Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH3:21][C:22]1([CH3:34])[CH2:28][CH2:27][CH2:26][NH:25][C:24]2[CH:29]=[CH:30][C:31]([NH2:33])=[CH:32][C:23]1=2.Cl>O1CCOCC1.COCCO>[Cl:20][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[N:7][C:2]([NH:33][C:31]2[CH:30]=[CH:29][C:24]3[NH:25][CH2:26][CH2:27][CH2:28][C:22]([CH3:34])([CH3:21])[C:23]=3[CH:32]=2)=[N:3][CH:4]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: CC1(C)CCCNc2ccc(N)cc21
Agent: Cl
Solvent: COCCO
Solvent: C1COCCO1
Product: CC1(C)CCCNc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)cc21
Yield: 17.2 %

Procedure:
Combined N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (112 mg, 0.330 mmol), 5,5-Dimethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamine (76 mg, 0.399 mmol), 4 N HCl in dioxane (99 ul) and 2-methoxyethanol (4 mL). Heated reaction to 120° C. for 24 hours. Concentrated under reduced pressure and purified with normal phase chromatography to yield a brown solid, N-{(1R,2R)-2-[5-Chloro-2-(5,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide (28 mg, 17%). LCMS: m/z=493.30 (M+H+), 1H NMR (400 MHz, CDCl3) δ 7.89 (s, 1H), 7.25 (m, 2H), 7.06 (br s, 1H), 6.68 (d, 1H, J=8.1 Hz), 5.76 (br s, 1H), 5.42 (m, 1H), 3.82 (m, 1H), 3.75 (m, 2H), 3.53 (m, 2H), 3.21 (m, 1H), 3.03 (m, 2H), 2.78 (s, 3H), 2.16 (m, 2H), 1.88 (m, 2H), 1.79 (m, 2H), 1.64 (m, 2H), 1.40 (m, 6H), 1.33 (m, 4H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11]([CH3:24])=[CH:12][N:13]2C(OC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].C(Cl)(Cl)Cl>CO.O>[CH2:1]([O:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11]([CH3:24])=[CH:12][NH:13]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)n1cc(C)c2c(OCc3ccccc3)c(OC)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1ccc2[nH]cc(C)c2c1OCc1ccccc1
Yield: 98.7 %

Procedure:
The 4-benzyloxy-5-methoxy-1-methoxycarbonyl-3-methylindole (5.3 g) was dissolved in methanol (60 ml). A solution of potassium hydroxide (40.0 g) in water (60 ml) was added to the solution, and the mixture was heated under reflux for 2 hours. The reaction mixture was poured into water, and chloroform extraction was conducted. The extract was washed with saturated saline and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (Wako Gel C-200, 100 g). Elution with chloroform gave 4-benzyloxy-5-methoxy-3-methylindole (4.3 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C@H:4]([OH:21])[C@@H:5]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[H-].[Na+].Cl.C(OCC1C=CC=CC=1)C1C=CC=CC=1>CN(C)C=O.CCOCC>[CH3:1][O:2][C:3](=[O:22])[C@H:4]([O:21][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C@@H:5]([NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: BrCc1ccccc1
Reactant: COC(=O)[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccc(COCc2ccccc2)cc1
Solvent: CCOCC
Product: COC(=O)[C@H](OCc1ccccc1)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
(S)-3-t-butoxycarbonylamino-(R)-2-hydroxy-4-cyclohexylbutyric acid methyl ester (4.58 g., 14.52 mmol) was dissolved in anhydrous dimethylformamide (30 ml.) together with benzyl bromide (2.6 ml., 21.7 mmol) and cooled to 0° C. Sodium hydride (freed of oil by washing with hexane, 450 mg., 19.6 mmol) was added in one portion and the mixture was stirred under nitrogen and allowed to warm to 25° C. over a period of about 15 minutes. The mixture was poured slowly into a stirred ice-cooled mixture of ether (500 ml.) and excess aqueous 1N hydrochloric acid, and was then combined with two previous reaction mixtures where a total of 4.27 mmol (1.34 g.) of this hydroxy methyl ester had been etherified and worked up in an identical fashion. The ether layer was separated and the aqueous layer was extracted thoroughly with ether. The ether layers were combined and washed with 1M lithium chloride solution (2×30 ml.), and dried over magnesium sulfate. The concentrate was chromatographed on silica (0.032-0.064 mm) in 1:6 ether-hexane. Several impure fractions were combined, concentrated, and rechromatographed on 50 g. silica, eluting with 1:10 ether-hexane. The pure fractions combined and concentrated gave 6.45 g. (85%) of the benzyl ether.
Reaction SMILES: CC([O-])(C)C.[K+].[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([OH:28])[CH2:22][NH:23][C:24](=[O:27])[CH2:25]Cl)=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CC(O)(CC)C.C1COCC1>[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:22][NH:23][C:24](=[O:27])[CH2:25][O:28]2)=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(CCl)NCC(O)c1ccc(OCc2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCC(C)(C)O
Solvent: C1CCOC1
Product: O=C1COC(c2ccc(OCc3ccccc3)cc2)CN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of KOtBu (6.68 g; 59.5 mmol) in 2-methyl-2-butanol (100 mL) was added dropwise a solution of N-[2-(4-benzyloxy-phenyl)-2-hydroxy-ethyl]-2-chloro-acetamide (17.30 g; 54.1 mmol) in THF (100 mL). The resulting mixture was stirred for 1 hour at RT and then concentrated in vacuo. The residue was dissolved in CH2Cl2 and treated with a 1M aqueous solution of HCl, at 0° C. The layers were separated and the aqueous layer extracted with CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo to afford 6-(4-benzyloxy-phenyl)-morpholin-3-one (14.10 g).
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:15]=1>CO>[CH3:20][C:17]1[CH:18]=[CH:19][C:14]2[N:15]([CH:2]=[C:3]([C:4]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[O:5])[N:13]=2)[CH:16]=1
Reactant: Cc1ccc(N)nc1
Reactant: O=C(CBr)C(=O)c1ccccc1
Solvent: CO
Product: Cc1ccc2nc(C(=O)c3ccccc3)cn2c1
Temperature: 4 °C
Reaction time: 15 h
Yield: 30.7 %

Procedure:
To a solution of 454 mg of 3-bromo-1-phenylpropane-1,2-dione in 1 mL of methanol is added dropwise at 4° C. a solution of 179 mg of 2-amino-5-methylpyridine in 4 mL of methanol. The reaction mixture is stirred for 15 hours at 4° C. and then refluxed for 2 hours. After evaporating off the solvent under reduced pressure, the residue is taken up in dichloromethane and basified with normal sodium hydroxide solution. The basic aqueous phase is extracted with dichloromethane and the combined organic phases are washed with water and then with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The residue is chromatographed on a cartridge of 20 g of silica, eluting with an 85/15 and then 65/35 mixture of cyclohexane and ethyl acetate. The fractions containing the expected product are combined and concentrated to dryness under reduced pressure to give 120 mg of (6-methylimidazo[1,2-a]pyridin-2-yl)phenylmethanone in the form of a beige-colored solid.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([CH3:9])=[CH:5][C:4]([C:10]([OH:12])=O)=[CH:3]1.[C:13]([O:17][C:18](=[O:35])[NH:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[C:22]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:21]=1)([CH3:16])([CH3:15])[CH3:14].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1.O>[C:13]([O:17][C:18](=[O:35])[NH:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:10]([C:4]2[CH:5]=[C:6]([CH3:9])[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=2)=[O:12])=[C:22]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:21]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)c(NCc2ccccc2)c1
Reactant: Cc1cc(C(=O)O)cn(C)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2ccc(NC(=O)OC(C)(C)C)cc2NCc2ccccc2)cn(C)c1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1,5-Dimethyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid D1 (5.000 g; 16 mmol) and (4-Amino-3-benzylamino-phenyl)-carbamic acid tert-butyl ester E-1.5 (3.200 g; 19 mmol) are dissolved in THF and and cooled to 0° C. DIPEA (6.186 g; 48 mmol) is then added, the mixture is stirred for 15 min Finally HATU (12.133 g; 32 mmol) is added. The mixture is stirred at room temperature for 1 hr. The reaction is diluted with water and extracted with MeOH/DCM. The combined organic layer is dried over Na2SO4 and concentrated in vacuum. The residue is used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C:4](=O)[CH2:3]1.[CH2:14]([NH2:17])[C:15]#[CH:16]>>[CH3:1][C:2]1([CH3:13])[CH2:3][C:4]2[N:17]=[CH:14][CH:15]=[CH:16][C:5]=2[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]1=2
Reactant: CC1(C)CC(=O)Cc2ccccc21
Reactant: C#CCN
Product: CC1(C)Cc2ncccc2-c2ccccc21
Yield: 49 %

Procedure:
The title compound is prepared from 4,4-dimethyl-3,4-dihydro-1H-naphthalen-2-one and propargylamine following a procedure analogous to that described in Step 1 of Intermediates 1 and 2. Yield: 49% of theory; LC (method 1): tR=2.40 min; Mass spectrum (ESI+): m/z=210 [M+H]+.
Reaction SMILES: O=[C:2]1[NH:8][CH2:7][CH2:6][CH:5]([C:9]([O-])=[O:10])[CH2:4][CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C1COCC1.O>[NH:8]1[CH2:2][CH2:3][CH2:4][CH:5]([CH2:9][OH:10])[CH2:6][CH2:7]1
Reactant: O=C1CCC(C(=O)[O-])CCN1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCC1CCCNCC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
A solution of the obtained 7-oxoazepane-4-carboxylate (2.02 g) in THF (29 mL) was added dropwise to a suspension of lithium aluminum hydride (2.07 g) in THF (80 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 3 hr and at 60° C. overnight. The reaction mixture was ice-cooled, diluted with THF (200 mL), and water (2.02 mL) was slowly added dropwise. Furthermore, 15% aqueous sodium hydroxide solution (2.02 mL) was added dropwise, then water (4.04 mL) was added, and the mixture was stirred at room temperature for 3 hr. The solid was separated by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (1.41 g).
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH3:36])[C:5]([C:7]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:11]([OH:21])[N:10]=[C:9]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[N:8]=1)=[O:6].C(OC1C(=O)N=C(CC2C=CC=CC=2C2C=CC=CC=2)N2CCN(C)C(=O)C=12)C1C=CC=CC=1>>[CH2:14]([O:13][C:12]1[C:11](=[O:21])[N:10]=[C:9]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[N:8]2[CH2:2][CH2:3][N:4]([CH3:36])[C:5](=[O:6])[C:7]=12)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CN(CCO)C(=O)c1nc(Cc2ccccc2-c2ccccc2Cl)nc(O)c1OCc1ccccc1
Agent: CN1CCn2c(Cc3ccccc3-c3ccccc3)nc(=O)c(OCc3ccccc3)c2C1=O
Product: CN1CCn2c(Cc3ccccc3-c3ccccc3Cl)nc(=O)c(OCc3ccccc3)c2C1=O
Yield: 52 %

Procedure:
9-Benzyloxy-6-(2′-chloro-biphenyl-2-ylmethyl)-2-methyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (11-02) (201 mg, 52.5%) was synthesized as a white solid from 5-benzyloxy-2-(2′-chloro-biphenyl-2-ylmethyl)-6-hydroxypyrimidine-4-carboxylic acid (2-hydroxyethyl)-methyl-amide (10-02) (400 mg, 0.795 mmol) following the procedure as described for 9-benzyloxy-6-biphenyl-2-ylmethyl-2-methyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (11-01).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:12][CH2:13][CH3:14])[C:7](=[O:15])[N:6]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:5]=2[NH:4][N:3]=1.[CH2:23](Cl)[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=O.C([O-])([O-])=O.[K+].[K+].[I-].[K+]>C(#N)C>[CH2:16]([N:6]1[C:5]2=[N:4][N:3]3[CH:23]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[NH:1][C:2]3=[C:10]2[C:9](=[O:11])[N:8]([CH2:12][CH2:13][CH3:14])[C:7]1=[O:15])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCCn1c(=O)c2c(N)n[nH]c2n(Cc2ccccc2)c1=O
Reactant: O=C(CCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCCn1c(=O)c2c(nn3cc(-c4ccccc4)[nH]c23)n(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 41.2 %

Procedure:
A suspension of 3-amino-7-benzyl-5-propylpyrazolo [3,4-d]pyrimidine-4,6(5H,7H)-dione (2.0 g), phenacyl chloride (4.4 g), K2CO3 (2.5 g) and potassium iodide (1.4 g) in acetonitrile (150 ml) was stirred for 3 days at room temperature. Precipitating crystals were collected by filtration and washed with water. The filtrate was concentrated to give a syrup. The syrup was crystallized by the addition of isopropyl ether. The crystals were combined and dissolved in toluene (200 ml). To the solution was added p-toluenesulfonic acid (0.1 g), followed by heating for 3 hours under reflux. The reaction mixture was concentrated to dryness and then was added isopropyl ether to give crude crystals, followed by recrystallization from methanol to afford colorless crystals (1.1 g, 43%), m.p. 261°-262° C.
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][NH:3][C:2]1=O.B.C1COCC1>C1COCC1>[CH2:5]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:1][CH2:2][NH:3][CH2:4]1
Reactant: O=C1Cc2ccccc2CCN1
Agent: B
Solvent: C1CCOC1
Product: c1ccc2c(c1)CCNCC2
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 69.9 %

Procedure:
A solution of 4,5-dihydro-1H-benzo[d]azepin-2(3H)-one (3.5 mmol) was in THF (25 mL) was stirred at 0° C. for 5 min. A solution of 1M BH3.THF (4 mL) was added dropwise to the reaction mixtureat 0° C. over a period of 30 min. The ice bath was removed and the reaction stirred at RT for 30 min. The reaction mixture was heated at 60° C. overnight, then cooled to 0° C. and additional 1M BH3.THF (2.5 mL) was added dropwise into the reaction mixtureat 0° C. over a period of 15 min. The ice bath was removed and it was stirred at RT for 30 min then heated at 60° C. for 7 h. The reaction mixture was cooled to RT, then further cooled with an ice-bath. The reaction was quenched by the addition of 2M HCl (15 mL). The mixture was heated for 30 min and then 20% NaOH (7.5 mL) was added with ice cooling. The solution was extracted with chloroform (3×) and the organic layer was washed with H2O. The organic layer was dried (Na2SO4), concentrated and redissolved in 2 mL of EtOAc and acidified with 3M HCl/EtOAc. The solid was filtered and dried under vacuum to obtain 2,3,4,5-tetrahydro-1H-benzo[d]azepine as a shiny powder (0.36 g, 69% yield). LC-MS (EI) m/z: 148.2 (M+H+).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[CH:23][CH:24]=3)[CH2:19]2)[CH2:15][CH2:16][CH3:17])[CH2:10][CH2:9]1)C1C=CC=CC=1>C(O)C.[OH-].[Pd+2].[OH-]>[CH3:29][O:28][C:22]1[CH:21]=[C:20]2[C:25]([CH2:26][CH2:27][CH:18]([N:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH2:15][CH2:16][CH3:17])[CH2:19]2)=[CH:24][CH:23]=1
Reactant: CCCN(C1CCN(Cc2ccccc2)CC1)C1CCc2ccc(OC)cc2C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCCN(C1CCNCC1)C1CCc2ccc(OC)cc2C1
Reaction time: 20 h
Yield: 96 %

Procedure:
A solution of (1-benzyl-piperidin-4-yl)-(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amine (6.86 g, 14.47 mmol) in absolute ethanol (100 mL) was poured onto a slurry of 20% Palladium hydroxide/C (1.4 g) in absolute ethanol (10 mL). The mixture was placed under a hydrogen atmosphere on the Parr shaker at 50 psi for 20 h. The reaction mixture was filtered, and concentrated to give (7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-piperidin-4-yl-propyl-amine (4.2 g).
Reaction SMILES: [C:1]1([PH:7](=[O:15])[CH:8]([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][CH2:17][CH2:18]Br>>[C:1]1([P:7](=[O:15])([CH2:16][CH2:17][CH3:18])[CH:8]([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(OCC)[PH](=O)c1ccccc1
Reactant: CCCBr
Product: CCCP(=O)(c1ccccc1)C(OCC)OCC

Procedure:
Following a procedure analogous to that of Example 11 but using phenyl(diethoxymethyl)phosphine oxide instead of tertiary-butyl(diethoxymethyl)phosphine oxide and n-propyl bromide instead of iso-butyl bromide there is obtained phenyl(n-propyl)(diethoxymethyl)phosphine oxide as a colourless oil. 31P NMR 35.845 ppm (CDCl3)
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][OH:14])=O)(C)(C)C.[CH3:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[OH:22].CCOC(/N=N/C(OCC)=O)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.FC(F)(F)C(O)=O>C1COCC1>[CH3:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[OH:22].[CH3:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[O:14][CH2:13][C@@H:9]1[CH2:10][CH2:11][CH2:12][NH:8]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cc1ccncc1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: Cc1ccncc1OC[C@@H]1CCCN1
Reaction time: 0.08 h

Procedure:
(S)-1-t-Butoxycarbonyl-2-pyrrolidinemethanol (590 mg, 2.94 mmol), 4-methyl-3-pyridinol (320 mg, 2.94 mmol), DEAD (509 uL, 3.23 mmol) and PPh3 (848 mg, 3.23 mmol) in THF (100 mL) were allowed to react as described in Example 2a. Solvent was removed, and the residue was chromatographed with CHCl3 /MeOH (10:1) to provide 1.8 g of the crude mixture. This material was immediately treated with trifluoroacetic acid (2.0 mL) at room temperature for 3 hours, and excess trifluoroacetic acid was removed under reduced pressure. Water (3 mL) and EtOAc (20 mL) were added, and the mixture was stirred for 5 minutes. The organic layer was decanted, and the residue washed with EtOAc (3×10 mL). The combined organic layers were dried (Na2SO4) and evaporated. The crude product was purified by flash chromatography on silica gel eluting with CHCl3 /MeOH/NH4OH (10:1:0.02 and 10:1.5:0.1) to provide 52 mg (14% yield from 4-methyl-3-pyridinol) of the title compound. TLC Rf 0.18 (10:1:0.02 CHCl3 /MeOH/NH40H). MS (DCI/NH3) m/e 193 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 8.16 (s, 1H, ArH), 8.12 (d, J=6.9 Hz, 1H, ArH), 7.07 (d, J=6.9 Hz, 1H, ArH), 4.12-4.00 (m, 2H, OCH2), 3.75-3.63 (m, 1H, NCH), 3.18-3.02 (m, 2H, NCH2), 2.24 (s, 3H, NCH3), 2.08-1.64 (m, 4H, 2CH2).
Reaction SMILES: [Cl:1][C:2]1([Cl:12])[C:5]2([CH2:10][CH2:9]O[CH2:7][CH2:6]2)[CH2:4][C:3]1=[O:11].[CH2:13]=C1CCCCC1.ClC(Cl)(Cl)C(Cl)=O>CCOCC>[Cl:1][C:2]1([Cl:12])[C:5]2([CH2:10][CH2:9][CH2:13][CH2:7][CH2:6]2)[CH2:4][C:3]1=[O:11]
Reactant: C=C1CCCCC1
Reactant: O=C1CC2(CCOCC2)C1(Cl)Cl
Agent: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCOCC
Product: O=C1CC2(CCCCC2)C1(Cl)Cl
Reaction time: 3 h
Yield: 97.2 %

Procedure:
This was prepared according to a literature procedure (Tetrahedron 1993, 49(36), 8159). Activated zinc (5.00 g; 76.5 mmol) (prepared according to Example 150, Step B) and methylenecyclohexane (2.40 g; 25.0 mmol) in dry ether (100 mL) under nitrogen were mixed in a 250 mL 3-neck flask with an addition funnel and condenser attached. The mixture was placed in a sonic bath at 25° C. Trichloroacetyl chloride (5.91 g; 32.5 mmol) in dry ether (50 mL) was added dropwise as the solution was sonicated. The sonication was continued for 3 hours. The mixture was filtered through Celite® and the solution was washed with saturated aqueous ammonium chloride solution (50 mL) and aqueous sodium bicarbonate solution (50 mL). The solution was dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was passed through a plug of silica gel using ether. The filtrate was evaporated to give the product as a yellow oil (5.03 g).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:32])[C:6]2[CH:11]=[C:10]([N:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]4([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=5[OH:28])[CH2:21][CH2:20]4)[C:13]3=[O:29])[C:9]([CH3:30])=[C:8]([F:31])[CH:7]=2)[CH2:3][CH2:2]1.Br[CH2:34][CH2:35][Cl:36].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Cl:36][CH2:35][CH2:34][O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1([NH:18][C:14]2[C:13](=[O:29])[N:12]([C:10]3[CH:11]=[C:6]([CH:7]=[C:8]([F:31])[C:9]=3[CH3:30])[C:5]([NH:4][CH:1]3[CH2:2][CH2:3]3)=[O:32])[CH:17]=[CH:16][N:15]=2)[CH2:21][CH2:20]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3O)CC2)c1=O
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3OCCCl)CC2)c1=O

Procedure:
N-Cyclopropyl-3-fluoro-5-[3-[[1-(2-hydroxyphenyl)cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzamide (Example 259c 5 g), 1-bromo-2-chloroethane (9.58 mL) and cesium carbonate (37.5 g) were stirred together in acetonitrile (200 mL) at 80° C. under nitrogen for 16 h. The cooled reaction mixture was evaporated to dryness, diluted with water (500 mL) and extracted with dichloromethane (3×300 mL). The combined organics were dried (MgSO4), filtered and evaporated. The residue was triturated with 1:1 iso-hexane:diethyl ether to give the subtitle compound (4.60 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=3)[CH:10]=2)[N:5]=[C:4]([O:25][CH:26]([CH3:28])[CH3:27])[CH2:3]1.[Li+].[OH-]>C1COCC1.CCO>[CH3:1][C:2]1([CH3:29])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:23][CH:24]=3)[CH:10]=2)[N:5]=[C:4]([O:25][CH:26]([CH3:27])[CH3:28])[CH2:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC(OC(C)C)=N3)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)OC1=Nc2ccc(C#Cc3ccc(C(=O)O)cc3)cc2C(C)(C)C1

Procedure:
A solution of 0.023 mg (0.06 mmol) of ethyl 4-[(4,4-dimethyl-2-iso-propoxy-3,4-dihydro-6-quinolinyl)ethynyl]benzoate (Compound 6) in 2 ml of THF, 1 ml of EtOH, and 2 ml of 1N LiOH was stirred at room temperature for 1 h. Aqueous work up yielded the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5](=[O:9])[N:4]([CH3:10])[C:3]1=[O:11].[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[C:12]([C:6]1[C:5](=[O:9])[N:4]([CH3:10])[C:3](=[O:11])[N:2]([CH3:1])[C:7]=1[CH3:8])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cc(=O)n(C)c(=O)n1C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: Cc1c(C(=O)c2ccccc2)c(=O)n(C)c(=O)n1C
Temperature: 0 °C
Yield: 28.1 %

Procedure:
A mixture of 1,3,6-trimethyl-compound 2 (12.3 g, 80 mmol), benzoyl chloride (11.5 g, 9.5 mL, 82 mmol) and anhydrous zinc chloride (10.8 g, 79 mmol) in toluene (100 mL) was heated to reflux for 6 h. The mixture was poured over ice (200 g), and the separated toluene layer was concentrated in vacuo. The crude residue was purified by flash chromatography to yield 3 (5.8 g, 28%): mp 132-134° C.; MS (ES+) (m/z): [M+1]+ calculated for C14H15N2O3, 259.28. found 259.09. This compound matched analytical data as reported (see, e.g., Tsupak et al., Khimiya Geterotsiklicheskikh Soedinenii. 7:1096-1102 (2003)).