Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([O:9][C:10]1[C:11]([C:24](=O)[CH3:25])=[CH:12][C:13]2[C:14]([CH3:23])([CH3:22])[CH2:15][CH2:16][C:17]([CH3:21])([CH3:20])[C:18]=2[CH:19]=1)[CH2:7][CH3:8].C(=O)([O-])O.[Na+].OC(C1C=C2C(=CC=1OCCC)C(C)(C)CCC2(C)C)=CCl.[OH-].[Na+]>O1CCOCC1.O.[Cl-].[Na+].O.CN(C)C=O>[C:24]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:10]=1[O:9][CH2:6][CH2:7][CH3:8])[C:17]([CH3:21])([CH3:20])[CH2:16][CH2:15][C:14]2([CH3:22])[CH3:23])#[CH:25]
Reactant: CCCOc1cc2c(cc1C(C)=O)C(C)(C)CCC2(C)C
Agent: CCCOc1cc2c(cc1C(O)=CCl)C(C)(C)CCC2(C)C
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Product: C#Cc1cc2c(cc1OCCC)C(C)(C)CCC2(C)C
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 39 %

Procedure:
Phosphorus oxychloride (0.234 grams, 0.142 ml, 1.52 mmol) was added dropwise to dimethyl formamide (DMF) (4 ml) at room temperature under a nitrogen atmosphere. The solution was stirred for 30 minutes. The 1-(3-propoxy-5,6,7,8-tetrahydro-5,5,8,8,-tetramethylnaphthalen-2-yl)ethanone was added quickly (in one portion) to the orange solution, the reaction solution was heated to 60° C. and was stirred for 12 hours. The obtained dark brown solution was poured into ice water and the aqueous layer was adjusted to pH 7 with solid sodium hydrogen carbonate. Ethyl acetate extraction afforded the crude product, the chloroenal (6-[1-hydroxy,2-chloro-ethenyl]-1,1,4,4-tetramethyl-7-propoxy-1,2,3,4-tetrahydronaphthalene), 0.128 grams, as an orange/brown oil. A solution of the crude chloroenal in dioxane:water (3:2; 5 ml) was added to a solution of NaOH (0.061 grams, 1.52 mmol) in dioxane: H2O (3:2; 20 ml), at 80° C., and the reaction mixture was stirred for 2 hours, to yield an orange reaction solution. The reaction solution was cooled to room temperature, poured into brine and extracted with EtOAc. The organic phase was dried (MgSO4), filtered, and concentrated to afford an orange oil which was purified by radial chromatography (10:1 hexane:ethyl acetate) to give the product 6-ethynyl-1,1,4,4,-tetramethyl-7-propoxy-1,2,3,4-tetrahydronaphthalene (39%) as a yellow oil [1H-NMR (400 MHz, CDCl3): d 7.38(s, 1H, Ar—H), 6.76(s,1H, Ar—H), 3.98 (t, J=6.6 Hz, 2H, OCH3), 3.19 (s, 1H, CH),1.83 (m, 2H, CH2),1.66 (m, 2H, 2CH2),1.26 (s, 6H, 2CH3),1.23 (s, 6H, 2CH3), 0.93 (t, J=7.4 Hz, 3H, CH3)].
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8](=[O:10])[CH3:9])=[N:4][C:3]=1[CH3:11].[CH:12]([C:14]1[O:18][C:17](B(O)O)=[CH:16][CH:15]=1)=[O:13].C(=O)(O)[O-].[Na+].O>CN1C(=O)CCC1.[Pd](Cl)Cl>[CH:12]([C:14]1[O:18][C:17]([C:2]2[S:6][C:5]([NH:7][C:8](=[O:10])[CH3:9])=[N:4][C:3]=2[CH3:11])=[CH:16][CH:15]=1)=[O:13]
Reactant: CC(=O)Nc1nc(C)c(Br)s1
Reactant: O=Cc1ccc(B(O)O)o1
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(=O)Nc1nc(C)c(-c2ccc(C=O)o2)s1
Yield: 37.6 %

Procedure:
To a solution of 3.0 g of N-(5-bromo-4-methylthiazol-2-yl)acetamide in 50 mL of NMP was added 3.0 g of 5-formylfuran-2-ylboronic acid. To the stirred solution was then added 300 mg of 1,1 bis-(diphenylphosphino)-ferrocene) palladium dichloride followed by 10 mL of saturated sodium bicarbonate. The resulting biphasic mixture was irradiated at 150° C. in a microwave for 20 min. The resulting mixture was poured into 200 mL of water and filtered. The filtrate was extracted with ether and the ether layers were combined, dried over sodium sulfate and concentrated. The resulting oil was precipitated with methylene chloride and filtered, yielding 1.2 g of N-(5-(5-formylfuran-2-yl)-4-methylthiazol-2-yl)acetamide as an orange solid which was used without further purification. LC/MS: 251.07 (M+H)/2.18 min.
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][CH2:11][N:12]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)(=[O:8])[O:5]CC)C.C(O)(C)C>Cl>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:12]([CH2:11][CH2:10][CH2:9][P:4](=[O:3])([OH:5])[OH:8])[CH2:13][C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[CH:27][CH:26]=1
Reactant: CCOP(=O)(CCCN(Cc1ccc(Cl)cc1)Cc1ccc(Cl)cc1)OCC
Agent: Cl
Solvent: CC(C)O
Product: O=P(O)(O)CCCN(Cc1ccc(Cl)cc1)Cc1ccc(Cl)cc1

Procedure:
3-[N,N-bis-(4-chlorobenzyl)amino]propyl phosphonic acid diethyl ester (prepared according to Example 1) was dissolved in 8N HCl (25 ml), then a small amount of isopropyl alcohol added to effect solution. After heating for 6 hours, evaporation gave the title compound as a glass.
Reaction SMILES: C([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[CH:16]=[C:15]([CH3:17])[C:14](N3C=NC=N3)=[N:13][C:12]2=[O:23])[CH2:8][C@@H:7]1[N:24]=[N+:25]=[N-:26])(=O)C.O.NN>CC#N.CCO.N>[N:24]([C@@H:7]1[C@@H:6]([CH2:5][OH:4])[O:10][C@@H:9]([N:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[N:13][C:12]2=[O:23])[CH2:8]1)=[N+:25]=[N-:26]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(C)c(-n3cncn3)nc2=O)C[C@@H]1N=[N+]=[N-]
Agent: N
Agent: NN
Solvent: CCO
Solvent: O
Solvent: CC#N
Product: Cc1cnc(=O)n([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c1

Procedure:
1-(5-O-Acetyl-3-azido-2,3-dideoxy-β-D-erythro-pentofuranosyl)-5-methyl-4-(1,2,4-triazol-1-yl)-2-(1H)-pyrimidinone (0.5 g, 1.4 mMol) was dissolved in CH3CN (10 mL) and treated with 85% hydrazine hydrate (0.105 g, 2.1 mMol) for 30 minutes at ambient temperature, analogous to the procedure described in D. Cech and A. Holy, Coll. Czech. Chem. Comm. 42, 2246 (1977). The solvents were evaporated in vacuo and the residue chromatographed on silica gel with 9:1 CHCl3 /MeOH (v/v) as the eluting solvent. Collection and evaporation of appropriate fractions yielded a solid. The solid was dissolved in EtOH (50 mL) containing Ag2O (0.35 g, 1.5 mMol, 1.5 eq) and refluxed for 90 minutes. Filtration of the hot suspension through a bed of celite followed by removal of solvents in vacuo gave a solid. The solid was chromatographed on silica gel and eluted with 20:1 CHCl3 /MeOH (v/v). Combination and evaporation of appropriate fractions gave a solid which was dissolved in NH3 -saturated MeOH (50 mL) for 3 hours. Evaporation of the solvents in vacuo yielded an oil which was chromatographed on silica gel eluted with 20:1 CHCl3 /MeOH (v/v). The appropriate fractions were combined and solvents evaporated in vacuo to give an oil which slowly solidified upon standing: mp =62°-63° C.; UV (nm): at ph 1λmax =326, 212 (ε=7700, 13000), λmin =263(ε=200); at pH 13λmax 322,218(ε=22700, 10800), λmin =246 (ε=400); H'NMR: (DMSO-d6) δ8.46(d, 1H, H4, J=3.28 Hz), 8.28(d, 1H, H6, J=3.23 Hz), 6.00(t, 1H, H1', J=5.08 Hz), 5.31(t, 1H, 5'OH, J=5.12 Hz), 4.4-4.3(m, 1H, H3 '), 3.95-3.89(m, 1H, H4 '), 3.8-3.6(m, 2H, H5 '), 2.5-2.3(m, 2H, H2 '), 2.03(s, 3H, 5-CH3).
Reaction SMILES: [H-].[Na+].O1C[CH2:6][CH2:5][CH2:4]1.[OH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:25]=[CH:24][C:23]([O:26][CH2:27][CH3:28])=[CH:22][N:21]=2)=[CH:16][CH:15]=1.C(Br)CC>O>[CH2:4]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:25]=[CH:24][C:23]([O:26][CH2:27][CH3:28])=[CH:22][N:21]=2)=[CH:18][CH:19]=1)[CH2:5][CH3:6]
Reactant: CCOc1cnc(-c2ccc(CCCCCO)cc2)nc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCCBr
Product: CCCOCCCCCc1ccc(-c2ncc(OCC)cn2)cc1
Reaction time: 5 h

Procedure:
A mixture of 1.2 g of sodium hydride (60-65 wt. %) and 150 ml of tetrahydrofuran was treated with 8.5 g of 2-[4-(5-hydroxy-1-pentyl)phenyl]-5-(ethoxy)pyrimidine while gassing with nitrogen, stirred for 5 hours, treated with 4 g of propyl bromide and subsequently stirred at room temperature overnight. The reaction mixture was treated with 500 ml of water and extracted three times with 50 ml of diethyl ether each time. The combined organic phases were washed twice with 500 ml of concentrated sodium chloride solution each time, dried over magnesium sulfate, filtered and subsequently concentrated. Chromato- graphy of the residue on silica gel with hexane/ethyl acetate (vol. 9:1) and recrystallization from ethyl alcohol gave 7.5 g of pure 2-[4-(5-[propyloxy]-1-pentyl)phenyl]-5-(ethoxy)pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1/[CH:24]=[CH:25]/[C:26](O)=[O:27]>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:26](=[O:27])/[CH:25]=[CH:24]/[C:20]3[O:19][CH:23]=[CH:22][CH:21]=3)[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Reactant: O=C(O)/C=C/c1ccco1
Product: C[C@]1(c2cc(NC(=O)/C=C/c3ccco3)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and (E)-3-furan-2-yl-acrylic acid following procedure I yielded the title compound after purification by preparative HPLC. MS (ISP): m/z=380.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:13]C=O)([CH3:12])[CH3:11])[CH:5]=[CH:6][C:7]=1[F:8].Cl.[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH2:13])([CH3:11])[CH3:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(Cc1ccc(F)c(F)c1)NC=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(N)Cc1ccc(F)c(F)c1

Procedure:
4.00 g (18.5 mmol) of N-[2-(3,4-difluorophenyl)-1,1-dimethylethyl]formamide is dissolved in ethanol, combined with concentrated hydrochloric acid, and refluxed overnight. The reaction solution is poured onto ice water, made alkaline with sodium hydroxide, and extracted with tert-butylmethyl ether. The organic phases are washed with water, dried with sodium sulfate, and evaporated down. Yellow oil. Yield: 3.2 g (92%); mass spectrometry: [M+H]+=186.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@H:4]([C@@H:5]([OH:30])[CH2:6][C@@H:7]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:29])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:20])[CH2:13][CH2:14][C:15](=[O:19])[CH:16]([CH3:18])[CH3:17])[CH2:3]1.[BH4-].[Na+]>CO>[OH:1][C@@H:2]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@H:4]([C@@H:5]([OH:30])[CH2:6][C@@H:7]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:29])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:20])[CH2:13][CH2:14][CH:15]([OH:19])[CH:16]([CH3:18])[CH3:17])[CH2:3]1
Reactant: CC(C)C(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C[C@H](O)[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)C(O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C[C@H](O)[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
To the solution of 3α,6α-dihydroxy-5β-cholestan-24-one (2.6 g) in methanol (200 ml) was added sodium borohydride (2 g) and stirred for one hour under cooling with ice. After decomposition of excess sodium borohydride with aqueous solution of acetic acid, the mixture was evaporated to reduce the volume to about 100 ml and the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over magnesium sulfate and evaporated to give 2.0 g of 3α,6α,24-trihydroxy-5β-cholestane having a melting point of 169°-173° C. after recrystallization from chloroform.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1[N:23]=[C:24]=S>CO.O=[Hg]>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1[NH:23][C:24]1[O:7][C:6]([C:5]2[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=2)=[N:8][N:9]=1
Reactant: NNC(=O)c1ccc(O)cc1
Reactant: FC(F)(F)c1ccc(Cl)c(N=C=S)c1
Agent: O=[Hg]
Solvent: CO
Product: Oc1ccc(-c2nnc(Nc3cc(C(F)(F)F)ccc3Cl)o2)cc1
Temperature: 25 °C
Yield: 88.2 %

Procedure:
Mercury (II) oxide yellow (1.82 g, 8.41 mmol) was suspended in ca. 50 mL of anhydrous methanol. 4-Hydroxybenzoic acid hydrazide (1.28 g, 8.41 mmol) was added to this bright-orange suspension, followed by 2-chloro-5-trifluoromethyl-phenylisothiocyanate (2.0 g, 8.41 mmol). The reaction mixture was brought to reflux and refluxed for 2 hours. The reaction mixture turned pitch-black in color and formed black precipitate. Then it was cooled down to ambient temperature and filtered through a short pad of Celite, then through a short pad of silica gel. Then methanol was removed in vacuo and the resulting grey solid was re-crystallized from ca. 20 mL of EtOAc. The formed white precipitate was filtered, washed with anhydrous Et2O and dried in vacuo to give the title product as a white solid (2.638 g). Yield 88.1%
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[Br:10][CH2:11][CH2:12]Br.[OH-].[Na+]>O>[Br:10][CH2:11][CH2:12][O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:9])[CH:4]=1
Reactant: Cc1cc(O)ccc1Cl
Reactant: BrCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(OCCBr)ccc1Cl

Procedure:
A mixture of 4-chloro-3-methylphenol (100 g.) and 1,2-dibromoethane (158.2 g.) in water (160 ml.) was stirred and heated to reflux during the slow dropwise addition of a solution of sodium hydroxide (30.8 g.) in water (140 ml.). Stirring and heating were continued for a total of 6 hours and the mixture was cooled and extracted exhaustively with ether. The ethereal extract was washed exhaustively with 5N-sodium hydroxide, dried over potassium carbonate, filtered and evaporated. The residual oil was distilled under reduced pressure to give 1-bromo-2-(4-chloro-3-methylphenoxy)ethane, b.p. 106°-112° 10.65 mm.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N+:12]([O-])=O)=[O:5])[CH2:3][CH2:2]1>CO.[Pd]>[CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH2:12])=[O:5])[CH2:2][CH2:3]1
Reactant: O=C(c1ccccc1[N+](=O)[O-])C1CC1
Agent: [Pd]
Solvent: CO
Product: Nc1ccccc1C(=O)C1CC1
Yield: 85 %

Procedure:
A mixture of o-nitrophenyl cyclopropyl ketone (100 mg, 0.52 mmole) and a catalytic amount of 10% Pd on carbon in methanol is stirred under hydrogen at atmospheric pressure until reaction is complete by TLC. The reaction mixture is filtered and the filtrate is concentrated in vacuo to give a bright yellow oil. The oil is flash chromatographed to give the title product as an off-white crystalline solid, 72 mg (85% yield), identified by 1HNMR.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=1[Br:11].C1C(=O)N([Br:20])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[C:9]([CH2:10][Br:20])=[CH:8][CH:7]=[CH:6][C:5]=1[Br:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1c(C)cccc1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(Br)cccc1CBr
Temperature: 25 °C

Procedure:
2-Bromo-6-methyl-benzoic acid methyl ester (2.18 g), NBS (4.89 g), and AIBN (0.486 g) were taken into CCl4 (15 mL) and heated at reflux for 8 h. After cooling to RT, the solid was removed by filtration, and the filtrate was concentrated to give an orange oil as crude material. Purification by chromatography (silica gel, 100 g, 5-15% EtOAc/hexanes) afforded 2-bromo-6-bromomethyl-benzoic acid methyl ester as colorless oil.
Reaction SMILES: [NH2:1][C@H:2]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:20]([O:19][C:17]([C@@H:2]([NH:1][S:31]([C:28]1[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=1)(=[O:33])=[O:32])[CH2:3][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(OCCCC(=O)O)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCC(=O)O)cc1)NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
200 mg of 4-[4-((2S)-2-amino-2-tert-butoxycarbonyl-ethyl)-phenoxy]-butyric acid were dissolved in 2 ml of DMF and cooled to 0° C. 220 mg of 4-chlorobenzenesulfonyl chloride and 270 mg of diisopropylethylamine were added and the reaction mixture was stirred at 0° C. for 2 hours. The reaction mixture was cooled to −25° C. for 16 hours and then warmed to room temperature. The reaction was quenched by the addition of water, and the mixture was extracted three times with dichloromethane. The combined organic phases were dried with sodium sulfate, filtered and the solvent was removed in vacuo. The residue was chromatographed on silica gel eluting with dichloromethane/methanol/water/acetic acid (9/1/0.1/0.1). Yield 84 mg. MS (ES+): m/e=498.1 (M+H)+; 442.1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:27]([CH:29]([CH3:31])[CH3:30])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23]O)=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1.S(Cl)(Cl)=O.[Cl-].[CH:37]1([NH2:42])[CH2:41][CH2:40][CH2:39][CH2:38]1>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:3]([N:27]([CH:29]([CH3:31])[CH3:30])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23][NH:42][CH:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1
Reactant: NC1CCCC1
Reactant: CC(C)N(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Agent: [Cl-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)N(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CNC3CCCC3)c1)=N2

Procedure:
The title compound was prepared from 8-chloro-4-[3-(5-hydroxymethyl-[1,2,3]triazol-1yl)-phenyl]-7-(isopropyl-methyl-amino)-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 96) (220 mg, 0.50 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with cyclopentylamine in DMF according to the method described in Example 45. Obtained as a light yellow solid (170 mg, 67%).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[CH2:14][N:13]([CH2:16][C:17]([F:20])([F:19])[F:18])[CH2:12][CH2:11]2)(=O)C.CO.C([O-])([O-])=O.[K+].[K+]>O>[F:20][C:17]([F:18])([F:19])[CH2:16][N:13]1[CH2:12][CH2:11][C:10]2[C:15](=[C:6]([CH2:5][OH:4])[CH:7]=[CH:8][CH:9]=2)[CH2:14]1
Reactant: CC(=O)OCc1cccc2c1CN(CC(F)(F)F)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: OCc1cccc2c1CN(CC(F)(F)F)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 5 dram vial, added 7-4 (21.7 mg, 0.076 mmol) to methanol (504 μl) and water (252 μl). Added K2CO3 (52.2 mg, 0.378 mmol) and allowed to stir at RT. After 1 h at RT, LCMS showed complete consumption of SM to desired product. Partitioned reaction contents into 10 mL EtOAc+5 mL H2O. Separated layers, back-extracted aqueous with 3×5 mL EtOAc. Dried combined organics over Na2SO4, filtered, concentrated to give 7-5 as a pale yellow oil. Carried crude material forward to subsequent step.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si](C(C)(C)C)(C)C)[C@H:9]1[C:21](=[O:35])[NH:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33]#[N:34])=[CH:25][CH:24]=1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C:33]([C:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:23]([NH:22][C:21]([C@@H:9]2[C@@H:10]([OH:13])[CH2:11][CH2:12][NH:8]2)=[O:35])=[CH:24][CH:25]=1)#[N:34]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)Nc1ccc(C#N)c2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(NC(=O)[C@H]2NCC[C@@H]2O)c2ccccc12
Yield: 63.2 %

Procedure:
A solution of 30C (700 mg, 1.4 mmol) in dry CH2Cl2 (2.8 ml) and TFA (2.8 ml) was stirred at RT for 4 days. The reaction mixture was diluted with CH2Cl2 (35 ml), concentrated to a syrup and stripped with toluene (35 ml) and ether (2×20 ml). The residual syrup was dissolved in water (7.0 ml), basified with 1.0 N NaHCO3 (5.0 ml) to pH 8.0, extracted with CH2Cl2 (2×100 ml) and the combined organic extracts were dried (Na2SO4) and concentrated. Purification by automated flash chromatography (35 g silica gel column, EtOAc/hexane gradient) gave the title compound as an off-white solid (249 mg, 83.4%), m.p. 174–176° C. MS (ES): m/z 282 [M+1]+.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10](=[O:18])[NH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:25]1([CH3:37])[CH:30]=[CH:29][C:28]([S:31]([N:34]=[C:35]=[O:36])(=[O:33])=[O:32])=[CH:27][CH:26]=1>>[C:19]1([CH:7]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10](=[O:18])[N:9]2[C:35]([NH:34][S:31]([C:28]2[CH:29]=[CH:30][C:25]([CH3:37])=[CH:26][CH:27]=2)(=[O:33])=[O:32])=[O:36])[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C1NN(C(c2ccccc2)c2ccccc2)C1c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Product: Cc1ccc(S(=O)(=O)NC(=O)N2C(=O)C(c3ccccc3)N2C(c2ccccc2)c2ccccc2)cc1
Yield: 68 %

Procedure:
Following the procedure of Example 2 and using 1-(diphenylmethyl)-4-phenyl-1,2-diazetidin-3-one (prepared according to Example 1C.) and p-toluenesulfonylisocyanate there is obtained 1.1 g (68%) of the title compound having a melting point of 154°-156° C.
Reaction SMILES: [Cl:1][CH:2]([Cl:7])[C:3]([O:5][CH3:6])=[O:4].[CH3:8][O:9][C:10](=[O:13])[CH:11]=[CH2:12].C[O-].[Na+]>O>[Cl:1][C:2]([Cl:7])([CH2:12][CH2:11][C:10]([O:9][CH3:8])=[O:13])[C:3]([O:5][CH3:6])=[O:4]
Reactant: C=CC(=O)OC
Reactant: COC(=O)C(Cl)Cl
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)CCC(Cl)(Cl)C(=O)OC
Reaction time: 2.5 h

Procedure:
In a 3000 liter reactor, methyl dichloroacetate and acrylic acid methyl ester are added. The stirring is controlled to start and a first controlled temperature is adjusted to 0-60° C. Then, sodium methoxide is added slowly to form a first reaction mixture. After the sodium methoxide is added, the first reaction mixture is stirred at the first controlled temperature for 1-4 hours. Subsequently, 100-300 liter of water is added to wash the first reaction mixture. The first reaction mixture is washed with water twice. The organic phase is then separated and distillation under reduced pressure is set to obtain dimethyl 2, 2-dichloroglutarate.
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]([C:12]#[N:13])[C:9](O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:22])=O>C1(C)C=CC=CC=1>[C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]([C:12]#[N:13])[C:9]([Cl:22])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: N#CC(C(=O)O)=C(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: N#CC(C(=O)Cl)=C(c1ccccc1)c1ccccc1
Yield: 92 %

Procedure:
To 100 ml. of toluene solution containing 50 g. (0.2 mole) of β,β-diphenyl-α-cyanoacrylic acid, 30 g. (0.25 mole) of thionyl chloride is added and the solution is refluxed overnight. After cooling, yellow prisms are collected to give 49.5 g., 92% yield of product, m.p. 157°-158° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH:11]([CH3:25])[C:12]([C:18]1[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=1)([OH:17])[C:13]([F:16])([F:15])[F:14])[C:5](O)=[O:6].[CH3:26][O:27][C:28](=[O:36])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH2:35])[CH:30]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH3:26][O:27][C:28](=[O:36])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH:35][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][C:10]([CH:11]([CH3:25])[C:12]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=3)([OH:17])[C:13]([F:16])([F:14])[F:15])=[C:2]([Cl:1])[CH:3]=2)[CH:30]=1
Reactant: CC(c1ccc(C(=O)O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Reactant: COC(=O)c1cccc(N)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COC(=O)c1cccc(NC(=O)c2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)c1

Procedure:
In analogy to Example 26, step 4, 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-benzoic acid, Example 26, step 3, was reacted with methyl-3-aminobenzoate and HBTU at 80° C. 4 h to give the title compound as a white solid. MS (m/e)=527.3 [M+H+].