Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=[O:33])[CH2:31]Br)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:31][C:30]([C:27]2[CH:28]=[CH:29][C:24]([O:23][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:25][CH:26]=2)=[O:33])[CH:7]=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc[nH]1
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccn1CC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 50 °C

Procedure:
A suspension of 200 mg (1.60 mmol) 1H-pyrrole-2-carboxylic acid methyl ester and 1.56 g (4.79 mmol) cesium carbonate in 3 ml DMF is heated to 50° C. under stirring. Then a solution of 488 mg (1.60 mmol) 1-(4-benzyloxy-phenyl)-2-bromo-ethanone in 1 ml DMF is added within 3 minutes. The reaction mixture is stirred for 18 hours at 50° C. The reaction mixture is filtered with suction and the filtrate is evaporated. The residue is crystallized from diethyl ether to give 1-[2-(4-benzyloxy-phenyl)-2-oxo-ethyl]-1H-pyrrole-2-carboxylic acid methyl ester as beige crystals; HPLC/MS 2.51 min (A), [M+H] 350.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7](Cl)[S:8][C:4]=2[CH:3]=1.NC(N)=[S:14]>CO>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([SH:14])[S:8][C:4]=2[CH:3]=1
Reactant: NC(N)=S
Reactant: Clc1nc2ccc(Br)cc2s1
Solvent: CO
Product: Sc1nc2ccc(Br)cc2s1
Temperature: 120 °C
Yield: 81.3 %

Procedure:
A mixture of 6-bromo-2-chlorobenzo[d]thiazole (250 mg, 1 mmol) and thiourea (228 mg, 3 mmol) in 2 mL of MeOH in a microwave tube was heated in a microwave reactor for 10 min at 120° C. The mixture was concentrated and the solid was collected through filtration and washed with water and dried under high vacuum to afford 6-bromobenzo[d]thiazole-2-thiol as a yellow solid (200 mg, 81%). MS (ESI) m/z 247.9 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]([CH2:10][CH:11]=C)([CH3:9])[C:5]([O:7][CH3:8])=[O:6].CSC.C(Cl)Cl.C[OH:21]>>[CH3:1][O:2][C:3](=[O:13])[C:4]([CH3:9])([CH2:10][CH:11]=[O:21])[C:5]([O:7][CH3:8])=[O:6]
Reactant: CO
Reactant: C=CCC(C)(C(=O)OC)C(=O)OC
Solvent: CSC
Solvent: ClCCl
Product: COC(=O)C(C)(CC=O)C(=O)OC
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of the product of Example 31A (1.1 gm, 5.9 mmol) was dissolved in CH2Cl2/MeOH 10:1 (15 mL) and cooled to −78° C. To the solution was bubbled O3 over 20 minutes. The reaction solution was purged with N2 for a further 10 minutes and dimethyl sulfide (DMS) (3.6 gm, 59 mmol) was added and the reaction warmed to ambient temperature and stirred for a further 2 hours. The solvent was evaporated in vacuo and product purified by flash column chromatography (hexane/EtOAc 100:0 to 70:30) to collect Example 31B as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][NH2:8])=[O:6].CN1CCCC1=O.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[C:19]([NH:8][NH:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NNC(=O)c1cccc(Br)c1
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(NNC(=O)c1cccc(Br)c1)c1ccccc1
Yield: 96 %

Procedure:
Subsequently, 5.0 g (23 mmol) of 3-bromobenzohydrazine obtained in (i) above was put in a 300-mL three-neck flask, 10 mL of N-methyl-2-pyrrolidone was added therein, and the mixture was stirred. Thereafter, a mixed solution of 10 mL of N-methyl-2-pyrrolidone and 3.2 mL (28 mmol) of benzoyl chloride was dripped to the above mixture through a 50-mL dropping funnel. After the dripping, the mixture was heated and stirred at 80° C. for 3 hours so as to be reacted. After the reaction, water was added to the reaction solution, and a solid was precipitated. The precipitated solid was collected by suction filtration to obtain another solid. The obtained solid was washed with approximately 1 L of water and collected by suction filtration. The collected solid was washed with methanol and collected by suction filtration; thus, 7.1 g of a white solid that was an object was obtained (yield: 96%).
Reaction SMILES: [OH:1][CH:2]([CH:19]([CH3:21])[CH3:20])[C:3]([CH3:18])([CH3:17])[CH2:4][O:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[C:7]=1[C:8]#[N:9].[C:22](Cl)(=[O:24])[CH3:23]>>[C:22]([O:1][CH:2]([CH:19]([CH3:21])[CH3:20])[C:3]([CH3:17])([CH3:18])[CH2:4][O:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[C:7]=1[C:8]#[N:9])(=[O:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: CC(C)C(O)C(C)(C)COc1cccc([N+](=O)[O-])c1C#N
Product: CC(=O)OC(C(C)C)C(C)(C)COc1cccc([N+](=O)[O-])c1C#N
Yield: 50 %

Procedure:
Prepared as in Example 231c from 2-(3-hydroxy-2,2,4-trimethylpentyloxy)-6-nitrobenzonitrile (Example 243d) and acetyl chloride in 50% yield. MS 335 (MH+).
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][O:5][C:3]1=[O:4].[C:8]([O:12][C:13]([NH:15][NH:16][C:17](=[S:40])[C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:28][C@H:27]([CH2:29][NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[O:26][C:25]2=[O:38])=[CH:20][C:19]=1[F:39])=[O:14])([CH3:11])([CH3:10])[CH3:9]>>[C:8]([O:12][C:13]([NH:15][N:16]=[C:17]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:28][C@H:27]([CH2:29][NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[O:26][C:25]2=[O:38])=[CH:20][C:19]=1[F:39])[S:40][CH:2]1[CH2:7][CH2:6][O:5][C:3]1=[O:4])=[O:14])([CH3:9])([CH3:11])[CH3:10]
Reactant: O=C1OCCC1Br
Reactant: CC(C)(C)OC(=O)NC[C@H]1CN(c2ccc(C(=S)NNC(=O)OC(C)(C)C)c(F)c2)C(=O)O1
Product: CC(C)(C)OC(=O)NC[C@H]1CN(c2ccc(C(=NNC(=O)OC(C)(C)C)SC3CCOC3=O)c(F)c2)C(=O)O1

Procedure:
Prepared from α-bromo-γ-butyrolactone (0.021 ml, 0.227 mmol) and N′-{4-[5(S)-(tert-butoxycarbonylaminomethyl)-2-oxo-oxazolidin-3-yl]-2-fluorothiobenzoyl}-hydrazinecarboxylic acid tert-butyl ester (0.100 g, 0.206 mmol) according to the procedure of Example 1, Intermediate II (0.95 g, 80%); MS (m/z): [M+H]+=569.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([NH:16][C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=3[O:26][CH3:27])[C:20]([OH:22])=[O:21])(=[O:15])=[O:14])=[CH:10][CH:11]=2)[C:6]([NH:28][C:29]([NH2:31])=[NH:30])=[N:5][CH:4]=1.[H-].[Na+].Cl[C:35]1C2C(=CC=C(S(NC3C=C(C=CC=3OC)C(OC)=O)(=O)=O)C=2)C(Cl)=CN=1>CS(C)=O>[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([NH:16][C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=3[O:26][CH3:27])[C:20]([O:22][CH3:35])=[O:21])(=[O:14])=[O:15])=[CH:10][CH:11]=2)[C:6]([NH:28][C:29]([NH2:31])=[NH:30])=[N:5][CH:4]=1
Reactant: COC(=O)c1ccc(OC)c(NS(=O)(=O)c2ccc3c(Cl)cnc(Cl)c3c2)c1
Reactant: COc1ccc(C(=O)O)cc1NS(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(OC)c(NS(=O)(=O)c2ccc3c(Cl)cnc(NC(=N)N)c3c2)c1
Temperature: 60 °C
Yield: 79.5 %

Procedure:
3-{[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]amino}-4-methoxybenzoic acid hydrochloride ##STR12## Guanidine hydrochloride (179.8 mg, 1.88 mmol) was added in one portion to a suspension of NaH (54.9 mg, 80% dispersion by wt in mineral oil, 1.83 mmol) in DMSO (10 mL) and the mixture was heated at 60° C. under N2 for 20 min. Methyl 3-{[(1,4-dichloro-7-isoquinolinyl)sulphonyl]amino}-4-methoxybenzoate (238.6 mg, 0.541 mmol) was added and the mixture heated at 90° C. for 24 h. The solvents were evaporated in vacuo and the residue was purified by column chromatography upon silica gel using CH2Cl2 -MeOH-0.880NH3 (97:3:0.3 to 90:10:1) as eluant to give methyl 3-{[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]amino}-4-methoxybenzoate (203.2 mg, 0.43 mmol) as a pale yellow solid.
Reaction SMILES: Cl[C:2]1C=[CH:6][C:5]([C:8]2[CH:12]3[CH2:13][N:14]([C:16]4[N:25]=[C:24]5[C:19]([C:20](=[O:37])[C:21]([C:34]([OH:36])=[O:35])=[CH:22][N:23]5[C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=5[F:33])=[CH:18][C:17]=4[F:38])[CH2:15][CH:11]3[O:10][N:9]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.FC(F)(F)C(O)=O.[N:53]1C=CC=C(C2[C@@H]3CNC[C@@H]3ON=2)C=1>>[F:33][C:27]1[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:26]=1[N:23]1[C:24]2[C:19](=[CH:18][C:17]([F:38])=[C:16]([N:14]3[CH2:15][CH:11]4[CH:12]([C:8]([C:5]5[CH:6]=[N:53][CH:2]=[CH:3][CH:4]=5)=[N:9][O:10]4)[CH2:13]3)[N:25]=2)[C:20](=[O:37])[C:21]([C:34]([OH:36])=[O:35])=[CH:22]1
Reactant: c1cncc(C2=NO[C@H]3CNC[C@@H]23)c1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2nc(N3CC4ON=C(c5ccc(Cl)cc5)C4C3)c(F)cc2c1=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2nc(N3CC4ON=C(c5cccnc5)C4C3)c(F)cc2c1=O

Procedure:
The title compound was prepared in an analogous manner to acid 101, but using a suitably substituted TFA salt 4f. Acid 105 was isolated as a beige solid.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH:3]=[CH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(CC)CC)C.[Br:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[C:21]([Cl:28])[CH:20]=1>C1(C)C=CC=CC=1>[Br:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([C:4](=[CH:3][N:2]([CH3:10])[CH3:1])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:24])=[C:21]([Cl:28])[CH:20]=1
Reactant: CCOC(=O)C=CN(C)C
Reactant: O=C(Cl)c1ccc(Br)cc1Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CN(C)C)C(=O)c1ccc(Br)cc1Cl
Temperature: 25 °C
Yield: 68 %

Procedure:
30.2 g of ethyl 3-dimethylaminoacrylate and 29.3 ml of triethylamine were dissolved in 180 ml of toluene and heated to reflux. At this temperature there was added dropwise thereto a solution of 53 g of 4-bromo-2-chloro-benzoyl chloride in 50 ml of toluene over 30 min. and the mixture was subsequently stirred at reflux for a further 1 hr. The mixture was left to cool to room temperature and was stirred in an ice bath for a further 30 min. The suspension was filtered and the triethylamine hydrochloride was washed with 40 ml of ice-cold toluene. The filtrate was concentrated to half of the volume and then, for crystallization, diluted with 100 ml of hexane and stirred in an ice bath for a further 1 hr. 51.2 g (67%) of ethyl 2-(4-bromo-2-chlorobenzoyl)-3-dimethylamino-acrylate were obtained as white crystals. M.p. 101°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]2[CH2:16][CH2:17][CH:18]=O.[NH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][CH2:21]1.C([O-])(=O)C.[Na+]>ClC(Cl)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]2[CH2:16][CH2:17][CH2:18][N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][CH2:21]1
Reactant: CCOC(=O)c1[nH]c2c(Br)cccc2c1CCC=O
Reactant: c1ccc2c(c1)CCCN2
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1[nH]c2c(Br)cccc2c1CCCN1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of EXAMPLE 103A (325 mg) and 1,2,3,4-tetrahydroquinoline (160 mg) in dichloroethane (10 mL) was added sodium acetate (310 mg). The mixture was stirred at ambient temperature overnight, diluted with ethyl acetate (200 mL) and washed with 1N NaOH, water, and brine. After drying over sodium sulfate and concentration, the concentrate was loaded on a silica gel cartridge and eluted with 5% ethyl acetate in hexane.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][CH:7]([CH3:26])[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:13][CH:12]=1.C(N(CC)CC)C.Cl>ClCCl>[CH3:6][CH:7]([CH3:26])[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:18][C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])=[CH:13][CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)CCOc1ccc(NCC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CCOc1ccc(N(CC(=O)OC(C)(C)C)S(C)(=O)=O)cc1
Reaction time: 3 h
Yield: 55.4 %

Procedure:
Methanesulfonylchloride (93 mg, 63 μL, 0.82 mmol) was added in one portion to a stirred solution of 1,1-dimethylethyl N-{4-[(3-methylbutyl)oxy]phenyl}glycinate (intermediate 6, 0.20 g, 0.68 mmol) and triethylamine (138 mg, 189 μL, 1.36 mmol) in dichloromethane (2 mL) at room temperature under a nitrogen atmosphere. Stirring was continued for 3 h then aqueous hydrochloric acid (1.0 M; 2 mL) was added. The organic phase was separated and the aqueous phase washed with dichloromethane (3×5 mL). The organic phases were combined, dried (magnesium sulfate) then evaporated to dryness. The residue was chromatographed on silica gel (30% diethyl ether:cyclohexane) to give the title compound as a white solid (140 mg, 56%). LC/MS: 3.72 min; z/e 389, calcd (M+18) 389. 1H NMR (400 MHz; CDCl3): 0.95 (6H), 1.45 (9H), 1.70 (2H), 1.85 (1H), 3.10 (3H), 3.95 (2H), 4.30 (2H), 6.85 (2H), 7.35 (2H).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][N:4]=[C:5]=[S:6].[NH2:9][C:10]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]#[N:18])[N:11]=1>C(#N)C>[F:1][C:2]([F:8])([F:7])[CH2:3][NH:4][C:5](=[S:6])[NH:9][C:10]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]#[N:18])[N:11]=1
Reactant: FC(F)(F)CN=C=S
Reactant: N#CCCn1ccc(N)n1
Solvent: CC#N
Product: N#CCCn1ccc(NC(=S)NCC(F)(F)F)n1
Reaction time: 18 h

Procedure:
2,2,2-Trifluoroethylisothiocyanate (3.4 g.) was added to a solution of 3-amino-1-(2-cyanoethyl)-pyrazole (2.72 g.) in acetonitrile (10 ml.) and the solution left at room temperature for 18 hours. The mixture was was evaporated to dryness and the residue recrystallised from ethanol to give 3-[3-(2,2,2-trifluoroethyl)thioureido]-1-(2-cyanoethyl)pyrazole, m.p. 164°-165°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])[CH:5]=[CH:4][C:3]=1[NH:33][C:34]([NH:36][C@@H:37]1[CH2:41][CH2:40][NH:39][CH2:38]1)=[O:35].[CH:42]1([CH2:45][C:46](O)=[O:47])[CH2:44][CH2:43]1.C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[CH:42]1([CH2:45][C:46]([N:39]2[CH2:40][CH2:41][C@@H:37]([NH:36][C:34]([NH:33][C:3]3[CH:4]=[CH:5][C:6]([C:8]([N:10]4[CH2:11][CH2:12][N:13]([CH2:16][C:17]5[CH:18]=[CH:19][C:20]([C:23]([OH:32])([C:24]([F:25])([F:26])[F:27])[C:28]([F:30])([F:31])[F:29])=[CH:21][CH:22]=5)[CH2:14][CH2:15]4)=[O:9])=[CH:7][C:2]=3[F:1])=[O:35])[CH2:38]2)=[O:47])[CH2:44][CH2:43]1
Reactant: O=C(O)CC1CC1
Reactant: O=C(Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F)N[C@@H]1CCNC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F)N[C@@H]1CCN(C(=O)CC2CC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.8 %

Procedure:
To a stirring solution of (R)-1-(2-fluoro-4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)-3-(pyrrolidin-3-yl)urea (0.123 mmol, 73 mg), 2-cyclopropylacetic acid (0.123 mmol, 12.4 mg) and triethylamine (0.370 mmol, 35.5 mg) in dichloromethane (2 mL) was added 1-propanephosphonic acid cyclic anhydride (0.370 mmol, 118 mg; 50% solution in ethyl acetate). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane (2 mL) and washed with saturated aqueous sodium hydrogen carbonate solution (3 mL). The organic phase was concentrated and the resulting residue was purified by HPLC and then treated with strong cation exchange column chromatography to afford the title compound (28 mg). MS (ESI) m/z 674.3 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:22])=[C:5]([C:18]([O:20][CH3:21])=[O:19])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].[CH2:23]([Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:24]=[CH2:25].B(F)(F)F.CCOCC>C(Cl)(Cl)Cl>[CH3:22][C:4]12[CH2:25][CH:24]([CH2:23][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:7]([C:8]([O:10][CH3:11])=[O:9])([CH:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:5]1[C:18]([O:20][CH3:21])=[O:19])[C:2]([CH3:1])=[N:3]2
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1ccccc1
Reactant: C=CC[Si](C)(C)C
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: COC(=O)C1C(c2ccccc2)C2(C(=O)OC)C(C)=NC1(C)CC2C[Si](C)(C)C
Reaction time: 4 h

Procedure:
To 1.0 g (3.3 mmol) dimethyl 2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylate (1) [B. Loev. et al., J. Med. Chem., 17, 956 (1974)] in 50 ml chloroform cooled in an ice-bath to 0°-5° there was added 7.5 g (66 mmol) commercially obtained allyltrimethylsilane (2) followed by 1.41 g (10 mmol) boron trifluoride etherate added dropwise via syringe. The reaction mixture was then stirred for 4 hours at 0°-10° and quenched by addition of saturated aqueous NaHCO3 solution. After the addition of 50 ml Et2O, the organic phase was separated, washed with brine and dried. Solvent removal left an oil that was purified by column chromatograhy on silica gel eluting with 7% isopropanol/hexane to give pure 3 as of oil, which crystallized after standing, mp. 152°-155°, formula: C23H33NO4Si; m.w., 415.606. mmr (CDCl3) δ 0.78(9H, s), 0.27(1H, dd), 0.47(1H, dd), 0.83(1H, dd), 1.57(3H, s), 2.46(1H, dd), 2.55(3H, s), 2.60(1H, dd), 2.76(1H, m), 3.58(3H, s), 3.74(1H, d), 3.79(3H, s), 7.16(2H, dd), 7.30(3H, m).
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][CH2:9][C:10](=O)[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([NH2:23])=[CH:21][CH:22]=1>C(O)(=O)C.C1(C)C=CC=CC=1>[CH2:15]([O:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:21][CH:22]=1)[CH3:14]
Reactant: CC(=O)CCC(=O)c1ccccc1
Reactant: CCOc1ccc(N)cc1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOc1ccc(-n2c(C)ccc2-c2ccccc2)cc1
Temperature: 25 °C

Procedure:
To a solution of 1-phenyl-1,4-pentanedione (1.06g, 6.0 mmol) and toluene (50 mL) was added p-phenetidine (0.78 mL, 6.0 mmol) and 5 drops of glacial acetic acid. The mixture was heated at reflux overnight. After cooling to rt, the mixture was concentrated in vacuo and purified by flash chromatography on silica gel (15-25% EtOAc/hexanes) to give 1-(p-ethoxyphenyl)-5-methyl-2-phenyl-pyrrole as a yellow solid: 1H NMR (CDCl3, 500 MHz) δ 7.17-7.13 (m, 2H), 7.10-7.05 (m, 5H), 6.89-6.84 (m, 2H), 6.35 (d, 1H), 6.08 (d, 1H), 4.04 (q, 2H), 2.13 (s, 3H), 1.44 (t, 3H); MS (ESI) 278 (M+H)+.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[CH:5]1([N:15]=[C:16]=[O:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1>CCOCC>[OH:2][CH2:1][CH2:3][NH:4][C:16]([NH:15][CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1)=[O:17]
Reactant: O=C=NC1CCCc2ccccc21
Reactant: NCCO
Solvent: CCOCC
Product: O=C(NCCO)NC1CCCc2ccccc21
Yield: 91.9 %

Procedure:
To a stirred solution of 2.42 grams (0.04 mole) of ethanolamine in 200 ml. of ether is added a solution of 6.95 grams (0.04 mole) of 1,2,3,4-tetrahydro-1-naphthyl isocyanate in 150 ml. of ether over a period of 30 minutes. Additional ether is added to facilitate stirring as the product precipitates. One hour after the isocyanate addition is complete, the mixture is filtered. The filter cake is washed with ether and dried to give 8.61 grams white solid, melting point 146° to 149° C. Recrystallization from nitromethane gives the analytical sample, melting point 147° C. to 149° C. Analysis calculated for C13H18N2O2 : C, 66.64; H, 7.74; N, 11.96. Found: C, 66.35; H, 7.78; N, 11.90.
Reaction SMILES: [C:1]1(=[N:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:9][C:10]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]>C(Cl)Cl>[Cl:9][C:10]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:11]=1[C:12]([O:14][C:1]1([N:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:13]
Reactant: ON=C1CCCCC1
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Solvent: ClCCl
Product: O=NC1(OC(=O)c2ccc(Cl)cc2Cl)CCCCC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
1-Nitrosocyclohexyl 2,4-dichlorobenzoate was prepared according to General Method 3. A solution of cyclohexanone oxime (2.66 g, 23.5 mmol) in DCM (50 ml) was added dropwise to a solution of lead tetra acetate (10.42 g, 23.5 mmol) and 2,4 dichlorobenzoic acid (45.0 g, 235 mmol) in DCM (300 ml) at 0° C. A blue color gradually appears on addition of the oxime solution. Upon complete addition (1 hour) the reaction was allowed to warm to ambient temperature and stirring was continued for a further 2-3 hours. The reaction was quenched by the addition of water, the phases separated and the organics dried over Na2SO4 and concentrated in vacuo to afford 1-nitrosocyclohexyl 2,4-dichlorobenzoate which was purified by column chromatography on silica gel with hexane:EtOAc as the eluent to afford the title compound as a blue oil in 9% yield. δH (400MHz, DMSO-d6) δ 8.02 (1H, d, 8.4 Hz), 7.85 (1H, d, 2.0 Hz), 7.64 (1H, dd, 8.4, 2.0 Hz), 2.03-2.12(2H, m), 1.38-1.93 (8H, m).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[O:9]=O>C=CCCCCCC.C(O)CC.O.Cl[Pd]Cl>[CH2:6]([C:7]([CH3:8])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: C=CCCCCCC
Reactant: O=O
Agent: Cl[Pd]Cl
Solvent: CCCO
Solvent: O
Product: CCCCCCC(C)=O
Reaction time: 6 h

Procedure:
The autoclave described above was charged with 17 g of ME containing 1-octene as compound to be oxidized and having the following composition (in % by weight including catalyst): 54% of 1-octene, 7.7% of Igepal, 1.9% of Triton 100, 19.2% of n-propanol, 10.7% of water and 0.8% of PdCl2 /5.7% of Fe(NO3)3 as catalyst. The oxidation was carried out for 6 hours at 50° C. and 1 bar using pure oxygen. Methyl hexyl ketone was obtained as product. The selectivity was 54% at a conversion of 14%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:29][CH3:30])=[C:16]([CH2:19][N:20]([CH3:28])[C:21]4([C:25]([NH2:27])=[O:26])[CH2:24][NH:23][CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH3:41][O:42][CH2:43][CH2:44]Cl.[I-].[K+]>C(#N)C>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:29][CH3:30])=[C:16]([CH2:19][N:20]([CH3:28])[C:21]4([C:25]([NH2:27])=[O:26])[CH2:24][N:23]([CH2:44][CH2:43][O:42][CH3:41])[CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COCCCl
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CNC1
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COCCN1CC(C(N)=O)(N(C)Cc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)C1
Yield: 36.1 %

Procedure:
A solution of the hydrochloride salt of 3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]azetidine-3-carboxamide (55 mg, 0.11 mmol Example 74), diisopropylethylamine (84 μl, 0.48 mmol), 2-chloroethyl methyl ether (29 μl, 0.32 mmol) and potassium iodide (18 mg, 0.11 mmol) in acetonitrile (0.5 ml) was heated in a microwave at 145° C. for 30 minutes. Purification of the crude product on preparative HPLC (standard basic condition) gave the title product (20 mg, 36%) as a white solid; 1H NMR Spectrum: (CDCl3) 2.41 (s, 3H), 2.76 (t, 2H), 3.34 (s, 3H), 3.36 (d, 2H), 3.44 (t, 2H), 3.66 (d, 2H), 3.96 (s, 3H), 4.00 (s, 2H), 5.38 (brs, 1H), 7.16 (m, 2H), 7.24 (s, 1H), 7.21 (s, 1H), 7.42 (brs, 1H), 7.87 (brs, 1H), 8.01 (s, 1H), 8.75 (m, 1H); Mass Spectrum: (M+H)+ 503.