Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[N:6]=[C:7]([CH2:35][NH:36][C:37](=[O:39])[CH3:38])[C:8]2[C:13]([C:14]=1[CH2:15][C:16]1[C:17]([NH:28][CH2:29][CH3:30])=[N:18][C:19]3[C:24]([CH:25]=1)=[CH:23][C:22]([O:26][CH3:27])=[CH:21][CH:20]=3)=[CH:12][C:11]([O:31][CH3:32])=[C:10]([O:33][CH3:34])[CH:9]=2)(=O)C.N>C(Cl)Cl.CO>[CH2:29]([NH:28][C:17]1[C:16]([CH2:15][C:14]2[C:13]3[C:8](=[CH:9][C:10]([O:33][CH3:34])=[C:11]([O:31][CH3:32])[CH:12]=3)[C:7]([CH2:35][NH:36][C:37](=[O:39])[CH3:38])=[N:6][C:5]=2[OH:4])=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:26][CH3:27])[CH:23]=2)[N:18]=1)[CH3:30]
Reactant: CCNc1nc2ccc(OC)cc2cc1Cc1c(OC(C)=O)nc(CNC(C)=O)c2cc(OC)c(OC)cc12
Agent: N
Solvent: ClCCl
Solvent: CO
Product: CCNc1nc2ccc(OC)cc2cc1Cc1c(O)nc(CNC(C)=O)c2cc(OC)c(OC)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(acetamidomethyl)-4-((2-(ethylamino)-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxyisoquinolin-3-yl acetate 56 (20 mg, 38 μmol) in CH2Cl2 (9 mL) in a 25 mL round-bottomed flask equipped with a magnetic stirrer was added a 7 N NH3 solution in MeOH (1 mL) and the reaction mixture was stirred overnight at RT then diluted with CH2Cl2:MeOH=9:1 (50 mL) and the organic solution was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 90:10) gave N-((4-((2-(ethylamino)-6-methoxyquinolin-3-yl)methyl)-3-hydroxy-6,7-dimethoxyisoquinolin-1-yl)methyl)acetamide. The free base was dissolved in MeOH (3 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.4 M HCl solution in MeOH (1 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford N-((4-((2-(ethylamino)-6-methoxyquinolin-3-yl)methyl)-3-hydroxy-6,7-dimethoxyisoquinolin-1-yl)methyl)acetamide dihydrochloride 57 as a pale yellow solid (17 mg, 79% yield).
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=2)=[C:8]([CH:21]=1)[C:9]([O:11]CC1C=CC(C#N)=CC=1)=[O:10]>O.C1COCC1>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]#[N:31])=[CH:28][CH:29]=2)=[C:8]([CH:21]=1)[C:9]([OH:11])=[O:10]
Reactant: N#Cc1ccc(COC(=O)c2cc(Br)ccc2OCc2ccc(C#N)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(COc2ccc(Br)cc2C(=O)O)cc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Lithium hydroxide (281 mg, 6.71 mmol) in water (20 ml) was added dropwise to a stirred solution of (4-cyanophenyl)methyl 5-bromo-2-{[(4-cyanophenyl)methyl]oxy}benzoate (may be prepared as described in Description 23; 300 mg, 0.67 mmol) in THF (20 ml) over 5 min. The reaction mixture was stirred at 20° C. for 16 h. The organic phase was evaporated and the aqueous phase (20 ml) was extracted with ethyl acetate (20 ml). The aqueous phase (20 ml) was adjusted to pH 2 with 2M hydrochloric acid (1 ml). The aqueous phase was then extracted with ethyl acetate (3×20 ml). The organic phase was then evaporated in vacuo to yield the title compound as a light yellow solid. 145 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].[C:13]([S-])(=[S:17])OCC.[K+]>N1C=CC=CC=1>[S:17]=[C:13]1[NH:1][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[O:12]1
Reactant: CCOC(=S)[S-]
Reactant: COC(=O)c1ccc(N)c(O)c1
Agent: [K+]
Solvent: c1ccncc1
Product: COC(=O)c1ccc2[nH]c(=S)oc2c1
Temperature: 25 °C

Procedure:
Methyl 4-amino-3-hydroxybenzoate (16.7 g, 100 mmol, Chemical Abstracts number 63435-16-5, available from Alfa Chemicals, 26 Parkridge Rd, Ward Hill, Mass. 01835-8099) and potassium O-ethyl carbonodithioate (20.8 g, 130 mmol) were combined in pyridine (100 mL) and refluxed for two hours. The reaction mixture was cooled to ambient temperature and the product was filtered, washed with water, and dried in a vacuum oven overnight at 45° C. to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.87 (d, 3 H) 7.34 (d, J=8.33 Hz, 1 H) 7.92 (d, J=1.59 Hz, 1 H) 7.97 (dd, J=12.69, 1.59 Hz, 1 H); MS (ESI−)m/z 207.9 (M−H)−.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[N:13]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.C1(C)C=CC(S(Cl)(=O)=[O:28])=CC=1.[Cl-]>O>[C:1]1([CH:7]2[NH:13][C:8](=[O:28])[CH2:9][CH2:10][CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: ON=C1CCCCC1c1ccccc1
Agent: [Cl-]
Solvent: O
Solvent: c1ccncc1
Product: O=C1CCCCC(c2ccccc2)N1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a 250 ml round-bottomed flask equipped with N2 inlet were added 7.33 g (38.8 mmol) 2-phenylcyclohexanone oxime (Chem. Ber., 55, 3664 (1922)) and 25 ml pyridine. The solution was cooled to 0° C. and 9.61 g (50.4 mmol) p-toluenesulfonyl chloride was added. The reaction was allowed to stir overnight as the ice melted, and then poured into water. Excess chloride was skimmed off the surface, and the reaction mixture was stirred at pH 4 for 3 hours. The precipitate was filtered, washed with water, and dried to a solid, 4.65 g (55%), mp 135°-137° C. (J. Am. Chem. Soc., 82, 4671 (1960)gives mp 139°-141° C.).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].I[CH2:26][CH2:27][CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:18]([CH2:26][CH2:27][CH3:28])[S:19]([CH:22]([CH3:24])[CH3:23])(=[O:20])=[O:21])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CC(C)S(=O)(=O)NCc1cccc(-c2cccc(S(C)(=O)=O)c2)c1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CCCN(Cc1cccc(-c2cccc(S(C)(=O)=O)c2)c1)S(=O)(=O)C(C)C

Procedure:
In analogy to example 10, step 3, propane-2-sulfonic acid (3′-methanesulfonyl-biphenyl-3-ylmethyl)-amide was reacted with 1-iodopropane and cesium carbonate in N,N-dimethylacetamide to give propane-2-sulfonic acid (3′-methanesulfonyl-biphenyl-3-ylmethyl)-propyl-amide as a colorless, waxy solid. MS: 427.2 ([M+NH4]+)
Reaction SMILES: [CH:1]1([C:4]2[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.Br[C:13]1C=CC(C2CCC2)=CC=1.[Li]CCCC.CCCCCC.CN(C=O)C>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([CH:8]=[O:9])=[CH:10][CH:11]=2)[CH2:3][CH2:2][CH2:13]1
Reactant: O=Cc1ccc(C2CC2)cc1
Reactant: Brc1ccc(C2CCC2)cc1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=Cc1ccc(C2CCC2)cc1
Yield: 67 %

Procedure:
The title compound was synthesized in analogy to 4-cyclopropyl benzaldehyde (described in example S1-A) using 830 mg of 1-bromo-4-cyclobutyl-benzene (3.93 mmol), 2.7 ml of a 1.6 molar solution of n-BuLi in hexane (4.32 mmol) and 605 μl of DMF (7.86 mmol). The isolated residue was purified by flash column chromatography (5:95 EtOAc/cyclohexane) to give 422 mg of 4-cyclobutyl-benzaldehyde (67%) as a colourless liquid. 1H NMR (CDCl3, 300 MHz): δ 1.89 (m, 1H), 1.97-2.26 (m, 3H), 2.40 (m, 2H), 3.63 (quint, J=8.5 Hz, 1H), 7.36 (d, J=8.0 Hz, 2H), 7.81 (d, J=8.0 Hz, 2H), 9.97 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH:11]([O:27][CH:28]([OH:31])[CH2:29][CH3:30])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:32](Cl)([C:35]1[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=1)(=[O:34])=[O:33]>C(N(CC)CC)C>[S:32]([C:35]1[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=1)([O:31][CH:28]([O:27][CH:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:10])[CH2:29][CH3:30])(=[O:34])=[O:33]
Reactant: CCCCCCCCCCCCCCCC(OC(O)CC)C(C)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCC(OC(CC)OS(=O)(=O)c1ccc(C)cc1)C(C)OCc1ccccc1
Temperature: 65 °C
Reaction time: 36 h

Procedure:
In 24 ml of triethylamine were dissolved 1.3 g (3 mmole) of 1-(2-benzyloxy-3-octadecyloxy)propanol and 1.7 g (9 mmole) of tosyl chloride, and the solution was warmed at 65° C. and stirred for 1.5 days. The reaction solution was concentrated to dryness under reduced pressure, and the residue was dissolved in chloroform. The solution was washed with water, dried over potassium carbonate. The solvent was distilled off under reduced pressure, and the residue was subjected to separation and purification by chromatography on a column of 40 g of silica gel. From the eluate of n-hexane-ethyl acetate (4:1), there was obtained the objective compound in the form of a colorless oil. Yield of 1.4 g (83%).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(O)(=O)C.[Cl:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[C:17](=O)[CH2:16][CH2:15]2.C([BH3-])#N.[Na+]>CO>[Cl:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[CH:17]([NH:4][CH:1]1[CH2:3][CH2:2]1)[CH2:16][CH2:15]2
Reactant: NC1CC1
Reactant: O=C1CCc2cccc(Cl)c21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Clc1cccc2c1C(NC1CC1)CC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.9 %

Procedure:
To a cooled solution of 4.16 ml (60 mmol) of cyclopropylamine and 4.3 ml (75 mmol) of acetic acid, together with 5 g of 3 Å molecular sieves, in 80 ml of methanol, are added 5 g (30 mmol) of 7-chloro-2,3-dihydro-1H-inden-1-one. The reaction mixture is stirred for 4 hrs at reflux. The reaction mixture is then cooled to ambient temperature and 2.83 g (45 mmol) of sodium cyanoborohydride are slowly added. The reaction mixture is further stirred for 2 hrs at reflux. The solvent is removed under vacuum and 100 ml of water are then added to the residue and the pH is adjusted to 10 with sodium hydroxide. The watery layer is extracted three times with dichloromethane (3×50 ml); the combined organic layers are dried over magnesium sulphate and concentrated in vacuum to yield 5.6 g (80% yield) of 7-chloro-N-cyclopropyl-2,3-dihydro-1H-inden-1-amine as an brown oil (M+1=208).
Reaction SMILES: [C:1]1(B(O)O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:17]([N+:27]([O-:29])=[O:28])[CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>O.C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]1([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:17]([N+:27]([O-:29])=[O:28])[CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: O=[N+]([O-])c1cc(Br)ccc1-c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1cc(-c2cccc3ccccc23)ccc1-c1ccccc1

Procedure:
1.62 g (1.40 mmol) of Pd(PPh3)4 are added to a well-stirred, degassed suspension of 46 g (268 mmol) of 1-naphthylboronic acid, 71 g (255.3 mmol) of 4-bromo-2-nitrobiphenyl and 93 g (433.9 mmol) of potassium carbonate in a mixture of 700 ml of water and 700 ml of THF, and the mixture is heated under reflux for 17 h. After cooling, the organic phase is separated off, washed three times with 400 ml of water and once with 400 ml of saturated, aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to dryness in vacuo in a rotary evaporator. The grey residue is recrystallised from hexane. The deposited crystals are filtered off with suction, washed with a little MeOH and dried in vacuo; yield: 83.1 g, 97.9% of theory; purity: 99.0% according to HPLC.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.C(N(CC)C(C)C)(C)C.[C:22]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)(=[O:24])[CH3:23]>ClCCl>[C:22]([N:25]1[CH2:30][CH2:29][N:28]([C:4]2[CH:5]=[CH:6][C:7]([C:8]([F:11])([F:10])[F:9])=[C:2]([Cl:1])[N:3]=2)[CH2:27][CH2:26]1)(=[O:24])[CH3:23]
Reactant: FC(F)(F)c1ccc(Cl)nc1Cl
Reactant: CC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCN(c2ccc(C(F)(F)F)c(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 13.3 %

Procedure:
To a solution of 2,6-dichloro-3-(trifluoromethyl)pyridine (2.38 g, 11.0 mmol) in anhydrous dichloromethane (20 ml) was added dropwise N,N-diisopropylethylamine (3.7 ml, 225 mmol). A solution of 1-acetylpiperazine (1.69 g, 13.2 mmol) in anhydrous dichloromethane (10 ml) was added dropwise at 0° C., and the mixture was stirred at room temperature for 5 hrs. The mixture was warmed, heated under reflux for 2.5 hrs, and stirred at room temperature for 14 hrs. The reaction mixture was diluted with dichloromethane and washed with water. The aqueous layer was extracted twice with dichloromethane, and the combined organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4→ethyl acetate→ethanol:ethyl acetate=1:20) to give 1-acetyl-4-[6-chloro-5-(trifluoromethyl)pyridin-2-yl]piperazine (451 mg, yield 13%) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][C:7](=O)[NH:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.[Br:14]C1C=CC2CNC(=O)CCC=2C=1>O1CCCC1>[Br:14][C:12]1[CH:5]=[CH:6][C:7]2[NH:8][CH2:9][CH2:10][CH2:4][CH2:3][C:2]=2[CH:13]=1
Reactant: O=C1CCc2cc(Br)ccc2CN1
Reactant: O=C1Cc2ccc(Br)cc2CCN1
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)CCCCN2
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a 1000-mL round-bottom flask was added the mixture of 7-bromo-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one and 7-bromo-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one (12.6 g, 52.4 mmol) and tetrahydrofuran (260 mL). The solution was cooled to 0° C. and borane-methylsulfide complex (12.4 mL, 210 mmol) was slowly added. The reaction mixture was stirred at 0° C. for 10 min, warmed to room temperature and stirred for 3 h, then heated at reflux for 4 h. Upon cooling to room temperature, the mixture was quenched with MeOH (50 mL) to remove excess borane. The solvent was then evaporated to give 7-bromo-2,3,4,5-tetrahydro-1H-benzoazepine and 7-bromo-2,3,4,5-tetrahydro-1H-benzoazepine as sticky oil. LCMS: (FA) ES+ 226 and 228.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH2:16][CH2:17][CH3:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][C:20]1[O:24][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:22][C:21]=1[CH2:31][CH2:32]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:32][CH2:31][C:21]2[N:22]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:24][C:20]=2[CH3:19])=[C:11]([CH2:16][CH2:17][CH3:18])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Reactant: CCCc1cc(OCc2ccccc2)ccc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCc1cc(OCc2ccccc2)ccc1OCCc1nc(-c2ccccc2)oc1C
Reaction time: 18 h
Yield: 68 %

Procedure:
A solution of 4-benzyloxy-2-propylphenol (1.00 g, 4.13 mmol), 2-(5-methyl-2-phenyloxazol-4-yl)ethanol (Japan Tobacco Inc WO 9518125) (0.84 g, 4.13 mmol), and triphenylphosphine (1.41 g, 5.37 mmol) in THF (17 mL) was treated dropwise at ambient temperature with diisopropyl azodicarboxylate (0.96 mL, 5.0 mmol). After 18 h, the reaction mixture was concentrated in vacuo. The residue was diluted with EtOAc, washed with brine (40 mL), dried (Na2SO4), and concentrated. The crude product was purified by radial chromatography using 10-15% ethyl acetate in hexanes to give the product (1.2 g, 68%). 1H. NMR (400 MHz, CDCl3) δ 7.98 (dd, J=7.8, 2.4 Hz, 2H), 7.45-7.30 (m, 8H), 6.78-6.69 (m, 3H), 4.99 (s, 2H), 4.19 (t, J=6.6 Hz, 2H), 2.96 (t, J=6.4 Hz, 2H), 2.50 (t, J=7.6 Hz, 2H), 2.38 (s, 3H), 1.53 (q, J=7 Hz, 2H), 0.88 (t, J=7 Hz, 3H); MS (FIA) m/e 428 (M+1).
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:30](Cl)([O:32]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C>C1COCC1>[C:22]([N:19]1[CH2:20][CH2:21][CH:16]([N:15]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[O:8][C:30]2=[O:32])[CH2:17][CH2:18]1)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2C(O)c2ccccc2)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)OC(c3ccccc3)c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Phenyl-(2-(1-Boc-4-piperidinylamino)phenyl) carbinol from Step 2 above (1.8 g, 4.7 mmol) was stirred in dry THF in an ice bath under nitrogen, and triphosgene (0.47 g, 1.57 mmol) was added followed by triethylamine (1.96 mL, 1.42 g, 14.1 mmol). The ice bath was removed and the mixture was stirred at ambient temperature for 18 hours. Water was added, and the mixture was extracted with ethyl acetate. The combined ethyl acetate fractions were washed with 1N HCl followed by saturated sodium bicarbonate, dried over sodium sulfate, filtered, and evaporated to dryness in vacuo to give 1-(1-Boc-4-piperidyl)-4-phenyl-3,1-benzoxazin-2-one.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7]([C:11]1[N:16]=[C:15](Cl)[CH:14]=[C:13]([CH:18]2[CH2:20][CH2:19]2)[N:12]=1)([CH3:10])([CH3:9])[CH3:8]>C(O)C>[C:7]([C:11]1[N:16]=[C:15]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH:14]=[C:13]([CH:18]2[CH2:20][CH2:19]2)[N:12]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: C1CNCCN1
Reactant: CC(C)(C)c1nc(Cl)cc(C2CC2)n1
Solvent: CCO
Product: CC(C)(C)c1nc(C2CC2)cc(N2CCNCC2)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
25.1 g of piperazine (291.4 mmol) were dissolved in 100 ml of ethanol and heated to 50° C. 17 g of 2-tert-butyl-4-chloro-6-cyclopropyl-pyrimidine (81 mmol), dissolved in 100 ml of ethanol, were added dropwise within 2 h. After heating to reflux at 70° C. for 5 h the reaction mixture was stirred at room temperature overnight. The ethanol was evaporated and the residue suspended in 200 ml of water. The aqueous phase was extracted 4 times with 100 ml of dichloromethane each. Drying over magnesium sulfate, filtration, and evaporation to dryness gave 19.2 g (90.9%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=3)[N:11]=[CH:10][N:9]=2)=[N:3]1.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([S:26]([CH3:29])(=[O:28])=[O:27])[C:21]=1F.C(O[K])(C)(C)C.O>CN(C)C(=O)C>[F:19][C:20]1[CH:21]=[C:22]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:23]=[CH:24][C:25]=1[O:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]=[C:8]2[NH:7][C:4]1[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=1
Reactant: CS(=O)(=O)c1cccc(F)c1F
Reactant: Cn1ccc(Nc2ncnc3ccc(O)cc23)n1
Agent: CC(C)(C)O[K]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cn1ccc(Nc2ncnc3ccc(Oc4ccc(S(C)(=O)=O)cc4F)cc23)n1
Temperature: 77 °C
Reaction time: 12 h
Yield: 28.1 %

Procedure:
4-[(1-Methyl-1H-pyrazol-3-yl)amino]quinazolin-6-ol (250 mg; 1.033 mmol) and 424 mg (2.219 mmol) of the above-prepared sulfone compound were added to a solution of 320 mg (2.857 mmol) of tert-butoxy potassium in 24 ml of N,N-dimethylacetamide and the mixture was stirred at 77° C. for 12 hours. To the reaction solution was added water followed by extracting with chloroform. The organic layer was dried and concentrated and the resulting residue was purified by a reversed phase preparative HPLC (0.1% TFA-containing water:acetonitrile=90:10→10:90) to give 120 mg (yield: 28%) of the title compound as a yellow solid.
Reaction SMILES: [CH:1]1([N:7]([CH2:30][CH:31]([O:34][CH3:35])[O:32][CH3:33])[C:8](=[O:29])[CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16](B3OC(C)(C)C(C)(C)O3)[CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[C:43]1[N:44]([CH3:49])[CH:45]=[C:46]([CH3:48])[N:47]=1>CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1([N:7]([CH2:30][CH:31]([O:32][CH3:33])[O:34][CH3:35])[C:8](=[O:29])[CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:43]3[N:44]([CH3:49])[CH:45]=[C:46]([CH3:48])[N:47]=3)[CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(CN(C(=O)CCOCCc1cccc(B2OC(C)(C)C(C)(C)O2)c1)C1CCCCC1)OC
Reactant: Cc1cn(C)c(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(CN(C(=O)CCOCCc1cccc(-c2nc(C)cn2C)c1)C1CCCCC1)OC
Temperature: 120 °C

Procedure:
N-Cyclohexyl-N-(2,2-dimethoxyethyl)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenethoxy)propanamide [Example 34, Step i)] (390 mg), potassium carbonate (220 mg), Pd(Ph3P)4 (46 mg) and 2-bromo-1,4-dimethyl-1H-imidazole (279 mg) in MeOH (3 mL) was loaded into a microwave vial, flushed with nitrogen and sealed. The vial was heated within a Discover microwave at 120° C. for 30 min. After cooling, the reaction and the filtrate washed with DCM. Volatiles were removed and the residue purified on silica using 20%-100% EtOAc/iso gradient to afford the subtitled compound (358 mg). MS [M+H]+=458 (MultiMode+) 1H NMR (400 MHz, CDCl3) δ 7.51-7.47 (m, 1H), 7.43-7.40 (m, 1H), 7.37-7.30 (m, 1H), 7.27-7.22 (m, 1H), 6.67 (s, 1H), 4.61 and 4.37 (2×t, J=5.2 Hz, 1H), 4.25-4.16 and 3.61-3.51 (2×m, 1H), 3.81-3.74 (m, 2H), 3.73-3.65 (m, 2H), 3.68 (s, 3H), 3.41 (s, 3H), 3.39 (s, 3H), 3.37 and 3.29 (2×d, J=4.9 Hz, 2H), 2.96-2.89 (m, 2H), 2.73-2.65 (m, 2H), 2.26 (s, 3H), 1.85-1.74 (m, 2H), 1.73-1.05 (m, 8H); a ˜2:1 mixture of rotamers is observed.
Reaction SMILES: [CH:1]1([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.[Li+].CC([N-]C(C)C)C>C1COCC1>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][C:1]1([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrCCCCBr
Reactant: CCCCOC(=O)C1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCOC(=O)C1(CCCCBr)CCCC1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 49 %

Procedure:
Under a N2 atmosphere at −60° C., a solution of butyl cyclopentanecarboxylate (prepared according to Payne, G. B.; Smith, C. W., J. Org. Chem., 1957, 22, 1680-1682, 80.0 g, 0.42 mol) and 1,4-dibromobutane (183.3 g, 0.84 mol) in dry THF (700 mL) was added drop wise to a mixture of LDA (2M in THF/heptane/ethylbenzene, 250 mL, 0.50 mol) and dry THF (250 mL) in 1.5 h. After that, the reaction mixture was allowed to slowly reach rt during 3.5 h. Then, the reaction mixture was poured into ice-cold saturated aqueous NH4Cl (1 L). The organic layer was decanted and concentrated in vacuo to a smaller volume. The aqueous layer was extracted with Et2O (3×250 mL). The combined organic layers were washed with saturated aqueous NH4Cl (250 mL) and brine (2×250 mL), dried (Na2SO4) and evaporated in vacuo. The remaining residue was purified by fractional distillation to give butyl 1-(4-bromo-butyl)-cyclopentanecarboxylate (62.8 g, 49%) as a light yellow liquid. bp: T=116-117° C. (p=0.040-0.051 Torr). 1H NMR (CDCl3): δ=4.07 (t, J=6.6 Hz, 2H), 3.38 (t, J=6.8 Hz, 2H), 2.16-2.10 (m, 2H), 1.83 (quintet, J=7.1 Hz, 2H), 1.65-1.59 (m, 8H), 1.50-1.31 (m, 6H), 0.94 (t, J=7.2 Hz, 3H). 13C NMR (CDCl3): δ=177.6, 64.1, 53.9, 38.2, 36.0 (2×), 33.3, 33.0, 30.6, 24.8 (2×), 24.6, 19.1, 13.6. HRMS calcd for C14H25BrO2 (M+): 304.1038, found: 304.1042.