Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[F:22][C:23]1[CH:24]=[C:25]([CH:42]=[CH:43][CH:44]=1)[CH2:26][N:27]1[CH:31]=[C:30](C2OC(C)(C)C(C)(C)O2)[C:29]([CH3:41])=[N:28]1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:30]3[C:29]([CH3:41])=[N:28][N:27]([CH2:26][C:25]4[CH:42]=[CH:43][CH:44]=[C:23]([F:22])[CH:24]=4)[CH:31]=3)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1nn(Cc2cccc(F)c2)cc1C1OC(C)(C)C(C)(C)O1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cn(Cc4cccc(F)c4)nc3C)c3cc(Br)cnc32)cc1
Yield: 78.5 %

Procedure:
Using similar reaction conditions as described in step-i of example-1,5-bromo-3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (Intermediate 1) (300 mg, 0.709 mmol) was coupled with 1-(3-fluorobenzyl)-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 12) (270 mg, 0.851 mmol) using sodium carbonate (220 mg, 2.12 mmol) and Pd(PPh3)2Cl2 (25 mg, 0.035 mmol) in acetonitrile/water (10/2.5 ml) to afford 300 mg (78.5% yield) of the pure product after column purification using 40% ethyl acetate in hexane as eluent. MS: m/z=539.2 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.CN(C)C=O.Cl[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:16]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: ClCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCc2ccccc2)cc1
Reaction time: 10 h
Yield: 50.4 %

Procedure:
12.2 g of 4-hydroxybenzaldehyde is mixed with 35 ml of dimethylformamide, 16.9 g of (2-chloroethyl)benzene and 16.6 g of potassium carbonate. The resulting mixture is stirred in a stream of nitrogen at 80°-90° C. for 10 hours and then cooled. The cooled mixture is added to 500 ml of water and then extracted with 500 ml of chloroform. The extract is washed with water until it becomes neutral. The washed extract is dried with anhydrous sodium sulfate and then chloroform is distilled away. The resulting residue is distilled under reduced pressure to obtain 11.4 g of 4-phenethyloxybenzaldehyde. Thus obtained 4-phenethyloxybenzaldehyde has a boiling point of 173°-181° C./2-3 mmHg.
Reaction SMILES: [CH3:1][CH:2]([Si:4]([CH:17]([CH3:19])[CH3:18])([CH:14]([CH3:16])[CH3:15])[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12]O)=[CH:8][CH:7]=1)[CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[Br:44]Br.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OCC)C.C(#N)C.O>[Br:44][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][Si:4]([CH:17]([CH3:19])[CH3:18])([CH:14]([CH3:16])[CH3:15])[CH:2]([CH3:3])[CH3:1])=[CH:7][CH:8]=1
Reactant: BrBr
Reactant: CC(C)[Si](Oc1ccc(CO)cc1)(C(C)C)C(C)C
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CC#N
Solvent: O
Product: CC(C)[Si](Oc1ccc(CBr)cc1)(C(C)C)C(C)C
Temperature: 0 °C

Procedure:
To a solution of (4-{[tris(1-methylethyl)silyl]oxy}phenyl)methanol (Step 2, 1.0 g, 3.56 mmol) in diethyl ether (20 mL) and acetonitrile (7.5 mL) was added triphenylphosphine (0.94 g, 3.57 mmol) and imidazole (243 mg, 3.57 mmol). After being cooled to 0° C., a solution of bromine (184 μL, 3.56 mmol) in diethyl ether (2.5 mL) was added dropwise. The reaction mixture was stirred at rt over night. Then water was added, and it was extracted with ethyl acetate. The organic extract was washed with water and brine, dried over anhydrous magnesium sulfate and filtered. After evaporation of the solvent, the crude material was treated with pentane. Precipitated triphenylphosphine oxide (TPPO) was removed by filtration. The solvent was evaporated in vacuo. The product thus obtained (1.42 g) still contained some TPPO (as judged by tlc) but was used for subsequent reactions without further purification.
Reaction SMILES: [CH2:1]([N:5]([CH2:39][CH2:40][CH2:41][CH3:42])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:18][C:17]([CH:19]=O)=[CH:16][CH:15]=2)=[C:8]([O:21][Si:22]([C:35]([CH3:38])([CH3:37])[CH3:36])([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:43]([C:45]1[C:46](=[C:53]([C:56]#[N:57])[C:54]#[N:55])[O:47][C:48]([CH3:52])([CH3:51])[C:49]=1[CH3:50])#[N:44].C([O-])(=O)C.[NH4+]>C(O)C.O1CCCC1>[CH2:39]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:18][C:17]([CH:19]=[CH:50][C:49]3[C:48]([CH3:51])([CH3:52])[O:47][C:46](=[C:53]([C:54]#[N:55])[C:56]#[N:57])[C:45]=3[C:43]#[N:44])=[CH:16][CH:15]=2)=[C:8]([O:21][Si:22]([C:35]([CH3:38])([CH3:37])[CH3:36])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:7]=1)[CH2:40][CH2:41][CH3:42]
Reactant: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)s2)c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(C)C)s2)c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 47 h
Yield: 56.5 %

Procedure:
In 12 ml of ethanol and 4 ml of tetrahydrofuran were dissolved 500 mg (0.84 mmol) of 5-[2-[4-dibutylamino-2-(tert-butyldiphenylsiloxy)phenyl]vinyl]thiophene-2-carboaldehyde and 185 mg (0.93 mmol) of 2-(3-cyano-4,5,5-trimethyl-2(5H)-furanylidene)propanedinitrile. To this mixture was added 65 mg of ammonium acetate, and the mixture was stirred at room temperature for 47 hours. The solvent was evaporated off and the residue was washed with ethanol. The residue was purified by silica gel column chromatography and washed with ethanol to give 369 mg of a dark greenish brown crystal (yield: 56.6%; mp: 218-219° C.).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH2:17][CH3:18])=[O:14])=[C:11]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[C:10]2[C:5](=[CH:6][C:7]([O:31][CH3:32])=[C:8]([O:29][CH3:30])[CH:9]=2)[N:4]=1.[SH:33][C:34]1[N:35]([CH3:39])[CH:36]=[CH:37][N:38]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:30][O:29][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[O:31][CH3:32])[N:4]=[C:3]([CH2:2][S:33][C:34]1[N:35]([CH3:39])[CH:36]=[CH:37][N:38]=1)[C:12]([C:13]([O:15][CH2:16][CH2:17][CH3:18])=[O:14])=[C:11]2[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1
Reactant: Cn1ccnc1S
Reactant: CCCOC(=O)c1c(CBr)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOC(=O)c1c(CSc2nccn2C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.3 %

Procedure:
A mixture of propyl 2-bromomethyl-6,7-dimethoxy-4- (3,4-dimethoxyphenyl)quinoline-3-carboxylate (3.3 g), 2-mercapto-1-methylimidazole (821 mg), potassium carbonate (1.08 g) and N,N-dimethylformamide (60 ml) was stirred at room temperature for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), and the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography on silica gel. From the fraction eluted with chloroform/ethyl acetate (7:3, v/v), propyl 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2- [(1-methylimidazol-2-yl)thiomethyl]quinoline-3-carboxylate (1.77 g, 51%) was obtained and recrystallized from acetone/isopropyl ether.
Reaction SMILES: C[CH:2]([C@H:6]1[CH2:11][CH2:10][NH:9][C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH2:7]1)[C:3]([O-:5])=[O:4].[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O.[CH3:31][C:32]([C:34]#[CH:35])=[CH2:33]>CO.[Au](Br)(Br)Br>[CH3:33][C:32](=[CH2:31])[C:34]#[C:35][C@H:22]([N:9]1[CH2:10][CH2:11][C@H:6]([CH2:2][C:3]([OH:5])=[O:4])[CH2:7][C@@H:8]1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][CH:13]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=Cc1ccccc1
Reactant: C#CC(=C)C
Reactant: CC(C(=O)[O-])[C@H]1CCN[C@@H](c2ccc(C(F)(F)F)cc2)C1
Agent: Br[Au](Br)Br
Solvent: O
Solvent: CO
Product: C=C(C)C#C[C@@H](c1ccccc1)N1CC[C@H](CC(=O)O)C[C@@H]1c1ccc(C(F)(F)F)cc1
Temperature: 70 °C
Yield: 9.5 %

Procedure:
(±)-Methyl{(2R*,4S*)-2-[4-(trifluoromethyl)phenyl]piperidin-4-yl}acetate (Example 3 Step 3, 150 mg, 0.5 mmol), benzaldehyde (159 mg, 1.5 mmol), gold (III) bromide (22 mg, 0.05 mmol) and water (0.5 ml) were combined in a sealed microwave tube. The mixture was de-gassed and placed under an N2-atmosphere before 2-methyl-1-buten-3-yne (99 mg, 1.5 mmol) was added via syringe, followed by heating to 70° C. using microwave irradiation for 20 min. The reaction mixture was diluted with MeOH and loaded onto a SCX cartridge, which was washed with MeOH, then eluted with 2M ammonia in MeOH. The eluant was treated with 6M aq. NaOH (0.25 ml) and heated to reflux for 2 h. The volatiles were removed under vacuum and the residue partitioned between 2M HCl and DCM. The DCM layer was evaporated and the residue purified by preparative reverse phase HPLC to give 21 mg of the title compound as the TFA salt.
Reaction SMILES: CS([Cl:5])(=O)=O.[CH3:6][S:7]([C:10]1[CH:11]=[C:12]([CH2:16]O)[CH:13]=[CH:14][CH:15]=1)(=[O:9])=[O:8].C(N(CC)CC)C.O>ClCCl>[Cl:5][CH2:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([S:7]([CH3:6])(=[O:9])=[O:8])[CH:11]=1
Reactant: CS(=O)(=O)c1cccc(CO)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)c1cccc(CCl)c1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
0.267 ml (3.45 mmol) methanesulphonyl-chloride is added to o a solution of 584 mg (3.14 mmol) (3-methanesulphonyl-phenyl)-methanol and 0.66 ml (4.71 mmol) triethylamine in 6 ml dichloromethane. This reaction mixture is stirred at room temperature for 1 h and at 50° C. for additional 3 h. The reaction mixture is then poured into water and extracted twice with dichloromethane. The combined organic layers are washed with water and brine, dried, filtered and concentrated in vacuo to afford the title compound, which is used in the next step without further purification.
Reaction SMILES: B1([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)C2CCCC1CCC2.Br[C:18]1[C:26]2[C:21](=[CH:22][C:23]([CH2:27][N:28]([CH:36]3[CH2:38][CH2:37]3)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:24][CH:25]=2)[N:20]([CH2:39][CH2:40][CH2:41][O:42][CH3:43])[N:19]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCCC1.CN(C)C=O.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>[CH2:10]([C:18]1[C:26]2[C:21](=[CH:22][C:23]([CH2:27][N:28]([CH:36]3[CH2:38][CH2:37]3)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:24][CH:25]=2)[N:20]([CH2:39][CH2:40][CH2:41][O:42][CH3:43])[N:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COCCCn1nc(Br)c2ccc(CN(C(=O)OC(C)(C)C)C3CC3)cc21
Reactant: c1ccc(CB2C3CCCC2CCC3)cc1
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: COCCCn1nc(Cc2ccccc2)c2ccc(CN(C(=O)OC(C)(C)C)C3CC3)cc21
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A 0.5M solution of B-benzyl-9-BBN in tetrahydrofuran (1.8 ml) was added to a solution of tert-butyl {[3-bromo-1-(3-methoxypropyl)-1H-indazol-6-yl]methy}cyclopropylcarbamate (200 mg), potassium phosphate (290 mg), palladium acetate(II) (4 mg) and S-Phos (15 mg) in N,N-dimethylformamide (5 ml) under argon atmosphere and the mixture was stirred at 60° C. for 18 hours. Water was added to the reaction mixture under ice-cooling and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate and concentrated in vacuo. The resulted residue was purified with a silica gel column chromatography (eluting solvent: n-hexane to n-hexane/ethyl acetate=2/1) to give tert-butyl {[3-benzyl-1-(3-methoxypropyl)-1H-indazol-6-yl]methy}cyclopropylcarbamate (198 mg) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9]([CH:12]1[CH2:17][CH2:16]O[C:13]1=[O:14])(=O)[CH3:10].[OH-].[Na+].P(Cl)(Cl)([Cl:22])=O>>[Cl:22][CH2:16][CH2:17][C:12]1[C:13](=[O:14])[N:3]2[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]2=[N:1][C:9]=1[CH3:10]
Reactant: CC(=O)C1CCOC1=O
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cccnc1N
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc2c(C)cccn2c(=O)c1CCCl
Temperature: 100 °C

Procedure:
To a solution of 2-amino-3-picoline (3.3 9, 30 mmol) in phosphorus oxychloride (11 ml) was added 2-acetylbutyrolactone (3.25 ml, 30 mmol). The mixture was heated at 100° C. for 18 hours, cooled, poured on ice, made basic with a 2N sodium hydroxide solution and extracted with ethyl acetate. The organic layer was separated, dried, concentrated and purified by silica gel column chromatography (dichloromethane/methanol=95/5). Yield 2.5 g (35%) of white solid.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].CCN(C(C)C)C(C)C.[F:23][C:24]([F:28])([F:27])[CH2:25][NH2:26]>C(Cl)Cl>[F:23][C:24]([F:28])([F:27])[CH2:25][NH:26][C:2](=[O:3])[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCC(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(F)(F)F)Oc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 4-nitrophenyl chloroformate (4578 mg, 22715 μmol) and DIEA (2638 μL, 15143 μmol) in DCM (100 mL) at 0° C. was added 2,2,2-trifluoro-ethylamine (1500 μL, 15143 μmol). The resulting mixture was then stirred at 0° C. for 4 h and at RT for overnight. Then, the mixture was concentrated and a white precipitation was observed. The mixture was then filtered to give the title compound as a white solid, which was used in the next step without purification requirement.
Reaction SMILES: C(O[C:4](=[O:21])[C:5](=[CH:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[OH:21][C:4]1[C:14]2[C:13](=[CH:18][CH:17]=[C:16]([O:19][CH3:20])[CH:15]=2)[N:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(=CNc1ccc(OC)cc1)C(=O)OCC
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2ccc(OC)cc2c1O
Temperature: 250 °C

Procedure:
Diethyl({[4-(methyloxy)phenyl]amino}methylidene)propanedioate (100 g, 0.34 mol) was taken up in Dowtherm (500 mL) and heated at 250° C. for 1.5 h; 75% conversion. The reaction solution was cooled, treated with hexanes (750 mL) and cooled to 0° C. in ice bath. The brown solid was filtered off and washed with hexanes (2×) and dried under vacuum to give 60 g (71%).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:17])=[C:4]([CH3:16])[C:5]2[O:9][CH:8]([CH2:10][CH2:11][CH2:12][OH:13])[S:7][C:6]=2[C:14]=1[CH3:15].[H-].[Na+].[CH3:20][O:21][CH2:22]Cl.O>CN(C)C=O.C1C=CC=CC=1>[OH:1][C:2]1[C:3]([CH3:17])=[C:4]([CH3:16])[C:5]2[O:9][CH:8]([CH2:10][CH2:11][CH2:12][O:13][CH2:20][O:21][CH3:22])[S:7][C:6]=2[C:14]=1[CH3:15]
Reactant: Cc1c(C)c2c(c(C)c1O)SC(CCCO)O2
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: COCOCCCC1Oc2c(C)c(C)c(O)c(C)c2S1
Temperature: 0 °C

Procedure:
5.0 g of 3-(5-hydroxy-4,6,7-trimethyl-1,3-benzoxathiole-2-yl)propanol (prepared as described in Example 71) were dissolved in 40 ml of dimethylformamide, and 260 mg of a 55% w/w oily suspension of sodium hydride was added at room temperature. The reaction mixture was then heated for 1 hour at 40°-45° C., after which it was cooled with ice-water, and then a solution of 1.6 g of chloromethyl methyl ether in 5 ml of benzene was added dropwise. After completion of the addition, the temperature of the mixture was gradually raised and then the mixture was heated for 1 hour at 50°-55° C. The reaction mixture was then poured into water and extracted with benzene. The extract was washed with water and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel Lobar column chromatography, and the title compound was obtained from the fraction eluted with a 100:3 by volume mixture of benzene and ethyl acetate.
Reaction SMILES: [OH:1][N:2]=[C:3]([C@@H:5]1[C@:22]2([CH3:23])[C@H:8]([C:9]3[C@H:19]([CH2:20][CH2:21]2)[C@:17]2([CH3:18])[C:12]([CH2:13][C@@H:14]([O:24][CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)[CH2:15][CH2:16]2)=[CH:11][CH:10]=3)[CH2:7][CH2:6]1)[CH3:4].[H-].[Na+].[CH3:33][C:34]1([O:37][CH2:36]1)[CH3:35].C(OCC)C>CN(C)C=O>[OH:37][C:34]([CH3:36])([CH3:35])[CH2:33][O:1][N:2]=[C:3]([C@@H:5]1[C@:22]2([CH3:23])[C@H:8]([C:9]3[C@H:19]([CH2:20][CH2:21]2)[C@:17]2([CH3:18])[C:12]([CH2:13][C@@H:14]([O:24][CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)[CH2:15][CH2:16]2)=[CH:11][CH:10]=3)[CH2:7][CH2:6]1)[CH3:4]
Reactant: CC(=NO)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC1(C)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(=NOCC(C)(C)O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A portion (606 mg) of the 20-hydroxyimino-3β-(2-tetrahydropyranyloxy)-5,7-pregnadiene obtained in (a) was dissolved in 10 ml of dry dimethylformamide, and after addition of 100 mg of sodium hydride (60% in oil), the solution was vigorously stirred for 30 minutes at room temperature. After addition of 0.5 ml of isobutylene oxide, the mixture was heated on an oil bath (80°-100° C.) for 1 hour. After cooling, diethyl ether was added, and the mixture was washed with water and dried, followed by the distilling off of the solvent under vacuum. The residue was subjected to silica gel column chromatography to obtain 271 mg of 20-(2-hydroxy-2-methylpropyloxyimino)-3β-(2-tetrahydropyranyloxy)-5,7pregnadiene.
Reaction SMILES: [CH2:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH2:4][CH2:3][CH:2]1[NH2:14].[F:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1.N1C=CC=CC=1>C(#N)C>[F:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:14][C:2]2[CH:3]=[CH:4][C:5]3[O:6][C:7]4[CH2:13][CH2:12][CH2:11][CH2:10][C:8]=4[C:9]=3[CH:1]=2)=[O:21])=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: NC1CCc2oc3ccccc3c2C1
Solvent: CC#N
Solvent: c1ccncc1
Product: O=C(Nc1ccc2oc3c(c2c1)CCCC3)c1ccc(F)cc1
Yield: 65.9 %

Procedure:
Following the procedure of Example 1, tetrahydro-dibenzofuran-2-ylamine (0.50 g, 2.7 mmol), 4-fluorobenzoyl chloride (0.32 mL, 2.7 mmol), and pyridine (0.54 mL, 6.7 mmol) in acetonitrile (30 mL) provided 4-fluoro-N-(6,7,8,9-tetrahydrodibenzo[b,d]furan-2-yl)benzamide (0.55 g) after filtering the precipitate from the reaction mixture. MS (ESI) m/z 310 ([M+H]+).
Reaction SMILES: [OH:1][CH:2]([C:19]1[CH:20]=[C:21]([Si:24]([CH3:27])([CH3:26])[CH3:25])[O:22][CH:23]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].[C:28](OC(=O)C)(=[O:30])[CH3:29].N1C=CC=CC=1>>[C:28]([O:1][CH:2]([C:19]1[CH:20]=[C:21]([Si:24]([CH3:26])([CH3:25])[CH3:27])[O:22][CH:23]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])(=[O:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCCCC(O)c1coc([Si](C)(C)C)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC(CCCCCCCCO[Si](C)(C)C(C)(C)C)c1coc([Si](C)(C)C)c1

Procedure:
A solution of 4-(1-hydroxy-9-t-butyldimethylsiloxynonyl)-2-trimethylsilylfuran (0.892 g, 2.17 mmol), acetic anhydride (5 ml) and pyridine (0.729 g, 8.66 mmol) was stirred at room temperature until no starting material was visible by TLC. The reaction mixture was concentrated and the residue was taken up in ethyl ether, washed with 10% hydrochloric acid, saturated sodium bicarbonate, aqueous 5% cupric sulfate solution, water, saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give the title compound which was carried on without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.Cl[CH:19]([C:22]1([C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[N:31]=[CH:30][CH:29]=[CH:28]3)[CH2:24][CH2:23]1)[CH:20]=O.C(N(CC)CC)C>C(O)(C)C>[N:31]1[C:32]2[C:27](=[CH:26][C:25]([C:22]3([C:19]4[N:3]5[N:4]=[C:5]([C:8]6[CH:9]=[CH:10][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:16][CH:17]=6)[CH:6]=[N:7][C:2]5=[N:1][CH:20]=4)[CH2:24][CH2:23]3)=[CH:34][CH:33]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: O=CC(Cl)C1(c2ccc3ncccc3c2)CC1
Reactant: COC(=O)c1ccc(-c2cnc(N)nn2)cc1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: COC(=O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3n2)cc1
Temperature: 110 °C
Yield: 44.1 %

Procedure:
A mixture of methyl 4-(3-amino-1,2,4-triazin-6-yl)benzoate (160 mg, 0.70 mmol) and chloro(1-quinolin-6-ylcyclopropyl)acetaldehyde (200 mg, 0.83 mmol) in isopropyl alcohol (6 mL) was heated at 110° C. for 24 h. The mixture was adjusted to pH 9 by adding triethylamine and then the volatiles were removed under reduced pressure. The residue was purified by chromatography on silica gel with EtOAc in CH2Cl2 (0-60%) to afford the desired product (130 mg, 44%). LCMS: (M+H)=421.1.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH2:12][C@H:11]([CH3:13])[NH:10][CH2:9][C@H:8]2[CH3:14])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:24][CH2:25][C:26](Cl)=[O:27]>ClCCl>[Cl:24][CH2:25][C:26]([N:10]1[CH2:9][C@H:8]([CH3:14])[N:7]([CH2:6][C:5]2[CH:15]=[CH:16][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:12][C@H:11]1[CH3:13])=[O:27]
Reactant: C[C@@H]1CN[C@@H](C)CN1Cc1ccc(F)cc1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)CCl
Reaction time: 0.5 h
Yield: 84.9 %

Procedure:
To a solution of (2R,5S)-1-(4-fluoro-benzyl)-2,5-dimethyl-piperazine (2.5 g, 11.2 mmol) in dry dichloromethane (11 mL) at 0° C. was added triethylamine (1.57 mL, 11.2 mmol) followed by chloroacetyl chloride (0.86 mL, 11.2 mmol). The resulting reaction mixture was stirred for 30 minutes. The reaction was then filtered through a pad of celite, washed with dichloromethane and the resulting filtrate was concentrated. Chromatography on silica gel gave the title compound (2.84 g).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH:6]=O)[CH2:2]1.[ClH:8].[NH2:9][OH:10]>C(O)C>[OH:10][N:9]=[C:6]([Cl:8])[CH:3]1[CH2:4][CH2:5][O:1][CH2:2]1
Reactant: O=CC1CCOC1
Reactant: Cl
Reactant: NO
Solvent: CCO
Product: ON=C(Cl)C1CCOC1

Procedure:
Tetrahydrofuran-3-carboxaldehyde (50% solution in water, 2.5 mL, 12.5 mmol) in ethanol (5.0 mL) is stirred with hydroxylamine-hydrochloride (1.3 g, 18.7 mmol) for 3 h. The reaction is quenched with 0.1 M HCl and extracted with EtOAc, dried over MgSO4, filtered, and concentrated to give the oxime as a colorless oil. A solution of the oxime (115 mg, 1.0 mmol) in DMF (1 mL) is then treated with N-chlorosuccinimide (147 mg, 1.1 mmol) at 40° C. for 2 h. The reaction is then cooled to room temperature, poured on to ice water and extracted with diethyl ether (3×10 mL). The combined organics are dried over MgSO4, filtered, and concentrated to give tetrahydrofuran-3-carbonyl chloride oxime, which is used without further purification.