Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:20]=[C:19]([CH3:21])[C:13]2[N:14]=[C:15]([NH2:18])[N:16]=[N:17][C:12]=2[CH:11]=1.Br[C:23]1[CH:24]=[C:25]([S:29]([NH:32][CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:20]=[C:19]([CH3:21])[C:13]2[N:14]=[C:15]([NH:18][C:23]3[CH:24]=[C:25]([S:29]([NH:32][CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])(=[O:30])=[O:31])[CH:26]=[CH:27][CH:28]=3)[N:16]=[N:17][C:12]=2[CH:11]=1
Reactant: COc1ccc(Cl)c(-c2cc(C)c3nc(N)nnc3c2)c1
Reactant: CN(C)CCNS(=O)(=O)c1cccc(Br)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1ccc(Cl)c(-c2cc(C)c3nc(Nc4cccc(S(=O)(=O)NCCN(C)C)c4)nnc3c2)c1
Temperature: 100 °C

Procedure:
7-(2-chloro-5-methoxy-phenyl)-5-methyl-benzo[1,2,4]triazin-3-ylamine (0.333 mmol, 1.0 equiv), 3-bromo-N-(2-dimethylamino-ethyl)-benzenesulfonamide (0.499 mmol, 1.5 equiv), Cs2CO3 (0.999 mmol, 3.0 equiv), Pd2(dba)3 (0.0333 mmol, 0.1 equiv), and Xantphos (0.0666 mmol, 0.2 equiv) were dissolved in 7 mL dioxane. The reaction was placed under an argon atmosphere and refluxed at 100° C. for 18 h. The organics were filtered to remove excess inorganics, dissolved in EtOAc, washed with saturated NaHCO3 and brine, dried over Na2SO4 and concentrated under reduced pressure to give 3-[7-(2-chloro-5-methoxy-phenyl)-5-methyl-benzo[1,2,4]triazin-3-ylamino]-N-(2-dimethylamino-ethyl)-benzenesulfonamide, which was precipitated using EtOAc/hexanes (1:5 v/v) to give a dark orange solid (168.4 mg, 96% yield). Rf=0.50 MS (ES+) m/z=527.
Reaction SMILES: [CH2:1](O)[CH3:2].[ClH:4].Cl.[N:6]1([C:11]2[CH:24]=[CH:23][C:14]([C:15](C3CCNCC3)=O)=[CH:13][CH:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1>[Pd].O>[ClH:4].[ClH:4].[N:6]1([C:11]2[CH:12]=[CH:13][C:14]([CH2:15][N:6]3[CH2:2][CH2:1][CH2:9][CH2:8][CH2:7]3)=[CH:23][CH:24]=2)[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: O=C(c1ccc(N2CCCC2)cc1)C1CCNCC1
Reactant: CCO
Agent: [Pd]
Agent: Cl
Solvent: O
Product: c1cc(N2CCCC2)ccc1CN1CCCCC1
Reaction time: 2 h

Procedure:
In a solvent mixture of 20 ml of ethanol and 20 ml of water was added 3.33 g of the 4-(4-pyrrolidinobenzoyl)piperidine dihydrochloride (Compound No. 1) prepared in Example 11, followed by addition of 10% palladium-on-carbon, and the catalytic reduction was carried out at atmospheric temperature and pressure for 2 hours. After completion of the reaction, the solvent was distilled off and the residue was dissolved in a saturated aqueous solution of sodium chloride. The solution was made basic by addition of solid sodium hydrogen carbonate and extracted with acetonitrile. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off. After addition of 2N-methanolic hydrochloric acid to the oily residue, the solvent was distilled off and the residue was recrystallized from ethyl ether-methanol to give 0.4 g of colorless crystals melting at 152°-154° C.
Reaction SMILES: CC1(C)COB(B2OCC(C)(C)CO2)OC1.C([O-])(=O)C.[K+].Br[C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:34][CH2:33][N:32]([C:35](=[O:37])[CH3:36])[CH2:31][CH2:30]2)=[CH:25][CH:24]=1.Br[C:39]1[CH:40]=[C:41]2[C:45](=[CH:46][C:47]=1[Cl:48])[NH:44][N:43]=[C:42]2[C:49]([OH:51])=[O:50].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1(C)C=CC=CC=1.CCO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[C:35]([N:32]1[CH2:33][CH2:34][CH:29]([C:26]2[CH:27]=[CH:28][C:23]([C:39]3[CH:40]=[C:41]4[C:45](=[CH:46][C:47]=3[Cl:48])[NH:44][N:43]=[C:42]4[C:49]([OH:51])=[O:50])=[CH:24][CH:25]=2)[CH2:30][CH2:31]1)(=[O:37])[CH3:36]
Reactant: CC(=O)N1CCC(c2ccc(Br)cc2)CC1
Reactant: O=C(O)c1n[nH]c2cc(Cl)c(Br)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(=O)N1CCC(c2ccc(-c3cc4c(C(=O)O)n[nH]c4cc3Cl)cc2)CC1
Temperature: 100 °C
Reaction time: 16 h
Yield: 14.5 %

Procedure:
A mixture of 5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane (110 mg, 0.32 mmol), oven dried potassium acetate (139 mg, 1.41 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (26 mg, 0.032 mmol), and 1-(4-(4-bromophenyl)piperidin-1-yl)ethanone (86 mg, 0.30 mmol) in 1,4-dioxane (3.1 mL) was degassed with N2 for 10 minutes, and subjected to microwave irradiation at 115° C. for 1 hour. The cooled reaction mixture was filtered through cotton and concentrated in vacuo to give a dark solid. To the dark solid was added 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (68.9 mg, 0.25 mmol), 2N aqueous potassium carbonate solution (0.5 mL, 1.0 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (20.4 mg, 0.025 mmol). The reaction mixture was diluted with degassed toluene (0.8 mL) and EtOH (0.8 mL), sealed in a pressure tube and heated at 100° C. for 1 hour then 75° C. for an additional 16 hours. The cooled reaction mixture was concentrate in vacuo, and the residue was partitioned between 0.5N HCl (14 mL) and EtOAc (15 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3×8 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The resulting reddish solid was purified by reverse phase HPLC Column: Waters XBridge C18 19×100 mm, 5 μm; Mobile phase A: 0.03% NH4OH in water (v/v); Mobile phase B: 0.03% NH4OH in MeCN (v/v); 85.0% H2O/15.0% MeCN linear to 65.0% H2O/35.0% MeCN in 10.5 min, 65.0% H2O/35.0% MeCN linear to 0% H2O/100% MeCN in 0.5 min HOLD at 0% H2O/100% MeCN from 11.0 to 12.0 min. Flow: 25 mL/min) to give the title compound (14.4 mg, 15% yield). MS (ES+) 398.2 (M+H)+. Retention time=2.55 minutes (Column: Waters Atlantis dC18 4.6×50 mm, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); Gradient: 95:5 A:B linear to 5:95 A:B in 4.0 min, hold at 5:95 A:B to 5.0 min. Flow: 2 mL/min).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:18]3[CH:19]=[C:20](Br)[CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.C(O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:18]3[CH:19]=[C:20]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cnc3ccc(Br)cn23)CC1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2cnc3ccc(-c4ccccc4)cn23)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 118.4 %

Procedure:
To a solution of 120 mg of 1-(t-butoxycarbonyl)-4-(6-bromo-imidazo[1,2-a]pyridin-3-yl)-piperidine and 78 mg of phenylboronic acid in 5 mL of toluene and 2.5 mL of ethanol was added 8 mg of tetrakis(triphenylphosphine)-palladium(0), followed by 0.85 mL of 1.25N sodium hydroxide solution. The reaction was stirred at 100° C. for 8 hours. The mixture was concentrated under reduced pressure and the mixture was partitioned between EtOAc and water. Aqueous layer was extracted with EtOAc (3×). The combined organic phase was washed with brine and dried over MgSO4. The residue was purified by flash chromatography with 50% EtOAc in hexanes followed by 100% EtOAc to give 141 mg of the title compound as a viscous oil, which was used in next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH:6]1[CH:10]([CH2:11][C:12]#[C:13][CH2:14][CH3:15])[C:9](=[O:16])[CH:8]=[CH:7]1)=[O:4].[BH4-].[Na+].C(O)(=O)C>CO>[CH3:1][O:2][C:3]([CH2:5][CH:6]1[CH2:7][CH2:8][CH:9]([OH:16])[CH:10]1[CH2:11][C:12]#[C:13][CH2:14][CH3:15])=[O:4]
Reactant: CCC#CCC1C(=O)C=CC1CC(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCC#CCC1C(O)CCC1CC(=O)OC
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
4-Methoxycarbonylmethyl-5-(2-pentynyl)-2-cyclopentenone (890 mg) and 350 mg of sodium borohydride are dissolved in 20 ml of methanol, and the mixture is refluxed at 80° C. for one hour. On completion of the reaction, the mixture is cooled to room temperature. With addition of 60 ml of acetic acid, the mixture is stirred for 30 minutes and thereafter concentrated in a vacuum. The residue is purified with a silica gel column and distilled in a vacuum, affording 3-methoxycarbonylmethyl-2-(2-pentynyl)cyclopentanol (compound (1), R2 =CH3) in a yield of 94%, b.p. 65°-69° C./0.15 mm Hg.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C:11]2[C:12](Cl)=[N:13][CH:14]=[CH:15][C:16]=2[CH3:17])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[O-2].[Ca+2].[CH:21]1([NH2:24])[CH2:23][CH2:22]1>>[CH:21]1([N:24]2[C:2]3[N:3]=[CH:4][CH:5]=[CH:6][C:7]=3[C:8](=[O:9])[NH:10][C:11]3[C:16]([CH3:17])=[CH:15][CH:14]=[N:13][C:12]2=3)[CH2:23][CH2:22]1
Reactant: Cc1ccnc(Cl)c1NC(=O)c1cccnc1Cl
Reactant: NC1CC1
Agent: [Ca+2]
Agent: [O-2]
Product: Cc1ccnc2c1NC(=O)c1cccnc1N2C1CC1
Temperature: 130 °C
Reaction time: 0.75 h
Yield: 83.4 %

Procedure:
117.5 kg of 2-chloro-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide (4), 23.3 kg of calcium oxide and 59.4 kg of cyclopropylamine (molar ratio: 1:1:2.5) are heated to between 135° and 145° C. in 235 l ofdiglyme (diethylene glycoldimethylether) in a 500 l VA autoclave over a period of 6 to 8 hours. The reaction mixture is then cooled to a temperature of 20° to 30° C. and filtered. The filter cake is washed with 58.8 l of diglyme. The filtrates are combined and initially 200 l of solvent is distilled off. The residue is then diluted with a further 117.5 l of diglyme. The resultant diluted solution is added over a period of 20 to 40 minutes to a suspension of 45.0 kg of 60% sodium hydride in 352.5 l of diglyme, heated to 130° C. The storage vessel and conduits are rinsed with a further 55.8 l of diglyme, and the mixture is stirred at a temperature of between 130° and 140° C. for a further 30 to 60 minutes. The majority of the diglyme is then distilled off. Finally, the remaining residue is carefully mixed with 470 l of water. After cooling to a temperature of about 25° C., 235.0 l of cyclohexane and 57.11 of glacial acetic acid are added to the reaction mixture. The mixture is then stirred for about 1 hour at temperature of 10° to 25° C. The resultant suspension is centrifuged and the centrifuged material is then washed with 235.0 l of methyl-tert.-butylether and subsequently with 353.5 l of water and finally with 235 l of ethanol. In this way, after drying, 92.5 kg (83.5% of theory) of 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (nevirapine) is isolated.
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:26]([NH:28][CH2:29][C@H:30]([OH:45])[CH2:31][N:32]5[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]5)=[O:27])=[C:21]5[C:25]=4[O:24][CH2:23][CH2:22]5)[N:12]=[CH:11][C:10]=3[N:9]([CH3:46])[C:8](=[O:47])[C@H:7]2[CH2:48][CH3:49])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C(=O)(O)[O-].[Na+].Br[C:57]1([CH3:60])[CH2:59][CH2:58]1>ClCCl.C(N(CC)CC)C>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:26]([NH:28][CH2:29][C@H:30]([OH:45])[CH2:31][N:32]5[CH2:37][CH2:36][N:35]([CH2:60][CH:57]6[CH2:59][CH2:58]6)[CH2:34][CH2:33]5)=[O:27])=[C:21]5[C:25]=4[O:24][CH2:23][CH2:22]5)[N:12]=[CH:11][C:10]=3[N:9]([CH3:46])[C:8](=[O:47])[C@H:7]2[CH2:48][CH3:49])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)NC[C@H](O)CN4CCN(C(=O)OC(C)(C)C)CC4)c4c3OCC4)nc2N1C1CCCC1
Reactant: CC1(Br)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)NC[C@H](O)CN4CCN(CC5CC5)CC4)c4c3OCC4)nc2N1C1CCCC1
Reaction time: 0.5 h

Procedure:
Tert-butyl 4-[(2S)-3-[[7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carbonyl]amino]-2-hydroxy-propyl]piperazine-1-carboxylate 7d (300 mg, 0.44 mmol) was dissolved in 40 mL of dichloromethane. The reaction solution was filled with gas of hydrogen chloride and stirred for 0.5 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was dissolved in 41 mL of acetonitrile followed by the addition of 183 mL of triethylamine, sodium bicarbonate (148 mg, 1.76 mmol) and bromo-methyl-cyclopropane (130 mg, 0.97 mmol). The resulting solution was stirred for 12 hours and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 7-[[(7R)-8-cyclopentyl-7-ethyl-1-methyl-6-oxo-7H-pteridin-2-yl]amino]-N-[(2S)-3-[4-(cyclopropylmethyl)piperazin-1-yl]-2-hydroxy-propyl]-2,3-dihydrobenzofuran-4-carboxamide 7 (200 mg, yield: 72.0%) as a white solid.
Reaction SMILES: [CH3:1][CH:2]=[CH:3][SiH:4](Cl)Cl.[NH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1>CCCCCC>[N:7]1([CH:1]([CH:2]=[CH:3][SiH3:4])[N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: C1CCNC1
Reactant: CC=C[SiH](Cl)Cl
Solvent: CCCCCC
Product: [SiH3]C=CC(N1CCCC1)N1CCCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.9 %

Procedure:
Over a 1.5 hour period, 145 grams (1.03 mol) of methylvinyldichlorosilane was added with stirring to a mixture under nitrogen at 0.C of 1 L of dry hexane and 293 grams (4.12 mols) of pyrrolidine. The resulting mixture was allowed to stir for about 12 hours while warming to room temperature. A solid white precipitate was filtered and washed with dry hexane under nitrogen. The solvent was removed under reduced pressure and the product was distilled giving 158 grams (73% yield) of bis(pyrrolidinyl)methylvinylsilane, having a boiling point of 50°-52° C. at less than 1 torr. There was added dropwise to 28.4 grams (135 millimoles) of bis(pyrrolidinyl) methylvinylsilane, which was stirring under nitrogen at 0° C., 26.7 grams (270 millimoles) of butylisocyanate. The reaction was stirred at 0° C. for a period of 12 hours. The mixture was then allowed to warm to room temperature over a 60 minute period. There was obtained a quantitative yield of bis(1,1-tetramethylene-3-butylureidomethylvinylsilane in the form of a clear viscous oil. Its identity was confirmed by IR and NMR. It is referred to hereinafter as the "bis(uriedo) coupler".
Reaction SMILES: ICI.[CH3:4][C:5]12[C:13]3([OH:17])[C:14]([CH3:16])([CH3:15])[CH:8]([CH2:9][CH:10]1[CH:11]=[CH:12]3)[CH2:7][CH2:6]2.[CH2:18](O)C=CCCCCCCC>CCOCC.[Zn]>[CH3:4][C:5]12[C:13]3([OH:17])[C:14]([CH3:16])([CH3:15])[CH:8]([CH2:9][CH:10]1[CH:11]1[CH:12]3[CH2:18]1)[CH2:7][CH2:6]2
Reactant: CCCCCCCC=CCO
Reactant: CC1(C)C2CCC3(C)C(C=CC13O)C2
Agent: [Zn]
Solvent: CCOCC
Solvent: ICI
Product: CC1(C)C2CCC3(C)C(C2)C2CC2C13O

Procedure:
A suspension of 19 g of zinc dust and 29 g of cuprous chloride powder in 125 ml of ether are stirred under reflux for thirty minutes. Diiodomethane (14.8 ml) is added dropwise over a twenty minute period. No external heat is required and the addition is carried out at a rate sufficient to maintain reflux (36°-41° C). 1.5 g of the product produced in Example VI, 9,10,10-trimethyl-tricyclo-(4.3.1.04,9)-dec-2-en-1-ol, is then added dropwise over a twenty minute period without external heating. Reflux is maintained (41°-46° C) throughout addition of the dec-2-en-1-ol. The reaction mass is refluxed daily for 8.5 hours for 5 days (42 hours in all) adding more ether and diiodomethane as required. The course of the reaction is followed by GLC (20 feet × 1/4 inch 5% SE-30 prog. 100°-220° C at [4°/min.).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[C:10]1([CH:16]2[CH2:20][CH2:19][NH:18][CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:18]2[CH2:19][CH2:20][CH:16]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:17]2)=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: c1ccc(C2CCNC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Brc1ccc(CN2CCC(c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 2 %

Procedure:
5.632 g of 4-Bromobenzyl bromide and 2.211 of 3-Phenylpyrrolidine (Array) in 50 mL of acetonitrile were stirred at room temperature and 6.229 g of potassium carbonate was added. The reaction was stirred at room temperature overnight. The solution was filtered through Celite and concentrated in vacuo to afford a brown solid. Purification was done by flash chromatography to afford product. Wt: 33 mg, 2% yield, ES MS m/z 316/318
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](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[CH2:42]([N:44]1[CH2:49][CH2:48][CH:47]([NH2:50])[CH2:46][CH2:45]1)[CH3:43]>CN(C)C=O>[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:50][CH:47]5[CH2:48][CH2:49][N:44]([CH2:42][CH3:43])[CH2:45][CH2:46]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN1CCC(N)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(F)(F)C(=O)N4C)c(OC)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.1 %

Procedure:
To a mixture of 0.10 g (0.22 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), 0.2 mL (1.1 mmole) of ethyldiisopropyl amine and 0.034 g (0.26 mmole) of 1-ethyl-piperidin-4-ylamine in 4.0 mL of dimethylformamide was added 0.11 g (0.25 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The mixture was extracted three times with dichloromethane. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-80:20) gave 0.070 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)-N-(1-ethyl-piperidin-4-yl)-3-methoxy-benzamide (I-67) as a white solid.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:5](=[CH:7][CH:8]=[CH:9][C:10]=2[OH:11])[CH:6]=1.CS[C:14]1[CH:19]=CC=C[C:15]=1SC>>[C:10]([C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)(=[O:11])[C:9]1[CH:8]=[CH:7][CH:19]=[CH:14][CH:15]=1
Reactant: Oc1cccc2ccccc12
Reactant: CSc1ccccc1SC
Product: O=C(c1ccccc1)c1ccccc1
Yield: 80 %

Procedure:
Thereafter, this naphthol compound was coupled with 1,2-dimethylthiobenzene in the same manner as in Example 17 to obtain a benzophenone derivative represented by the following formula (50) at a yield of 80%.
Reaction SMILES: [C:1]1([CH:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:20]3=[CH:19][CH:18]=[CH:17][C:16]=5[OH:23])=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][CH2:32][CH2:33][CH2:34][Cl:35].O>CN(C=O)C>[C:1]1([CH:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:16]([O:23][CH2:31][CH2:32][CH2:33][CH2:34][Cl:35])=[CH:17][CH:18]=[CH:19][C:20]=53)=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClCCCCBr
Reactant: Oc1cccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: ClCCCCOc1cccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Temperature: 85 °C
Yield: 57.3 %

Procedure:
To a mixture of 1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-ol (0.5 g, 1.66 mmol) in dry DMF (5 mL) is added potassium carbonate (1.15 g, 8.3 mmol) and 1-bromo-4-chlorobutane (1.4 g, 8.3 mmol). The mixture is heated at 85° C., under argon, for 4 h. The mixture is then cooled to room temperature and water (50 mL) is added. The mixture is transferred to a separatory funnel and partitioned between water and ether. The ether layer is washed with water (50 mL) then dried over anhydrous sodium sulfate. The ether filtrates are then concentrated. Column chromatography (50 mL silica) using hexanes followed by hexanes/methylene chloride (1:1) gave 0.373 g (57%) of the title compound.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][N:24](COCC[Si](C)(C)C)[C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14](S(C)(=O)=O)[N:13]=2)[CH2:6]1)(=[O:4])=[O:3].[CH3:39][N:40]([CH3:47])[CH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1.CS(C)(=O)=O>O1CCOCC1>[CH3:39][N:40]([CH3:47])[CH:41]1[CH2:46][CH2:45][N:44]([C:14]2[N:13]=[C:12]([NH:11][C@H:7]3[CH2:8][CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6]3)[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][NH:24][C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=2)[CH2:43][CH2:42]1
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cnc(S(C)(=O)=O)nc3N[C@H]3CCCN(S(C)(=O)=O)C3)cnc21
Reactant: CN(C)C1CCNCC1
Agent: CS(C)(=O)=O
Solvent: C1COCCO1
Product: CN(C)C1CCN(c2ncc(-c3cnc4[nH]ccc4n3)c(N[C@H]3CCCN(S(C)(=O)=O)C3)n2)CC1

Procedure:
In a dioxane solution of ((S)-1-methanesulfonyl-piperidin-3-yl)-{2-methanesulfonyl-5-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidin-4-yl}-amine derived from Example 84, step 1, dimethylpiperidin-4-ylamine was used to displace the methylsulfone similar to examples above and the de-protection step was similar to step 5, Example 76, to give [2-(4-dimethylamino-piperidin-1-yl)-5-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-pyrimidin-4-yl]-((S)-1-methanesulfonyl-piperidin-3-yl)-amine. MS: (ES+): 500.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([O:15][CH3:16])[CH:9]=1)=[O:7])(=[O:3])[CH3:2].Br[CH2:18][CH2:19][CH2:20][Cl:21].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([O:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:18][CH2:19][CH2:20][Cl:21])=[C:10]([O:15][CH3:16])[CH:9]=1)=[O:7])(=[O:3])[CH3:2]
Reactant: ClCCCBr
Reactant: COc1cc(C(=O)COC(C)=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(C(=O)COC(C)=O)ccc1OCCCCl
Yield: 91.9 %

Procedure:
A mixture of 31.5 g (0.14 mol) of 2-(acetyloxy)-1-(4-hydroxy-3-methoxyphenyl)ethanone, 44.1 g (0.28 mole) of 1-bromo-3-chloropropane and 58 g (0.42 mole) of anhydrous potassium carbonate in 1 liter of acetone was heated at reflux for 16 hr. The mixture was cooled, filtered, and the filtrate concentrated to give a solid residue. The solid was triturated with petroleum ether (30°-60° C.), collected by filtration and dried to yield 38.7 g (92%) of title compound as a pale-yellow solid. An analytical sample, mp 93°-96° C., was prepared from 2-propanol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[O:17][C:18](Br)=[CH:19][CH:20]=2)=[O:15])[CH:8]=1)[CH3:2].[F:23][C:24]([F:39])([F:38])[C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1>>[CH2:1]([O:3][C:4](=[O:22])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[O:17][C:18]([C:27]3[CH:28]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:30]=[C:25]([C:24]([F:23])([F:39])[F:38])[CH:26]=3)=[CH:19][CH:20]=2)=[O:15])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2ccc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)o2)c1
Temperature: 100 °C

Procedure:
The furyl bromide (99)(70 mg, 0.19 mmol) was coupled to 3,5-bis-trifluoromethyl-phenylboronic acid (55 mg, 0.21 mmol) acid using Method E, except that the reaction was heated at 100° C. The crude product was purified by column chromatography eluting with a stepped gradient of 0-10% EtOAc in heptane to give the title compound.