Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([NH:6][C:7]2[CH:15]=[C:14]([C:16]([OH:18])=O)[C:13]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[CH:12][C:8]=2[C:9]([OH:11])=O)=[CH:4][CH:3]=1.P(=O)(O)(O)O.CO>O.C(NN(NCC)S(C1C2=C3C(C4C5C(=CC=CC2=5)C=CC=4)=CC=CC3=CC=1CCC)(=O)=O)C>[CH:3]1[C:2]([Cl:1])=[CH:28][C:27]2[C:9]([C:8]3[C:7]([NH:6][C:5]=2[CH:4]=1)=[CH:15][C:14]1[C:16]([C:21]2[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=2[NH:19][C:13]=1[CH:12]=3)=[O:18])=[O:11]
Reactant: O=C(O)c1cc(Nc2ccc(Cl)cc2)c(C(=O)O)cc1Nc1ccc(Cl)cc1
Agent: CCCc1cc2cccc3c4cccc5cccc(c(c1S(=O)(=O)N(NCC)NCC)c23)c54
Agent: O=P(O)(O)O
Solvent: O
Solvent: CO
Product: O=c1c2cc(Cl)ccc2[nH]c2cc3c(=O)c4cc(Cl)ccc4[nH]c3cc12
Temperature: 113 °C
Reaction time: 3 h
Yield: 94.1 %

Procedure:
To 300 g of polyphosphoric acid (117% phosphoric acid) heated at 80° C. was added 2.5 g N,N-diethylaminopropyl perylenesulfonamide followed by 50 g of 2,5-di(4-chloroanilino)terephthalic acid added over a period of 40 minutes, the temperature being maintained below 110° C. by adjustment of the addition rate. The mixture was heated at 113° C. for 4.5 hours. After the melt was cooled to 98° C., the acid strength was adjusted to 111% by the dropwise addition of phosphoric acid. The resultant melt was slowly poured into 525 g of methanol, the temperature being maintained below 64° C. by external cooling and adjustment of melt addition rate. The slurry was heated at reflux for one hour, cooled to below 60° C., diluted with water, filtered, and washed until acid free. The presscake was dried to obtain 44.1 g of crude dichloroquinacridone, which was then salt ground for three hours using 306 g of a microsized salt and 57.9 g of a glycol. The salt was extracted using a slightly alkaline water slurry at 65° C. for one hour. After the slurry was filtered, the presscake was reslurried in slightly acidic water and held at 65° C. for one hour. The solid component was collected by filtration and washed with water. The wet cake can be dried or used as is for specific applications. Here, the wet cake was dried in an oven at 60° C. to give approximately 43 g of 2,9-dichloroquinacridone as a magenta pigment.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=O)[CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[IH:21].[NH2:22][NH:23][C:24]([NH:26][CH3:27])=[NH:25]>I.C(O)CC>[IH:21].[CH3:27][NH:26][C:24]([NH:23][N:22]=[C:10]([CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH:9]=[CH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[NH:25]
Reactant: O=C(C=Cc1ccc(Cl)cc1)C=Cc1ccc(Cl)cc1
Reactant: CNC(=N)NN
Agent: I
Solvent: CCCO
Product: CNC(=N)NN=C(C=Cc1ccc(Cl)cc1)C=Cc1ccc(Cl)cc1
Yield: 53.3 %

Procedure:
A mixture consisting of 3.03 grams of 1,5-bis(p-chlorophenyl)-1,4-pentadien-3-one, 2.16 grams of 1-amino-3-methylguanidine hydroiodide, 3 drops of 57 percent hydroiodic acid, and 50 ml. of n-propanol is stirred and heated under refluxing conditions for two hours. Cooling failed to yield a product. After concentration to about 15 ml. of volume, and addition of 60 ml. of ether, a yellow product is obtained. Recrystallization from ethanol gives 2.67 grams of the subject compound melting 213°-214.5° C.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[CH:13][C:6]([CH2:7][CH:8]([C:11]#[N:12])[C:9]#[N:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:29][C:30]([F:33])([F:32])[F:31])(=O)=O>CN(C)C=O>[F:31][C:30]([F:33])([F:32])[CH2:29][C:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:15])([F:16])[F:1])=[CH:14][CH:13]=1)([C:11]#[N:12])[C:9]#[N:10]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: N#CC(C#N)Cc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(Cc1ccc(C(F)(F)F)cc1)CC(F)(F)F
Yield: 44 %

Procedure:
Using 1.0 g of (4-(trifluoromethyl)benzyl)malononitrile, 8 ml of N,N-dimethylformamide, 0.73 g of cesium carbonate, and 1.0 g of 2,2,2-trifluoroethyl trifluoromethanesulfonate, and according to the process described in the Production Example 1, there was obtained 0.58 g of 2-(2,2,2-trifluoroethyl)-2-(4-(trifluoromethyl)benzyl)malononitrile (the present compound (72)).
Reaction SMILES: N#N.[O:3]=[C:4]([CH3:17])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[O:10][CH:11]=[C:12]([C:14](O)=[O:15])[N:13]=1.CN(C=O)C.C(Cl)(=O)C([Cl:26])=O>C1(C)C=CC=CC=1>[O:3]=[C:4]([CH3:17])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[O:10][CH:11]=[C:12]([C:14]([Cl:26])=[O:15])[N:13]=1
Reactant: CC(=O)CCCCc1nc(C(=O)O)co1
Reactant: O=C(Cl)C(=O)Cl
Agent: N#N
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(=O)CCCCc1nc(C(=O)Cl)co1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a suspension of 2-(5-oxo-hexyl)-oxazole-4-carboxylic acid (403 mg, 1.91 mmol) in toluene (19 mL) was treated at 0° C. with a drop of DMF followed by oxalyl chloride (0.20 mL, 2.29 mmol) and the resulting yellow solution was stirred at rt for 1 h. The solvent was then removed under reduced pressure (coevaporation with toluene) to give 2-(5-oxo-hexyl)-oxazole-4-carbonyl chloride as a brown oil.
Reaction SMILES: [ClH:1].ClC1C=[CH:24][CH:23]=[CH:22][C:4]=1[CH2:5][CH2:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[C:13]([NH2:15])=O)=O>O1CCOCC1>[Cl:1][C:5]1[CH:4]=[CH:22][CH:23]=[CH:24][C:6]=1[CH2:7][NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[C:13]#[N:15]
Reactant: NC(=O)c1ccc([N+](=O)[O-])c(NC(=O)CCc2ccccc2Cl)c1
Reactant: Cl
Solvent: C1COCCO1
Product: N#Cc1ccc([N+](=O)[O-])c(NCc2ccccc2Cl)c1

Procedure:
One milliliter of 35% hydrochloric acid was added to a solution of 850 mg of 3-[N-(2-chlorobenzyl)acetylamino]-4-nitrobenzamide in 10 ml of 1,4-dioxane, and the mixture was heat-refluxed for 4 days. After the solvent was distilled off from the reaction solution under reduced pressure, the residue was separated by being poured in a mixture solution of water and chloroform. The organic layer was washed with water, and was dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified through column chromatography [50 ml, chloroform] to give 230 mg of 3-[N-(2-chlorobenzyl)amino]-4-nitrobenznitrile.
Reaction SMILES: C([O-])(=[O:3])C.[Na+].[C:6]([C:14]1[C:15](=[O:25])[CH:16]=[C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[O:18][CH:19]=1)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.OO>CN(C)C=O.O>[C:6]([C:14]12[O:3][CH:19]1[O:18][C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][C:15]2=[O:25])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)c1cc(=O)c(C(=O)c2ccccc2)co1
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1=CC(=O)C2(C(=O)c3ccccc3)OC2O1
Reaction time: 1 h

Procedure:
Solid sodium acetate (2.0 g) was added to a stirred solution of this ester (5.4 g) in dimethylformamide (80 ml) at 0°-5° C. 30% Hydrogen peroxide solution (10 ml) was added dropwise over 15 minutes and the mixture was stirred for a further 1 hour at 0°-5° C. then slowly diluted with water (240 ml). The solid product was dried and recrystallised from ether-petroleum ether 40°-60° C. to give the epoxide, ethyl 6-benzoyl-5-oxo-2,7-dioxabicyclo-[4.1.0]hept-3-ene-3-carboxylate (mp 96°-98° C.).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH:7]=O)[CH2:3][CH2:2]1.[NH2:9][OH:10].C([O-])(=O)C.[Na+]>C(O)C.O>[O:1]1[CH2:6][CH2:5][CH:4]([CH:7]=[N:9][OH:10])[CH2:3][CH2:2]1
Reactant: NO
Reactant: O=CC1CCOCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=CC1CCOCC1
Temperature: 90 °C
Yield: 50.2 %

Procedure:
To a suspension of tetrahydro-pyran-4-carbaldehyde (36.9 g, 259 mmol) and hydroxylamine (27.2 g, 388 mmol) in ethanol (246 mL) and water (246 mL) was added sodium acetate (42.9 g, 517 mmol) and the resulting mixture heated at 90° C. overnight. After cooling to room temperature the resulting mixture was then evaporated and extracted with diethylether and water. The organic extract was then washed with water, brine, dried over sodium sulfate and evaporated. Purification by chromatography (silica, heptane:ethyl acetate=1:1) afforded the title compound (16.8 g, 50%) which was obtained as a yellow liquid. MS: m/e=129.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:7]=[C:6]([OH:29])[CH:5]=1.[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:5]=[C:6]([O:29][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:7]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:9]=1
Reactant: BrCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(O)cc(C(=O)OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCc2ccccc2)cc(C(=O)OC)c1
Reaction time: 50 h
Yield: 89.3 %

Procedure:
A mixture of 3.0 g (7.1 mmol) of 3-hydroxy-5-(octadecyloxy) benzoic acid methyl ester, 0.93 ml (7.85 mmol) of benzyl bromide and 2.0 g (14.5 mmol) of potassium carbonate in 50 ml of DMF was stirred at 85° for 50 hours. The solvent was removed at reduced pressure and the residue was extracted with methylene chloride. The extract was concentrated and recrystallized from methylene chloride-methanol to give 3.24 g (89% yield, mp 62°-64°) of 3-(octadecyloxy)-5-(phenylmethoxy)benzoic acid methyl ester. A solution of 3.24 g (6.3 mmol) of 3-(octadecyloxy)-5-(phenylmethoxy) benzoic acid methyl ester and 3 ml (18 mmol) of 6N NaOH in 100 ml of methanol and 25 ml of dioxane was stirred at reflux for 3.5 hours. The solvents were removed at reduced pressure and the residue was acidified and extracted with ethyl acetate. The dried extract was concentrated to a solid which was recrystallized from methylene chloride-hexane to give 2.77 g (88% yield, mp 101°-103°) of 3-(octadecyloxy)-5-(phenylmethoxy)benzoic acid.
Reaction SMILES: [CH:1]1([N:4]=[C:5]2[C:9]3[N:10]([CH3:18])[C:11]4[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][C:16]=4[C:8]=3[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.B.FC(F)(F)C(O)=O>C1COCC1>[CH:1]1([NH:4][CH:5]2[CH:9]3[N:10]([CH3:18])[CH:11]4[CH:16]([CH:8]3[CH2:7][CH2:6]2)[CH:15]=[C:14]([OH:17])[CH:13]=[CH:12]4)[CH2:2][CH2:3]1
Reactant: Cn1c2c(c3cc(O)ccc31)CCC2=NC1CC1
Agent: B
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CN1C2C=CC(O)=CC2C2CCC(NC3CC3)C21
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
3-Cyclopropylimino-4-methyl-1,2,3,4-tetrahydrocyclopent[b]indol7-ol (8.7 grams) was placed in a 3-neck flask and cooled to 0° C. in an ice-water bath. A 1M solution of borane in THF (540 ml) was added in a dropwise manner. The mixture was stirred for 1 hours while it was slowly warmed to room temperature. The mixture was cooled back down to 0° C. and trifluoroacetic acid (119 ml) was added in a dropwise manner. The solution was stirred for 15 minutes and THF was removed in vacuo. The mixture was neutralized with 10% NaOH solution, extracted with methylene chloride (4×500 ml), dried (Na2SO4) and concentrated to give 3-(N-cyclopropyl)amino-1,2,3,3a,4,8a-hexahydro-4-methylcyclopent[b]indol-7-ol (8.8 grams).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]([CH3:16])[CH2:11][C:12](=[O:15])[NH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].[CH2:17](Br)[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O.C([O-])(=O)C.[Na+]>C(O)C>[CH3:16][CH:10]1[C:9]([C:4]2[CH:3]=[C:2]3[C:7](=[CH:6][CH:5]=2)[NH:8][CH:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:17][NH:1]3)=[N:14][NH:13][C:12](=[O:15])[CH2:11]1
Reactant: O=C(CBr)c1ccccc1
Reactant: CC1CC(=O)NN=C1c1ccc(N)c(N)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC1CC(=O)NN=C1c1ccc2c(c1)NCC(c1ccccc1)N2
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A solution containing 0.3 g of 6-(3,4-diaminophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)one, 0.3 g of phenacyl bromide and 0.14 g of sodium acetate in 2.6 ml of ethanol was stirred for 3.5 h at room temperature. The product was washed with water and ethanol. Yield 0.1 g (23%), m.p. 209°-215° C.
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=1.[C:21]1([CH3:28])[C:26]([OH:27])=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:21]1([CH3:28])[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=1[O:27][C:15]1[CH:16]=[CH:17][C:12]([C:11]([NH:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([OH:2])=[O:20])=[O:19])=[CH:13][CH:14]=1
Reactant: Cc1ccccc1O
Reactant: COC(=O)c1ccccc1NC(=O)c1ccc(I)cc1
Product: Cc1ccccc1Oc1ccc(C(=O)Nc2ccccc2C(=O)O)cc1

Procedure:
In analogy to example 2,2-(4-o-Tolyloxy-benzoylamino)-benzoic acid was prepared from 2-(4-iodo-benzoylamino)-benzoic acid methyl ester [75541-84-3] and o-cresol. MS (m/e): 346.1 (M−H−, 100%).
Reaction SMILES: ClC1C=[C:10]2[C:5]([C:6](=O)[C:7]([CH2:18][NH:19][C:20](=[O:31])OC3C=CC([N+]([O-])=O)=CC=3)=CN2C2C=CC=CC=2)=CC=1.C1([NH2:38])CCCC1>>[CH:18]1([NH:19][C:20](=[O:31])[NH2:38])[CH2:7][CH2:6][CH2:5][CH2:10]1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: NC1CCCC1
Product: NC(=O)NC1CCCC1

Procedure:
7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-3-cyclopentyl-urea was prepared starting from intermediate M and cyclopentylamine. MS calcd. for C22H23ClN3O2 [(M+H)+] 396.1, obsd. 396.0.
Reaction SMILES: [N:1]1([C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=1[O:31][CH3:32].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[S:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:7]([N:1]2[CH2:6][CH2:5][N:4]([CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=3[O:31][CH3:32])[CH2:3][CH2:2]2)=[N:8]1
Reactant: COc1cc(C(C)=O)ccc1OCCCCBr
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C(C)=O)ccc1OCCCCN1CCN(c2nsc3ccccc23)CC1
Yield: 38.7 %

Procedure:
A mixture of 3-(1-piperazinyl)-1,2-benzisothiazole (4.0 g, 18.2 mmol), 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone (6.0 g, 20.0 mmol), K2CO3 (3.0 g, 21.8 mmol), KI (200 mg), and acetonitrile (125 ml) was stirred at reflux under N2 for 5 hours. Most of the solvent was removed in vacuo and the resultant gummy residue was partitioned between ethyl acetate and water. The organic extract was washed with water, dried with MgSO4, and concentrated to yield 7.8 g. Purification by preparative HPLC (Waters Associates Prep LC/System 500, utilizing 2 silica gel columns and 4% methanol-methylene chloride as eluent) afforded 6.5 g of a damp, off-white solid. The product was recrystallized twice from toluene to provide 3.1 g (39%) of 1-[4-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butoxy]-3-methoxy-phenyl]ethanone as a white solid, m.p.=114-116° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH2:28][O:29][CH3:30])[C:25](O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:16]([O:20][C:21](=[O:22])[NH:23][C@H:24]([C:25](=[O:26])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:28][O:29][CH3:30])([CH3:19])([CH3:17])[CH3:18]
Reactant: Nc1ccc(F)cc1Nc1ccccc1
Reactant: COC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.8 %

Procedure:
A mixture of 4-fluoro-N2-phenylbenzene-1,2-diamine (450 mg, 2.2 mmol), (S)-2-tertbutoxycarbonylamino-3-methoxypropionic acid (525 mg, 2.4 mmol), HOAt (330 mg, 2.4 mmol), 4-methylmorpholine (0.53 mL, 4.8 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (460 mg, 2.4 mmol) in DCM (10 mL) was stirred at RT for 18 h. The reaction mixture was partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic phase was washed with brine, dried (MgSO4) concentrated in vacuo and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-30% EtOAc in cyclohexane) to afford [(S)-1-(4-fluoro-2-phenylaminophenylcarbamoyl)-2-methoxyethyl]carbamic acid tert-butyl ester (0.655 g, 74%). A solution of the compound thus obtained (0.655 g) in AcOH (10 mL) was heated at 70° C. for 56 h. After cooling to RT, the volatiles were removed in vacuo and the resulting residue partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic layer was washed with brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-30% EtOAc in cyclohexane) to afford the title compound (227 mg, 28%). LCMS (Method J): RT 3.59 and 3.70 min [M+H]+ 386.2
Reaction SMILES: [OH:1][CH:2]([C@H:4]1[C@H:7]([CH:8]=[CH2:9])[NH:6][C:5]1=[O:10])[CH3:3].C([Li])CCC.CCCCCC.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>O1CCCC1.C(O)(=O)C.O.C(OCC)(=O)C>[OH:1][CH:2]([C@H:4]1[C@H:7]([CH:8]=[CH2:9])[N:6]([Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[C:5]1=[O:10])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=C[C@@H]1NC(=O)[C@H]1C(C)O
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C[C@H]1[C@H](C(C)O)C(=O)N1[Si](C)(C)C(C)(C)C
Temperature: -65 °C
Yield: 55.3 %

Procedure:
In an argon stream, a solution of trans-3-(1-hydroxyethyl)-4-vinyl-2-azetidinone (0.10 g) in dry tetrahydrofuran (10 ml) is cooled to -75° C. and a commercial n-butyllithium (1.6M)-hexane solution (0.9 ml) is added dropwise to the solution while maintaining a temperature at -65° C. or lower. The mixture is stirred at -75° C. for an hour and a solution of tert-butyldimethylsilyl chloride (0.16 g) in dry tetrahydrofuran (2 ml) is added dropwise at -70° C. or lower. The reaction mixture is further stirred at -73° C. for 0.5 hour and poured into a mixture of ethyl acetate (70 ml), water (50 ml) and acetic acid (2 ml). The organic layer is separated, adjusted to pH 7.0 with aqueous sodium hydrogen carbonate, washed with aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure to give 0.1 g of trans-3-(1-hydroxyethyl)-1-(tert-butyldimethylsilyl)-4-vinyl- 2-azetidinone.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[C:6][C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][CH2:12][NH:13]2)=[CH:9][CH:8]=1)([CH3:4])[CH3:3].Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1>CN1CCCC1=O>[CH3:28][O:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][C:23]=1[O:29][CH3:30])[N:20]=[CH:19][N:18]=[C:17]2[N:13]1[C:14]2[C:10](=[CH:9][CH:8]=[C:7]([C:6]#[C:5][Si:2]([CH3:3])([CH3:4])[CH3:1])[CH:15]=2)[CH2:11][CH2:12]1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: C[Si](C)(C)C#Cc1ccc2c(c1)NCC2
Solvent: CN1CCCC1=O
Product: COc1cc2ncnc(N3CCc4ccc(C#C[Si](C)(C)C)cc43)c2cc1OC
Yield: 93 %

Procedure:
Utilizing a procedure analogous to that described in Example 47, this product was prepared in 93% yield from 6-trimethylsilanylethynyl-indoline (1.1 eq.), and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in N-methyl-pyrrolidinone. (LC-MS: 404 (MH+); anal. RP18-HPLC RT: 6.49 min.).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:14]>O=S(Cl)Cl.C1COCC1>[CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([NH2:14])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N
Reactant: O=C(O)CCCCC1CCCCC1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: NC(=O)CCCCC1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
A solution of cyclohexanepentanoic acid (2 g, 10.9 mmol) in SOCl2 (8 mL) was heated on a steam bath for 3 h. The SOCl2 was removed under vacuum. Chloroform (2×10 mL) was added and reevaporated to give the crude acid chloride as a yellow liquid. A saturated solution of ammonia in dry THF (ammonia gas bubbled through 10 mL of THF for 5 min), was slowly added to a solution of the acid chloride in dry THF (50 mL) while cooling in an ice bath. The reaction mixture was allowed to stir at room temperature for 3 h and was then concentrated to half of its volume and poured onto water (100 mL). The solid was removed by filtration, washed with water and dried (MgSO4). Recrystallization from aqueous MeOH gave 5-cyclohexylvaleramide (1.1 g, 55%); mp 121-122° C. (reported mp 122-123° C.) (Katsellson and Dubinin, Compt. Rend. Acad. Sci. U.R.S.S. [N.S.] 4:405 (1936); Chem. Abstr. 31:3449 (1937)). A suspension of the amide (183 mg, 1 mmol) in anhydrous Et2O (9 mL) was slowly added to a stirred suspension of LiAlH4 (114 mg, 3 mmol) in Et2O (15 mL). After addition was complete, the mixture was heated at reflux for 2 h and then allowed to stir overnight at room temperature. The reaction mixture was cooled to 0° C. and excess LiAlH4 was decomposed by successive addition of water (2 mL), 2N NaOH (2 mL) and water (5 mL). After stirring vigorously for 20 min, the mixture was filtered and the inorganic residue was washed with warm Et2O (3×8 mL). The combined Et2O solution was dried over anhydrous K2CO3 and evaporated to dryness. The residue was distilled under reduced pressure to yield a clear oil (99 mg, 59%); bp 30-36° C. (0.35 mm), Lit. bp 108≥113° C. (15 nm) (Skinner, C. G., et al., J. Am. Chem. Soc. 79:2844 (1957)). A solution of the free base in anhydrous Et2O was added to a solution of oxalic acid (52 mg) in anhydrous Et2O (8 mL) with continuous shaking. The precipitated solid was recrystallized from MeOH/anhydrous Et2O; mp 164° C. (see Table 8).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5](=[CH:11]OCC)[C:6]([O:8]CC)=[O:7])[CH3:2].Cl.NO.C([N:21](CC)CC)C.Cl>C(O)C.O>[CH2:1]([O:3][C:4]([C:5]1[C:6](=[O:7])[O:8][NH:21][CH:11]=1)=[O:15])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c[nH]oc1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 65.8 %

Procedure:
2-Ethoxymethylene-malonic acid diethyl ester (5.00 g, 23.1 mmol), hydroxylamine hydrochloride (4.01 g, 57.8 mmol) and triethylamine (8.06 mL, 57.8 mmol) were dissolved in ethanol (100 mL), the solution was stirred at room temperature for 17 hours, then, the solution was stirred for 4.5 hours under reflux. The reaction solution was cooled to room temperature, water was added, and 1N hydrochloric acid was added until a salt precipitated. The precipitated salt was collected by filtration, and a hydrochloride salt of the title compound (2.39 g, 15.2 mmol, 66%) was obtained as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([CH3:18])(=[O:17])=[O:16])(C)(C)C.[ClH:20]>O1CCOCC1.C(Cl)(Cl)Cl>[ClH:20].[CH3:18][S:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][NH2:7])(=[O:16])=[O:17]
Reactant: CC(C)(C)OC(=O)NCc1ccccc1S(C)(=O)=O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccccc1CN
Temperature: 25 °C
Reaction time: 20 h
Yield: 89.3 %

Procedure:
(2-Methanesulfonyl-benzyl)-carbamic acid tert-butyl ester (1.55 g, 5.43 mmol) was dissolved in warm dioxane (50 mL) and cooled to room temperature. HCl solution (4M solution in dioxane, 20 ml, 80 mmol) was added. After 20 h, a white precipitate had formed. The reaction was diluted with CHCl3 (50 mL) and filtered. The white solid was washed with CHCl3 and dried in-vacuo to yield 1.075g of 2-methanesulfonyl-benzylamine hydrochloride as an off white solid, m/z 186.6 (M+1)+.