Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]([CH2:16][CH:17]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[O:18]1)CC1C=CC=CC=1)C1C=CC=CC=1.[H][H]>C(O)(=O)C.[Pd]>[NH2:8][CH2:16][CH:17]1[CH2:26][CH:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[O:18]1
Reactant: [H][H]
Reactant: C1=C(c2ccccc2)c2ccccc2OC1CN(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: NCC1CC(c2ccccc2)c2ccccc2O1

Procedure:
2-(N,N-dibenzylaminomethyl)-4-phenyl-3-chromene (2.2 g) was hydrogenated at 651b in -2 in glacial acetic acid in the presence of 5% palladium on carbon (15 mg) until no more hydrogen was taken up. After filtration and removal of solvent in vacuo the residue was treated with ethereal HBr and the resulting solid recrystallised from ethanol/ether to give the title compound as the hydrobromide salt (0.9 g), mp 243°-245° C.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7](=[O:10])[CH2:8][CH3:9])=[CH:5][N:6]=1.[CH3:11][S:12]([O-:14])=[O:13].[Na+]>CS(C)=O.C(OCC)(=O)C.[Cu](I)I>[CH3:11][S:12]([C:2]1[S:3][C:4]([C:7](=[O:10])[CH2:8][CH3:9])=[CH:5][N:6]=1)(=[O:14])=[O:13]
Reactant: CS(=O)[O-]
Reactant: CCC(=O)c1cnc(Br)s1
Agent: I[Cu]I
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCC(=O)c1cnc(S(C)(=O)=O)s1
Temperature: 120 °C
Yield: 56.3 %

Procedure:
To a solution of 1-(2-bromo-thiazol-5-yl)-propan-1-one (75 mg, 0.34 mmol) in dimethyl sulfoxide (3 mL) was added the sodium methylsulfinate (41 mg, 0.34 mmol) followed by copper iodide (65 mg, 0.34 mmol). The mixture was heated in a microwave at 120° C. for 1 h. The reaction was diluted with ethyl acetate (20 mL) and washed with sat. sodium bicarbonate solution (120 ml) and brine (10 ml). The aqueous phase was extracted with ethyl acetate (2×10 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated to give 1-(2-methanesulfonyl-thiazol-5-yl)-propan-1-one (42 mg, 56%) that was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]([CH3:18])[CH3:17])=[CH:13][CH:14]=3)[C:9]([S:19][CH2:20][CH:21]3[CH2:23][CH2:22]3)=[C:8]2[CH2:24][C:25]([CH3:30])([CH3:29])[C:26](O)=[O:27])=[CH:4][CH:3]=1.[Al]([NH2:36])(C)C>C(Cl)Cl.CCCCCC.C(Cl)Cl>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]([CH3:18])[CH3:17])=[CH:13][CH:14]=3)[C:9]([S:19][CH2:20][CH:21]3[CH2:23][CH2:22]3)=[C:8]2[CH2:24][C:25]([CH3:30])([CH3:29])[C:26]([NH2:36])=[O:27])=[CH:4][CH:3]=1
Reactant: CC(C)c1ccc2c(c1)c(SCC1CC1)c(CC(C)(C)C(=O)O)n2Cc1ccc(Cl)cc1
Reactant: C[Al](C)N
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)c1ccc2c(c1)c(SCC1CC1)c(CC(C)(C)C(N)=O)n2Cc1ccc(Cl)cc1

Procedure:
To a solution of 110 mg of methyl 1-(p-chlorobenzyl) α,α- dimethyl-5-isopropyl-3-cyclopropylmethylthioindole-2-propanoate (from Example 108) in 1 ml CH2Cl2 was added 1 ml of aminodimethylalane (Me2AlNH2) in hexane/CH2Cl2 (1.0M) and the reaction heated at 65° for 16h. The reaction was quenched with 2N HCl at 0° C., 0.5M NaK tartrate was added and the solution extracted with ether. The product from ether was purified by chromatography on silica gel (Toluene/Acetone/Acetic acid) 85:15:1 to yield the title compound, m.p. 137°-138°.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:22]=2[NH:21][C:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:19]3[CH2:28][CH2:29][CH2:30][O:31][C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=[CH:34][CH:33]=2)=[C:10]([CH3:42])[CH:9]=1)=[O:7])(C)(C)C>ClCCl.C(O)(C(F)(F)F)=O>[CH2:26]([O:25][C:23]([C:20]1[NH:21][C:22]2[C:18]([C:19]=1[CH2:28][CH2:29][CH2:30][O:31][C:32]1[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=[CH:34][CH:33]=1)=[CH:17][CH:16]=[CH:15][C:14]=2[C:11]1[CH:12]=[CH:13][C:8]([C:6]([OH:7])=[O:5])=[CH:9][C:10]=1[CH3:42])=[O:24])[CH3:27]
Reactant: CCOC(=O)c1[nH]c2c(-c3ccc(C(=O)OC(C)(C)C)cc3C)cccc2c1CCCOc1cccc2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c2c(-c3ccc(C(=O)O)cc3C)cccc2c1CCCOc1cccc2ccccc12

Procedure:
A mixture of EXAMPLE 98C in dichloromethane (5 mL) and TFA (5 mL) was stirred at room temperature overnight and concentrated. The concentrate was partitioned between water (50 mL) and ethyl acetate (200 mL), and the organic phase was washed with brine and dried (Na2SO4), filtered and concentrated. 1H NMR (300 MHz, DMSO-d6) δ 12.88 (m, 1H), 11.00 (s, 1H), 8.22 (m, 1H), 7.85 (m, 3H), 7.86 (m, 1H), 7.73 (d, 1H), 7.32-7.55 (m, 5H), 7.08 (m, 2H), 6.92 (d, 1H), 4.25 (m, 4H), 3.36 (t, 2H), 2.24 (t, 2H), 2.10 (s, 3H), 1.26 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]#[C:10][C:11]2[CH:16]=[C:15]([S:17]([CH2:20][CH2:21][CH3:22])(=[O:19])=[O:18])[CH:14]=[CH:13][C:12]=2[CH3:23])[CH:3]=1.[CH2:24]([O:26][C:27](=[O:34])[CH:28](Br)[CH2:29][CH:30]([CH3:32])[CH3:31])[CH3:25]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:28]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:27]([O:26][CH2:24][CH3:25])=[O:34])=[C:4]([C:9]#[C:10][C:11]2[CH:16]=[C:15]([S:17]([CH2:20][CH2:21][CH3:22])(=[O:19])=[O:18])[CH:14]=[CH:13][C:12]=2[CH3:23])[CH:3]=1
Reactant: CCCS(=O)(=O)c1ccc(C)c(C#Cc2cc(Cl)ccc2O)c1
Reactant: CCOC(=O)C(Br)CC(C)C
Product: CCCS(=O)(=O)c1ccc(C)c(C#Cc2cc(Cl)ccc2OC(CC(C)C)C(=O)OCC)c1
Yield: 81 %

Procedure:
Following the general method as outlined in Intermediate 268, starting from 4-chloro-2-{[2-methyl-5-(propylsulfonyl)phenyl]ethynyl}phenol (Intermediate 267) and 2-bromo-4-methyl-pentanoic acid ethyl ester, the title compound was obtained as a colorless sticky solid in 81% yield.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:14]([OH:16])=O)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH2:24]([O:26][C:27]([CH:29]1[CH2:38][CH2:37][C:32]2[N:33]=[C:34]([NH2:36])[S:35][C:31]=2[CH2:30]1)=[O:28])C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1>CN(C=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:14]([NH:36][C:34]3[S:35][C:31]4[CH2:30][CH:29]([C:27]([O:26][CH3:24])=[O:28])[CH2:38][CH2:37][C:32]=4[N:33]=3)=[O:16])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: O=C(O)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: CCOC(=O)C1CCc2nc(N)sc2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)C1CCc2nc(NC(=O)C(OC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)sc2C1
Yield: 41.1 %

Procedure:
The compound of example A6 was obtained by similar method described in example A1 using 2-(4-cyclopropanesulfonyl-phenyl)-2-[(tetrahydro-pyran-4-yloxy)]-acetic acid (Preparation 4, 0.340 g, 1.0 mmol), 2-Amino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid ethyl ester (Preparation 49; 0.286 g, 1.0 mmol), HOBt (0.162 g, 1.2 mmol), and EDCl (0.229 g, 1.2 mmol), N-methyl morpholine (0.36 g, 3.58 mmol) in DMF (6 mL) to provide the title compound (0.22 g).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10](O)[CH2:11][OH:12].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[O:12][CH2:11][CH2:10][O:7]2)=[CH:4][CH:3]=1
Reactant: OCCO
Reactant: O=Cc1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1ccc(C2OCCO2)cc1
Yield: 94 %

Procedure:
4-Bromo-benzaldehyde (4.00 g, 21.6 mmol), ethane-1,2-diol (6.03 mL, 108 mmol) and toluene-4-sulfonic acid monohydrate (186 mg, 1.08 mmol) were dissolved in toluene (80 mL), and the solution was stirred under reflux for 4 hours. An aqueous solution of saturated sodium bicarbonate was added to the reaction solution at 0° C., which was then extracted with ethyl acetate, the organic layer was washed with brine, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=20:1), and the title compound (4.66 g, 20.3 mmol, 94%) was obtained as a colorless oil.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[N:6]1[C:19](=[O:20])[C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:8]([C@@H:9]2[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([OH:12])[CH2:10]2)[C:7]1=[O:25].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CC(C)=O.[Ag]=O>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[N:6]1[C:19](=[O:20])[C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][N:8]([C@@H:9]2[O:16][C@H:13]([CH2:14][O:15][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@@H:11]([OH:12])[CH2:10]2)[C:7]1=[O:25]
Reactant: BrCc1ccccc1
Reactant: O=c1c(C(F)(F)F)cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1C1CCCO1
Agent: O=[Ag]
Solvent: CC(C)=O
Product: O=c1c(C(F)(F)F)cn([C@H]2C[C@H](O)[C@@H](COCc3ccccc3)O2)c(=O)n1C1CCCO1
Reaction time: 5 h

Procedure:
3.66 Grams of 3-(2-tetrahydrofuranyl)-2'-deoxy-5-trifluoromethyluridine was dissolved in 40 ml of acetone. Thereto were added 5.13 g of benzyl bromide and 5.79 g of silver oxide. The mixture was stirred for 5 hours with refluxing. The reaction mixture was filtered and the filtrate was concentrated. The residue was subjected to silica gel column chromatography (developing solvent : chloroform-methanol=40 : 1). The eluate was recrystallized from dichloromethane-petroleum ether to obtain 0.19 g yield: 4.1%) of 3-(2-tetrahydrofuranyl)-2'-deoxy-5'-O-benzyl-5-trifluoromethyluridine (compound 21) having the melting point of 145° to 147° C.
Reaction SMILES: [OH-].[Na+].Cl.Cl.[CH:5]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:7])[CH3:6].[CH:14]([C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1)=[O:15]>O.C1(C)C=CC=CC=1>[CH:5]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:24]=[CH:23][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=2)=[O:15])[CH2:10][CH2:9]1)([CH3:7])[CH3:6]
Reactant: O=Cc1ccc(C(=O)Cl)cc1
Reactant: CC(C)N1CCNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 101 %

Procedure:
A solution of NaOH (24.0 g, 0.600 mol) in de-ionized H2O (240 mL) and toluene (60 mL) at 0° C. was treated with isopropyl piperazine dihydrochloride salt (39.0 g, 194 mmol). The resulting biphasic solution was stirred at 0° C. for 30 min. A solution of 4-formyl-benzoyl chloride in toluene was added in a slow stream via an addition funnel over 1 h, with vigorous mechanical agitation. The mixture was allowed to warm to room temperature over 16 h, then cooled to 0° C., and the pH adjusted to 10 with 1 N NaOH. The phases were separated and the aqueous layer was extracted with toluene (2×200 mL). The organic layers were combined, washed with brine (200 mL), and concentrated to yield 4-(4-isopropyl-piperazine-1-carbonyl)-benzaldehyde (52.5 g, mass balance 101%) as a pale, yellow-brown oil. The oil was dissolved in EtOH (600 mL) and, with vigorous mechanical agitation, was treated with a solution of NaHSO3 (23.1 g, 222 mmol) in de-ionized H2O (50 mL) which was added via an addition funnel over 30 min. The resulting mixture was stirred at room temperature for 48 h, and then cooled to 0° C. Methyl-tert-butyl ether (500 mL) was added and the resulting the slurry was stirred for 30 min. The precipitate was collected by suction filtration through a medium porosity glass frit, washed with cold EtOH/EtOAc (5:1, 3×60 mL). The solids were dried under vacuum for 2 h, then at 40° C. in a vacuum oven for 16 h to yield the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]([CH3:23])([CH3:22])[CH2:3][O:4][C:5](=[O:21])[C@H:6]([CH:18]([CH3:20])[CH3:19])[NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].N1C=CC=CC=1.Cl[C:31]([O:33][CH2:34][Cl:35])=[O:32]>ClCCl>[Cl:35][CH2:34][O:33][C:31]([NH:1][C:2]([CH3:23])([CH3:22])[CH2:3][O:4][C:5](=[O:21])[C@H:6]([CH:18]([CH3:19])[CH3:20])[NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])=[O:32]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(C)(C)N
Reactant: O=C(Cl)OCCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(C)(C)NC(=O)OCCl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-amino-2-methyl-1-(N-benzyloxycarbonyl-L-valyloxy)-propane (2.9 g, 9 mmole) and pyridine (2 ml) in dichloromethane (50 ml) was added chloromethyl chloroformate(1.55 g, 12 mmole) and the mixture was stirred for 3 hours at room temperature. The mixture was evaporated under reduced pressure and ethyl acetate was added. The organic phase was washed with water, dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography with hexane/ethyl acetate. Yield: 1.1 g=29%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N:7]1[C:14]([Cl:15])=[N:13][C:11]([Cl:12])=[N:10][C:8]=1Cl.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1>[Cl:12][C:11]1[N:13]=[C:14]([Cl:15])[N:7]=[C:8]([N:1]2[CH2:6][CH2:5][N:4]([C:8]3[N:7]=[C:14]([Cl:15])[N:13]=[C:11]([Cl:12])[N:10]=3)[CH2:3][CH2:2]2)[N:10]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Clc1nc(Cl)nc(N2CCN(c3nc(Cl)nc(Cl)n3)CC2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.3 %

Procedure:
Piperazine (8.0 g, 92.9 mmol) is added over a 20 minute period to a mixture of 34.3 g (186 mmol) of cyanuric chloride, 19.7 g of sodium carbonate, 80 ml of water and 200 ml of toluene maintained at a temperature of 5°-10° C. The reaction mixture is stirred for 3 hours at ambient temperature. The precipitate is filtered and washed with water and toluene to obtain 26.0 g (73% yield) of N,N'-bis-(2,4-dichloro-1,3,5-triazin-6-yl)piperazine.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13])=[O:5].[Cl:19][CH2:20][C:21](Cl)=O>C(O)(=O)C>[Cl:19][CH2:20][C:21]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[C:4](=[O:5])[C:3]2[C:2](=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:18])[N:1]=1
Reactant: Cc1cccc(N)c1C(=O)Nc1ccccc1Cl
Reactant: O=C(Cl)CCl
Solvent: CC(=O)O
Product: Cc1cccc2nc(CCl)n(-c3ccccc3Cl)c(=O)c12
Yield: 23.9 %

Procedure:
Prepared according to Procedure B with 1g (2.18 g, 8.36 mmol) and chloroacetyl chloride (2.0 mL, 25.1 mmol) in acetic acid (40 mL). Purified by two chromatographies in CH2Cl2 and EtOAc/hexanes, followed by recrystallization from isopropanol to afford 638 mg of an off-white crystalline solid (24%). 1H NMR (DMSO-d6) δ: 7.73-7.80 (m, 3H); 7.58-7.64 (m, 3H); 7.41 (d, J=7.4 Hz, 1H); 4.40 (d, J=12 Hz, 1H), 4.26 (d, J=12 Hz, 1H); 2.74 (s, 3H). MS (ES): m/z 319.0 (M+).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.Cl[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[NH:13]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:19][O:18][C:14]1[N:13]=[N:12][C:17]([S:1][C:2]2[NH:3][C:4]3[C:9]([CH:10]=2)=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:16][CH:15]=1
Reactant: COC1=CC=CN(Cl)N1
Reactant: Sc1cc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(Sc2cc3ccccc3[nH]2)nn1
Yield: 31 %

Procedure:
To a solution of 2-mercaptoindole (6.7 mmol, 1.0 g) in acetone (20 mL) was added 2-chloro-6-methoxy-pyridazine (144 mmol, 1.52 g) and potassium carbonate (70 mmol, 0.98 g) and the reaction mixture was refluxed for 2 hours. Excess acetone was removed and the residue was partitioned between CHCl3 (20 mL) and H2O (20 mL). The CHCl3 layer was collected, dried, filtered and the filtrate was evaporated to a residue, which was purified by silica gel chromatography (eluent:hexanes:EtOAc::4:1) to obtain 3-methoxy-6-(indole-2-sulfenyl)-pyridazine (31%, 534 mg).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:17]=[C:14]([CH:15]=[O:16])[C:13]([OH:18])=[CH:12][CH:11]=1>CN(C)C=O.C(OCC)(=O)C>[I:1][C:12]1[CH:11]=[C:10]([Cl:9])[CH:17]=[C:14]([CH:15]=[O:16])[C:13]=1[OH:18]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1cc(Cl)cc(I)c1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.9 %

Procedure:
N-Iodosuccinimide (144.0 g, 0.641 mole) was added to a solution of 5-chlorosalicylaldehyde (100 g, 0.638 mole) in dimethylformamide (400 mL). The reaction mixture was stirred for 2 days at room temperature. Additional N-iodosuccinimide (20.0 g) was added and the stirring was continued for an additional 2 days. The reaction mixture was diluted with ethyl acetate (1 L), washed with hydrochloric acid (300 mL, 0.1N), water (300 mL), sodium thiosulfate (5%, 300 mL), brine (300 mL), dried (MgSO4) and was concentrated to dryness to afford the desired aldehyde (162 g, 90% yield) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH:22]4[CH2:24][CH2:23]4)=[CH:20][C:19]([CH:25]4[CH2:27][CH2:26]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:3]=1.[O:32]1[CH2:36][CH2:35][NH:34][C:33]1=[O:37]>>[CH:22]1([C:21]2[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:34]5[CH2:35][CH2:36][O:32][C:33]5=[O:37])=[CH:3][C:4]=4[S:28]([CH3:31])(=[O:30])=[O:29])=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=[C:19]([CH:25]3[CH2:27][CH2:26]3)[CH:20]=2)[CH2:24][CH2:23]1
Reactant: O=C1NCCO1
Reactant: CS(=O)(=O)c1cc(Br)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Product: CS(=O)(=O)c1cc(N2CCOC2=O)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 49.6 %

Procedure:
By reaction and treatment in the same manner as in Example 111 and using (4-bromo-2-methanesulfonylphenyl)[4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl]methanone (451 mg) described in Preparation Example 89 and oxazolidin-2-one (78 mg), the title compound (226.6 mg) was obtained.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6](OS(C(F)(F)F)(=O)=O)[CH:5]=[CH:4][C:3]1=2.[Cl:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:6]2[CH:7]=[C:8]3[C:3](=[CH:4][CH:5]=2)[C:2](=[O:1])[CH2:11][CH2:10][CH2:9]3)=[CH:23][CH:22]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=C1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Product: O=C1CCCc2cc(-c3ccc(Cl)cc3)ccc21

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester and 4-chlorophenyl boronic acid according to the coupling procedure as described in example 6. MS (ESI) m/z 257.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:24]4[O:23][CH2:22][C@H:21]([CH3:25])[N:20](C(OC(C)(C)C)=O)[CH2:19][C:18]=4[C:17]([F:33])=[C:16]([Cl:34])[CH:15]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.C(Cl)Cl.C(N(CC)C(C)C)(C)C.[CH3:47][S:48](Cl)(=[O:50])=[O:49]>>[Cl:34][C:16]1[CH:15]=[C:14]([CH:12]([N:8]2[C:4]3=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]3[C:10]([CH3:11])=[N:9]2)[CH3:13])[C:24]2[O:23][CH2:22][C@H:21]([CH3:25])[N:20]([S:48]([CH3:47])(=[O:50])=[O:49])[CH2:19][C:18]=2[C:17]=1[F:33]
Reactant: Cc1nn(C(C)c2cc(Cl)c(F)c3c2OC[C@H](C)N(C(=O)OC(C)(C)C)C3)c2ncnc(N)c12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nn(C(C)c2cc(Cl)c(F)c3c2OC[C@H](C)N(S(C)(=O)=O)C3)c2ncnc(N)c12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
tert-Butyl (3S)-9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-fluoro-3-methyl-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (13 mg, 0.026 mmol) was stirred in methylene chloride (100 μL, 2 mmol) with N,N-diisopropylethylamine (14 μL, 0.079 mmol) and cooled to 0° C. Methanesulfonyl chloride (2.6 μL, 0.034 mmol) was added, and the mixture was stirred at 0° C. for 1 hr. The mixture was evaporated and diluted with methanol. The reactions were purified by prep HPLC on C-18 column eluting water:acetonitrile gradient buffered pH 10 to give two enantiomers: Peak #1 (Example 35): LCMS calculated for C19H23ClFN6O3S (M+H)+: m/z=469.1; found: 469.1; Peak #2 (Example 36): LCMS calculated for C19H23ClFN6O3S (M+H)+: m/z=469.1; found: 469.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].[CH2:34]([O:36][CH2:37][CH2:38][N:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[C:40]1[NH:48][CH:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1)[CH3:35]>>[CH3:33][O:32][C:28]1[CH:27]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:52]2[CH2:51][CH2:50][CH:49]([NH:48][C:40]3[N:39]([CH2:38][CH2:37][O:36][CH2:34][CH3:35])[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=4[N:41]=3)[CH2:54][CH2:53]2)([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccc(F)cc3)C2)cc(OC)c1OC
Reactant: CCOCCn1c(NC2CCNCC2)nc2ccccc21
Product: CCOCCn1c(NC2CCN(CCC3(c4ccc(F)cc4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 16.7 using 1-(3,4,5-trimethoxybenzoyl)-3-(4-fluorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine (1.0 g, 3.5 mmol) and (1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine (1.6 g, 1.6 mmol). Purify by chromatography on silica gel eluting with 2% triethylamine/10% methanol/ethyl acetate to give the title compound: mp; 217-220° C. Rf=0.38 (silica gel, 2% triethylamine/5% methanol/ethyl acetate).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:23])([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:10]=1[C:24]1[CH2:29][CH2:28][CH2:27][C:26](=[O:30])[CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31](O)[CH2:32][OH:33].C1(C=CC(O)=CC=1)O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:32]1[O:33][C:26]2([CH2:27][CH2:28][CH:29]=[C:24]([C:10]3[CH:11]=[CH:12][C:13]([C:15]([CH3:22])([CH3:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:14][C:9]=3[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:25]2)[O:30][CH2:31]1
Reactant: CCCCCCC(C)(C)c1ccc(C2=CC(=O)CCC2)c(OCc2ccccc2)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Oc1ccc(O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCCCCCC(C)(C)c1ccc(C2=CCCC3(C2)OCCO3)c(OCc2ccccc2)c1

Procedure:
A solution of 500 mg. of 3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]cyclohex-2-en-1-one, 7.8 g. of ethylene glycol, 375 mg. of hydroquinone and 50 mg. of p-toluenesulfonic acid monohydrate in 50 ml. of benzene is heated at reflux for 12 hours using a Dean-Stark condenser filled with 3A molcular sieves. The reaction is cooled, added to 500 ml. saturated sodium bicarbonate and the quenched mixture extracted with three 150 ml. portions of ether, dried over magnesium sulfate and evaporated to a solid. This solid is purified via column chromatography on 50 g. of silica gel eluted with 50% ether-petroleum ether to yield the title product.