δ 8.03 (d, J=8.1 Hz, 1H); 7.98 (d, J=7.9 Hz, 1H); 7.49 (t, 1H); 3.84 (s, 3H); 2.65 (s, 3H).
Reaction SMILES: C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:19][C:20]1[CH:21]=[N:22][N:23]2[C:28]3[N:29]([CH2:32][CH3:33])[CH2:30][CH2:31][C:27]=3[C:26]([CH3:34])=[N:25][C:24]=12>C1C=CC=CC=1>[Br:19][C:20]1[CH:21]=[N:22][N:23]2[C:28]3[N:29]([CH2:32][CH3:33])[CH:30]=[CH:31][C:27]=3[C:26]([CH3:34])=[N:25][C:24]=12
Reactant: CCN1CCc2c(C)nc3c(Br)cnn3c21
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CCn1ccc2c(C)nc3c(Br)cnn3c21
Reaction time: 2 h
Yield: 41.1 %

Procedure:
2.16 g (8.92 mmoles) of benzoyl peroxide were added to a solution of 2.50 g (8.89 mmoles) of 3-bromo-7,8-dihydro-8-ethyl-5-methyl-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine (prepared as described in Example 8) dissolved in 30 ml of benzene, and the mixture was stirred for 2 hours. At the end of this time, the reaction mixture was washed with a 5% v/v aqueous solution of sodium bicarbonate and then with water, after which it was dried over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel (eluted with chloroform) and recrystallized from diisopropyl ether to afford 1.019 g (yield 41%) of the title compound as light yellow needles, melting at 113°-114° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][CH2:8][C:7](=O)[C:6]=2[CH:13]=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O.C(O)C.[Pt]=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:13]=1
Reactant: O=C1CCCOc2ccc(Br)cc21
Agent: O=[Pt]
Agent: CC[SiH](CC)CC
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: Brc1ccc2c(c1)CCCCO2
Reaction time: 2 h
Yield: 51 %

Procedure:
To a solution of 7-bromo-3,4-dihydro-1-benzoxepin-5(2H)-one (20.0 g) in trifluoroacetic acid (32 ml) was added at room temperature triethylsilane (29.2 ml), and the mixture was stirred for 2 hours and concentrated under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was distilled under reduced pressure (0.8 mmHg/123° C.) to give colorless oil. The obtained oil (13.12 g) was dissolved in ethanol (200 ml), and to the solution was added platinum oxide (0.4 g). The mixture was stirred under hydrogen atmosphere for 24 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane→ethyl acetate/hexane=1:19) to give colorless oil of 7-bromo-2,3,4,5-tetrahydro-1-benzoxepine (9.61 g).
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[S:6][C:7]([CH2:9][CH:10]3[CH2:14][CH2:13][N:12]([CH:15]4[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]4)[C:11]3=[O:21])=[CH:8][C:4]=2[CH:3]=1.[F:24][C:25]1[CH:30]=[C:29](B(O)O)[CH:28]=[CH:27][N:26]=1.[Li+].[Cl-].C([O-])([O-])=O.[Na+].[Na+]>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.O.O1CCOCC1>[CH:15]1([N:12]2[CH2:13][CH2:14][CH:10]([CH2:9][C:7]3[S:6][C:5]4[CH:22]=[CH:23][C:2]([C:29]5[CH:28]=[CH:27][N:26]=[C:25]([F:24])[CH:30]=5)=[CH:3][C:4]=4[CH:8]=3)[C:11]2=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: OB(O)c1ccnc(F)c1
Reactant: O=C1C(Cc2cc3cc(Br)ccc3s2)CCN1C1CCCCC1
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: [Cl-]
Solvent: C1COCCO1
Solvent: O
Product: O=C1C(Cc2cc3cc(-c4ccnc(F)c4)ccc3s2)CCN1C1CCCCC1
Temperature: 80 °C
Yield: 99.4 %

Procedure:
Add 3-(5-bromo-benzo[b]thiophen-2-ylmethyl)-1-cyclohexyl-pyrrolidin-2-one (250 mg, 0.64 mmol), 2-fluoropyridine-4-boronic acid (200 mg, 1 mmol), LiCl (10 eq) and Pd(PPh3)4 (0.05 eq) into a solution of dioxane (10 mL) and 2M Na2CO3 (2 mL) and heat at 80° C. for 1 hour. Pour the reaction mixture into water and extract with ethyl acetate. Dry over sodium sulfate, filter, and concentrate. Purify by silica gel (20-50% ethyl acetate in hexanes) to give the title compound as a pale yellow powder (260 mg, 58%): MS (APCI-pos mode) m/z (rel intensity): 409.2 (M+H, 100%).
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([CH:9]3[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[CH2:11][CH2:10]3)[C:5]=2[C:17](OC)=[O:18])[CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([CH:9]3[CH2:14][CH2:13][C:12]([CH3:15])([CH3:16])[CH2:11][CH2:10]3)[C:5]=2[CH2:17][OH:18])[CH2:3][CH2:2]1
Reactant: COC(=O)c1c(C2CCC(C)(C)CC2)noc1C1CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC1(C)CCC(c2noc(C3CC3)c2CO)CC1

Procedure:
(5-cyclopropyl-3-(4,4-dimethylcyclohexyl)isoxazol-4-yl)methanol (I-9F) was prepared by reaction of methyl 5-cyclopropyl-3-(4,4-dimethylcyclohexyl)isoxazole-4-carboxylate and LiAlH4 following the same protocol as described for I-6F. 1H NMR (400 MHz, CDCl3) δ 4.56 (s, 3H), 2.65 (m, 1H), 2.05-1.99 (m, 1H), 1.81-1.75 (m, 4H), 1.52-1.48 (m, 2H), 1.33-1.28 (m, 2H), 1.14-1.10 (m, 2H), 1.04-1.01 (m, 2H), 0.95 (s, 3H), 0.94 (s, 3H). MS m/z 250.1 (M+1).
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:17]=[CH:16][C:15]([S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])=[CH:14][C:10]=1[C:11]([NH2:13])=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C1COCC1.CCOC(C)=O>[Br:8][C:9]1[CH:17]=[CH:16][C:15]([S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])=[CH:14][C:10]=1[C:11]#[N:13]
Reactant: CC(C)S(=O)(=O)c1ccc(Br)c(C(N)=O)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)S(=O)(=O)c1ccc(Br)c(C#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
Triethylamine (0.23 mL, 1.65 mmol) was added to a solution of 2-bromo-5-(isopropylsulfonyl)benzamide (Preparation 24, 338 mg, 1.11 mmol) in THF (10 mL) followed by trifluoroacetic anhydride (0.18 ml, 1.32 mmol). The reaction mixture was stirred at room temperature for 1 hour, diluted with EtOAc (30 mL) and washed with 2M NaHCO3 (20 mL), brine (20 mL) and the organic layer was dried (MgSO4). The solvent was evaporated under reduced pressure to give a colourless solid, 86% yield, 273 mg.
Reaction SMILES: O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.[CH3:13][N:14]1[CH:18]=[C:17]([NH:19][C:20]([C:22]2[N:23]([CH3:27])[CH:24]=[CH:25][N:26]=2)=[O:21])[N:16]=[C:15]1[C:28](O)=[O:29].[CH3:31][O:32][C:33]([C:35]1[N:36]([CH3:50])[CH:37]=[C:38]([NH:40][C:41]([C:43]2[N:44]([CH3:49])[CH:45]=[C:46]([NH2:48])[N:47]=2)=[O:42])[CH:39]=1)=[O:34].C([O-])([O-])=O.[Na+].[Na+]>C(#N)C.C(Cl)(Cl)Cl.O>[CH3:31][O:32][C:33]([C:35]1[N:36]([CH3:50])[CH:37]=[C:38]([NH:40][C:41]([C:43]2[N:44]([CH3:49])[CH:45]=[C:46]([NH:48][C:28]([C:15]3[N:14]([CH3:13])[CH:18]=[C:17]([NH:19][C:20]([C:22]4[N:23]([CH3:27])[CH:24]=[CH:25][N:26]=4)=[O:21])[N:16]=3)=[O:29])[N:47]=2)=[O:42])[CH:39]=1)=[O:34]
Reactant: COC(=O)c1cc(NC(=O)c2nc(N)cn2C)cn1C
Reactant: Cn1cc(NC(=O)c2nccn2C)nc1C(=O)O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: COC(=O)c1cc(NC(=O)c2nc(NC(=O)c3nc(NC(=O)c4nccn4C)cn3C)cn2C)cn1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.1 %

Procedure:
Trimethylsilyl triflate (150 μL, 0.81 mmol) was added in a single portion to a mixture of 1-methyl-4-[(1-methyl-1H-imidazole-2-carbonyl)-amino]-1H-imidazole-2-carboxylic acid (200 mg, 0.80 mmol) in anhydrous acetonitrile (8.00 mL). The solution which formed within a few moments was transferred to solid N-(1-chloro-2-methylprop-1-enyl)-N-methyl aminomethylpolystyrene (1.55 mequiv/g, 1.04 g, 1.61 mequiv). After stirring at ambient temperature for 10 minutes, an equal volume of anhydrous CHCl3 (stabilized with amylenes) was added and the mixture was filtered in an inert atmosphere. The resin was washed with an additional 10 mL of anhydrous CHCl3 (stabilized with amylenes), and the combined filtrates containing the 1-methyl-4-[(1-methyl-1H-imidazole-2-carbonyl)-amino]-1H-imidazole-2-carbonyl chloride were added dropwise to a vigorously stirred 2-phase mixture of a solution of 4-[(4-amino-1-methyl-1H-imidazole-2-carbonyl)-amino]-1-methyl-1H-pyrrole-2-carboxylic acid methyl ester (171 mg, 0.62 mmol) in CHCl3 (10 mL), and a solution of Na2CO3 (170 mg, 1.60 mmol) in H2O (5 mL). The resulting reaction mixture was stirred for 5 minutes, and then was diluted with CHCl3 and H2O. The CHCl3 solution was isolated, dried (MgSO4), and concentrated to afford a 59% yield (240 mg) of 1-methyl-4-{[1-methyl-4-({1-methyl-4-[(1-methyl-1H-imidazole-2-carbonyl)-amino]-1H-imidazole-2-carbonyl}-amino)-1H-imidazole-2-carbonyl]-amino}-1H-pyrrole-2-carboxylic acid methyl ester as a very pure off-white solid. Reverse phase HPLC of this material was carried out on an Agilent 1100 system using a Vydac 4.6×250 mm Protein & Peptide C18 column eluted at 1.2 mL/min with a linear gradient of 20% MeCN:80% H2O to 40% MeCN:60% H2O over a 15 minute period. Both solvents contained 0.1% TFA. A single 304 nm HPLC peak eluted at 10.847 minutes. 1H NMR (CD3CN plus TFA): δ 10.90 (s, 1H), 10.71 (s, 1H), 9.49 (s, 1H), 7.85 (s, 1H), 7.76 (s, 1H), 7.65 (m, 2H), 7.46 (d, J=1.8 Hz, 1H), 6.92 (d, J=1.9 Hz, 1H), 4.15 (s, 3H), 4.12 (s, 3H), 4.11 (s, 3H), 3.92 (s, 3H), 3.80 (s, 3H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.O.[OH-].[Cs+].[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([O:17][CH3:18])=[CH:12][C:11]=1[NH:19][C:20]1[C:25]([C:26]#[N:27])=[CH:24][N:23]=[C:22]2[CH:28]=[C:29]([C:31]#[CH:32])[S:30][C:21]=12>CN1CCCC1=O>[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([O:17][CH3:18])=[CH:12][C:11]=1[NH:19][C:20]1[C:25]([C:26]#[N:27])=[CH:24][N:23]=[C:22]2[CH:28]=[C:29](/[CH:31]=[CH:32]/[N:2]3[N:3]=[CH:4][CH:5]=[N:1]3)[S:30][C:21]=12
Reactant: C#Cc1cc2ncc(C#N)c(Nc3cc(OC)c(Cl)cc3Cl)c2s1
Reactant: c1c[nH]nn1
Agent: [Cs+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cc(Nc2c(C#N)cnc3cc(/C=C/n4nccn4)sc23)c(Cl)cc1Cl
Temperature: 120 °C
Yield: 37.6 %

Procedure:
To a mixture of 1,2,3-triazole (50 μL, 0.81 mmol) and cesium hydroxide monohydrate (18 mg, 0.11 mmol) in 1-methyl-2-pyrrolidinone (5 mL) is added slowly 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-ethynylthieno[3,2-b]pyridine-6-carbonitrile (200 mg, 0.54 mmol). The mixture is heated to 120° C. for 12 hours, cooled to room temperature and partitioned between water and ethyl acetate. The organic layer is washed with water, dried over sodium sulfate, and concentrated in vacuo. The residue is purified by flash column chromatography eluting with a gradient of methanol in dichloromethane (0–2%) to provide 90 mg (38%) of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[(E)-2-(2H-1,2,3-triazol-2-yl)vinyl]thieno[3,2-b]pyridine-6-carbonitrile as a yelllow solid, mp 315–316° C.; 1H NMR (DMSO-d6-TFA) δ 3.88 (s, 3H), 7.50 (s, 1H), 7.65 (d, J=14 Hz, 1H), 7.85 (s, 1H), 7.88 (s, 1H), 8.15 (s, 2H), 8.32 (d, J=14 Hz, 1H), 9.01 (s, 1H); MS 443.0 (M+H)+.
Reaction SMILES: [H-].[Na+].C[CH:4]([CH2:8][CH3:9])[CH2:5][CH:6]=[O:7]>CCCCCC.C(COC)OC.COCC>[CH3:4][CH:9]([CH2:5][CH3:6])[CH2:8][CH:4]=[CH:5][C:6]([O:7][CH2:9][CH3:8])=[O:7]
Reactant: CCC(C)CC=O
Agent: CCOC
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: COCCOC
Product: CCOC(=O)C=CCC(C)CC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 122 %

Procedure:
Sodium hydride (60% dispersion, 2.4 g, 65 mmol) was washed with hexane and suspended in dimethoxyethane 60 mL. While cooling in ice water bath triethyl phosphonoacetate was slowly added, calcd. 5 minutes. The reaction was stirred for 15 minutes at 0° C. and a solution of 3-methyl-1-pentanal 11 (6.5 g, 65 mmol) in methoxyethane 20 mL was added. After refluxing overnight, it was concentrated, water and hexane were added, the organic phase was separated, and the aqueous portion discarded. The solution was washed twice with brine and dried on magnesium sulfate. The solvent was evaporated to give 12 (6.75 g, 61%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][C:8]2[O:9][C:10]3[C:17]([CH2:18]N(C)C)=[CH:16][C:15]([CH2:22][CH2:23][CH3:24])=[C:14]([OH:25])[C:11]=3[C:12]=2[CH3:13])=[CH:5][CH:4]=1.[BH4-].[Na+].[Cl-].[NH4+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2[O:9][C:10]3[C:17]([CH3:18])=[CH:16][C:15]([CH2:22][CH2:23][CH3:24])=[C:14]([OH:25])[C:11]=3[C:12]=2[CH3:13])=[CH:26][CH:27]=1
Reactant: CCCc1cc(CN(C)C)c2oc(Cc3ccc(OC)cc3)c(C)c2c1O
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCCc1cc(C)c2oc(Cc3ccc(OC)cc3)c(C)c2c1O
Yield: 91.3 %

Procedure:
To a solution of 2-(p-methoxybenzyl)-3-methyl-4-hydroxy-5-propyl-7-dimethylaminomethylbenzofuran (0.2 gm; 0.54 mmole) in ethanol (5 mL) was added sodium borohydride (0.2 gm, 5.45 mmoles) and the reaction mixture was refluxed for 10 minutes. The reaction mixture was cooled, poured in a saturated solution of ammonium chloride, and extracted with ether. The organic phase was washed with with brine, dried (Na2SO4), and concentrated in vacuo. The residue was chromatographed on silica gel using 20% ethylacetate in hexane as eluent to yield 160 mg (91%) of 2-(p-methoxybenzyl)-3,7-dimethyl-4-hydroxy-5-propylbenzofuran, mp. 102°-104° C.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].[Cl:7][C:8]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12](F)[C:9]=1[CH:10]=O>CN(C)C=O>[Cl:7][C:8]1[C:9]2[CH:10]=[C:2]([C:1]([O:5][CH3:6])=[O:4])[S:3][C:12]=2[CH:13]=[CH:14][C:15]=1[Cl:16]
Reactant: O=Cc1c(F)ccc(Cl)c1Cl
Reactant: COC(=O)CS
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(Cl)c(Cl)ccc2s1

Procedure:
In a similar manner to Example 18, methyl thioglycolate (9.3 ml) was reacted with 2,3-dichloro-6-fluorobenzaldehyde (15.46 g) in dimethylformamide to give methyl 4,5-dichlorobenzo[b]thiophene-2-carboxylate (7.28 g) as an off-white solid which was hydrolysed, chlorinated and reacted with N,O-dimethylhydroxylamine hydrochloride to give 4,5-dichloro-N-methoxy-N-methylbenzo[b]thiophene-2-carboxamide (1.96 g) as a colourless solid. Reaction of this amide with ethylmagnesium bromide gave 1-(4,5-dichlorobenzo[b]thiophen-2-yl)propan-1-one (1.09 g) as an oil which was used without further purification.
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:6][CH2:7][C:8]#[N:9])#[N:2].[H][H]>O1CCOCC1>[NH2:2][CH2:1][CH2:3][CH2:4][N:5]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:6][CH2:7][CH2:8][NH2:9]
Reactant: [H][H]
Reactant: CCCCCCCCCCCCN(CCC#N)CCC#N
Solvent: C1COCCO1
Product: CCCCCCCCCCCCN(CCCN)CCCN
Yield: 103.7 %

Procedure:
19.7 g of N,N-bis(2-cyanoethyl)dodecylamine, 1.97 g of RaneyCo, 80 ml of 1,4-dioxane was charged to an autoclave, and hydrogen addition reaction was carried out by supplying hydrogen at an initial pressure of 8.2 MPa at 120° C. for 2 hours. After removing a catalyst by filtration, the obtained filtrate was concentrated and dried to obtain 21.0 g of a target compound as pale red oily product. The same procedure was carried out to obtain a total amount of 40.8 g of the target compound as a pale red oily product.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].[CH2:8](OC(OCC)OCC)[CH3:9]>C(O)C>[CH2:8]([O:6][C:5](=[O:7])[C@@H:2]([CH2:3][SH:4])[NH2:1])[CH3:9]
Reactant: CCOC(OCC)OCC
Reactant: N[C@H](CS)C(=O)O
Solvent: CCO
Product: CCOC(=O)[C@H](N)CS
Temperature: 70 °C
Yield: 109.6 %

Procedure:
To a suspension of D-cysteine 1.5 hydrate hydrochloride (Q-1, Scheme Q where RQ-1 and RQ-1 are equal to hydrogen, RQ-3 is hydrogen and stereochemistry is (S)) (5 g, 27.1 mmol) in absolute ethyl alcohol (50 mL) was added triethylorthoformate (13.5 mL, 81.2 mmol) at ambient temperature. A stream of anhydrous HCl gas was bubbled through the solution for 30 min. The stream of anhydrous HCl gas was maintained as the mixture heated to 70° C. for 2 h. The reaction mixture was concentrated in vacuo and the resulting residue triturated with diethyl ether to afford D-cysteine ethyl ester (4.43 g) as a white solid which was used without further purification. Physical data as follows: 1H NMR (300 MHz, D2O) 4.36 (1H), 4.27 (2H), 3.12 (2H), 1.25 (3H); MS (ESI+) for C5H11NO2S m/z 150.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=O)[CH:5]=1.[Cl-].[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:19][NH2:20].CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7](=[O:9])[NH:20][CH2:19][C:18]2[CH:21]=[CH:22][C:23]([Cl:24])=[C:16]([Cl:15])[CH:17]=2)[CH:5]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)c1cccc(C(=O)O)c1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(C(=O)NCc2ccc(Cl)c(Cl)c2)c1
Temperature: 25 °C

Procedure:
Starting material (18(e)) was prepared as follows. A suspension of isophthalic acid monomethyl ester (18(a)), (2.65 g, 14.7 mmol) in CH2Cl2 (100 mL) and DMF (10 drops) was treated with oxallyl chloride (2.6 ml, 29.8 mmol) at 0° under argon. The reaction mixture was allowed to warm to room temperature over 18 h. The resulting solution was concentrated and azeotroped with toluene to give a crystalline yellow solid. This was then redissolved in CH2Cl2 (100 mL) and added dropwise to a stirred solution of 3,4-dichlorobenzylamine (2.6 g, 14.7 mmol) and Et3N (5 mL, 35.9 mmol) in CH2Cl2 (100 mL) at 0° under argon. The resulting solution was allowed to warm to room temperature over 4 hours, washed with 1N HCl(50 mL), saturated NaHCO3 (aq) (50 mL), dried over MgSO4, filtered and concentrated to an orange oil. This was then purified by flash chromatography on 9385 SiO2 eluting on a gradient of 25-50% EtOAc/i-Hexane to yield 3-(3,4-dichlorobenzyl-carbamoyl)-benzoic acid methyl ester (18(b)) as a pale yellow oil: 3.99 g (80%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:18])=[C:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:32][C:33]#[N:34]>CC(C)=O>[CH3:1][N:2]1[C:10]2[C:5](=[C:6]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:32][C:33]#[N:34])=[CH:13][CH:12]=3)[CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:18])=[C:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1c(-c2ccccc2)n(C)c2cccc(-c3ccc(O)cc3)c12
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1c(-c2ccccc2)n(C)c2cccc(-c3ccc(OCC#N)cc3)c12

Procedure:
The desired product was prepared using a procedure similar to step 5 of example 3. Thus, 4-(1,3-dimethyl-2-phenyl-1H-indol-4-yl)-phenol (0.300 g, 0.957 mmol) was reacted with K2CO3 (0.159 g, 1.148 mmol) and bromoacetonitrile (0.134 g, 1.148 mmol) in acetone (5 ml) to give the product (0.311 g, 0.882 mmol, 92%) as a viscous oil. 1H NMR (DMSO-d6) δ 1.66 (s, 3H), 3.55 (s, 3H), 5.17 (s, 2H), 6.82 (dd, J=0.9, 7.2 Hz, 1H), 7.08 (d, J=8.9 Hz, 2H), 7.16 (t, J=7.2 Hz, 1H), 7.34-7.43 (m, 6H), 7.48 (t, J=7.0 Hz, 2H); [ESI(+)], m/z 353 (M+H)+.