Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:38]=[CH:37][C:6]([CH2:7][C@@:8]2([CH3:36])[N:12]3[C:13]([S:16]([N:19]4[CH2:23][CH2:22][CH2:21][C@H:20]4[C:24]([NH2:26])=[O:25])(=[O:18])=[O:17])=[CH:14][N:15]=[C:11]3[N:10]([C:27]3[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=3)[C:9]2=[O:35])=[CH:5][CH:4]=1)#[N:2].[C:39](OC(=O)C)(=[O:41])[CH3:40]>>[C:39]([NH:26][C:24]([C@@H:20]1[CH2:21][CH2:22][CH2:23][N:19]1[S:16]([C:13]1[N:12]2[C@@:8]([CH2:7][C:6]3[CH:37]=[CH:38][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)([CH3:36])[C:9](=[O:35])[N:10]([C:27]3[CH:28]=[C:29]([Cl:34])[CH:30]=[C:31]([Cl:33])[CH:32]=3)[C:11]2=[N:15][CH:14]=1)(=[O:18])=[O:17])=[O:25])(=[O:41])[CH3:40]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(S(=O)(=O)N3CCC[C@H]3C(N)=O)n21
Product: CC(=O)NC(=O)[C@@H]1CCCN1S(=O)(=O)c1cnc2n1[C@](C)(Cc1ccc(C#N)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1
Temperature: 100 °C

Procedure:
(S)-1-[(R)-5-(4-Cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-sulfonyl]-pyrrolidine-2-carboxylic acid amide (98 mg, 0.17 mmol) was dissolved in acetic anhydride (3 mL, 0.05 M). The reaction was heated to 100° C. for 18 h. The mixture was concentrated, toluene added, and the mixture concentrated again. The residue was chromatographed over silica with a solvent system of 10% MeOH in methylene chloride to provide 19 mg of the title compound as a white solid (M+1, 615).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][OH:16])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1.O.NN.NC(C1C=CC=CC=1Cl)C1C=CC([Cl:36])=CC=1N1C(C)=NN=C1C1CC1>C(O)COCCO>[NH2:8][CH:7]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])[C:6]1[CH:24]=[CH:2][C:3]([Cl:36])=[CH:4][C:5]=1[N:11]1[C:10]([CH3:9])=[N:14][N:13]=[C:12]1[CH2:15][OH:16]
Reactant: Cc1nnc(C2CC2)n1-c1cc(Cl)ccc1C(N)c1ccccc1Cl
Reactant: OCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Agent: NN
Solvent: O
Solvent: OCCOCCO
Product: Cc1nnc(CO)n1-c1cc(Cl)ccc1C(N)c1ccccc1Cl

Procedure:
A mixture of 10.776 g. 8-chloro-6-(o-chlorophenyl)-1-hydroxymethyl-4H-s-triazolo[4,3-a] [1,4]benzodiazepine (111) (30.0 mmoles) and 7.50 ml. of hydrazine hydrate in 60 ml. of diethylene glycol is heated to 150°-160° C. for about 18 hours. The reaction is then quenched in a cold aqueous 5% sodium hydroxide solution and the product extracted with chloroform. The extracts thus obtained are dried over anhydrous magnesium sulfate and concentrated in vacuo to give 13.0 g. of oil which is crystallized from methanol/ethyl acetate to give 1.93 g. of a mixture of the A and B isomers (ratio 81/19) of 4-[α-amino-4-chloro-α-(o-chlorophenyl)-o-tolyl]-3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazole (I) m.p. 205°-215° C. The mixture thus obtained is recrystallized from the same solvent mixture to give 0.76 g. of 4-[α-amino-4-chloro-α-(o-chlorophenyl)-o-tolyl]-o-tolyl]-3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazole (I), (isomer A) melting at 218° - 223° C., and having infrared (mull) spectral absorptions at 3330, 3240, 3150, 3060, 2680, 1600, 1570, 1530, 1515 and 1485 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[CH2:19][CH2:18]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12](O)=[O:13])=[CH:4][CH:3]=1.C(O[C:35](=O)[N:36]([CH2:38][CH2:39][NH2:40])C)(C)(C)C.Cl>>[ClH:1].[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[CH2:19][CH2:18]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12]([NH:40][CH2:39][CH2:38][NH:36][CH3:35])=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(O)Cn1cc(C(=O)N2CCC(c3ccccc3F)CC2)c2ccc(Cl)cc21
Reactant: CN(CCN)C(=O)OC(C)(C)C
Agent: Cl
Product: CNCCNC(=O)Cn1cc(C(=O)N2CCC(c3ccccc3F)CC2)c2ccc(Cl)cc21

Procedure:
Following general procedure I, the coupling of {6-chloro-3-[4-(2-fluoro-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-acetic acid (preparation described herein), with (commercially available) (2-amino-ethyl)-methyl-carbamic acid tert-butyl ester gave, after treatment with HCl, the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][N+:6]#[C-:7])[CH3:2].[CH2:9]([C:16](=[CH2:19])[CH:17]=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:1]([O:3][C:4]([CH:5]1[CH:17]([C:16]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH2:19])[O:18][CH:7]=[N:6]1)=[O:8])[CH3:2]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: C=C(C=O)Cc1ccccc1
Product: C=C(Cc1ccccc1)C1OC=NC1C(=O)OCC

Procedure:
The starting material is manufactured as follows: By reaction of isocyanoacetic acid ethyl ester with 2-benzyl-propenal in a manner analogous to that described in Example 1 and after purification by column chromatography (silica gel; dichloromethane/ethyl acetate 98:2), 5-(3-phenyl-propen-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester is obtained in the form of a colourless oil, 1H-NMR (CDCl3): 3.33 (s, 2H, CH2); 4.37 (dd, 1H, C(4)--H); 4.87 (s, 1H); 5.07 (dd, 1H, C(5)--H); 5.16 (s, 1H).
Reaction SMILES: C([O:8][CH2:9][CH2:10][C:11]1([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:13][CH2:12]1)C1C=CC=CC=1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[C:17]([O:16][C:15](=[O:21])[NH:14][C:11]1([CH2:10][CH2:9][OH:8])[CH2:12][CH2:13]1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)NC1(CCOCc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(CCO)CC1
Temperature: 25 °C
Yield: 98.6 %

Procedure:
To a solution in ethanol (112 mL) of the compound (16.3 g) obtained in step (3) above, 20% palladium hydroxide/carbon (3.25 g) was added and the mixture was stirred at 60° C. for 23 hours in a hydrogen atmosphere. After being cooled to room temperature, the reaction mixture was filtered through Celite (registered trademark). The filtrate was concentrated under reduced pressure to give tert-butyl[1-(2-hydroxyethyl)cyclopropyl]carbamate as a colorless solid (11.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[C:14](=[O:15])[C@@H:13]([CH2:16][C:17]([CH3:19])=[CH2:18])[C@H:12]([OH:20])[C@@H:11]2[CH3:21])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]>CO.[Pd]>[Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[C:14](=[O:15])[C@@H:13]([CH2:16][CH:17]([CH3:18])[CH3:19])[C@H:12]([OH:20])[C@@H:11]2[CH3:21])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C=C(C)C[C@@H]1C(=O)N(c2ccc(C#N)c(Cl)c2)[C@@H](C)[C@H]1O
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@@H]1C(=O)N(c2ccc(C#N)c(Cl)c2)[C@@H](C)[C@H]1O
Reaction time: 48 h
Yield: 19.2 %

Procedure:
To a solution of 2-chloro-4-[(2S,3S,4S)-3-hydroxy-2-methyl-4-(2-methylprop-2-en-1-yl)-5-oxopyrrolidin-1-yl]benzonitrile (22.3 mg) in methanol (3.0 mL) was added palladium/fibroin (12.0 mg), and the mixture was stirred for 48 hr under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=50/1→1/1) to give the title compound as a pale-yellow oil (yield: 4.3 mg, 19.1%).
Reaction SMILES: O[C@@H:2]1[C@H:6]([CH2:7]/[CH:8]=[CH:9]\[CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C@@H:5](/[CH:16]=[CH:17]/[C@@H:18]([O:31][Si:32]([CH2:37][CH3:38])([CH2:35][CH3:36])[CH2:33][CH3:34])[CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)[C@H:4]([O:39][Si:40]([CH2:45][CH3:46])([CH2:43][CH3:44])[CH2:41][CH3:42])[CH2:3]1.C(Cl)(=O)C1C=CC=CC=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:45]([Si:40]([CH2:41][CH3:42])([CH2:43][CH3:44])[O:39][C@@H:4]1[CH2:3][C@@H:2]2[O:14][C:13](=[O:15])[CH2:12][CH2:11][CH2:10][CH:9]=[CH:8][CH2:7][C@@H:6]2[C@H:5]1/[CH:16]=[CH:17]/[C@@H:18]([O:31][Si:32]([CH2:37][CH3:38])([CH2:35][CH3:36])[CH2:33][CH3:34])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1)[CH3:46]
Reactant: CC[Si](CC)(CC)O[C@H](/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@H]1O[Si](CC)(CC)CC)COc1cccc(C(F)(F)F)c1
Agent: CC[Si](CC)(CC)O[C@H](/C=C/[C@@H]1[C@H]2C/C=C\CCCC(=O)O[C@H]2C[C@H]1O[Si](CC)(CC)CC)COc1cccc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Solvent: O=C(Cl)c1ccccc1
Solvent: ClCCl
Product: CC[Si](CC)(CC)O[C@H](/C=C/[C@@H]1[C@H]2CC=CCCCC(=O)O[C@H]2C[C@H]1O[Si](CC)(CC)CC)COc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (Z)-7-((1R,2R,3R,5S)-5-hydroxy-3-((triethylsilyl)oxy)-2-((R,E)-3-((triethylsilyl)oxy)-4-(3-(trifluoromethyl)phenoxy)but-1-en-1-yl)cyclopentyl)hept-5-enoic acid (1.5 g, 2.19 mmole) and N,N-diisopropylethylamine (0.48 g from Example 16) in methylene chloride (30 mL) at room temperature under nitrogen, benzoyl chloride (0.30 g, 2.13 mmole) was added and the resulting mixture was stirred for 1 hr at room temperature. The reaction mixture was cooled to −15 to −20° C. and a solution of 4-dimethylaminopyridine (0.45 g, 3.69 mmole) in methylene chloride (5 mL) was added dropwise over 5 minutes. The reaction mixture was further stirred for 30 minutes at −15 to −16° C. The reaction mixture was quenched with saturated sodium bicarbonate solution (30 mL). The organic layer was separated. The aqueous layer was extracted with methylene chloride (30 mL). The combined organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 2.7 g of crude title compound. The crude title compound was purified by column chromatography providing 0.9 g of the title compound. (61.6% yield).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[N-:11]=[N+:12]=[N-:13].[Na+].CCCCCC.CCOCC>CN(C=O)C.O>[N:11]([CH2:2][CH2:3][O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[N+:12]=[N-:13]
Reactant: CCOC(=O)COCCCl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)COCCN=[N+]=[N-]
Yield: 114 %

Procedure:
A mixture of ethyl 2-chloroethoxyacetate (7.71 g, 36.3 mmol) and sodium azide (3.31 g, 50.9 mmol) in DMF (100 ml) was heated at 80°-90° C. for 3.5 h by which time tlc (hexane; ether 1:1) indicated that the reaction was complete. The cooled mixture was poured into H2O (1 l) and extracted with ether (250 ml×3). The extracts washed with H2O (×2) and brine (×1) were dried (MgSO4) and evaporated yielding 7.16 g (41.4 mmol 89.4%) of ethyl 2-azidoethoxyacetate as a yellowish oil: 1Hmr (CDCl3) δ: 1.30 (3H, t, J=7 Hz, --OCH2CH3), 3.3-4.0 (4H, m, --OCH2CH2N3), 4.13 (2H, s, --COCH2O--), 4.23 ppm (2H, q, J=7 Hz, --OCH2CH3); ir (neat) νmax : 2100 (N3) and 1750 cm-1 (C=O ester). This material was used in the next step without further purification.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]1[C:10]2([CH2:13][NH:12][CH2:11]2)[CH2:9][NH:8]1.Cl[C:15]1[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:18]=[N:17][N:16]=1>C(O)C>[C:20]1([N:19]2[C:15]([N:8]3[CH2:9][C:10]4([CH2:13][NH:12][CH2:11]4)[CH2:7]3)=[N:16][N:17]=[N:18]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: C1NCC12CNC2
Reactant: Clc1nnnn1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: c1ccc(-n2nnnc2N2CC3(CNC3)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.3 %

Procedure:
To potassium carbonate (76 mg) taken in ethanol (2.0 mL), a solution of 2,6-diazaspiro[3.3]heptane (220 mg in 2.0 ml of ethanol) was added at room temperature. The reaction mixture was stirred for 30 minutes at room temperature and a solution of 5-chloro-1-phenyl tetrazole (0.1 g) in ethanol (2.0 mL) was added very slowly. The reaction mixture was allowed to stir for 5 hours at room temperature. The reaction mixture was evaporated to give a residue which was partitioned between water (10 mL) and EtOAc (20 mL). The aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure gave crude product which was purified by column chromatography using methanol\dichloromethane (1:9) as eluent to afford 2-(1-phenyl-1H-tetrazol-5-yl)-2,6-diazaspiro[3.3]heptane (50 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]#[N:11])[CH:5]=[CH:6][CH:7]=1.[N+:16]([O-])([OH:18])=[O:17].S(=O)(=O)(O)O>O>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[N+:16]([O-:18])=[O:17]
Reactant: Cc1cccc(-c2ccccc2C#N)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1cc(-c2ccccc2C#N)ccc1[N+](=O)[O-]
Reaction time: 0.08 h

Procedure:
2-(3-Methylphenyl)benzonitrile (18.1 mmoles, 3.5 g) was added slowly at -5° C. to a mixture of 10 ml nitric acid and 10 ml sulfuric acid. After 5 minutes, the reaction was diluted with cold water. The solid was collected, dissolved in THF. The solution was dried and concentrated. The solid was recrystallized from ether and hexane to yield 2.45 g of 2-(3-methyl-4-nitrophenyl)benzonitrile. (MS)
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:10]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:11]1[CH:12]=[C:13](/[CH:18]=[CH:19]/[C:20]([O:22]C)=[O:21])[CH:14]=[C:15]([F:17])[CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>O1CCCC1.CO>[CH2:24]([N:10]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:11]1[CH:12]=[C:13](/[CH:18]=[CH:19]/[C:20]([OH:22])=[O:21])[CH:14]=[C:15]([F:17])[CH:16]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC(=O)/C=C/c1cc(F)cc(N(Cc2ccccc2)Cc2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)/C=C/c1cc(F)cc(N(Cc2ccccc2)Cc2ccccc2)c1
Temperature: 80 °C
Yield: 91.7 %

Procedure:
Sodium hydroxide (2 mL, 2 mmol, 1.00 N solution) was added to a solution of 19B (0.467 g, 1.24 mmol) in tetrahydrofuran (2 mL) and methanol (1 mL). The reaction was heated at 80° C. for 1 h. Hydrochloric acid (1 N) was added and the reaction mixture was extracted with ethyl acetate (2×). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to give 19C (0.411 g, 91%) as a pale yellow solid. LC-MS m/z: 362.4 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH:6]=[CH:7][C:8]2[S:12][C:11]([C:13](Cl)=[O:14])=[CH:10][CH:9]=2)[C:3]2[CH:16]=[CH:17][CH:18]=[CH:19][C:2]1=2.CC1(C)OC(CO)C[O:22]1>N1C=CC=CC=1>[S:1]1[CH:5]=[C:4]([CH:6]=[CH:7][C:8]2[S:12][C:11]([C:13]([OH:22])=[O:14])=[CH:10][CH:9]=2)[C:3]2[CH:16]=[CH:17][CH:18]=[CH:19][C:2]1=2
Reactant: CC1(C)OCC(CO)O1
Reactant: O=C(Cl)c1ccc(C=Cc2csc3ccccc23)s1
Solvent: c1ccncc1
Product: O=C(O)c1ccc(C=Cc2csc3ccccc23)s1

Procedure:
The acid chloride of 5-[2-(benzo[b]thiophen-3-yl)ethenyl]thiophene-2-carboxylic acid was prepared as described in Example 9. To a solution of 5-[2-(benzo[b]thiophen-3-yl)ethenyl]thiophene-2-carboxylic acid chloride (5.0 g) and pyridine (50 ml) was added 2,2-dimethyl-1,3-dioxolane-4-methanol (2.17 g). After refluxing overnight, the mixture was evaporated. The residue was dissolved in ethyl acetate, filtered, and concentrated. The residue was purified by high performance liquid chromatography (silica gel, loaded and eluted in 2:1 ethyl acetate:hexane). The appropriate fractions were combined and evaporated. Trituration of the residue with hexane yielded 2.60 g (39%) of product, mp 77°-79° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[C:4]#[N:5].C(N(CC)CC)C.C(N(CC)C1C=CN=CC=1)C.[CH2:29]([O:31][P:32]([CH2:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][CH:39]=1)([O:34][CH2:35][CH3:36])=[O:33])[CH3:30]>ClCCl.O>[CH2:35]([O:34][P:32]([CH2:37][C:38]1[CH:39]=[CH:40][C:41]([C:42]([NH:1][C:2]2[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=2[C:4]#[N:5])=[O:43])=[CH:45][CH:46]=1)([O:31][CH2:29][CH3:30])=[O:33])[CH3:36]
Reactant: CCOP(=O)(Cc1ccc(C(=O)Cl)cc1)OCC
Reactant: N#Cc1cc(Br)ccc1N
Agent: CCN(CC)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOP(=O)(Cc1ccc(C(=O)Nc2ccc(Br)cc2C#N)cc1)OCC
Reaction time: 10 h

Procedure:
3.94 Grams (20 mM) of 2-amino-5-bromobenzonitrile, 2.22 g (22 mM) of triethylamine and 0.49 g (4 mM) of 4-diethylaminopyridine were dissolved in 40 ml of anhydrous dichloromethane. To this solution was added dropwise 40 ml of anhydrous dichloromethane solution with 5.81 g (20 mM) of 4-diethoxyphosphinoylmethylbenzoyl chloride at 0° C. with stirring. After the stirring was continued for 10 hours at room temperature, 50 ml of water was added to the reaction mixture, and the whole mixture was extracted with chloroform. The chloroform extracts were dried over anhydrous sodium sulfate and concentrated. Thus obtained residue was purified by means of a silica gel column chromatography (eluted with chloroform:ethyl acetate=1:2). The crude crystals were recrystallized from benzene-n-hexane to yield 2.94 g of 4-diethoxyphosphinoylmethyl-N-(4-bromo-2-cyanophenyl)benzamide as colorless crystals.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[CH:7][CH:6]=1)(=O)C.[CH3:14][Mg]Cl>C1COCC1>[OH:13][C:11]([C:8]1[CH:7]=[CH:6][C:5]([OH:4])=[CH:10][CH:9]=1)([CH3:12])[CH3:14]
Reactant: CC(=O)Oc1ccc(C(C)=O)cc1
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(O)cc1
Temperature: 25 °C
Yield: 47 %

Procedure:
To a solution of 4-acetylphenyl acetate (250 mg, 1.4 mmol) in anhydrous THF (5 mL) cooled to −10° C. under nitrogen was added 3M methylmagnesium chloride solution in THF (2.81 mL, 8.42 mmol) over 10 minutes, keeping the internal temperature below −5° C. The resulting pale yellow solution was allowed to warm to room temperature for 5 hours. The reaction mixture was cooled in an ice bath and quenched with saturated aqueous ammonium chloride solution (20 mL). The resulting clear solution was extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine (50 mL), dried over MgSO4, filtered and concentrated in vacuo. The solid residue was purified by silica gel column chromatography eluting with 10-50% EtOAc in heptanes to afford the title compound as white solid (100 mg, 47%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[NH:7][C:6](=[O:12])[C:5]2([CH3:14])[CH3:13].[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH:20]=O.C(O)(=O)C>C(O)C>[CH3:13][C:5]1([CH3:14])[C:4]2[C:8](=[CH:9][C:10]3[NH:11][C:20]([C:16]4[S:15][CH:19]=[CH:18][CH:17]=4)=[N:1][C:2]=3[CH:3]=2)[NH:7][C:6]1=[O:12]
Reactant: CC1(C)C(=O)Nc2cc(N)c(N)cc21
Reactant: O=Cc1cccs1
Solvent: CCO
Solvent: CC(=O)O
Product: CC1(C)C(=O)Nc2cc3[nH]c(-c4cccs4)nc3cc21
Reaction time: 1 h

Procedure:
A solution of 3.8 g. (20 mmol) 5,6-diamino-3,3-dimethylindolin-2-one, 2.25 g. (20 mmol) thiophene-2-aldehyde and 4 ml. glacial acetic acid in 40 ml. ethanol is heated under reflux for 1 hour and then further boiled for 1 hour, while passing through air. The reaction mixture is then distilled to dryness and the residue stirred up with ethyl acetate and filtered off with suction. The crystallisate obtained is recrystallised from acetone. Yield: 1.7 g. (30% of theory); m.p. 332°-336° C.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:24]=2[CH:33]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[CH3:41][C@@H:39]1[CH2:40][N:35]([C:21]2[C:20]([CH2:19][OH:18])=[CH:33][C:24]3[C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:26][O:27][C:23]=3[C:22]=2[F:34])[CH2:36][C@H:37]([CH3:42])[O:38]1
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204, 693 mg, 1.17 mmol) was dissolved in THF (3 ml) along with acetic acid (0.134 ml, 2.35 mmol). TBAF (1N in THF, 1.290 ml, 1.29 mmol) was added and the reaction was stirred at room temperature for 30 minutes. The reaction was diluted with water and extracted 2× with ethyl acetate. The organic layers were combined, washed with brine, dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography to give the title compound.
Reaction SMILES: [C:1]([NH:7][CH2:8][C:9]([O:11]CC)=[O:10])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[OH-].[Na+:15]>CO>[C:1]([NH:7][CH2:8][C:9]([O-:11])=[O:10])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Na+:15]
Reactant: CCOC(=O)CNC(=O)C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)C(=O)NCC(=O)[O-]
Reaction time: 2 h

Procedure:
To a solution of ethyl N-pivaloylglycinate (11.3 g) in 50 mL of methanol was added 69.2 mL of 1N sodium hydroxide, and the solution stirred for 2 hr. Solvents were evaporated in vacuo. Fresh methanol was added and reevaporated to give 12.45 g of off-white solid.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)[S:6][CH:7]=1.S(Cl)([Cl:22])=O>ClCCl>[Cl:22][CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)[S:6][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(-c2nc(CO)cs2)cc(OC)c1OC
Solvent: ClCCl
Product: COc1cc(-c2nc(CCl)cs2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Hydroxymethyl-2-(3,4,5-trimethoxyphenyl)thiazole (2.0 g) was dissolved in dichloromethane (60 mL), and to the solution thionyl chloride (1.1 g) was added at 0° C. After 30 minutes, the mixture was warmed to room temperature and stirred for 4 hours. The reaction mixture was washed with water and saturated brine and dried over anhydrous sodium sulfate. After concentrating the reaction mixture under reduced pressure, the resultant crude crystals were recrystallized from chloroform-hexane to obtain the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=O)[NH:8][C:6](=O)[C:5]2=[CH:11][CH:12]=1.[ClH:13]>O1CCCC1>[Cl:13][C:11]1[CH:12]=[CH:2][CH:3]=[C:4]2[C:5]=1[CH2:6][NH:8][CH2:9]2
Reactant: Cl
Reactant: O=C1NC(=O)c2cc(Cl)ccc21
Solvent: C1CCOC1
Product: Clc1cccc2c1CNC2

Procedure:
To a solution of 4-chlorophthalimide (60 g) in 1 liter of tetrahydrofuran was added borane-methyl sulfide complex (100 ml of 10M), and the mixture was refluxed overnight. After cooling, 100 ml of 6N hydrochloric acid was added slowly, the mixture refluxed for 2 hours, and then filtered. The filtrate was concentrated under reduced pressure, and the resulting aqueous solution washed with ethyl acetate. The aqueous layer was then basified with ammonium hydroxide and extracted with methylene chloride. Solvent was removed from the extract, and the residue distilled under vacuum to give 4-chloroisoindoline, a white solid, m.p. 48°-50° C.
Reaction SMILES: [H][H].Cl[C:4]1[N:5]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C:6]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)=[CH:7][N:8]=1>[Pd]>[O:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH:18]1[N:5]1[C:6]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)=[CH:7][N:8]=[CH:4]1
Reactant: [H][H]
Reactant: CC1(C)OB(c2cnc(Cl)n2C2CCCCO2)OC1(C)C
Agent: [Pd]
Product: CC1(C)OB(c2cncn2C2CCCCO2)OC1(C)C

Procedure:
1-(Tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazole was prepared by hydrogen with palladium reduction of 2-chloro-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazole.
Reaction SMILES: C1COCC1.C(N(CC)CC)C.[CH2:13]1[CH2:17][CH2:16][CH2:15][CH:14]1[CH:18]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)[C:19]([OH:21])=[O:20]>O>[CH:14]1([C@@H:18]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[C:19]([OH:21])=[O:20])[CH2:15][CH2:16][CH2:17][CH2:13]1
Reactant: Cc1ccc(C(C(=O)O)C2CCCC2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc([C@@H](C(=O)O)C2CCCC2)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
2.4 l of THF and 129.7 g (1.28 mol) of triethylamine are added, with stirring, to a suspension of 560 g (2.57 mol) of the compound from Example I in 4.8 l of water. The resulting solution is heated to 60° C., 155.4 g (1.28 mmol) of (S)-(-)-phenethylamine are added and the resulting suspension is stirred for 2 h at 60° C. The reaction mixture is cooled to 20° C., the precipitate is filtered off by suction, washed with 2.4 l of water/THF (2:1) and dried under reduced pressure.