Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7]/[C:8](/[CH3:16])=[CH:9]/[CH:10]=[CH:11]/[CH2:12][CH2:13][CH2:14][OH:15].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7]/[C:8](/[CH3:16])=[CH:9]/[CH:10]=[CH:11]/[CH2:12][CH2:13][CH2:14][O:15][S:25]([CH3:24])(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: C/C(=C\C=C\CCCO)CCC1OCCO1
Solvent: CCN(CC)CC
Product: C/C(=C\C=C\CCCOS(C)(=O)=O)CCC1OCCO1
Reaction time: 2.5 h
Yield: 89 %

Procedure:
Methanesulfonic acid (4E,6E)-9-[1,3]dioxolan-2-yl-7-methyl-nona-4,6-dienyl ester was synthesized using the following procedure. To a cooled (0° C.) solution of (4E,6E)-9-[1,3]dioxolan-2-yl-7-methyl-nona-4,6-dien-1-ol (1.60 g, 7.20 mmol), triethylamine (1.2 mL, 8.6 mmol), and 15 mL of CH2CI2 was added dropwise methanesulfonyl chloride (0.61 mL, 7.9 mmol). The reaction mixture was stirred at 0° C. to room temperature for 2.5 h, quenched with a saturated NaHCO3 solution, extracted with EtOAc, dried (Na2SO4), and concentrated to give 1.95 g (6.41 mmol, 89%) of methanesulfonic acid (4E,6E)-9-[1,3]dioxolan-2-yl-7-methyl-nona-4,6-dienyl ester which was used without further purification: 1H NMR δ6.28 (dd, 1H, J-15.0, 10.9 Hz), 5.82 (d, 1H,J-10.7 Hz), 5.52 (dt, 1H,J-15.0, 7.0 Hz), 4.85 (t, 1H,J-4.8 Hz), 4.23 (t, 2H, J-6.4 Hz), 4.00-3.75 (m, 4H), 3.00 (s, 3H), 2.25-2.12 (m, 4H), 1.90-1.75 (m, 4H), 1.74 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][CH2:10][CH2:11][C:12]2[N:13]=[CH:14][NH:15][CH:16]=2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.[N:17]1([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1.Cl.ClCCl.CO>CO>[Br:1][C:2]1[C:3]([NH:9][CH2:10][CH2:11][C:12]2[N:13]=[CH:14][NH:15][CH:16]=2)=[N:4][C:5]([NH:29][C:26]2[CH:25]=[CH:24][C:23]([CH2:22][N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:28][CH:27]=2)=[N:6][CH:7]=1
Reactant: Nc1ccc(CN2CCCC2)cc1
Reactant: Clc1ncc(Br)c(NCCc2c[nH]cn2)n1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: Brc1cnc(Nc2ccc(CN3CCCC3)cc2)nc1NCCc1c[nH]cn1
Yield: 4.6 %

Procedure:
A mixture of 5-bromo-4-(2-(1H-imidazol-4-yl)-ethylamino)-2-chloro-pyrimidine (60 mg), 4-pyrrolidin-1-ylmethyl-phenylamine (35 mg) and hydrochloric acid (37% in water, 40 μL) in methanol (2 mL) was refluxed overnight. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution, the organic phase dried (Na2SO4) and evaporated, which gave, after chromatography on silica using dichloromethane/methanol, the title compound (4 mg).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[C:14]([CH2:15][CH2:16][NH2:17])=[C:6]2[C:7]3[CH2:13][CH2:12][O:11][C:8]=3[CH:9]=[CH:10][N:5]2[N:4]=1.C(N(CC)CC)C.[C:27](Cl)(=[O:29])[CH3:28]>O1CCCC1.C(=O)([O-])O.[Na+]>[F:19][C:2]([F:1])([F:18])[C:3]1[C:14]([CH2:15][CH2:16][NH:17][C:27](=[O:29])[CH3:28])=[C:6]2[C:7]3[CH2:13][CH2:12][O:11][C:8]=3[CH:9]=[CH:10][N:5]2[N:4]=1
Reactant: NCCc1c(C(F)(F)F)nn2ccc3c(c12)CCO3
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NCCc1c(C(F)(F)F)nn2ccc3c(c12)CCO3
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
To a solution of 2-[2-(trifluoromethyl)-8,9-dihydrofuro[3,2-c]pyrazolo[1,5-a]pyridin-1-yl]ethanamine (70 mg, 0.26 mmol) and triethylamine (72 μL, 0.52 mmol) in tetrahydrofuran (3 mL) was added acetyl chloride (22 μL, 0.31 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=70/30→100/0) and recrystallization (ethyl acetate/hexane) to give the title compound (61.8 mg, yield 76%).
Reaction SMILES: ClN1C(=O)CCC1=O.CSC.[C:12]([Si:16]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[O:17][C@H:18]1[CH2:23][C@@H:22]([O:24][Si:25]([C:38]([CH3:41])([CH3:40])[CH3:39])([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:21]/[C:20](=[CH:42]/CO)/[C:19]1=[CH2:45])([CH3:15])([CH3:14])[CH3:13].[CH2:58]([Cl:60])Cl>>[Cl:60][CH2:58]/[CH:42]=[C:20]1\[C:19](=[CH2:45])[C@@H:18]([O:17][Si:16]([C:12]([CH3:15])([CH3:14])[CH3:13])([C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:23][C@@H:22]([O:24][Si:25]([C:38]([CH3:41])([CH3:40])[CH3:39])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:21]\1
Reactant: C=C1/C(=C\CO)C[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C[C@@H]1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: ClCCl
Agent: O=C1CCC(=O)N1Cl
Solvent: CSC
Product: C=C1/C(=C\CCl)C[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C[C@@H]1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.31 g (9.81 mmol) of N-chloro-succinimide in 34 ml of abs. CH2Cl2 was treated at -10° with 749 μl (10.2 mmol) of dimethyl sulfide. 15 Minutes later, 2.95 g (4.559 mmol) of (Z)-(3S,5S)-2-[3,5-bis-(tert-butyl-diphenyl-silanyloxy)-2-methylene-cyclohexylidene]-ethanol, dissolved in 10 ml of CH2Cl2, was slowly added to the resultant white suspension at the same temperature and then stirred for additional 30 minutes at RT. The reaction mixture was then poured onto crushed ice, extracted with ether, washed with water, dried over sodium sulfate and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=97.5/2.5) yielded 2.76 g of (Z)-(3S,5S)-1-(2-chloro-ethylidene)-3,5-bis-(tert-butyl-diphenyl-silanyloxy)-2-methylene-cyclohexane as yellowish foam.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][NH:4]1.[S:13](=O)(=[O:16])([OH:15])[OH:14]>O>[OH:16][S:13]([O:1][CH2:2][C@@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][NH:4]1)(=[O:15])=[O:14]
Reactant: O=S(=O)(O)O
Reactant: OC[C@@H]1Cc2ccccc2CN1
Solvent: O
Product: O=S(=O)(O)OC[C@@H]1Cc2ccccc2CN1
Temperature: 110 °C

Procedure:
A solution of (S)-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline (41 g.) in a mixture of sulphuric acid (d = 1.83; 13 cc.) and water (70 cc.) is heated at 110° C. Water (about 50 cc.) is distilled off and the mixture is then concentrated under reduced pressure (20 mm. Hg) at 100° C. The brown oily residue is taken up in a mixture of sulphuric acid (d = 1.83; 13 cc. ) and water (70 cc.); water (50 cc.) is again distilled off and the mixture is then concentrated as previously described, after which the concentration is finished at 100° C. under reduced pressure (1 mm. Hg). The residue, which crystallises on cooling, is recrystallised from a mixture of ethanol (140 cc.) and water (60 cc.) After cooling for 15 hours at about 5° C., the crystals which have appeared are filtered off and washed with a mixture of ethanol and water (3:1 by volume) (20 cc.) and then with ethanol (2 × 25 cc.). After drying at 60° C . under reduced pressure (1 mm. Hg), (S)-3-hydroxysulphonyloxymethyl-1,2,3,4-tetrahydroisoquinoline (48 g.) is obtained in the form of white crystals.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH2:21][CH2:20][CH2:19][N:11]3[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:29][O:30][CH2:31]Br>C(Cl)Cl>[CH3:29][O:30][CH2:31][S:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH2:21][CH2:20][CH2:19][N:11]3[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: Sc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Reactant: COCBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCSc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Temperature: 25 °C

Procedure:
To an ice-bath cooled solution containing 1.0 g (3.4 mmole) of 2-(4-mercaptophenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]-pyrrolo[1,2 -a]imidazole prepared as in Example 16 and 0.5 ml (3.6 mmole) of triethylamine in 10 ml of methylene chloride is added 0.27 ml (3.5 mmole) of bromomethyl methyl ether. The reaction is allowed to warm to room temperature and stirred at room temperature for several hours. Workup and chromatography in a manner analogous to that outlined in example 18 affords the desired titled compound.
Reaction SMILES: [OH:1][C:2]1([C:15]([O:17]C)=[O:16])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[C@@:19]12([OH:28])[N:26]([CH3:27])[C@@H:23]([CH2:24][CH2:25]1)[CH2:22][CH:21]=[CH:20]2.[Na].O>C(#N)C>[C@@:19]12([OH:28])[N:26]([CH3:27])[C@@H:23]([CH2:24][CH2:25]1)[CH2:22][CH:21]=[CH:20]2.[OH:1][C:2]1([C:15]([O-:17])=[O:16])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=2[C:9]2[C:14]1=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: COC(=O)C1(O)c2ccccc2-c2ccccc21
Agent: CN1[C@@H]2CC=C[C@@]1(O)CC2
Agent: [Na]
Solvent: O
Solvent: CC#N
Product: O=C([O-])C1(O)c2ccccc2-c2ccccc21

Procedure:
13.4 g (0.056 mol) of methyl ester 3a, 11.65 g (0.084 mol) of tropenol, and 0.3 g of sodium are heated as a melt at 75 mbar for 4 hours over a bath of boiling water with occasional agitation. After cooling, the sodium residues are dissolved with acetonitrile, the solution is evaporated to dryness, and the residue is extracted with dichloromethane/water. The organic phase is washed with water, dried over magnesium sulfate (MgSO4), and the solvent is distilled off. The product is purified by recrystallization from diethyl ether. Yield: 11.40 g of white crystals (29% of theoretical yield).
Reaction SMILES: [CH2:1]([Si:3]([CH2:7][CH3:8])([CH2:5][CH3:6])Cl)[CH3:2].[O:9]1[CH2:13][CH2:12][NH:11][C:10]1=[O:14]>>[CH2:1]([Si:3]([CH2:7][CH3:8])([CH2:5][CH3:6])[N:11]1[CH2:12][CH2:13][O:9][C:10]1=[O:14])[CH3:2]
Reactant: CC[Si](Cl)(CC)CC
Reactant: O=C1NCCO1
Product: CC[Si](CC)(CC)N1CCOC1=O

Procedure:
Following the previous example, but replacing the trimethylchlorosilane with triethylchlorosilane (63.3 g; 0.42 mol) and operating under similar conditions, the result is the compound of the above heading; a colorless fluid liquid, obtained with a similar yield. 2-oxazolidinone, calculated: 42.82%; found; 42.70%. Distills at 100°C between 2 and 4 mm.
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([I:10])[CH:5]=[CH:4][N:3]=1.N1C=CN=C1.[CH3:16][C:17]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])[CH3:18].C(OCC)C>C(Cl)Cl>[Si:20]([O:9][CH2:8][C:7]1[C:2]([F:1])=[N:3][CH:4]=[CH:5][C:6]=1[I:10])([C:17]([CH3:19])([CH3:18])[CH3:16])([CH3:22])[CH3:21]
Reactant: OCc1c(I)ccnc1F
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCc1c(I)ccnc1F
Yield: 88.1 %

Procedure:
To a solution of (2-fluoro-4-iodopyridin-3-yl)methanol (3.52 g, 13.91 mmol) in CH2Cl2 (80 mL) at room temperature was sequentially added imidazole (1.894 g, 27.8 mmol) and TBDMS-Cl (2.52 g, 16.69 mmol). The reaction was stirred at room temperature for 1 h before diethylether was added and the insoluble salts were filtered. Silica gel was added to the filtrate prior to the solvent removal under vacuum. The dry silica gel was packed, and the adsorbed product was purified by flash chromatography (hexane/EtOAc 10:0 to 7:3) to give 3-(((tert-butyldimethylsilyl)oxy)methyl)-2-fluoro-4-iodopyridine as a white solid (4.5 g). LC/MS m/z 368 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=2)[N:4]([CH3:18])[C:3]=1[C:19]([OH:21])=[O:20].[C:22](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:22][O:20][C:19]([C:3]1[N:4]([CH3:18])[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=2)=[N:6][C:2]=1[Br:1])=[O:21]
Reactant: O=C([O-])[O-]
Reactant: Cn1c(-c2cccc(OC(F)(F)F)c2)nc(Br)c1C(=O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1c(Br)nc(-c2cccc(OC(F)(F)F)c2)n1C
Reaction time: 70 h
Yield: 93.4 %

Procedure:
A stirred solution of 1.826 g (5.0 mmol) of 5-bromo-3-methyl-2-(3-trifluoromethoxy-phenyl)-3H-imidazole-4-carboxylic acid (example 72) in 20 ml of DMF was treated at RT with 2.073 g (15.0 mmol) of potassium carbonate, followed by addition of 0.62 ml=1.42 g (10.0 mmol) of iodomethane. After 70 hours, the reaction mixture was poured into crashed ice and extracted twice with Et2O; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (n-heptane/CH2Cl2 1:0 to 0:1) to give 1.77 g (93%) of the title compound as light yellow oil. MS: 379.0 (MH+, 1Br).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:8][C:9]([CH:12]=O)=[CH:10][N:11]=1.[NH:14]1[CH2:19][CH2:18][CH:17]([CH2:20][OH:21])[CH2:16][CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:8][C:9]([CH2:12][N:14]2[CH2:19][CH2:18][CH:17]([CH2:20][OH:21])[CH2:16][CH2:15]2)=[CH:10][N:11]=1
Reactant: O=Cc1cnc(-c2ccccn2)s1
Reactant: OCC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: OCC1CCN(Cc2cnc(-c3ccccn3)s2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
The compound prepared in Example 139 (0.569 g), piperidin-4-ylmethanol (0.689 g) and sodium triacetoxyborohydride (1.902 g) were suspended in 1,2-dichloroethane (15 mL) and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed sequentially with saturated aqueous sodium bicarbonate solution, ammonium chloride solution and brine. The organics were then dried over magnesium sulfate, filtered and concentrated under reduced pressure and to afford the crude material, which was purified by flash column chromatography (eluant: 10% (9:1 methanol/concentrated ammonium hydroxide)/ethyl acetate) to furnish the title compound (0.571 g) having the following physical properties.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[NH2:9])=[CH:4][CH:3]=1.[F:16][C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:20]([N+:26]([O-:28])=[O:27])=[C:19](F)[CH:18]=1.C(N(CC)CC)C>CO>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[NH:9][C:19]2[C:20]([N+:26]([O-:28])=[O:27])=[CH:21][C:22]([N+:23]([O-:25])=[O:24])=[C:17]([F:16])[CH:18]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccccc1Nc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(F)cc1F
Solvent: CCN(CC)CC
Solvent: CO
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(Nc2ccccc2Nc2ccc(Cl)cc2)cc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The solid from step B was added to a solution of 1,3-difluoro-4,6-dinitrobenzene (46 g) in methanol (200 mL), then triethylamine (31.4 mL) was added, and stirred at rt for 4 h. The reaction mixture was filtered, and the cake was washed with methanol to give 80.6 g of red solid.
Reaction SMILES: [Br-].[C:2]([CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:3].[OH-].[Na+].[F:26][C:27]1[CH:41]=[CH:40][C:30]([O:31][C:32]2[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=2)=[CH:29][CH:28]=1>O.C(Cl)Cl>[F:26][C:27]1[CH:41]=[CH:40][C:30]([O:31][C:32]2[CH:39]=[CH:38][C:35]([CH:36]=[CH:4][C:2]#[N:3])=[CH:34][CH:33]=2)=[CH:29][CH:28]=1
Reactant: N#CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(Oc2ccc(F)cc2)cc1
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: N#CC=Cc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.2 %

Procedure:
To a solution of (cyanomethyl)triphenylphosphonium bromide (10.61 g, 27.8 mmol) and NaOH (1.387 g, 34.7 mmol) in water (30 mL) and DCM (15 mL) was added 4-(4-fluorophenoxy)benzaldehyde (5 g, 23.13 mmol) at 0° C. The mixture was stirred at room temperature for 4 h. DCM (50 mL) and water (50 mL) was added to the mixture, the organic phase was washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate and concentrated. Purification via flash chromatography afforded the title compound (5.1 g, 21.09 mmol, 91% yield) as white solid. LCMS: rt=1.60 min, [M+H+]=240
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].CN(C)C(=O)C.[CH:32]1([SH:38])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>O>[CH:32]1([S:38][C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: CC(C)(C)OC(=O)CNS(=O)(=O)c1ccc(F)cc1
Reactant: SC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)CNS(=O)(=O)c1ccc(SC2CCCCC2)cc1
Temperature: 60 °C
Reaction time: 40 h

Procedure:
The N-[(4-flourophenyl)sulphonyl]glycine, 1,1-dimethylethyl ester from Example 5a (4.5 mmol, 1.30 g) was combined with dried 325 mesh K2CO3 (5.0 mmol, 0.69 g) and N,N-dimethylacetamide (4.5 mL). Cyclohexyl mercaptan (5 mmol, 0.61 mL) was added, and the mixture was stirred under argon at 60° C. for 40 hours. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (125 mL). The organic phase was dried using magnesium sulphate, filtered through silica, and concentrated. The N-[[4-(cyclohexyl-thio)phenyl]sulfonyl]glycine, 1,1-dimethylethyl ester, a white solid (528 mg), was obtained following chromatography eluting with hexane:ethyl acetate (4:1). NMR indicated the presence of about 20% starting material after chromatography, but the mixture was used as is in the next step. The structure was confirmed spectroscopically.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][CH2:20][N:21]1[C:25]2[CH:26]=[CH:27][C:28]([C:30](=[O:32])[CH3:31])=[CH:29][C:24]=2[O:23][C:22]1=[O:33].C([O-])([O-])=O.[K+].[K+].C(#N)C>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][CH2:20][N:21]4[C:25]5[CH:26]=[CH:27][C:28]([C:30](=[O:32])[CH3:31])=[CH:29][C:24]=5[O:23][C:22]4=[O:33])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CC(=O)c1ccc2c(c1)oc(=O)n2CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(=O)c1ccc2c(c1)oc(=O)n2CCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 30.5 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.0 g, 9 mmol), N-(3-chloropropyl)-6-acetyl-2-benzoxazolinone (2.4 g, 9 mmol), K2CO3 (3.6 g), a few crystals of KI, and acetonitrile (50 ml) was stirred and refluxed for 13 hours. The reaction was poured into water, and a dark, brown solid that separated was collected to afford 3.3 g of crude product. The solid was chromatographed on a Waters Prep 500 HPLC. Concentration of appropriate fractions afforded 2.3 g of a yellow solid, and recrystallization from ethyl acetate yielded 1.2 g (31%) of N-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl]-6-acetyl-2-benzoxazolinone, m.p.=152-154° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:3]=1.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([C@@H:41]([C:43]2[CH:44]=[C:45](B(O)O)[C:46]([F:49])=[N:47][CH:48]=2)[CH3:42])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].CC([O-])=O.[K+]>O1CCOCC1.O>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:4]2[N:5]=[C:6]([CH3:8])[N:7]=[C:2]([C:45]3[CH:44]=[C:43]([C@H:41]([N:38]4[CH2:37][CH2:36][N:35]([C:33]([O:32][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:34])[CH2:40][CH2:39]4)[CH3:42])[CH:48]=[N:47][C:46]=3[F:49])[CH:3]=2)=[CH:12][CH:13]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(Cl)nc(C)n2)cc1
Reactant: C[C@H](c1cnc(F)c(B(O)O)c1)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(-c3cc([C@@H](C)N4CCN(C(=O)OC(C)(C)C)CC4)cnc3F)nc(C)n2)cc1
Temperature: 100 °C
Yield: 43.5 %

Procedure:
6-chloro-N,N-bis(4-methoxybenzyl)-2-methylpyrimidin-4-amine (Example 177) (0.766 g, 1.996 mmol), (5-((1R)-1-(4-(tert-butoxycarbonyl)-1-piperazinyl)ethyl)-2-fluoro-3-pyridinyl)boronic acid (Example 146, Step 4) (0.705 g, 1.996 mmol), PdCl2AmPhos (0.071 g, 0.100 mmol), and KOAc (0.588 g, 5.99 mmol) in a mixture of dioxane (16.6 mL) and water (3.3 mL) was sparged with nitrogen and then heated at 100° C. for 2.5 h. The yellow reaction mixture was subsequently partitioned between CH2Cl2 (60 mL) and water (50 mL). The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (2×50 mL). The combined organic extracts were then dried over Na2SO4 and concentrated. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a silica gel column (80 g), eluting with a gradient of 0% to 100% EtOAc in hexane, to provide tert-butyl 4-((1R)-1-(5-(6-(bis(4-methoxybenzyl)amino)-2-methyl-4-pyrimidinyl)-6-fluoro-3-pyridinyl)ethyl)-1-piperazinecarboxylate (0.570 g, 0.868 mmol, 43.5% yield) as light-yellow foam. m/z (ESI, +ve) 657.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.43 (d, J=8.22 Hz, 1H); 8.18 (s, 1H); 7.18 (d, J=7.24 Hz, 4H); 6.82-6.89 (m, 5H); 4.75 (br. s., 4H); 3.79 (s, 6H); 3.60 (d, J=7.04 Hz, 1H); 3.43 (br. s., 4H); 2.63 (s, 3H); 2.30-2.53 (m, 4H); 1.44 (s, 12H).
Reaction SMILES: [CH:1](=[O:5])[CH2:2][CH2:3][CH3:4].[CH2:6]([OH:10])[CH:7]=[CH:8][CH3:9]>C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.[Ti].C1(C)C=CC=CC=1>[CH2:1]([O:5][CH:6]([O:10][CH2:1][CH:2]=[CH:3][CH3:4])[CH2:7][CH2:8][CH3:9])[CH:2]=[CH:3][CH3:4]
Reactant: CC=CCO
Reactant: CCCC=O
Agent: [Ti]
Agent: CC(=O)/C=C(/C)O
Solvent: Cc1ccccc1
Product: CC=CCOC(CCC)OCC=CC
Temperature: 20 °C
Reaction time: 12 h
Yield: 190.7 %

Procedure:
In a 300-ml three-necked flask, 72 g (1 mole) of n-butanal, 144 g of crotyl alcohol, 3 mg of titanium acetylacetonate, 80 g of molecular sieve 4A and 50 g of toluene were charged. The resulting mixture was stirred at 20° C. under atmospheric pressure for 12 hours in a nitrogen atmosphere. After the removal of the molecular sieve 4A from the reaction mixture, the solvent (toluene) and the unreacted starting materials were distilled off under reduced pressure. Distillation of the residue under reduced pressure gave 189.1 g of n-butanal dicrotyl acetal (boiling point: 116° C./25 mmHg) (yield: 95.5%).
Reaction SMILES: [F:1][CH:2]([F:18])[CH2:3][N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([NH2:17])[C:13]([O:15][CH3:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33]([CH:36]([CH3:38])[CH3:37])(=[O:35])=[O:34])[C:23]([Cl:39])=[CH:22][N:21]=1>>[Cl:39][C:23]1[C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33]([CH:36]([CH3:38])[CH3:37])(=[O:35])=[O:34])=[N:25][C:20]([NH:17][C:12]2[C:13]([O:15][CH3:16])=[CH:14][C:7]3[CH2:6][CH2:5][N:4]([CH2:3][CH:2]([F:1])[F:18])[CH2:10][CH2:9][C:8]=3[CH:11]=2)=[N:21][CH:22]=1
Reactant: COc1cc2c(cc1N)CCN(CC(F)F)CC2
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n1)CCN(CC(F)F)CC2

Procedure:
The title compound was prepared from 3-(2,2-Difluoro-ethyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and (2,5-Dichloro-pyrimidin-4-yl)-[2-(propane-2-sulfonyl)-phenyl]-amine in an analogous manner to Example 61e. Product isolated as an off-white foam (0.064 g, 65%). MP: 71-78° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 9.50 (s, 1H), 8.55 (d, 1H, J=8.3 Hz), 8.16 (s, 1H), 7.99 (s, 1H), 7.95-7.91 (m, 1H), 7.63-7.57 (m, 1H), 7.50 (s, 1H), 7.29-7.23 (m, 1H), 6.65 (s, 1H), 5.91 (tt, 1H, J=56.1 Hz and 4.2 Hz), 3.87 (s, 3H), 3.26 (sept, 1H, J=6.9 Hz), 2.97-2.70 (m, 10H, 1.32 (d, 6H, J=7.1 Hz). MS: 566.49 (MH)+.