Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:19])([F:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])=[O:6].[CH3:20][O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([CH2:29]Br)=[CH:25][CH:24]=1>CCCCCC.CN(C=O)C>[CH3:20][O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=2[N+:15]([O-:17])=[O:16])[C:5](=[O:6])[C:4]([F:18])([F:19])[F:3])=[CH:25][CH:24]=1
Reactant: Cc1ccc(NC(=O)C(F)(F)F)c([N+](=O)[O-])c1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN(C(=O)C(F)(F)F)c2ccc(C)cc2[N+](=O)[O-])cc1
Reaction time: 0.5 h
Yield: 59 %

Procedure:
A portion of 60% NaH in mineral oil (2.9 g, 71.8 mmol, 1.1 eq) was pre-washed with hexane and suspended in dry DMF under nitrogen. The slurry was cooled in an ice bath and a solution of 2,2,2-trifluoro-N-(4-methyl-2-nitrophenyl)-acetamide (16.2 g, 65.3 mmol, 1.0 eq) in dry DMF was added dropwise over 15 min. The cooling bath was removed and the mixture was stirred for 30 min. The reaction mixture was cooled again and a solution of 4-bromomethylbenzoic acid methyl ester (20 g, 65.3 mmol, 1.0 eq) in dry DMF was added dropwise over 10 min. The reaction mixture was stirred at room temperature for 18 h and evaporated under reduced pressure to give a residue. The residue was partitioned between ethyl acetate and water. The organic layer was washed sequentially with water and brine, dried (Na2SO4) and concentrated to give a yellow solid. The yellow solid was purified by column chromatography. (Silica gel 230-400 mesh: eluent CHCl3 MeOH:0→5%) to give 4-{[(4-methyl-2-nitrophenyl)-(2,2,2-trifluoroacetyl)amino]methyl}benzoic acid methyl ester, yield: 59%. 1H NMR (400 MHz, CDCl3): 7.97 (m, 3H); 7.27 (m, 3H); 6.76 (d, J=8 Hz, 1H); 5.66 & 4.26(2H); 3.92 (s, 3H); 2.46(s, 3H).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][NH:16][C:17]([C:19]1[CH:28]=[C:27]([C:29]([O:31]C)=[O:30])[C:26]2[C:25]3[NH:33][C:34]([C:36]([O:38]C)=[O:37])=[CH:35][C:24]=3[C:23]3(OCC[O:40]3)[C:22](=[O:44])[C:21]=2[N:20]=1)=[O:18])=[N+:2]=[N-:3].Cl.C(Cl)Cl.CO.[Li+].[OH-]>C1COCC1.C(Cl)Cl.CO>[N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][NH:16][C:17]([C:19]1[CH:28]=[C:27]([C:29]([OH:31])=[O:30])[C:26]2[C:25]3[NH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:24]=3[C:23](=[O:40])[C:22](=[O:44])[C:21]=2[N:20]=1)=[O:18])=[N+:2]=[N-:3]
Reactant: COC(=O)c1cc2c([nH]1)-c1c(C(=O)OC)cc(C(=O)NOCCOCCOCCOCCN=[N+]=[N-])nc1C(=O)C21OCCO1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: [N-]=[N+]=NCCOCCOCCOCCONC(=O)c1cc(C(=O)O)c2c(n1)C(=O)C(=O)c1cc(C(=O)O)[nH]c1-2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of the product from EXAMPLE 5 (6, 250 mg, 0.4 mMol) in THF (36 mL) was treated with 1N HCl (0.4 mL) was kept at 45-47° C. in for 24 hours. The reaction mixture was cooled to room temperature. TLC (DCM-MeOH 95:5) shows no 4 (Rf=0.75) and one major product (Rf=0.45). The solution was concentrated on a rotary evaporator to remove THF. The resulting mixture was partitioned between EtOAc (100 mL) and saturated aqueous NaCl (50 mL). The organic layer was separated and allowed to stand for 15 minutes. The organic solution was decanted from some aqueous droplets. The last two steps (standing and decanting) were repeated. The resulting EtOAc solution was then evaporated at reduced pressure to give an orange gum. The gum was dissolved in DCM (20 mL) and evaporated at reduced pressure twice to give an orange foam which was further dried in vacuo for 4 hours. The foam was dissolved in 0.5 M LiOH (3.4 mL, 1.7 mMol). The resulting black solution was stirred at room temperature for 24 hours. The reaction mixture was then acidified by dropwise addition of concentrated HCl (0.25 mL, 3 mMol) to give red solution. The solution was partitioned between EtOAc (50 mL), water (5 mL) and saturated aqueous NaCl (5 mL). The organic layer was separated and allowed to stand for 15 minutes. The organic solution was decanted from some aqueous droplets. Evaporation of solvent at reduced pressure gave a red gum. The gum was triturated with DCM and the resulting slurry was evaporated at reduced pressure. The resulting solid was triturated with DCM-hexanes (1:1), the solvent was decanted from the red-brown solid, and the solid was dried in vacuo to afford 7 (94 mg 43%). MS (AP− taken from a MeOH solution) 577 (M+MeOH-1), 545 (M−1).
Reaction SMILES: O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].[C:14]1([C:20]#[CH:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:22][C:23]1[CH:24]=[C:25]([CH:37]=[CH:38][CH:39]=1)[CH:26]=[C:27]1[C:32](=[O:33])[O:31][C:30]([CH3:35])([CH3:34])[O:29][C:28]1=[O:36]>O.ClCCl.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:14]1([C:20]#[C:21][C@@H:26]([CH:27]2[C:28](=[O:36])[O:29][C:30]([CH3:34])([CH3:35])[O:31][C:32]2=[O:33])[C:25]2[CH:24]=[C:23]([CH3:22])[CH:39]=[CH:38][CH:37]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cccc(C=C2C(=O)OC(C)(C)OC2=O)c1
Reactant: C#Cc1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Solvent: O
Solvent: ClCCl
Product: Cc1cccc([C@@H](C#Cc2ccccc2)C2C(=O)OC(C)(C)OC2=O)c1
Temperature: 0 °C
Yield: 86.7 %

Procedure:
A solution of copper (II) acetate monohydrate (20 mg, 0.10 mmol) in water (0.4 ml) was treated with sodium (L)-ascorbate (40 mg, 0.20 mmol), the mixture was stirred until the mixture was turned bright orange (3 min). Subsequently, (R,M)-3-{[4-(2-diphenylphosphanyl-7-methoxy-naphthalen-1-yl)-phthalazin-1-ylamino]-phenyl-methyl}-pentan-3-ol (1st diastereomer, 66.2 mg, 0.10 mmol) and phenylacetylene (0.55 ml, 5.0 mmol) were added, the resulting mixture was stirred for 10 min at 23° C., cooled to 0° C., stirred for 5 min and treated with 5-(3-methylbenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (123 mg, 0.50 mmol). The reaction mixture was stirred vigorously at 0° C. for 66 hrs, diluted with dichloromethane (2 ml) and subjected directly to flash chromatography on silica gel (hexane/EtOAc 3:1→1:1) to give 151 mg of the pure title compound as a white solid. (yield: 87%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[C:4]([CH3:10])[CH:3]=1.[CH3:11][O:12][CH:13](Cl)Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:13]([O:12][CH3:11])=[C:6]([CH:7]=1)[CH:5]=[O:8]
Reactant: COC(Cl)Cl
Reactant: COc1ccc(Cl)cc1C
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1c(C)cc(Cl)cc1C=O
Temperature: 0 °C
Reaction time: 0.05 h
Yield: 17.8 %

Procedure:
Titanium tetrachloride (24.3 g, 0.128 mole) is added to a solution of 4-chloro-2-methylanisole (10 g, 0.064 mol) in methylene chloride (150 ml) at 0° C. alpha,alpha-Dichloromethyl methyl ether (8.04 g, 0.070 mol) was then added dropwise with stirring over a three minute period at 0° C. The mixture was stirred for 30 minutes at 0° C. then poured into a saturated aqueous solution of sodium bicarbonate (700 ml). The organic layer was then separated and the aqueous phase extracted with methylene chloride. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on a silica gel (300 g) column using hexane-ether (6-1) as eluent. Fractions of 15 ml each were collected. Fractions 21-50 were combined and evaporated in vacuo to a white solid (8.9 g). This solid was rechromatographed on silica gel (300 g), eluting with hexane (15 ml fractions). Fractions 174-215 were combined and evaporated in vacuo to give 2.1 g of the title product as a white solid.
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:7]([N:8]=[N+:9]=[N-:10])[CH2:6][C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][C@H:3]1[O:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19].C(N(CC)CC)C.[C:29](OC(=O)C)(=[O:31])[CH3:30]>C(Cl)Cl>[C:29]([NH:1][C@@H:2]1[C@@H:7]([N:8]=[N+:9]=[N-:10])[CH2:6][C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][C@H:3]1[O:16][CH:17]([CH2:18][CH3:19])[CH2:20][CH3:21])(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](N)[C@@H](N=[N+]=[N-])C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N=[N+]=[N-])C1
Temperature: 20 °C
Reaction time: 3 h
Yield: 53.2 %

Procedure:
Ethyl (3R,4R,5S)-4-Amino-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate (14 gm) was added to triethyl amine (10 gm) and methylene chloride (110 ml) and then the contents were cooled to 20° C. To the contents added acetic anhydride (5.6 gm) at 20-25° C. for 1 hour and then stirred for 3 hours at 20-25° C. The reaction mass was quenched into water (140 ml) and then separated the layers. The organic layer was washed with 8% sodium bicarbonate solution (140 ml) and then washed with 30% sodium chloride solution (140 ml). The organic layer was distilled and recrystallized from n-hexane (70 ml) to give 8.5 gm of Ethyl (3R,4R,5S)-4-(Acetylamino)-5-azido-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][C:14]([O:17][C:18]([N:20]([C:28]1[S:29][CH:30]=[CH:31][N:32]=1)[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:19])([CH3:16])[CH3:15].[CH2:33]([Sn:37](Cl)([CH2:42][CH2:43][CH2:44][CH3:45])[CH2:38][CH2:39][CH2:40][CH3:41])[CH2:34][CH2:35][CH3:36]>C1COCC1>[CH3:26][C:23]([O:22][C:21]([N:20]([C:28]1[S:29][C:30]([Sn:37]([CH2:38][CH2:39][CH2:40][CH3:41])([CH2:42][CH2:43][CH2:44][CH3:45])[CH2:33][CH2:34][CH2:35][CH3:36])=[CH:31][N:32]=1)[C:18](=[O:19])[O:17][C:14]([CH3:13])([CH3:15])[CH3:16])=[O:27])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccs1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCC[Sn](CCCC)(CCCC)c1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)s1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
n-Butyl lithium (1.6M in hexanes, 30 mL, 0.48 mol), was added to diisopropylamine (6.7 mL, 0.48 mol) in THF (480 mL) at 0° C. The mixture was stirred at 0° C. for 30 mins then cooled to −78° C. tert-Butyl N-[(2-methylpropan-2-yl)oxycarbonyl]-N-(1,3-thiazol-2-yl)carbamate (12 g, 0.05 mol) was added and solution stirred for 30 minutes. Tributyltin chloride (16.3 mL) was added and solution stirred for 30 minutes before allowing to warm to RT. The reaction was quenched with a saturated aqueous solution of ammonium chloride (20 mL) and the product extracted with ethyl acetate. The organics were dried over sodium sulphate, concentrated in vacuo and chromatographed on silica, eluting with 5-15% ethyl acetate in hexane, to give the desired material as a clear oil (9 g).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][C:19](OC)=[O:20])[CH2:14][CH2:13]2)[CH:9]2[CH2:11][CH2:10]2)=[O:7])=[CH:4][CH:3]=1.[BH4-].[Li+].CO>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH:9]2[CH2:10][CH2:11]2)[C@H:12]2[CH2:13][CH2:14][C@H:15]([CH2:18][CH2:19][OH:20])[CH2:16][CH2:17]2)=[O:7])=[CH:23][CH:24]=1
Reactant: COC(=O)C[C@H]1CC[C@H](N(C(=O)c2ccc(Cl)cc2)C2CC2)CC1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(c1ccc(Cl)cc1)N(C1CC1)[C@H]1CC[C@H](CCO)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-(trans-4-(4-chloro-N-cyclopropylbenzamido)cyclohexyl)acetate (0.182 g, 0.52 mmol) in THF (3 mL) was added lithium borohydride (2 M solution in THF, 3.5 ml) and MeOH (0.5 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was then quenched with saturated NH4Cl (10 mL) and extracted with EtOAc twice. The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude product was purified through silica gel chromatography eluting with 5% MeOH—CH2Cl2. The desired alcohol product was obtained as a white solid (0.115 g). MS: 322 (M+1), C18H24ClNO2.
Reaction SMILES: C([O:5][C:6](=[O:21])[CH2:7][C:8]1[CH:9]=[N:10][C:11]([N:16]2[CH:20]=[N:19][N:18]=[N:17]2)=[CH:12][C:13]=1[CH2:14][CH3:15])(C)(C)C.C1(SC)C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:14]([C:13]1[CH:12]=[C:11]([N:16]2[CH:20]=[N:19][N:18]=[N:17]2)[N:10]=[CH:9][C:8]=1[CH2:7][C:6]([OH:21])=[O:5])[CH3:15]
Reactant: CCc1cc(-n2cnnn2)ncc1CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc(-n2cnnn2)ncc1CC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl[4-ethyl-6-(1H-tetrazol-1-yl)pyridin-3-yl]acetate (165 mg, 0.570 mmol) in DCM containing thioanisole (0.405 ml, 3.42 mmol) was added TFA (0.879 ml, 11.41 mmol) at 0° C. The mixture was stirred at RT overnight, concentrated. The residue was triturated with ether:hexane (1:1) to give [4-ethyl-6-(1H-tetrazol-1-yl)pyridin-3-yl]acetic acid: LC-MS: [(M+1]+=234.17.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:21]=[CH:20][C:8]([O:9][CH:10]([CH3:19])[C:11](=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:6]=1.[BH4-].[Na+]>>[Cl:1][C:2]1[CH:25]=[C:24]([C:26]([F:27])([F:29])[F:28])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:21]=[CH:20][C:8]([O:9][CH:10]([CH3:19])[CH:11]([OH:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:6]=1
Reactant: CCOC(=O)CC(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Product: CCOC(=O)CC(O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1

Procedure:
The process of Example 17 is repeated using ethyl 4-[4-(2-chloro-4-trifluoromethylphenoxy)phenoxy]-3-oxopentanoate (400 mg) and NaBH4 (100 mg) to give ethyl 4-[4-(2-chloro-4-trifluoromethylphenoxy)phenoxy]-3-hydroxypentanoate, MS m/e 432 (M+).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[CH:8][C:9]2[O:14][CH2:13][C:12](=[O:15])[NH:11][C:10]=2[CH:16]=1)([O-:5])=[O:4].[CH2:17](Br)[C:18]#[CH:19].O>CN(C)C=O.C1(C)C=CC=CC=1>[N+:3]([C:6]1[CH:7]=[CH:8][C:9]2[O:14][CH2:13][C:12](=[O:15])[N:11]([CH2:19][C:18]#[CH:17])[C:10]=2[CH:16]=1)([O-:5])=[O:4]
Reactant: C#CCBr
Reactant: O=C1COc2ccc([N+](=O)[O-])cc2N1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: C#CCN1C(=O)COc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
While kept under N2, 0.81 g (20 mmol) of sodium hydride (60% dispersion in oil) was washed with 3 ml of pentanes and suspended in 20 ml of anhydrous dimethylformamide. While cooling with an ice/brine bath, 3.59 g (18.5 mmol) of 6-nitro-2H-1,4-benzoxazin-3(4H)-one was added through a dry powder funnel (exotherm of about 5° C.). An additional 10 ml of DMF was added and the mixture was stirred at 0° C. for 30 minutes. There was then added 2.06 ml (18.5 mmol) of an 80% solution of propargyl bromide in toluene and the mixture was stirred at room temperature for 12 hrs. The reaction mixture was poured into 50 ml of water and extracted with EtOAc (2×50 ml). The organic layers were combined, washed with water (2×50 ml) and dried (MgSO4). The solvent was removed in vacuo to yield 6-nitro-4-propargyl-2H-1,4-benzoxazin-3(4H)-one as a yellow solid, 4 g (93% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.O>ClCCl.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][S:21]([C:18]2[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=2)(=[O:23])=[O:22])[CH2:10][C@H:9]1[CH3:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)O[C@@H]2C[C@@H](C)N(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
To a solution of 1.02 g of (2R,4R)-1-(t-butoxycarbonyl)-4-hydroxy-2-methylpyrrolidine (J. Med. Chem., 1988, 31, 1598-1611) in 10 ml of anhydrous dichloromethane, 1.7 ml of triethylamine and 1.16 g of p-toluenesulfonyl chloride were added, and then the mixture was stirred at room temperature overnight. The reaction solution was mixed with water, and followed by extraction with ethyl acetate twice. The organic layers were combined, washed in turn with water, 1N hydrochloric acid and a 1N aqueous sodium hydroxide solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.54 g of the objective compound as a colorless oily product.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([F:31])=[CH:29][C:25]([C:26]([OH:28])=O)=[C:24]([F:32])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.C[N:41](C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[Cl-].[NH4+]>O.C(OCC)(=O)C.CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([F:31])=[CH:29][C:25]([C:26]([NH2:41])=[O:28])=[C:24]([F:32])[CH:23]=4)=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3cc(F)c(C(=O)O)cc3F)ncc21
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3cc(F)c(C(N)=O)cc3F)ncc21
Reaction time: 0.33 h
Yield: 57.4 %

Procedure:
A mixture of 0.0697 g (0.154 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2,5-difluoro-benzoic acid (I-232), 4 mL of dimethylformamide, 0.0783 g (0.20 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate and 0.103 mg (0.804 mmole) of diisopropylethylamine was stirred for 20 minutes, then 0.0166 g (0.31 mmole) of ammonium chloride was added. The reaction mixture was stirred for 1.5 hours and then 150 mL of ethyl acetate and 25 mL of water was added. The organic layer was washed with 25 mL of ammonium chloride solution, 25 mL of water, 25 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.040 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2,5-difluoro-benzamide (I-241).
Reaction SMILES: [Br-].[CH2:2]([O:4][C:5]([CH2:7][CH2:8][CH2:9][P+](CC)(CC)CC)=[O:6])[CH3:3].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CC(C)([O-])C.[K+]>CC(OC)(C)C>[C:18]1(/[CH:17]=[CH:9]\[CH2:8][CH2:7][C:5]([O:4][CH2:2][CH3:3])=[O:6])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)CCC[P+](CC)(CC)CC
Reactant: O=Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: COC(C)(C)C
Product: CCOC(=O)CC/C=C\c1ccccc1
Reaction time: 8 h

Procedure:
3-Ethoxycarbonylpropyltriethylphosphonium bromide (5.488 g, 12.00 mmol), benzaldehyde (3.820 g, 36.00 mmol) and potassium tert-butoxide (4.040 g, 36.00 mmol) were taken up in MTBE (300 mL) at room temperature and was stirred overnight. The reaction mixture was washed with water (1×100 mL) and the aqueous phase was extracted with MTBE (3×100 mL). Solvent was removed from the combined organic phase under reduced pressure and the resulting oil purified by column chromatography (0–10% EtOAc/n-hexane, silica) to give (Z)-ethyl 5-phenylpent-4-enoate as a pale yellow oil. 1H NMR (CDCl3): δ 7.36–7.31 (m, 2H), 7.28–7.21 (m, 3H), 6.47 (d, 1H, J=11.6, Ph-CH), 5.63 (dt, 1H, J1=11.6, J2=7.2), 4.14 (q, 2H, J=7.2), 2.66 (dq, 2H, J1=7.3, J2=1.7), 2.43 (t, 2H, J=7.6), 1.24 (t, 3H, J=7.1). Contains ca. 33% (E)-ethyl 5-phenylpent-4-enoate
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18]>C1COCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:21]#[C:20][Si:17]([CH3:19])([CH3:18])[CH3:16])=[CH:4][CH:3]=1
Reactant: Fc1ccc(I)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccc(F)cc1
Temperature: 23 °C
Reaction time: 18 h

Procedure:
4-Fluoroiodobenzene (112 mL, 0.97 mol) and triethylamine (176 mL, 1.26 mol) are dissolved in dry THF (1.2 L) and nitrogen gas was bubbled through the solution for about 20 min. Copper (I) iodide (1.08 g, 5.7 mmol) and bis(triphenyphosphine)palladium dichloride (2.15 g, 3 mmol) are added and then trimethylsilylacetylene (178 mL, 1.3 mol) was added dropwise over about 40 min with the temperature being maintained at about 23° C. A large amount of precipitate forms (presumably Et3NHCl) which necessitates mechanical stirring. Following complete addition of the trimethylsilylacetylene the mixture was allowed to stir at room temperature for about 18 h. The mixture was filtered and the solid washed with cyclohexane. The combined filtrates are concentrated under reduce pressure to give a brown oil. Application of this oil to a pad of silica gel followed by elution with cyclohexane gave a yellow solution. Removal of the solvent gave the title compound as a yellow oil; 182.8 g (95%).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([OH:23])[CH2:18][NH:19][CH2:20][CH2:21][CH3:22])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH2:25][C:26](Cl)=[O:27].[OH-].[K+]>O.ClCCl.C(O)(C)C>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]2[CH2:18][N:19]([CH2:20][CH2:21][CH3:22])[C:26](=[O:27])[CH2:25][O:23]2)=[CH:15][CH:16]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(Cl)CCl
Reactant: CCCNCC(O)c1ccc(OCc2ccccc2)cc1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CC(C)O
Product: CCCN1CC(c2ccc(OCc3ccccc3)cc2)OCC1=O
Temperature: 25 °C
Yield: 66.7 %

Procedure:
Sodium hydroxide (22.5 g, 0.56 mol) in water (100 ml) was added to the amine from example 26 (26.0 g, 0.09 mol) in dichloromethane (400 ml) and the solution vigorously stirred at room temperature. Chloroacetylchloride (8.6 ml, 0.11 mol) was then added and the reaction mixture stirred for a further 60 minutes. The layers were separated and the aqueous layer re-extracted with dichloromethane (200 ml). The organic extracts were combined, dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give a colourless oil. Potassium hydroxide (15.0 g, 0.27 mol), isopropyl alcohol (400 ml) and the colourless oil residue were stirred together as an opaque solution with water (30 ml) for 2 hours. The reaction mixture was concentrated in vacuo and the yellow residue dissolved in ethyl acetate (200 ml). This was partitioned with water (200 ml) then brine (200 ml). The organic fraction was dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give the title compound as a white solid (19.9 g, 0.06 mol, 67%). 1H NMR (CDCl3, 400 MHz) δ: 0.95 (t 3H), 1.62 (m, 2H), 3.34 (m, 2H), 3.51 (m, 2H), 4.32 (d, 1H), 4.41 (d, 1H), 4.72 (dd, 1H), 5.04 (s, 2H), 6.98 (d, 2H), 7.31-7.43 (m, 7H). LRMS: m/z 326 (M-H+).