Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3][CH2:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[NH2:42][C@H:43]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:44][CH2:45][CH2:46][CH2:47][NH:48][C:49]([O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:50]>ClCCCl>[O:50]=[C:49]([NH:48][CH2:47][CH2:46][CH2:45][CH2:44][C@@H:43]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[NH:42][C:24](=[O:26])[NH:1][C@H:2]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3][CH2:4][C:5]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:14])[O:51][CH2:52][C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1
Reactant: CC(C)(C)OC(=O)[C@@H](N)CCCCNC(=O)OCc1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)[C@@H](N)CCC(=O)OCc1ccccc1
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 2 h
Yield: 229.5 %

Procedure:
To a solution of L-Glu(OBn)-OtBu hydrochloride (3.13 mg, 9.49 mmol) and triphosgene (923 mg, 3.13 mmol) in DCE (70 mL) cooled to −78° C. was added triethylamine (2.80 mL) under nitrogen. After stirring at −78° C. for 2 h, a solution of L-Lys(Z)-OtBu (3.88 g, 10.40 mmol) and TEA (1.5 mL) in DCE (10 mL) was added. The mixture was allowed to come to room temperature over a period of 1 h and stirred at room temperature overnight. The reaction was quenched with 1N HCl, and extracted with DCM. The organic layer was dried and concentrated under reduced pressure and the residue was purified utilizing a Biotage SP4 to afford (9S,13S)-15-benzyl 13,9-di-tert-butyl 3,11-dioxo-1-phenyl-2-oxa-4,10,12-triazapentadecane-9,13,15-tricarboxylate as a colorless oil (4.71 g, 76%). 1H NMR (400 MHz, CDCl3) δ 7.34-7.29 (m, 10H), 5.13-5.04 (m, 6H), 4.97 (brs, 1H), 4.38-4.28 (m, 2H), 3.18-3.14 (m, 2H), 2.50-2.35 (m, 2H), 2.19-2.10 (m, 1H), 1.94-1.85 (m, 1H), 1.79-1.72 (m, 1H), 1.58-1.33 (m, 21H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]2[O:13][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1>O.C(OCC)C>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C@@H:11]2[CH2:12][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][C@H:10]2[OH:13])=[CH:17][CH:16]=1
Reactant: c1ccc(CN2CC3OC3C2)cc1
Reactant: Oc1ccc(Cl)cc1
Solvent: CCOCC
Solvent: O
Product: O[C@@H]1CN(Cc2ccccc2)C[C@H]1Oc1ccc(Cl)cc1

Procedure:
A mixture of 12.3 g. of 1-benzyl-3,4-epoxypyrrolidine, 18.0 g. of p-chlorophenol and 3 drops of water was heated at 120° C. under nitrogen gas for 20 hr. The mixture was cooled and dissolved in 100 ml. diethyl ether. The ethereal solution was extracted with 2×50 ml. 5% sodium hydroxide and then washed with water. After being dried with anhydrous sodium sulfate, the solvent was evaporated and the residue weighed 14.3 g. Two crystallizations from cyclohexane gave 4.7 g. (29%) of analytically pure product which melted at 101°-104° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([O:22][CH3:23])=[O:21]>CC(=O)CC>[CH3:23][O:22][C:20](=[O:21])[CH2:19][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1
Reactant: COC(=O)CBr
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)COc1cccc(C(F)(F)F)c1

Procedure:
A mixture of 3-trifluoromethyl-phenol (5.000 g; 30.843 mmol), potassium carbonate (5.328 g; 38.554 mmol), and methyl bromoacetate (3.54 ml; 38.554 mmol) in butanone (210 ml) was heated at reflux for 3 h. Filtration, concentration to dryness under reduced pressure, and purification by FC (heptane/EA, 4/1) afforded (3-trifluoromethyl-phenoxy)-acetic acid methyl ester as a pale yellow oil (7.220 g; 99%). LC-MS: tR=0.95 min.; [M+H]+: no ionisation.
Reaction SMILES: C1(=O)CCCCC1.[H][H].[C:10]([O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)(=[O:12])[CH3:11]>C(O)(=O)C>[C:10]([O:13][C:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)OC1CCCCC1
Reactant: [H][H]
Solvent: CC(=O)O
Solvent: O=C1CCCCC1
Product: CC(=O)OC1=CCCCC1
Reaction time: 1.58 h

Procedure:
Acetic acid in an amount of 15.1 g. was reacted with 6.1 g. cyclohexanone over the catalyst (0.5 g.) described in Example 1. The reaction started at room temperature (25°C.) in the presence of hydrogen and was stopped after 95 minutes, the temperature reaching a high of 84°C. by application of heat. Cyclohexyl acetate was identified as a reaction product by VPC analysis. This reaction in the presence of Amberlyst-15 resin gives a small amount of 1-acetoxycyclohexene; with conventional platinum-on-alumina catalyst it gives cyclohexanol; and with a loose physical mixture of Amberlyst-15 resin and the conventional platinum-on-alumina, the product is cyclohexanol. By "loose" physical mixture is meant a slurry of the type described in Example 2.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])[C:8]([CH2:20][NH:21][CH3:22])=[CH:7]2.Cl[C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[N:26]=[CH:27][N:28]2[CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1>CCO>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])[C:8]([CH2:20][N:21]([CH3:22])[C:24]1[N:32]=[CH:31][N:30]=[C:29]3[C:25]=1[N:26]=[CH:27][N:28]3[CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1)=[CH:7]2
Reactant: CNCc1cc2cccc(C)c2c(=O)n1-c1ccccc1C
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCO
Product: Cc1ccccc1-n1c(CN(C)c2ncnc3c2ncn3C2CCCCO2)cc2cccc(C)c2c1=O
Temperature: 25 °C
Yield: 50.5 %

Procedure:
8-Methyl-3-((methylamino)methyl)-2-o-tolylisoquinolin-1(2H)-one (233 mg, 0.8 mmol) (4001) and 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (4002) (238 mg, 1.0 mmol) were dissolved in EtOH (50 mL) and the resulting mixture was stirred at reflux for 2 h. The mixture was allowed to cool to RT, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (2-20% MeOH/DCM) to afford the product, 8-Methyl-3-((methyl(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)amino)methyl)-2-o-tolylisoquinolin-1(2H)-one (4003) (200 mg, 51% yield) as a slight yellow solid.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[S:10][C:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:8]([CH3:26])[NH:7][C:6]1=[O:27])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37]Cl.[C:40]([OH:47])(=[O:46])/[CH:41]=[CH:42]/[C:43]([OH:45])=[O:44]>C(OCC)(=O)C.O.CC(C)=O>[C:40]([OH:47])(=[O:46])/[CH:41]=[CH:42]/[C:43]([OH:45])=[O:44].[C:1]([O:4][C@H:5]1[C@@H:11]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[S:10][C:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:8]([CH3:26])[N:7]([CH2:37][CH2:36][N:35]([CH3:39])[CH3:34])[C:6]1=[O:27])(=[O:3])[CH3:2]
Reactant: CN(C)CCCl
Reactant: COc1ccc([C@H]2SC(c3ccccc3)=C(C)NC(=O)[C@H]2OC(C)=O)cc1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1ccc([C@H]2SC(c3ccccc3)=C(C)N(CCN(C)C)C(=O)[C@H]2OC(C)=O)cc1
Temperature: 25 °C
Yield: 43.8 %

Procedure:
A mixture of 1.7 g (0.0044 mol) of cis-rac.-6-(acetyloxy)-6,7-dihydro-7-(4-methoxyphenyl)-3-methyl-2-phenyl-1,4-thiazepin-5(4H)-one, 0.7 g (0.005 mol) of powdered potassium carbonate and 0.6 g (0.0049 mol) of 2-dimethylaminoethyl chloride in 30 ml of ethyl acetate was stirred at reflux for 2 hours, then twice an additional 0.2 g of dimethylaminoethyl chloride was added at 2 hour intervals. The mixture was heated at reflux for a total of 12 hours, then cooled to room temperature and diluted with water. The organic solution was separated, washed with brine then dried (MgSO4) and the solvent was removed under reduced pressure. The residue was dissolved in acetone and passed through a 10 g silica gel pad which was washed with acetone (12×30 ml). The solvent was evaporated to give 1.8 g (0.039 mol) of crude base which was dissolved in acetone and 0.5 g (0.04 mol) of fumaric acid was added. The resulting crystals were collected to give 1.1 g (44%) cis-rac.-6-(acetyloxy)-6,7-dihydro-7-(4-methoxyphenyl)-3-methyl-4-[2-(dimethylamino)ethyl]-2-phenyl-1,4-thiazepin-5(4H)-one (E)-2-butenedioate, mp 176°-177°.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].[CH3:8][O:9][C:10]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:11]=1[CH:12]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:8][O:9][C:10]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:11]=1[CH2:12][NH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:7])[CH3:1]
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: CN(C)CCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CNCCCN(C)C)c(OC)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 95.3 %

Procedure:
A mixture of 3-dimethylaminopropylamine (3.06 g), 2,4-dimethoxybenzaldehyde (6.0 g) and sodium triacetoxyborohydride (9.54 g) in methanol (20 mL) was stirred at room temperature for 10 hours. The mixture was concentrated under vacuum and the residue was dissolved in ethyl acetate and washed with water and brine, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness to give N-(2,4-dimethoxybenzyl)-N-(3-dimethylaminopropyl)amine (7.2 g) as a brown oil which was used directly without further characterisation.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:17])=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([OH:16])=[O:15])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.N([O-])=O.[Na+].S(=O)(=O)(O)[NH2:24].[CH3:28][C:29]1[CH:30]=[C:31]([N:36]2[C:40]([OH:41])=[CH:39][C:38]([CH3:42])=[N:37]2)[CH:32]=[CH:33][C:34]=1[CH3:35]>O.C(N(CC)CC)C.CO>[CH3:35][C:34]1[CH:33]=[CH:32][C:31]([N:36]2[N:37]=[C:38]([CH3:42])/[C:39](=[N:24]/[NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([C:8]4[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([OH:16])=[O:15])[CH:9]=4)[C:3]=3[OH:17])/[C:40]2=[O:41])=[CH:30][C:29]=1[CH3:28]
Reactant: Cc1cc(O)n(-c2ccc(C)c(C)c2)n1
Reactant: NS(=O)(=O)O
Reactant: Nc1cccc(-c2cccc(C(=O)O)c2)c1O
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O
Product: CC1=NN(c2ccc(C)c(C)c2)C(=O)/C1=N\Nc1cccc(-c2cccc(C(=O)O)c2)c1O
Temperature: 25 °C
Yield: 95.4 %

Procedure:
3′-Amino-2′-hydroxybiphenyl-3-carboxylic acid (“BPCA”) Form I (90 g, 392.6 mmol), was added slowly with stirring at room temperature to a solvent mixture of tech. methanol (1.8 L) and 4 M hydrochloric acid (0.245 L, 981.5 mmol) in 3 L reactor. The resulting red solution was stirred for thirty minutes. The solution was then cooled to 0-5° C. and a cold solution of sodium nitrite (27 g, 391.3 mmol) in 90 mL of water was added over twenty minutes such that the reaction mixture temperature did not rise above 10° C. The reaction mixture was stirred for one hour at 5-10° C. Sulfamic acid (4 g, 41.2 mmol) in 90 mL of water was added at 5° C. and the resulting mixture was stirred for additionally one hour at the same temperature. The reaction mixture was warmed to room temperature and triethylamine (ca 104 mL) was added to adjust pH 7-8. 1-(3,4-dimethylphenyl)-3-methyl-1H-pyrazol-5-ol (“pyrazole”) form I (72 g, 357.8 mmol), was added in one portion to the reaction mixture and the resulting mixture was stirred for additionally two hours at room temperature. Hydrochloric acid (4M, ca 140 mL) was slowly added with stirring over twenty minutes to adjust pH to 1.8. A solid precipitated and was collected by filtration, washed with of mixture MeOH:water (1:1, 100 mL) and dried at 40° C./0 bar in vacuum oven for about 18 hours giving 151 g of crude orange to brown crystals of Eltrombopag crude (XRPD: form III with small percentage (less than 10%) of form I. (HPLC: 98.5%, Yield=95.4%)
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=[O:8].[O-:10][Mn](=O)(=O)=O.[K+].[OH-:16].[Na+]>>[S:4]1[CH:5]=[CH:6][C:2]([C:1]([OH:10])=[O:16])=[C:3]1[C:7]([OH:9])=[O:8]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1ccsc1C(=O)O
Reactant: [OH-]
Agent: [K+]
Agent: [Na+]
Product: O=C(O)c1ccsc1C(=O)O
Reaction time: 0.5 h

Procedure:
A solution of 3-Methyl-thiophene-2-carboxylic acid (0.5 mol; 71.09 g) in aqueous 15% NaOH (2300 ml) was heated to 75-80° C. before KMnO4 (0.42 mol; 67.05 g) was added with stirring. After stirring at 75-80° C. for 30 min another portion of KMnO4 (0.42 mol; 67.05 g) was added. This was repeated another three times. After adding the last portion of KMnO4, stirring was continued at 75-80° C. for 30 min before the mixture was refluxed for 3 h with stirring. The hot mixture was submitted to vacuum filtration and the filtrate was acidified by addition on conc. aqueous HCl. The formed precipitate was separated, washed with water and dried in vacuo at 80° C. to give the title compound as a slightly yellowish solid (43.9 g). 1H NMR (d6-DMSO, 200 MHz): δ=7.78 (d, 1H), 7.37 (d, 1H).
Reaction SMILES: [NH3:1].[CH2:2]([O:4][C:5]([C@H:7]1[CH2:12][CH2:11][C@@H:10]([N:13]2[C:17]3[N:18]=[CH:19][N:20]=[C:21](Cl)[C:16]=3[C:15]([I:23])=[CH:14]2)[CH2:9][CH2:8]1)=[O:6])[CH3:3]>>[CH2:2]([O:4][C:5]([C@H:7]1[CH2:12][CH2:11][C@@H:10]([N:13]2[C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH2:1])[C:16]=3[C:15]([I:23])=[CH:14]2)[CH2:9][CH2:8]1)=[O:6])[CH3:3]
Reactant: CCOC(=O)[C@H]1CC[C@@H](n2cc(I)c3c(Cl)ncnc32)CC1
Reactant: N
Product: CCOC(=O)[C@H]1CC[C@@H](n2cc(I)c3c(N)ncnc32)CC1
Temperature: -78 °C

Procedure:
Gaseous ammonia was bubbled into an'PrOH (1 mL) solution of cis-4-(4-chloro-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl)-cyclohexanecarboxylic acid ethyl ester (30 mg, 70% pure by HPLC peak area, 0.048 mmol) in a glass pressure tube, cooled to −78° C. in a dry ice/acetone bath, for 15 min. The tube was equipped with a Teflon washer, sealed and heated to 110° C. for 7 h. After that time, the excess NH3 and the solvent were evaporated. The residue was used for the next reaction without purification. A portion of above crude material were purified by HPLC to give the title compound as pale yellow oil. 1H NMR (CDCl3, 400 MHz): δ=1.31 (t, 3H, J=7.6 Hz), 1.63-1.98 (m, 6 H), 2.29-2.35 (m, 2 H), 2.73 (m, 1 H), 4.22 (q, 2 H, J=7.6 Hz), 4.64-4.71 (m, 1 H), 5.58 (brs, 2 H), 7.11 (s, 1 H), 8.26 (s, 1 H). MS (ES+): 415.0 [MH+]. tR=2.7 min (polar—5 min).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:13][C@H:14]([C:19]([O:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17].C(N(C(C)C)CC)(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:17][CH:16]([CH3:18])[CH2:15][C@H:14]([NH:13][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[C:19]([O:21][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26]1)=[O:20]
Reactant: CC(C)C[C@H](N)C(=O)OC1CCCC1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@H](NC(=O)c1ccc([N+](=O)[O-])cc1)C(=O)OC1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
4-Nitrobenzoyl chloride (0.60 g, 3.9 mmol) in DCM (2 ml) was added dropwise over 10 min to a solution of cyclopentyl L-leucinate (0.70 g, 3.5 mmol) and diisopropylethylamine (0.94 ml, 5.3 mmol) in DCM (10 ml) at −5° C. under an atmosphere of nitrogen. On completion of the addition, the reaction mixture was allowed to warm to RT and stirred for a further 30 min. The reaction mixture was poured on to sat. aq. NaHCO3 and the aqueous layer was extracted with DCM. The organic extracts were combined, washed with brine, dried over MgSO4 and evaporated under reduced pressure afford the title compound as an oily solid (1.2 g, 87%). m/z 347.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)[NH:11][C:10](=[S:20])[NH:9]2)=[CH:4][CH:3]=1.[CH3:21][I:22]>CCO>[IH:22].[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([C@H:12]2[C@@H:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)[NH:9][C:10]([S:20][CH3:21])=[N:11]2)=[CH:14][CH:15]=1
Reactant: CI
Reactant: Cc1ccc([C@H]2NC(=S)N[C@H]2c2ccc(C)cc2)cc1
Solvent: CCO
Product: CSC1=N[C@@H](c2ccc(C)cc2)[C@@H](c2ccc(C)cc2)N1
Product: I
Temperature: 25 °C
Yield: 96.8 %

Procedure:
A mixture of cis-4,5-bis-(4-methylphenyl)imidazolidine-2-thione (31) (5.2 g, 0.0184 mol) and methyl iodide (1.72 mL, 0.0276 mol) in abs. EtOH (30 mL) is heated at 90° C. overnight. The reaction mixture is cooled to rt, concentrated in vacuo, and the residue suspended in abs EtOH:Et2O. The insoluble material is filtered to give 7.56 g of the product 48. 1H NMR (DMSO-d6) δ 10.68 (s, 2 H), 7.00-6.85 (m, 8 H), 5.72 (s, 2 H), 2.79 (s, 3 H), 2.15 (s, 6 H); MS: m/z 297 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8](S(C3C=CC=CC=3)(=O)=O)[C:9]([C:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]=3)=[CH:10][C:3]=12.[OH-].[Na+].O>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9]([C:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]=3)=[CH:10][C:3]=12
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Br)ccnc3n2S(=O)(=O)c2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Br)ccnc3[nH]2)CC1

Procedure:
A mixture of Example 135C (3.00 g, 5.63 mmol) and 20% sodium hydroxide in water (2.5 mL, 5.63 mmol) in dioxane (35 mL) was heated at 90° C. for 6 hours. The solvent was evaporated. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO4, and filtered. The filtrate was concentrated to about 10 mL. The solid material was filtered, washed with ethyl acetate and dried to provide the title compound. MS (ESI+) m/z 378 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][O:6][C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)=[O:4].C(N(CC)CC)C.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([CH2:5][O:6][C:7](=[O:15])[C:8]1[CH:9]=[CH:10][C:11]([N:14]=[C:24]=[O:26])=[CH:12][CH:13]=1)=[O:4]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)COC(=O)c1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)COC(=O)c1ccc(N=C=O)cc1
Temperature: 75 °C

Procedure:
To a mixture of 4-amino-benzoic acid methoxycarbonylmethyl ester 6 (10 grams, 47.84 mmol) and triethylamine (9.68 grams, 95.67 mmol) in toluene (150 mL) under nitrogen atmosphere at 0° C. is added triphosgene (5.195 grams, 17.50 mmol) in one lot. Later the reaction mixture is heated to 75° C. over a period of one hour and maintained at this temperature for 20 hours. The reaction mixture is cooled to room temperature. The solids are filtered off, and the toluene is distilled under vacuum to give crude 11, which can be purified by a suitable method.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:9][CH:10]1[O:13][CH:11]1[CH3:12].Br[CH:15]([CH3:19])[CH:16]1[O:18][CH2:17]1>>[O:7]([CH:15]([CH3:19])[CH:16]1[O:18][CH2:17]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:7]([CH2:12][CH:11]1[O:13][CH:10]1[CH3:9])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: CC(Br)C1CO1
Reactant: CC1OC1CBr
Product: CC(Oc1ccccc1)C1CO1
Product: CC1OC1COc1ccccc1

Procedure:
Rowton et al., J. Org. Chem. 23 1057 (1958) discloses the reaction of phenol with 1-bromo-2,3-epoxybutane and 3-bromo-1,2-epoxybutane to yield 3-phenoxy-1,2-epoxybutane and 1-phenoxy-2,3-epoxybutane, respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24](OC)=[O:25])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=3[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]21.[CH:28]1([Mg]Br)[CH2:30][CH2:29]1.[Cl-].[NH4+].O1[CH2:39][CH2:38][CH2:37]C1>>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([C:24]([CH:37]2[CH2:38][CH2:39]2)([CH:28]2[CH2:30][CH2:29]2)[OH:25])=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: Br[Mg]C1CC1
Reactant: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)cc1Cl
Agent: [Cl-]
Agent: [NH4+]
Product: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C(O)(C4CC4)C4CC4)c23)c(Cl)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
To a solution of methyl 9-chloro-1-(2-chloro-4-methoxyphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxylate (100 mg, 0.246 mmol) in tetrahydrofuran (2.5 mL) was added a solution of cyclopropyl magnesium bromide in tetrahydrofuran (1.0 M, 1.5 mL, 1.5 mmol) at 0° C. The mixture was stirred at room temperature for 0.5 hr and at 50° C. for 1 hr. Aqueous ammonium chloride was added to the reaction mixture at room temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 30-70% ethyl acetate/n-hexane gradient mixture and recrystallization from ethyl acetate/n-hexane to give the title compound (58.6 mg, 0.128 mmol, 52%) as colorless crystals.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:26]([CH2:36][CH2:37][CH:38]=[O:39])=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12].[BH4-].[Na+]>C1COCC1.CO>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])[C:26]([CH2:36][CH2:37][CH2:38][OH:39])=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)ccc1CCC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)ccc1CCCO
Yield: 92.9 %

Procedure:
Compound 96B (5.5 g, 10.14 mmol) in THF (100 mL) and methanol (20 mL) was treated NaBH4 (0.767 g, 20.28 mmol). The reaction mixture was heated under reflux for 1 hour. The solvents were removed under vacuum. The residue was re-dissolved in EtOAc and treated with water. The organic layer was separated, and the aqueous layer was extracted with additional EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography to give 5.13 g of the title compound 96C (93%): APCI (+)LC/MS: 545 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:10][CH:11]([CH3:13])[CH3:12])=[C:6]([CH:9]=1)[CH:7]=[O:8].[Cu][C:15]#[N:16].CN(C=O)C.O>C(OCC)(=O)C>[C:15]([C:2]1[CH:3]=[CH:4][C:5]([O:10][CH:11]([CH3:13])[CH3:12])=[C:6]([CH:9]=1)[CH:7]=[O:8])#[N:16]
Reactant: N#C[Cu]
Reactant: CC(C)Oc1ccc(Br)cc1C=O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(C#N)cc1C=O

Procedure:
The title compound was prepared by the treatment of 5-bromo-2-isopropoxy-benzaldehyde (3.5 gm, 0.014 mol) with copper(I) cyanide (2.5 gm, 0.028 mol) in refluxing DMF for 28 hours. The cooled mixture was poured into a mixture of water (100 mL) and ethyl acetate (100 mL). The mixture was filtered through a pad of Celite, the organic layer separated, washed with saturated brine solution, dried (Na2SO4), and evaporated. The title compound was purified by flash chromatography eluting with 15% ethyl acetate in hexane; yield 1.9 gm of a white solid.