Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:30][CH2:31][OH:32])[C:6]=2[CH:33]=1.[C:34](OC(=O)C)(=[O:36])[CH3:35].O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:30][CH2:31][O:32][C:34](=[O:36])[CH3:35])[C:6]=2[CH:33]=1
Reactant: O=C(Nc1ccc(C(=O)N2CCCC(CCO)c3cc(Cl)ccc32)cn1)c1ccccc1Cl
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OCCC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3Cl)nc2)c2ccc(Cl)cc21
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 7-chloro-5-(2-hydroxyethyl)-1-[6-(2-chlorobenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.3 g) in pyridine (6 ml) is added acetic anhydride (0.09 ml), and the mixture is stirred at 80° C. for 2 hours. The reaction solution is poured into water, and extracted with ethyl acetate. The extract is washed successively with diluted hydrochloric acid, water and aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography, and recrystallized from dichloromethane-diethyl ether to give 7-chloro-5-(2-acetyloxyethyl)-1-[6-(2-chlorobenzoylamino )nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (230 mg) as white powder.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[Na].Br[CH:11]=[C:12]=[C:13]([CH3:15])[CH3:14].O>C(O)C>[C:1]([CH:3]([C:13]([CH3:15])([CH3:14])[C:12]#[CH:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CCOC(=O)CC#N
Reactant: CC(C)=C=CBr
Agent: [Na]
Solvent: O
Solvent: CCO
Product: C#CC(C)(C)C(C#N)C(=O)OCC
Reaction time: 20 h

Procedure:
Ethyl cyanoacetate (77.0 g.) was slowly added at 40° C. to a stirred solution of sodium (15.7 g.) in ethanol (400 ml.) and 15 minutes after the addition was completed 1-bromo-3,3-dimethylallene (100 g.) was carefully added over about 30 minutes. The mixture was then heated at the reflux temperature for a period of 2.5 hours and then kept at the ambient temperature for a further 20 hours. The mixture was then poured into an excess of water and extracted with chloroform. The extract was washed with water, dried over anhydrous magnesium sulphate and concentrated by evaporation of the solvent. The residual oil was distilled and ethyl 2-cyano-3,3-dimethylpent-4-ynoate was obtained as a colourless oil (boiling point 75°-76° C./0.1 mm Hg.).
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[N:13]([CH3:28])[C:14]3[C:19]([N:20]=2)=[C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:17]=[C:16](Cl)[N:15]=3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[N:29]1([C:33]2[NH:37][C:36]3[CH:38]=[CH:39][CH:40]=[CH:41][C:35]=3[N:34]=2)[CH2:32][CH2:31][CH2:30]1>>[N:29]1([C:33]2[N:34]([C:16]3[N:15]=[C:14]4[C:19]([N:20]=[C:12]([CH2:11][N:8]5[CH2:9][CH2:10][N:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:6][CH2:7]5)[N:13]4[CH3:28])=[C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:17]=3)[C:35]3[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=3[N:37]=2)[CH2:32][CH2:31][CH2:30]1
Reactant: Cn1c(CN2CCN(C(C)(C)C)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: c1ccc2[nH]c(N3CCC3)nc2c1
Product: Cn1c(CN2CCN(C(C)(C)C)CC2)nc2c(N3CCOCC3)nc(-n3c(N4CCC4)nc4ccccc43)nc21

Procedure:
4-(8-((4-tert-butylpiperazin-1-yl)methyl)-2-chloro-9-methyl-9H-purin-6-yl)morpholine (75 mg) was reacted with 2-(azetidin-1-yl)-1H-benzo[d]imidazole (33 mg) via General Procedure for Buchwald coupling to give 36.1 mg 454 following reverse phase purification. MS (Q1) 545.4 (M)+
Reaction SMILES: [OH:1][C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][CH:9]=[CH:10][C:3]=12.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[Br:23]N1C(=O)CCC1=O.O>CN(C=O)C>[OH:1][C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][CH:9]=[C:10]([Br:23])[C:3]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: Oc1nc[nH]c2nccc1-2
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Oc1nc[nH]c2ncc(Br)c1-2
Temperature: 40 °C
Reaction time: 2 h
Yield: 75.8 %

Procedure:
To a solution of 1.0 g of 4-hydroxypyrrolo[2,3-d]pyrimidine in 20 ml of DMF, 3.8 g (2.5 eq) of bis(trimethylsilyl)acetamide was added, and the resulting solution was stirred at 40° C. in an oil bath for about two hours. Completeness of silylation was indicated by NMR analysis of an aliquot showing disappearance of the N-3 proton signal. The reaction was cooled to ambient temperature and 1.6 g (1.2 eq) of N-bromosuccinimide (NBS), was added in one portion. The reaction mixture was protected from light and stirred at ambient temperature until completion was indicated by NMR analysis (disappearance of pyrrole C-H doublets and emergence of a single, finely split doublet at δ7.16, about 2 h). The mixture was poured into 50 mL of water, with stirring. After 1-2 hours, the product was collected by filtration, washed with water, dried, and reslurried in 10 volumes of 10% methanol in chloroform. Filtration and drying gave 1.2 g of 4-hydroxy-5-bromopyrrolo-[2,3-d]pyrimidine (75% yield), mp 269-°271° C. (dec). 1H NMR (300 MHz, DMSO-d6) δ7.16 (d, J=2.0 Hz, 1 H), 7.80 (d, J=2.1 Hz, 1 H), 11.87 (s, 1 H), 12.15 (s, 1 H). 13C NMR (75.5 MHz, DMSO-d6) 89.3, 105.5, 120.4, 144.3, 147.4, 157.5.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C@H:13]([OH:17])[CH:14]([CH3:16])[CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:37][C:38]1[CH:43]=[CH:42][C:41](O)=[CH:40][CH:39]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>CC1CCCO1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([O:17][C:41]2[CH:42]=[CH:43][C:38]([Cl:37])=[CH:39][CH:40]=2)[CH:14]([CH3:15])[CH3:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(C)[C@@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC1CCCO1
Product: CC(C)[C@H](Oc1ccc(Cl)cc1)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.8 %

Procedure:
(S)-3-((R)-1-hydroxy-2-methylpropyl)pyrrolidine-1-carboxylic acid t-butyl ester (35.0 g, 144 mmol, 1.0 eq.), triphenylphosphine (41.5 g, 158 mmol, 1.1 eq.), p-chlorophenol (37.0 g, 288 mmol, 2.0 eq.) and 2-methyl-tetrahydrofuran (300 mL) were combined and the vessel purged with nitrogen. Diisopropyl azodicarboxylate (31.2 mL, 1.1 eq.) was added slowly at room temperature over 2 hours. The mixture was then stirred at room temperature overnight. Hexanes (600 mL) were added and the resulting mixture was stirred at room temperature for 30 minutes. The phases were separated and the organic layer was washed with 1.0 M NaOH in water (600 mL), washed with diluted saturated aqueous NaCl (20 mL), then dried over Na2SO4 to yield the crude BOC-protected intermediate. Additional hexanes (50 mL) were added and the resulting mixture was stirred for 30 minutes. Solids were filtered off to yield the crude BOC-protected intermediate as a thick oil, which was then purified by silica gel chromatography (0-10-20% EtOAc in hexanes) to yield (S)-3-[(S)-1-(4-chlorophenoxy)-2-methylpropyl]pyrrolidine-1-carboxylic acid t-butyl ester (5.5 g).
Reaction SMILES: COC1C=CC(COC2C=CC(CO)=CC=2)=CC=1.C[O:20][C:21](=[O:49])[CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=3)=[CH:34][CH:33]=2)=[CH:26][C:25]=1[CH3:48]>>[CH3:47][O:46][C:43]1[CH:44]=[CH:45][C:40]([CH2:39][O:38][C:35]2[CH:36]=[CH:37][C:32]([CH2:31][S:30][C:27]3[CH:28]=[CH:29][C:24]([O:23][CH2:22][C:21]([OH:49])=[O:20])=[C:25]([CH3:48])[CH:26]=3)=[CH:33][CH:34]=2)=[CH:41][CH:42]=1
Reactant: COC(=O)COc1ccc(SCc2ccc(OCc3ccc(OC)cc3)cc2)cc1C
Agent: COc1ccc(COc2ccc(CO)cc2)cc1
Product: COc1ccc(COc2ccc(CSc3ccc(OCC(=O)O)c(C)c3)cc2)cc1

Procedure:
The title compound was prepared in the manner analogous to Example 3B using 33A. MS m/z 227 (M-Cl). Step 3. Preparation of {4-[4-(4-Methoxy-benzyloxy)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid methyl ester (Compound 33C)
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[CH:7]([NH:17][C:18](N1C=CN=C1)=[O:19])[CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:4])([CH3:3])[CH3:2].[CH3:26][O:27][C:28](=[O:39])[CH2:29][CH:30]([NH2:38])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([I:37])[CH:32]=1>ClCCCl.C(Cl)Cl>[C:1]([O:5][C:6](=[O:25])[C@@H:7]([NH:17][C:18]([NH:38][C@H:30]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([I:37])[CH:32]=1)[CH2:29][C:28]([O:27][CH3:26])=[O:39])=[O:19])[CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)CC(N)c1cccc(I)c1
Reactant: CC(C)(C)OC(=O)CCC(NC(=O)n1ccnc1)C(=O)OC(C)(C)C
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(=O)C[C@H](NC(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1cccc(I)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 48.8 %

Procedure:
2-[(Imidazole-1-carbonyl)-amino]-pentanedioic acid di-tert-butyl ester (370 mg, 1.05 mmol) was dissolved in DCE (10 mL) and cooled to 0° C. MeoTf (142 μL, 1.25 mmol) was added and the reaction was allowed to proceed for 20 min. (±)-3-Amino-3-(3-iodo-phenyl)-propionic acid methyl ester (356 mg, 1.045 mmol) was added and the reaction was allowed to warm to room temperature and then warmed to 55° C. and stirred overnight. The reaction was diluted with DCM (50 mL) and washed with water (30 mL), 5% aq. Citric acid (30 mL), sat. sodium bicarbonate (30 mL), water (30 mL) and brine (30 mL). The organic layer was dried over sodium sulfate and concentrated to afford the crude product. The product was purified by column chromatography to afford the desired product (303 mg, 0.51 mmol, 49%) as a white foam. 1H NMR (400 MHz, CDCl3) δ 7.66 (s, 1H), 7.57 (d, J=7.6 Hz, 1H), 7.29 (s, 1H), 7.07-7.02 (m, 1H), 5.74 (br, 1H), 5.17 (br, 2H), 4.30 (m, 1H), 3.63 (s, 1.5H), 3.62 (s, 1.5H), 2.88-2.76 (m, 2H), 2.38-2.24 (m, 2H), 2.10-2.00 (m, 1H), 1.90-1.80 (m, 1H), 1.46 (s, 9H), 1.44 (s, 9H).
Reaction SMILES: [BrH:1].C(O)(=O)C.[Cl:6][C:7]1[CH:8]=[C:9]([C:13](=O)[CH2:14][S:15][C:16]#[N:17])[CH:10]=[CH:11][CH:12]=1.O>C(O)(=O)C>[Br:1][C:16]1[S:15][CH:14]=[C:13]([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([Cl:6])[CH:8]=2)[N:17]=1
Reactant: N#CSCC(=O)c1cccc(Cl)c1
Reactant: Br
Solvent: O
Solvent: CC(=O)O
Product: Clc1cccc(-c2csc(Br)n2)c1
Temperature: 130 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A 25% hydrogen bromide/acetic acid (45 ml) solution was added to a solution of 2-(3-chlorophenyl)-2-oxoethyl thiocyanate (4.90 g, 23.2 mmol) in acetic acid (45 ml), and the mixture was stirred at 130° C. for 2 hours and at room temperature for 1 hour. Water (50 ml) was poured to the reaction mixture, and crystals were collected by filtration and washed with water to give 6.36 g (100%) of the desired product as a solid.
Reaction SMILES: B.CSC.[CH3:5][C:6]([NH:9][CH2:10][CH:11]([C:13]1[CH:14]=[CH:15][C:16]([OH:23])=[C:17]([CH:22]=1)[C:18](OC)=[O:19])[OH:12])([CH3:8])[CH3:7].C1(C)C(C([C@@](C(O)=O)(O)[C@@](C(C2C(C)=CC=CC=2)=O)(O)C(O)=O)=O)=CC=CC=1.C1(C)C(C([C@](C(O)=O)(O)[C@](C(C2C(C)=CC=CC=2)=O)(O)C(O)=O)=O)=CC=CC=1>CO>[CH3:8][C:6]([NH:9][CH2:10][C@H:11]([OH:12])[C:13]1[CH:14]=[CH:15][C:16]([OH:23])=[C:17]([CH2:18][OH:19])[CH:22]=1)([CH3:5])[CH3:7]
Reactant: COC(=O)c1cc(C(O)CNC(C)(C)C)ccc1O
Agent: B
Agent: Cc1ccccc1C(=O)[C@@](O)(C(=O)O)[C@](O)(C(=O)O)C(=O)c1ccccc1C
Agent: Cc1ccccc1C(=O)[C@](O)(C(=O)O)[C@@](O)(C(=O)O)C(=O)c1ccccc1C
Solvent: CO
Solvent: CSC
Product: CC(C)(C)NC[C@H](O)c1ccc(O)c(CO)c1

Procedure:
Several patents report synthetic routes using enantiomeric separation, however, the synthetic routes result in low yields of the enantiomerically pure product. Optically pure levalbuterol was synthesized by the borane-methylsulfide reduction of the enantiomerically pure precursor (Formula 2) as described in U.S. Pat. No. 5,399,765. The reaction dissolved a mixture of enantiomers of methyl 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoate and a chiral acid selected from (−)-di-toluoyl-L-tartaric acid and (+)-di-toluoyl-D-tartaric acid in methanol, upon cooling one stereoisomer crystallized, which was separated, and recrystallized as a diastereomer from methanol, the diastereomer was separated, treated with base, and upon reduction formed optically active levalbuterol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:13][C:14]([NH2:16])=[NH:15])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:17]([O:21][C:22](=[O:37])/[C:23](/O)=[C:24](\[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)/[C:25](O)=[O:26])([CH3:20])([CH3:19])[CH3:18].C[O-].[Na+]>CO.ClCCl>[C:17]([O:21][C:22]([C:23]1[C:24]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:25]([OH:26])[N:16]=[C:14]([CH2:13][C:8]2([C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:15]=1)=[O:37])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)/C(O)=C(\OCc1ccccc1)C(=O)O
Reactant: N=C(N)CC1(c2ccc(Br)cc2)CCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)c1nc(CC2(c3ccc(Br)cc3)CCCC2)nc(O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.5 %

Procedure:
To a mixture of the HCl-salt of 2-[1-(4-bromophenyl)-cyclopentyl]-acetamidine (229) (6.5 g, 20.47 mmol) and (E)-2-benzyloxy-3-hydroxy-but-2-enedioic acid 4-tert-butyl ester 1-methyl ester (4) (9.47 g, 30.71 mmol) in methanol (100 mL) was added sodium methoxide (3.32 g, 23.73 mmol, 25% in methanol) at 0° C. Then the reaction mixture was allowed to warm to room temperature and was stirred for 16 h. After completion of the reaction, solvent was reduced and the crude product was dissolved in dichloromethane (150 mL). The organic part was washed with 1N HCl, separated and dried over Na2SO4. After evaporation, the crude product was purified by 100-200 silica gel column chromatography using 20% ethyl acetate in hexane as the eluent to give 5-benzyloxy-2-[1-(4-bromophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester (230) (7.9 g, 71%) as a yellow solid.
Reaction SMILES: OC1C=C(CN/C=C2\C(=O)NC(=O)C3C\2=CC(I)=CC=3)C=CC=1NC(=O)C1C=CC=CC=1.[NH2:33][C:34]1[CH:55]=[CH:54][C:37]([CH2:38][NH:39]/[CH:40]=[C:41]2\[C:42](=[O:53])[NH:43][C:44](=[O:52])[C:45]3[C:50]\2=[CH:49][C:48]([Br:51])=[CH:47][CH:46]=3)=[CH:36][C:35]=1[O:56][Si](C(C)C)(C(C)C)C(C)C.[Cl:67][CH:68]([Cl:72])[C:69](Cl)=[O:70]>>[Br:51][C:48]1[CH:49]=[C:50]2[C:45](=[CH:46][CH:47]=1)[C:44](=[O:52])[NH:43][C:42](=[O:53])/[C:41]/2=[CH:40]\[NH:39][CH2:38][C:37]1[CH:54]=[CH:55][C:34]([NH:33][C:69](=[O:70])[CH:68]([Cl:72])[Cl:67])=[C:35]([OH:56])[CH:36]=1
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CC(C)[Si](Oc1cc(CN/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)ccc1N)(C(C)C)C(C)C
Agent: O=C1NC(=O)c2ccc(I)cc2/C1=C/NCc1ccc(NC(=O)c2ccccc2)c(O)c1
Product: O=C1NC(=O)c2ccc(Br)cc2/C1=C/NCc1ccc(NC(=O)C(Cl)Cl)c(O)c1

Procedure:
Following the acetylation and desilylation procedure employed for the preparation of N-[2-hydroxy-4-({[(Z)-(6-iodo-1,3-dioxo-2,3-dihydroisoquinolin-4(1H)-ylidene)methyl]amino}methyl)phenyl]benzamide, (4Z)-4-[({4-amino-3-[(triisopropylsilyl)oxy]benzyl}amino)methylene]-6-bromoisoquinoline-1,3(2H,4H)-dione (60 mg, 0.11 mmol) is reacted with dichloroacetyl chloride (110 μL, 1.1 mmol). Following desilylation and precipitation, N-[4-({[(Z)-(6-bromo-1,3-dioxo-2,3-dihydroisoquinolin-4(1H)-ylidene)methyl]amino}methyl)-2-hydroxyphenyl]-2,2-dichloroacetamide is obtained 8.8 mg, 16%).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=1)(=[O:3])[CH3:2].Cl[C:15]([O:17][CH2:18][CH3:19])=[O:16].O>N1C=CC=CC=1>[C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCCc1cccc(N)c1
Reactant: CCOC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)Nc1cccc(CCNC(C)=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
In pyridine (5 ml) was dissolved 1.7 g of N-acetyl-N-(3-aminophenethyl)amine (Preparation Example 29), followed by dropwise addition of ethyl chloroformate (1.4 ml) under ice-cooling. After stirring at room temperature for 1 hour, the mixture was ice-cooled again. Water was added thereto, followed by extracting with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give the title compound (2.358 g, 97%) as a yellow oil.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][NH:11][C:12]1[N:13]=[C:14]([C:21]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[O:22])[C:15]2[S:20][CH:19]=[CH:18][C:16]=2[N:17]=1)=O)CCC.[ClH:28]>CO.O1CCOCC1>[ClH:28].[ClH:28].[NH2:8][CH2:9][CH2:10][NH:11][C:12]1[N:13]=[C:14]([C:21]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[O:22])[C:15]2[S:20][CH:19]=[CH:18][C:16]=2[N:17]=1
Reactant: CCCCOC(=O)NCCNc1nc(C(=O)c2cccs2)c2sccc2n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NCCNc1nc(C(=O)c2cccs2)c2sccc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
A solution of 2-(2-butoxycarbonylaminoethylamino)thieno[3,2-d]pyrimidin-4-yl 2-thienylmethanone (58 mg, 0.14 mmol) in MeOH (5 mL) was treated with 4-M HCl in dioxane (0.5 mL), stirred at room temperature for 16 h and the resulting solid filtered and washed with ether to give the title compound (41 mg, 77%) as a white crystalline solid.
Reaction SMILES: O[N:2]=[C:3]([C:11](=O)[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[CH3:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>C(#N)C>[CH3:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]2[NH:25][C:11]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[C:3]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[N:2]=2)=[CH:22][CH:21]=1
Reactant: Cc1ccc(CN)cc1
Reactant: CC(C)(C)OC(=O)C(=NO)C(=O)c1ccncc1
Solvent: CC#N
Product: Cc1ccc(-c2nc(C(=O)OC(C)(C)C)c(-c3ccncc3)[nH]2)cc1

Procedure:
tert-Butyl 2-hydroxyimino-3-oxo-3-(4-pyridyl)propionate and 4-methylbenzylamine were dissolved in acetonitrile (80 ml). The mixture was reacted and treated in the same manner as in Starting Material Synthetic Example 5 to give tert-butyl 2-(4-methylphenyl)-5-(4-pyridyl)imidazole-4-carboxylate.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1.[F:19][C:20]([F:29])([F:28])[C:21]1[CH:22]=[C:23](O)[CH:24]=[CH:25][CH:26]=1>>[CH3:18][O:17][C@@H:13]([CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][O:1][C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([C:20]([F:29])([F:28])[F:19])[CH:26]=2)=[CH:7][CH:8]=1)[C:14]([OH:16])=[O:15]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: CO[C@@H](Cc1ccc(OCCCO)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCCOc2cccc(C(F)(F)F)c2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked to Wang's Resin Example 94, Step D) via Mitsunobu coupling with 3-trifluoromethylphenol and cleavage from the resin (Standard Procedure CG) gave an oily solid.
Reaction SMILES: [C:1]([C:3]1[CH:21]=[CH:20][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[O:8])=[CH:5][C:4]=1[CH3:22])#[N:2].[H-].[Na+].[CH3:25]I>CN(C=O)C>[C:1]([C:3]1[CH:21]=[CH:20][C:6]([C:7]([N:9]([CH3:25])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:18])([F:17])[F:19])=[CH:12][CH:11]=2)=[O:8])=[CH:5][C:4]=1[CH3:22])#[N:2]
Reactant: Cc1cc(C(=O)Nc2ccc(C(F)(F)F)cc2)ccc1C#N
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N(C)c2ccc(C(F)(F)F)cc2)ccc1C#N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
4-Cyano-3-methyl-N-(4-trifluoromethyl-phenyl)-benzamide from Example E118.1 (1.10 g, 3.6 mmol) was dissolved in DMF (10 ml) and cooled down to 0° C. Sodium hydride (60% dispersion in oil, 174 mg, 4.3 mmol) was added and the mixture was stirred for 30 min at room temperature. Methyl iodide (0.27 ml, 4.3 mmol) was added and the mixture was stirred for 20 h. Solvents were removed in vacuo and azeotroped with toluene. The residue was re-dissolved in EtOAc, washed with brine, dried and concentrated in vacuo to yield the title compound (1.08 g, 94%).
Reaction SMILES: O1CCCC1.Cl.[N:7]1([C:13]2[N:22]=[C:21]([NH2:23])[C:20]3[C:15](=[CH:16][C:17]([O:26][CH3:27])=[C:18]([O:24][CH3:25])[CH:19]=3)[N:14]=2)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[C:28](Cl)(=[O:37])[CH:29]=[CH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(N(CC)CC)C>[C:28]([N:10]1[CH2:11][CH2:12][N:7]([C:13]2[N:22]=[C:21]([NH2:23])[C:20]3[C:15](=[CH:16][C:17]([O:26][CH3:27])=[C:18]([O:24][CH3:25])[CH:19]=3)[N:14]=2)[CH2:8][CH2:9]1)(=[O:37])[CH:29]=[CH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc2nc(N3CCN(C(=O)C=Cc4ccccc4)CC3)nc(N)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 10 ml. of tetrahydrofuran were added 1.2 g. of 2-(piperazin-1-yl)-4-amino-6,7-dimethoxyquinazoline.hydrochloride and 1.33 g. of triethylamine and the resulting mixture was stirred for 30 minutes. Thereafter, 0.66 g. of cinnamoyl chloride was added thereto and the resulting mixture was stirred at room temperature overnight. The crystalline substance thus separated was recovered by filtration, washed thoroughly with water and ethanol and then dried to afford 0.66 g. of the desired product.
Reaction SMILES: [I-:1].Cl[C:3]1[N:4]([CH3:15])[N+:5]([CH3:14])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.[O-]C1C=CC=CC=1.[Na+].[CH3:24][N:25](C)[CH:26]=O>>[I-:1].[CH3:14][N+:5]1[N:4]([CH3:15])[C:3]([N:25]([CH3:26])[CH3:24])=[CH:7][C:6]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CN(C)C=O
Reactant: Cn1c(Cl)cc(-c2ccccc2)[n+]1C
Agent: [I-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Product: CN(C)c1cc(-c2ccccc2)[n+](C)n1C
Reaction time: 21 h

Procedure:
3-Chloro-1,2-dimethyl-5-phenylpyrazolium iodide (10.0 g, 0.03 mole) is treated with sodium phenoxide (5.64 g, 0.06 mole) in dimethylformamide (100 ml) and the mixture heated and stirred at 110° C. to 120° C. for 21 hours. The dimethylformamide is then removed in vacuo, the residual oil dissolved in aqueous sodium bicarbonate solution and is extracted with ether. The ether fraction yields some brown oil which is not further examined. Next the aqueous sodium bicarbonate solution is extracted with chloroform (2× 150 ml). Evaporation of the chloroform solution yields a white solid which is dried by azeotropic distillation of toluene. Crystallization from a chloroform/ether mixture yields a white solid, m.p. 181.5° C. to 182° C.
Reaction SMILES: [O:1]=[C:2]1[CH:10]([CH2:11][C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Br[CH2:25][CH2:26][CH2:27][CH2:28][C:29]#[N:30]>>[O:1]=[C:2]1[C:10]([CH2:11][C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)([CH2:25][CH2:26][CH2:27][CH2:28][C:29]#[N:30])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: N#CCCCCBr
Reactant: O=C1C(Cc2cnccn2)c2ccccc2N1c1ccccc1
Product: N#CCCCCC1(Cc2cnccn2)C(=O)N(c2ccccc2)c2ccccc21
Yield: 76 %

Procedure:
By substituting 2,3-dihydro-2-oxo-1-phenyl-3-(2-pyrazinylmethyl)1H-indole and 5-bromovaleronitrile in Example 1, the desired product was obtained in 76% yield as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N:12]1([CH:18]([C:21]2[CH:22]=[N:23][CH:24]=[N:25][CH:26]=2)[CH2:19][NH2:20])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[C:21]1[CH:22]=[N:23][CH:24]=[N:25][CH:26]=1)=[O:6]
Reactant: NCC(c1cncnc1)N1CCOCC1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: O=C(NCC(c1cncnc1)N1CCOCC1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 2-morpholin-4-yl-2-pyrimidin-5-yl-ethylamine.