Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].I[CH2:14][CH3:15]>CN(C=O)C>[CH2:14]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][CH:11]=[N:12][C:4]=1[NH2:3])[CH3:15]
Reactant: Nc1ncccc1C(=O)O
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccnc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.2 %

Procedure:
A 60% sodium hydride suspension in mineral oil (1.28 g, 32 mMol) was added to a stirring suspension of 2-aminonicotinic acid (4.21 g, 30 mMol) in DMF (50 mL), and the mixture was gently heated until gas evolution was observed. The suspension was stirred at room temperature for 4 hours, after which a homogeneous amber solution was observed. Iodoethane (4.75 g, 30 mMol) was added, and the mixture was allowed to stir overnight at room temperature. The solution was concentrated in-vacuo, the residue was taken up in 9:1 ethyl acetate/hexane (200 mL), washed with water (5×50 mL), and brine (50 mL), dried over sodium sulfate, then concentrated in-vacuo. The residue was purified over silica gel, eluting with 25%-50% ethyl acetate/hexane, to yield 3.6 g of colorless solids as product. NMR (500 MHz, DMSO) δ 8.20 (dd, 1 H, J=5 Hz, 2 Hz), 8.06 (dd, 1H, J=8 Hz, 2 Hz), 7.16 (s, 2H), 6.63 (dd, 1H, J=8 Hz, 5 Hz), 4.28 (q, 2H, J=7 Hz), 1.30 (t, 3 H, J=7 Hz). Yield=72%.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[S:6][C:7]([Br:10])=[CH:8][CH:9]=1)=[O:4].[C-:11]#[N:12].[K+]>C(O)C>[Br:10][C:7]1[S:6][C:5]([C:3](=[O:4])[CH2:2][C:11]#[N:12])=[CH:9][CH:8]=1
Reactant: [C-]#N
Reactant: O=C(CBr)c1ccc(Br)s1
Agent: [K+]
Solvent: CCO
Product: N#CCC(=O)c1ccc(Br)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.1 %

Procedure:
2-Bromo-1-(5-bromothiophen-2-yl)ethanone (5 g, 17.6 mmol) dissolved in ethanol (100 mL) was treated with an aqueous solution (10 mL) of potassium cyanide (6.19 g, 96.8 mmol) and stirred at ambient temperature overnight. The volatiles were removed in vacuo and crushed iced added to the residue which was acidified to pH 4 with acetic acid. The yellow precipitate that formed was collected by suction filtration and purified by flash chromatography on silica gel using a gradient of 10-30% of ethyl acetate in hexanes to yield a light gray solid (3 g).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:20]=[C:19]2[C:10]([CH:11]=[C:12]3[C:17](=[CH:18]2)[CH:16]=[CH:15][CH:14]=[CH:13]3)=[C:9]2[CH:21]=[CH:22][CH:23]=[CH:24][C:8]=12.[B:25](OC)([O:28]C)[O:26]C.O>C1COCC1>[CH:14]1[C:15]2[C:20]3[C:19]([CH:18]=[C:17]([B:25]([OH:28])[OH:26])[C:16]=2[CH:11]=[CH:12][CH:13]=1)=[CH:10][C:9]1[C:8](=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:7]=3
Reactant: Brc1cc2cc3ccccc3cc2c2ccccc12
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: OB(O)c1cc2cc3ccccc3cc2c2ccccc12
Reaction time: 2 h

Procedure:
52 ml (130 mmol) of n-butyllithium (2.5 M in n-hexane) are added dropwise with vigorous stirring at −78° C. to a suspension of 30.7 g (100 mmol) of 5-bromobenz[a]anthracene in 1000 ml of THF, and the mixture is stirred for a further 2 h. 16.7 ml (150 mmol) of trimethyl borate are added to the red solution in one portion with vigorous stirring, the mixture is stirred at −78° C. for a further 30 min., then warmed to room temperature over the course of 3 h, 300 ml of water are added, and the mixture is stirred for 30 min. The organic phase is separated off and evaporated to dryness in vacuo. The solid is taken up in 100 ml of n-hexane, filtered off with suction, washed once with 100 ml of hexane and dried in vacuo. Yield: 24.8 g (91 mmol), 91%, purity about 90% (NMR) of boronic acid, with varying amounts of boronic anhydride and borinic acid. The boronic acid can be used in this form without further purification.
Reaction SMILES: [C:1]([C:3]1([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=2)[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][CH2:4]1)#[N:2].[ClH:23]>O1CCOCC1>[ClH:23].[ClH:23].[CH3:22][C:18]1[N:17]=[C:16]([C:3]2([C:1]#[N:2])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]2)[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1cccc(C2(C#N)CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cccc(C2(C#N)CCNCC2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl 4-cyano-4-(6-methylpyridin-2-yl)piperidine-1-carboxylate (II-2) (5.41 g, 18 mmole) was added 4M HCl in dioxane (60 mL). The resulting reaction mixture was stirred for 2 h at rt. After this time, LCMS indicated that the reaction was completion. The reaction was concentrated to afford 4-(6-methylpyridin-2-yl)piperidine-4-carbonitrile dihydrochloride (II-3) as a white solid. Analytical LCMS: single peak (214 nm), 1.669 min. This product was used in next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:17])[CH:10]([N:12]1[CH:16]=[N:15][CH:14]=[N:13]1)[CH3:11].[H-].[Na+].[C:20]1([Se:26]Cl)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)(O)[O-].[Na+]>O1CCCC1.O.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:17])[C:10]([Se:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([N:12]1[CH:16]=[N:15][CH:14]=[N:13]1)[CH3:11]
Reactant: CC(C(=O)c1ccc(Cl)cc1Cl)n1cncn1
Reactant: Cl[Se]c1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC([Se]c1ccccc1)(C(=O)c1ccc(Cl)cc1Cl)n1cncn1
Yield: 47 %

Procedure:
To a solution of 2',4'-dichloro-2-(1H-1,2,4-triazol-1-yl)propiophenone (3 g, 11 mMole) in tetrahydrofuran (60 ml) cooled to 5° was added sodium hydride as a 50% by weight dispersion in oil (0.68 g of said dispersion which contained 14 mMole of sodium hydride). Thirty minutes later phenylselenenyl chloride was added in four equal portions over five minutes (2.95 g, 15.4 mMole). Fifteen minutes later glacial acetic acid was added (1.5 ml) and the mixture was poured into water (100 ml). Excess solid sodium bicarbonate was added to basify the solution, which was then extracted with ethyl acetate (3×50 ml). The organic extracts were combined, washed with saturated saline solution (3×50 ml) and dried over anhydrous magnesium sulphate. Evaporation gave an impure oil, weight 5.4 g. Purification was carried out by `flash` column chromatography under slight pressure (2 p.s.i.) on a `Merck Kieselgel 60` (trade mark) 230-400 mesh silica-packed column, eluting with ether and 40°-60° petrol (1:1). The appropriate fractions after collection and evaporation gave a solid which was recrystallized from cyclohexane to give the pure title compound, 2.57 g, m.p. 84°-86° (47% yield).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][C:18]([CH3:20])=O.C(Br)C#C>C1(C)C=CC=CC=1>[CH2:20]([O:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[CH:3]=1)[C:18]#[CH:17]
Reactant: CC(C)=O
Reactant: Oc1ccc2c(c1)OCO2
Agent: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C#CCOc1ccc2c(c1)OCO2
Temperature: 25 °C

Procedure:
A mixture of 12.9 g (0.092 moles) of 5-hydroxy-benzo[1.3]dioxole, 13.0 g (0.092 moles) of anhydrous potassium carbonate in ml 30 of acetone was added with 13.7 g (0.092 moles) of a solution of propargyl bromide in toluene (80% w/w) and the mixture was heated to reflux for 4 hrs. The mixture was then cooled to room temperature, filtered and the filtrate evaporated u.v (20 ° C./ 21 mbar). The residue was purified on silica gel column (eluant n-hexane: isopropyl ether 95: 5 v/v). A liquid product (13.6 g, 95.6% purity) was obtained whose NMR and MS analyses correspond to those of the aforementioned compound is obtained.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]Br.[CH2:15](N)[CH2:16]N.[C-]#[C-].[Li+].[Li+].[Cl-].[NH4+]>>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:15]#[CH:16]
Reactant: NCCN
Reactant: BrCCCCCCOC1CCCCO1
Agent: [C-]#[C-]
Agent: [Cl-]
Agent: [Li+]
Product: C#CCCCCCCOC1CCCCO1
Reaction time: 8 h

Procedure:
6-[(Tetrahydropyran-2-yl)oxy]-1bromohexane (2.0 g) is added, with a mild exotherm, to a stirred mixture of lithium acetylide ethylenediamine (4.9 g) at 20°-25°. The mixture is stirred overnight, then is poured into ice and aqueous ammonium chloride and extracted with ether/pentane. The extracts are dried over magnesium sulfate and concentrated to give the title compound, NMR (CDCl3) 1.3-2.5, 3.3-4.1 and 4.7 δ.
Reaction SMILES: C(=[N:14][C:15]1[CH:16]=[C:17]([C@@:21]2([CH3:30])[NH:26][C:25](=[S:27])[C:24]([CH3:29])([CH3:28])[O:23][CH2:22]2)[CH:18]=[CH:19][CH:20]=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl>>[NH2:14][C:15]1[CH:16]=[C:17]([C@@:21]2([CH3:30])[NH:26][C:25](=[S:27])[C:24]([CH3:29])([CH3:28])[O:23][CH2:22]2)[CH:18]=[CH:19][CH:20]=1
Reactant: CC1(C)OC[C@@](C)(c2cccc(N=C(c3ccccc3)c3ccccc3)c2)NC1=S
Agent: Cl
Product: CC1(C)OC[C@@](C)(c2cccc(N)c2)NC1=S

Procedure:
In analogy to step h) in the synthesis of Building block K, the hydrolysis of (R)-5-[3-(benzhydrylidene-amino)-phenyl]-2,2,5-trimethyl-morpholin-3-thione with hydrochloric acid yielded the title compound (Building block L) as an off-white solid (86% of theory). Mass (calculated) C13H18N2OS [250.37]; (found) [M+H]+=251.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[C:10]([Br:16])[CH:11]=[C:12]([Br:15])[CH:13]=2)[N:8]([CH3:17])[C:7]=1[CH2:18]Br)=[O:5])[CH3:2].[CH2:20]([O:22][C:23](=[O:33])[CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH3:21]>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[C:10]([Br:16])[CH:11]=[C:12]([Br:15])[CH:13]=2)[N:8]([CH3:17])[C:7]=1[CH2:18][N:25]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:24][C:23]([O:22][CH2:20][CH3:21])=[O:33])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(CBr)n(C)c2c(Br)cc(Br)cc12
Reactant: CCOC(=O)CNC(=O)OC(C)(C)C
Product: CCOC(=O)CN(Cc1c(C(=O)OCC)c2cc(Br)cc(Br)c2n1C)C(=O)OC(C)(C)C

Procedure:
Prepared in analogy to that of Example 1(c) from 5,7-dibromo-2-bromomethyl-1-methyl-1H-indole-3-carboxylic acid ethyl ester and tert-butoxycarbonylamino-acetic acid ethyl ester. The title compound, 1H NMR (200 MHz, CDCl3): δ (ppm)=8.36 (s, 1H), 7.62 (s, 1H), 5.18 (s, 2H), 4.4-3.79 (m, 8H), 1.6-1.0 (m, 15H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.C1C(=O)N([Br:16])C(=O)C1>C(#N)C>[Br:16][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[N:4][CH:5]=1
Reactant: COc1ccccn1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COc1ccc(Br)cn1
Temperature: 25 °C
Yield: 84.4 %

Procedure:
A solution of 2-methoxy-pyridine (100 g, 0.92 mole), NBS (180 g, 1.0 mole) in acetonitrile (1.0 L) was stirred at reflux for 21 h. TLC showed reaction complete. The reaction mixture was cooled to room temperature and concentrated. ˜900 ml solvent was collected. The resulting suspension was filtered and washed with n-hexane (˜400 mL). The filtrate was concentrated again to afford crude product. The crude product was distilled at reduced pressure (30° C./˜0.3 mmHg) to afford the title compound as clear oil (146 g, 84%). LCMS (m/z): 190.0 [M+1]+. 1H NMR (400 MHz, CDCl3): δ 3.90 (s, 3H), 6.65 (d, J=8.8 Hz, 1H), 7.62 (dd, J=8.8 Hz, 2.4 Hz, 1H), 8.19 (s, 1H).
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)(=[O:3])[CH3:2].[H-].[Na+].Br[CH2:16][CH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28].O>CN(C)C=O>[C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:16][CH2:17][N:18]2[C:19](=[O:28])[C:20]3[C:21](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:23])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1c[nH]c2ccccc12
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1cn(CCN2C(=O)c3ccccc3C2=O)c2ccccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.5 g (15.7 mmol) of 3-acetyl-1H-indole are dissolved in 100 ml of dimethylformamide, and 0.41 g (15.7 mmol) of sodium hydride and 4.0 g (16 mmol) of N-(2-bromo-ethyl)-phthalimide are added. The reaction mixture is stirred for 14 h at RT and for 3 h at 50°. 20 ml of water are added and the product is isolated by filtration. After drying at 50° under HV, N-[2-(3-acetyl-1H-indol-1-yl)-ethyl]-1H-isoindole-1,3(2H)-dione is obtained; 1H-NMR (CDCl3): 2.5 (3H,s), 4.1 (2H,t), 4.45 (2H,t), 7.2-7.9 (8H,m), 8.35 (1H n).
Reaction SMILES: [Br:1][C:2]1[C:13](=[O:14])[N:12]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:5]2[N:6]=[C:7]([S:10][CH3:11])[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:20].C1(N2C3N=C(S(C)=[O:37])N=CC=3C(C)=C(I)C2=O)CCCC1>>[Br:1][C:2]1[C:13](=[O:14])[N:12]([CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19]2)[C:5]2[N:6]=[C:7]([S:10]([CH3:11])=[O:37])[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:20]
Reactant: CSc1ncc2c(C)c(Br)c(=O)n(C3CCCC3)c2n1
Reactant: Cc1c(I)c(=O)n(C2CCCC2)c2nc(S(C)=O)ncc12
Product: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(S(C)=O)ncc12

Procedure:
Prepared from 6-bromo-8-cyclopentyl-5-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one following the procedure described for 8-cyclopentyl-6-iodo-2-methanesulfinyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one. MS (APCI) Calc'd for C14H16BrN3O2S: 371.01, 369.01. Found: 372.9 (M+1), 371.9. 1H NMR δ (400 MHz, CDCl3) 9.01 (s, 1H), 6.06–5.97 (m, 1H), 2.93 (s, 3H), 2.67 (s, 3H), 2.67 (s, 3H), 2.21–2.11 (m, 2H), 2.10–2.04 (m, 2H), 1.94–1.87 (m, 2H), 1.67–1.62 (m, 2H).
Reaction SMILES: [CH2:1]([C:6]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:7][CH:8]=O)[CH2:2][CH2:3][CH2:4][CH3:5].[C:15]([CH:19]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:17][CH3:18])=[O:16].ClCCl>C(Cl)(Cl)(Cl)Cl>[CH3:18][O:17][C:15](=[O:16])[CH:19]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:1][CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC(=CC=O)CCCCC
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCCCCC(=CC=CC(=O)OC)CCCCC
Yield: 100.1 %

Procedure:
As described in Example 99, 3-pentyl-2-octenal (7.85 g) was treated with (carbomethoxymethylene)triphenylphosphorane (15.3 g) in carbon tetrachloride (100 mL) containing dichloromethane (50 mL) for 3 days at room temperature. The usual work up furnished 10.1 g of 5-pentyl-2,4-decadienoic acid methyl ester which was then saponified in a refluxing mixture of methanol (40 mL) and 2N NaOH (30 mL). After 1 hour the acid was isolated in the usual way to give 8.15 g of 5-pentyl-2,4-decadienoic acid as an oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:11]2[O:12][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)(C)(C)C.O1CCOCC1.[ClH:27]>>[ClH:27].[CH3:19][S:16]([C:13]1[O:12][C:11]([C:8]2([NH2:7])[CH2:10][CH2:9]2)=[CH:15][CH:14]=1)(=[O:18])=[O:17]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(S(C)(=O)=O)o2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(C2(N)CC2)o1
Reaction time: 16 h

Procedure:
[1-(5-Methanesulfonyl-furan-2-yl)-cyclopropyl]-carbamic acid tert-butyl ester (0.430 g, 1.42 mmol) is dissolved in a 4M solution of HCl in dioxane (5.0 mL, 20 mmol) at room temperature. After stirring for 16 hours, the mixture is evaporated under a stream of nitrogen. The resulting oily solid is suspended in ethyl acetate (5 mL), ethyl ether (25 mL) is added, and the mixture is filtered to afford crude title product as a solid, which is used without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[CH:15]=[C:14]([CH2:16][CH2:17][CH:18]=O)[O:13][N:12]=1.[F:20][C:21]([F:36])([F:35])[C:22]1[CH:34]=[CH:33][CH:32]=[CH:31][C:23]=1[CH2:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[CH:15]=[C:14]([CH2:16][CH2:17][CH2:18][N:28]2[CH2:27][CH2:26][N:25]([CH2:24][C:23]3[CH:31]=[CH:32][CH:33]=[CH:34][C:22]=3[C:21]([F:35])([F:36])[F:20])[CH2:30][CH2:29]2)[O:13][N:12]=1
Reactant: COc1ccc(-c2cc(CCC=O)on2)c(OC)c1
Reactant: FC(F)(F)c1ccccc1CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(-c2cc(CCCN3CCN(Cc4ccccc4C(F)(F)F)CC3)on2)c(OC)c1
Yield: 79.7 %

Procedure:
About 2 min after dissolving 3-[3-(2,4-dimethoxypheny)isoxazol-5-yl]propanal (10 mg, 0.04 mmol) and 1-[2-(trifluoromethyl)benzyl]piperazine (8.0, 0.04 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (24 mg, 0.12 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 23.5 hr and followed the same processes as in Example 1 to obtain 15.6 mg (83.2%) of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]#[C:14]C(C)(O)C)[CH:7]=[CH:6]2.[OH-].[Na+].O>C1(C)C=CC=CC=1>[C:13]([C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:9]=1)#[CH:14]
Reactant: COc1ccc2cc(C#CC(C)(C)O)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: C#Cc1ccc2cc(OC)ccc2c1
Temperature: 25 °C
Yield: 79.5 %

Procedure:
A mixture of 4-(6-methoxy-2-naphthyl)-2-methyl-3-butyn-2-ol (16.9 g, 69.7 mmol), powdered sodium hydroxide (3.7 g, 93 mmol) in toluene (350 mL) was refluxed for 16 hours in a flask equipped with a Dean Stark water trap. The mixture was allowed to cool to room temperature and the solvent was evaporated. The residue was purified by flash chromatography using 2.5-3% ethyl acetate in hexane as an eluant. Drying at 68° C. for 20 minutes afforded 2-ethynyl-6-methoxynaphthalene as a light yellow solid (10.1 g, 80%), mp: 111-112° C. Mass spectrum (+EI, M+) m/z 182. 1HNMR (400 MHz, DMSO-d6): δ8.00 (s, 1H), 7.8-7.85 (m, 2H), 7.45 (dd, 1H, J=8.4 Hz and 1.6 Hz), 7.35 (d, 1H, J=2.4 Hz), 7.2 (dd, 1H, J=8.9 Hz and 2.6 Hz), 4.2 (s, 1H), and 3.9 ppm (s, 3H). Elemental Analysis for C13H10O: Calculated: C, 85.69; H, 5.53; N, 0.00. Found: C, 85.50; H, 5.22; N, 0.07.
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7]=[CH2:8])([CH3:4])([CH3:3])[CH3:2].C(OOC(C)(C)C)(C)(C)C.[C:19]1(=[O:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][C:19]1=[O:25])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCOC(C)(C)C
Reactant: O=C1CCCCC1
Agent: CC(C)(C)OOC(C)(C)C
Product: CC(C)(C)OCCCC1CCCCC1=O
Yield: 60 %

Procedure:
A solution of 114 g (1 mole) of allyl tert.-butyl ether and 29.2 g (0.2 mole) of di-tert.-butyl peroxide was added over 2 hours to 980 g (10 moles) of cyclohexanone at 140° C., while stirring, and the mixture was then kept at the same temperature for a further hour. Working up the reaction mixture by distillation gave 2-(3-tert-butoxy-prop-1-yl)-cyclohexanone in 60% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([C:17]2[CH:26]=[C:25]([CH3:27])[C:20]3[NH:21][C:22](=[O:24])[O:23][C:19]=3[CH:18]=2)=[O:16])[CH:12]=[C:11]([Cl:28])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH3:30]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([C:17]2[CH:26]=[C:25]([CH3:27])[C:20]3[N:21]([CH3:30])[C:22](=[O:24])[O:23][C:19]=3[CH:18]=2)=[O:16])[CH:12]=[C:11]([Cl:28])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C(=O)c2cc(Cl)nc(OCc3ccccc3)c2)cc2oc(=O)[nH]c12
Reactant: CI
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2cc(Cl)nc(OCc3ccccc3)c2)cc2oc(=O)n(C)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere and while cooling with ice 220 mg (5.06 mmol) sodium hydride (55%, suspension in mineral oil) were added to 2.00 g (5.07 mmol) 6-(2-benzyloxy-6-chloro-pyridine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one in 10 mL DMF. The reaction mixture was stirred for 30 min at RT. Then 0.312 mL (5.06 mmol) iodomethane were added and the mixture was stirred overnight at RT. The reaction mixture was poured onto water and the precipitated product was suction filtered, washed with water and dried. The residue was stirred with diethyl ether, suction filtered and dried.
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[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.[N:57]1([CH2:63][CH2:64][CH2:65][NH2:66])[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]1.[OH-].[Na+]>O.ClCCl.C(N(CC)CC)C>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:66][CH2:65][CH2:64][CH2:63][N:57]5[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: NCCCN1CCCCC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cc(C(=O)NCCCN2CCCCC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 2 h
Yield: 66.1 %

Procedure:
To a mixture of 0.051 g (0.114 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)-3-methoxy-benzoic acid (I-22), 0.0433 g (0.114 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 2.5 mL of dichloromethane, 0.05 mL of triethylamine was added followed by 0.0162 g (0.114 mmole) of 3-piperidin-1-yl-propylamine. After 2 hours, 6 mL of dichloromethane, 4 mL of water and 0.2 mL of 1 M sodium hydroxide was added. The dichloromethane layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with ethyl acetate-methanol-ammonium hydroxide (91:9:0.75) to give 0.0431 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)-3-methoxy-N-(3-piperidin-1-yl-propyl)-benzamide (I-84).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29](O)=[O:30])=[N:10][CH:11]=[C:12]([C:14](=[O:23])[NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[OH:22])[CH:13]=2)=[CH:4][CH:3]=1.CN(C(O[N:40]1N=N[C:42]2[CH:43]=[CH:44]C=C[C:41]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:41]([NH:40][C:29]([CH2:28][CH2:27][CH2:26][CH2:25][O:24][C:9]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:13][C:12]([C:14]([NH:15][C@@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]2[OH:22])=[O:23])=[CH:11][N:10]=1)=[O:30])[CH2:42][CH2:43][CH3:44]
Reactant: O=C(O)CCCCOc1ncc(C(=O)N[C@@H]2CCCC[C@H]2O)cc1-c1ccc(Cl)cc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCNC(=O)CCCCOc1ncc(C(=O)N[C@@H]2CCCC[C@H]2O)cc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.5 %

Procedure:
5-[3-(4-Chloro-phenyl)-5-((1R,2R)-2-hydroxy-cyclohexylcarbamoyl)-pyridin-2-yloxy]-pentanoic acid (20 mg) was dissolved in DMF (1 mL). To the solution was added TBTU (16 mg), N,N-diisopropylethyl amine (0.038 mL, 42) and (N)-butylamine (0.005 mL). The reaction mixture was stirred for 16 h at room temperature. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica (dichloromethane/methanol gradient) to yield 21 mg of the title compound as a white solid, MS (ISP) 502.1, 504.1 (M+H)+.