Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC(C)(C)C.CC(C)[C@@H](C1C=CC=CC=1)CN>O>[C:1]([C:9]1[CH:10]=[C:11]([C@H:15]([CH3:19])[C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C(=O)O)c1cccc(C(=O)c2ccccc2)c1
Agent: CC(C)[C@H](CN)c1ccccc1
Solvent: O
Solvent: COC(C)(C)C
Product: C[C@H](C(=O)O)c1cccc(C(=O)c2ccccc2)c1
Temperature: 10 °C
Yield: 37.6 %

Procedure:
To (±)-2-(3-benzoylphenyl)propionic acid (1200 g, 4.719 mol) were added methyl-t-butyl ether (hereinafter abbreviated to "MTBE") (4.8 L) and water (600 g, water/KET=0.50) and the mixture was dissolved with heating. Then, (S)-(+)-3-methyl-2-phenylbutylamine (388 g, 2.377 mol) was added dropwise with stirring at 50° C. to 55° C. This reaction solution was cooled to precipitate a crystal and then reheated from 35° C. to 50° C. This solution was again cooled and then reheated from 40° C. to 45° C. This solution was cooled slowly to 10° C. and stirred at 5° C. to 10° C. for one hour. Then, the crystal precipitated was filtered, and the filter cake was washed three times with cold MTBE (1 L) and dried. In this manner, a diastereomer salt (741 g, 1.775 mol) of (S)-(+)-2-(3-benzoylphenyl)propionic acid with (S)-(+)-3-methyl-2-phenylbutylamine was obtained. The yield of the product based on (S)-(+)-2-(3-benzoylphenyl)propionic acid contained in the starting material was 75.2% and the optical purity was 99.1% e.e.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:7]([NH2:32])=[CH:8][C:9]([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([CH:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].Cl.O[CH2:35][C:36](=N)[O:37][CH2:38][CH3:39].C(O)(=[O:43])C>>[CH2:1]([N:5]1[C:6]2[CH:11]=[CH:10][C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([CH:19]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:15][CH2:14]3)=[CH:8][C:7]=2[N:32]=[C:39]1[CH2:38][O:37][C:36](=[O:43])[CH3:35])[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)O
Reactant: CCOC(=N)CO
Reactant: CCCCNc1ccc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1N
Agent: Cl
Product: CCCCn1c(COC(C)=O)nc2cc(CN3CCN(C(c4ccccc4)c4ccccc4)CC3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.8 %

Procedure:
A mixture of 12.9 parts of N1 -butyl-4-[4(diphenylmethyl)-1-piperazinylmethyl]-1,2-benzenediamine, 4.6 parts of ethyl 2-hydroxyethanimidate hydrochloride and 100 parts of acetic acid is stirred overnight at room temperature. The whole is heated to reflux and stirring is continued for 3 hours at reflux temperature. The solvent is evaporated in vacuo and the residue is stirred in water. The free base is liberated in the conventional manner with ammonium hydroxide and extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The fractions with the highest Rf-value are collected and the eluent is evaporated. The residue is crystallized from 21 parts of 2,2'-oxybispropane. The product is filtered off, washed with 2,2'-oxybispropane and dried, yielding 3.5 parts (22.8%) of {1-butyl-5-[4-(diphenylmethyl)-1-piperazinylmethyl]-1H-benzimidazol-2-ylmethyl}acetate; mp. 151.2° C.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][N:10]2[C:15]3=[N:16][C:17]([Sn](C)(C)C)=[CH:18][N:19]=[C:14]3[NH:13][CH2:12][C:11]2=[O:24])[CH2:5][CH2:4]1.Br[C:26]1[C:27]([CH3:34])=[CH:28][C:29]([C:32]#[N:33])=[N:30][CH:31]=1.C(N(CC)CC)C.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=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.[Pd].[Pd].CN(C)C=O>[CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][N:10]2[C:11](=[O:24])[CH2:12][NH:13][C:14]3[N:19]=[CH:18][C:17]([C:26]4[C:27]([CH3:34])=[CH:28][C:29]([C:32]#[N:33])=[N:30][CH:31]=4)=[N:16][C:15]2=3)[CH2:5][CH2:4]1
Reactant: Cc1cc(C#N)ncc1Br
Reactant: CO[C@H]1CC[C@H](CN2C(=O)CNc3ncc([Sn](C)(C)C)nc32)CC1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CO[C@H]1CC[C@H](CN2C(=O)CNc3ncc(-c4cnc(C#N)cc4C)nc32)CC1
Temperature: 100 °C

Procedure:
1-(((trans)-4-Methoxycyclohexyl)methyl)-7-(trimethylstannyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (0.721 g, 1.64 mmol), 5-bromo-4-methylpicolinonitrile (0.323 g, 1.64 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.150 g, 0.164 mmol), triethylamine (0.687 mL, 4.93 mmol), tri-ortho-toylphosphine (0.100 g, 0.328 mmol) and dimethylformamide (8 mL) were combined in a sealed reaction vessel. Nitrogen was bubbled through the reaction for 5 min and reaction was heated at 100° C. for 3 h. Reaction is filtered, concentrated and purified by silica gel column chromatography (0-80% ethyl acetate in hexanes). Fractions were combined and concentrated to afford the crude title compound used directly for next step (0.607 g, 1.55 mmol, 94% yield). MS (ESI) m/z 393.5 [M+1]+.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([OH:11])=[C:6]([CH3:12])[CH:5]=1.Br[CH2:14][C:15]([OH:17])=[O:16]>C1COCC1>[Br:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([O:11][CH2:14][C:15]([OH:17])=[O:16])=[C:6]([CH3:12])[CH:5]=1
Reactant: Cc1cc(Br)cc(C)c1O
Reactant: O=C(O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Br)cc(C)c1OCC(=O)O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 85.4 %

Procedure:
To a suspension of sodium hydride (60%, 437 mg, 10.9 mmol) in THF (10 mL) at rt, was added a solution of 4-bromo-2,6-dimethylphenol (1.00 g, 4.97 mmol) in THF (10 mL), over 5 min. The reddish suspension was stirred at rt for 10 min, then a solution of bromoacetic acid (691 mg, 4.97 mmol) in 5 mL THF was added. The suspension was stirred at rt for 20 h. The volatile solvent was evaporated in vacuo, then the mixture was diluted with 20 mL H2O. The pH was adjusted to 7 with 1N HCl, then the aqueous phase was extracted with Et2O (2×). The aqueous phase was acidified to pH=2 with 1N HCl, then was extracted with EtOAc (2×). The combined organic extract washed with brine, dried (Na2SO4) and concentrated to afford 1.10 g (85%) of 79A as a colorless solid. MS (ESI) m/z 259.0 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:9]=[C:8]([OH:10])[CH:7]=[C:6]([CH3:11])[N:5]=1)[CH3:2].[CH:12](=O)[CH2:13][CH2:14][CH3:15].[H][H]>[Pd].C(O)CCC>[CH2:12]([C:7]1[C:8]([OH:10])=[N:9][C:4]([NH:3][CH2:1][CH3:2])=[N:5][C:6]=1[CH3:11])[CH2:13][CH2:14][CH3:15]
Reactant: CCNc1nc(C)cc(O)n1
Reactant: [H][H]
Reactant: CCCC=O
Agent: [Pd]
Solvent: CCCCO
Product: CCCCc1c(C)nc(NCC)nc1O
Temperature: 100 °C
Reaction time: 18 h

Procedure:
76.25 Parts of 2-ethylamino-4-hydroxy-6-methylpyrimidine, 41 parts of n-butyraldehyde and 7 parts of a 50% aqueous paste of 3% palladium on carbon catalyst are stirred in 400 parts of n-butanol in a closed container. Hydrogen is passed into the reaction vessel to a pressure of 3 bar and the temperature is raised to 100° C. The reaction mixture is stirred under a hydrogen pressure of 3 bar and a temperature of 95°- 100° C for 18 hours, and then cooled and the palladium on carbon catalyst removed by filtration. The filtrates are distilled under reduced pressure to rermove butanol. The residue is stirred in 200 parts of water and the pH adjusted to 12 with sodium hydroxide solution. The suspension is filtered and the filtrates adjusted to pH 6.9 with hydrochloric acid. The suspension is filtered and the filter cake dried to yield 37.0 parts of crude 5-butyl-2-ethylamino-4-hydroxy-6-methylpyrimidine.
Reaction SMILES: Cl[CH:2]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.[CH2:15]([SH:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[H-].[Na+]>O1CCCC1>[CH2:15]([S:23][CH:2]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCS
Reactant: CCCCCC(Cl)CCn1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCSC(CCCCC)CCn1ccnc1

Procedure:
500 Mg. of 1-(3-chlorooctyl)imidazole in 10 ml. tetrahydrofuran was added to a fully reacted mixture of 750 mg. of n-octylmercaptan and 200 mg. of 56% sodium hydride dispersion in mineral oil in 30 ml. of tetrahydrofuran. After stirring under reflux for 12 hours the solvent was evaporated under vacuum and 150 ml. of ether was added. The resulting mixture was washed twice with water and the ethereal solution dried and evaporated. The residue was chromatographed on silica gel, eluting with 20% acetone/dichloromethane to afford 1-(3-octylthiooctyl)imidazole, as an oil. This material was converted to the oxalate salt by treatment of an ethereal solution with oxalic acid in ether until precipitation was complete, which salt was recrystallized from ethyl acetate as snow-white microcrystals, m.p. 105°-108° C.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([NH:9][C:10]([NH:12][C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]3=[N:17][CH:18]=2)=[O:11])[CH2:4]1.[CH3:30][CH:31]([CH3:37])[CH2:32][S:33](Cl)(=[O:35])=[O:34]>>[CH3:30][CH:31]([CH3:37])[CH2:32][S:33]([N:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([NH:9][C:10]([NH:12][C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]3=[N:17][CH:18]=2)=[O:11])[CH2:4]1)(=[O:35])=[O:34]
Reactant: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NC3CCCNC3)cnc21
Reactant: CC(C)CS(=O)(=O)Cl
Agent: Cl
Product: CC(C)CS(=O)(=O)N1CCC[C@@H](NC(=O)Nc2cnc3c(ccn3COCC[Si](C)(C)C)n2)C1

Procedure:
1-[(R)-1-(2-Methyl-propane-1-sulfonyl)-piperidin-3-yl]-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea was prepared in the same manner from 1-piperidin-3-yl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea dihydrochloride and 2-methyl-propane-1-sulfonyl chloride.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1([CH:24]([CH3:26])[CH3:25])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([CH3:22])[C:14]1=[O:23].[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:39]=[C:40]([O:44][CH3:45])[C:41]=1[O:42][CH3:43])[CH2:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[CH:24]([C:13]1([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:36]2[CH2:35][CH2:34][N:33]([CH2:32][C:31]3[CH:39]=[C:40]([O:44][CH3:45])[C:41]([O:42][CH3:43])=[C:29]([O:28][CH3:27])[CH:30]=3)[CH2:38][CH2:37]2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([CH3:22])[C:14]1=[O:23])([CH3:26])[CH3:25]
Reactant: COc1cc(CN2CCNCC2)cc(OC)c1OC
Reactant: CC(C)C1(c2ccccc2OCCCCBr)C(=O)N(C)c2ccccc21
Product: COc1cc(CN2CCN(CCCCOc3ccccc3C3(C(C)C)C(=O)N(C)c4ccccc43)CC2)cc(OC)c1OC

Procedure:
Preparation in analogy to Example 3(d) from 3-[2-(4-bromo butoxy)phenyl]-3-isopropyl-1-methylindolin-2-one and 3,4,5-trimethoxybenzylpiperazine
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].[C:10]([N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]>>[C:13]([O:12][C:10]([N:17]1[CH2:22][CH2:21][CH:20]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=2)[CH2:19][CH2:18]1)=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NCc1cccc(Cl)c1
Product: CC(C)(C)OC(=O)N1CCC(NCc2cccc(Cl)c2)CC1
Yield: 89.6 %

Procedure:
Using general procedure A, 3-chlorobenzylamine (0.27 mL, 2.2 mmol) and 1-Boc-4-piperidone (484 mg, 2.4 mmol) afforded 4-(3-chloro-benzylamino)-piperidine-1-carboxylic acid tert-butyl ester as a colourless oil (640 mg, 89%).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].C([O-])(O)=O.[Na+].[CH3:14][O:15][C:16](Cl)=[O:17].Cl>O1CCCC1.O>[CH3:14][O:15][C:16]([NH:1][C@@H:2]([CH:3]([CH3:5])[CH3:4])[C:6]([OH:8])=[O:7])=[O:17]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: COC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
L-Valine (S) (0.213 mol) was dissolved in anhydrous tetrahydrofuran (645 mL) with NaHCO3 (0.640 mol) in water (645 mL). Methylchloroformate (0.235 mol) was added and the reaction mixture was stirred at room temperature overnight. The mixture was acidified to pH 3 with 1N HCl. The aqueous layer was extracted with EtOAc. The organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give compound 1 as a white solid in 98% yield. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 0.93 (d, J=7.00 Hz, 3H), 1.00 (d, J=7.00 Hz, 3H), 2.23 (m, 1H), 3.70 (s, 3H), 4.33 (m, 1H), 5.26 (brs, 1H), 8.50 (brs, 1H); and MS (ESI, EI+) m/z=176 (MH+).
Reaction SMILES: Br[CH:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:14][C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1>>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([S:21][C:18]1[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH3:7]
Reactant: CCCCCCC(Br)C(=O)OCC
Reactant: Fc1ccc(S)cc1
Product: CCCCCCC(Sc1ccc(F)cc1)C(=O)OCC

Procedure:
2-(4-Fluoro-phenylsulfanyl)-octanoic acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from ethyl 2-bromooctanoate (6.47 g, 24.7 mmol) and 4-fluorothiophenol (3 g, 23.4 mmol). Yield: 6.31 g (90%); clear oil; MS: 299 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=[N:12][S@@:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])#[N:2].[BH4-].[Na+]>C1COCC1>[C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C@H:7]2[NH:12][S@@:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])#[N:2]
Reactant: CC(C)(C)[S@@](=O)N=C1CCc2c(C#N)cccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[S@@](=O)N[C@@H]1CCc2c(C#N)cccc21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a flask containing the crude suspension of (R)-N-(4-cyano-2,3-dihydro-1H-indene-1-ylidene)-2-methylpropane-2-sulfinamide INT-48 under N2 was added THF (1.0 L) and the reaction mixture cooled to −78° C. Sodium borohydride (40.9 g, 1.08 mol) was added portion-wise over 30 mins. (The internal temperature did not rise during the addition). The reaction mixture was stirred at −78° C. for 30 mins, half out of the bath for 30 mins, then warmed to 0° C. over 1 h. The 0° C. reaction mixture was placed in an ice bath and quenched with brine (100 mL) followed by saturated sodium potassium tartrate (420 mL) and the Ti salts precipitated. The reaction mixture was diluted with EA (1.5 L) and stirred at room temperature overnight. The organic layers were decanted and washed successively with saturated NH4Cl, water, and brine. The organic layers were dried over MgSO4 and filtered through a pad of MgSO4. The filtrate was concentrated to produce 52.9 g of crude (R)-N-((R)-4-cyano-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide INT-49 as a brown oil, which was used directly in the next step. LCMS-ESI (m/z) calculated for C14H18N2OS: 262.3; found 263.1 [M+H]+, tR=2.99 min. 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J=7.7, 1H), 7.56 (t, J=6.8, 1H), 7.36 (t, J=7.7, 1H), 4.97 (q, J=7.5, 1H), 3.50 (d, J=7.6, 1H), 3.22 (ddd, J=16.9, 8.8, 3.9, 1H), 3.01 (dt, J=22.4, 6.9, 1H), 2.70-2.53 (m, 1H), 2.15-1.95 (m, 1H), 1.33-1.20 (m, 9H).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([Cl:15])=[CH:9][C:8]=1[Cl:16])=[O:5])#[N:2].[Br:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[O:25][CH2:26][CH3:27])[NH2:21].[CH2:28](OC(OCC)OCC)C>C(O)(C)C>[Br:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[O:25][CH2:26][CH3:27])[NH:21][CH:28]=[C:3]([C:1]#[N:2])[C:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([Cl:15])=[CH:9][C:8]=1[Cl:16])=[O:5]
Reactant: CCOc1ccc(N)cc1Br
Reactant: CCOC(OCC)OCC
Reactant: COc1cc(NC(=O)CC#N)c(Cl)cc1Cl
Solvent: CC(C)O
Product: CCOc1ccc(NC=C(C#N)C(=O)Nc2cc(OC)c(Cl)cc2Cl)cc1Br
Yield: 50.7 %

Procedure:
To a suspension of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)acetamide (715 mg, 2.74 mmol) in 50 mL of iso-propanol was added 3-bromo-4-ethoxyaniline (586 mg, 2.71 mmol). This mixture was heated to reflux and triethylorthoformate (2.7 mL, 16.2 mmol) was added dropwise. The reaction mixture was heated at reflux overnight. The mixture was filtered while still warm and the collected white solid was washed with iso-propanol to give 666 mg of 3-bromo-4-ethoxyanilino-N-(2,4-dichloro-5-methoxyphenyl)-2-cyano-2-propenamide, mp >250° C.; MS (ES) m/z 482.0, 484.0, 486.0 (M−H)−
Reaction SMILES: [N:1]1([CH:6]([C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH3:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19](Cl)(=[O:22])[CH2:20][CH3:21]>N1C=CC=CC=1.O1CCCC1>[N:1]1([CH:6]([C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:19](=[O:22])[CH2:20][CH3:21])[CH3:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(c1cccc(OCCCN)c1)N1CCCC1
Reactant: CCC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCC(=O)NCCCOc1cccc(C(C)N2CCCC2)c1
Yield: 71.3 %

Procedure:
211.8 mg of 3-[3-[1-(1-pyrrolidinyl)ethyl]phenoxy]propylamine was dissolved in 2 ml of dry pyridine, and the solution was stirred under ice cooling. A solution of 87 mg of propionyl chloride in 2 ml of dry tetrahydrofuran was added dropwise in small portions. After the addition, the reaction temperature was adjusted to room temperature, and the mixturwe was stirred for 2 hours. The solvent was distilled off, and 10 ml of water was added. Furthermore, 300 mg of potassium carbonate was added. The precipitated oily product was extracted with 30 ml of chloroform. The extract was dried over anhydrous potassium carbonate, and the solvent was distilled off. The residue was purified by TLC (developing solvent: chloroform/methanol=9/l) to afford 185 mg of N-[3-[3-[1-(1-pyrrolidinyl)ethyl]phenoxy]propyl] propionamide as an oil.
Reaction SMILES: [C:1]([C:3](=[C:7](SC)SC)[C:4]([NH2:6])=[O:5])#[N:2].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=1.O.[NH2:22][NH2:23]>CCO>[NH2:2][C:1]1[NH:23][N:22]=[C:7]([NH:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH3:12])[CH:15]=2)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: CSC(SC)=C(C#N)C(N)=O
Reactant: NN
Reactant: COc1cccc(N)c1
Solvent: O
Solvent: CCO
Product: COc1cccc(Nc2n[nH]c(N)c2C(N)=O)c1
Temperature: 75 °C

Procedure:
Dissolved 0.500 g 2-cyano-3,3-bis(methylthio)acrylamide in 15 mL EtOH and added m-Anisidine (1.0 eq.). Stirred reaction at 75° C. until starting amide was absent by HPLC. Once complete (18 hrs), reaction was brought to room temperature and filtered to obtain a light yellow powder as product. Product was allowed to dry under vacuum for 1 hr. Product was then suspended in 10 mL EtOH and hydrazine hydrate (1 eq.) was added dropwise. Reaction was heated at 75° C. until intermediate was absent (HPLC). Once intermediate was absent (18 hrs), reaction was brought to room temperature and filtered to obtain 5-amino-3-((3-methoxyphenyl)amino)-1H-pyrazole-4-carboxamide as a yellow powder. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[Cl:5][Ti:6](Cl)(Cl)Cl.O.C(=O)(O)[O-].[Na+]>>[Cl-:5].[Ti+4:6].[Cl-:5].[Cl-:5].[Cl-:5].[NH2:1][C:2]([NH2:4])=[O:3]
Reactant: Cl[Ti](Cl)(Cl)Cl
Agent: NC(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: [Cl-]
Product: [Ti+4]

Procedure:
600 Gms. of urea (11.0 moles) and 189.7 gms. (1.0 moles) of TiCl4 are mixed at room temperature. To this mixture is added 457.5 gms. of water (25.4 moles) and the reaction mixture stirred at room temperature for 15 minutes. This reaction mixture is then adjusted to a pH of 1.5 by the addition of sodium bicarbonate.
Reaction SMILES: [OH:1][N:2]=[C:3]1[CH:8]=[CH:7][C:6](=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:10]#[N:11])[CH:5]=[CH:4]1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29].O>C1COCC1>[CH3:27][S:28]([O:1][N:2]=[C:3]1[CH:8]=[CH:7][C:6](=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:10]#[N:11])[CH:5]=[CH:4]1)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(C(C#N)=C2C=CC(=NO)C=C2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(C#N)=C2C=CC(=NOS(C)(=O)=O)C=C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.9 %

Procedure:
15 g (59 mmol) of (4-Hydroxyimino-cyclohexa-2,5-dienylidene)-(4-methoxyphenyl)-acetonitrile are dissolved in 200 ml of THF and cooled in an ice bath. After adding 12.4 ml (89 mmol) of triethylamine to the solution, 5.03 ml (65 mmol) of methanesulfonyl chloride are added dropwise, keeping the temperature below 5° C. The reaction mixture is gradually warmed to room temperature, and stirred for 1 hr. The reaction mixture is poured into 300 ml of water, and extracted with ethyl acetate. The organic phase is washed with hydrochloric acid solution, water, and sodium chloride solution. The organic phase is dried over MgSO4, the solvent is distilled off, and the residue is purified by recrystallization from ethyl acetate. 6.8 g (35%) of (4-Methylsulfonyloxyimino-cyclohexa-2,5-dienylidene)-(4-methoxyphenyl)-acetonitrile are obtained in the form of orange crystals having a melting point of 161-162l° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][CH2:8][N:7]([CH2:13][CH2:14][O:15][CH3:16])[C:6]=2[N:17]=1.[CH3:18]N(C)C(=O)C.IC.[H-].[Na+]>O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:18])[C:10](=[O:12])[CH2:9][CH2:8][N:7]([CH2:13][CH2:14][O:15][CH3:16])[C:6]=2[N:17]=1
Reactant: COCCN1CCC(=O)Nc2cnc(Cl)nc21
Reactant: CC(=O)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COCCN1CCC(=O)N(C)c2cnc(Cl)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.102 g (0.0004 mole) of 2-chloro-9-(2-methoxy-ethyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-40), 1 mL of N,N-dimethylacetamide and 0.037 mL (0.0006 mole) of iodomethane at 0 degrees was added 0.024 g (0.0006 mole) of 60% sodium hydride in oil. The mixture was stirred at ambient temperature for 1 hour, then 20 mL of water was added. The precipitate was collected by filtration to give 0.087 g of 2-chloro-9-(2-methoxy-ethyl)-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-40) as an yellow solid.
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].Br[CH2:9][CH2:10][CH2:11][Cl:12].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C1(C)C=CC=CC=1>[Cl:12][CH2:11][CH2:10][CH2:9][S:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)CS
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)CSCCCCl
Temperature: 25 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
A mixture of 2.00 g of ethyl mercaptoacetate, 3.13 g of 1-bromo-3-chloropropane, 2.29 g of anhydrous potassium carbonate and 10 ml of N,N-dimethylformamide was stirred at room temperature for 3 hours. The reaction mixture was diluted with toluene and insoluble matters were filtered off. The filtrate was washed with an aqueous sodium hydroxide solution and water, in this sequence After drying over anhydrous magnesium sulfate, the solvent was distilled off. The residue was applied to silica gel column chromatography. Elution with a solvent mixture of hexane-ethyl acetate (15:1) gave 2.65 g of oily ethyl [(3-chloropropyl)thio]acetate.