Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].O.[C:4]([C:8]1[S:9][CH:10]=[CH:11][C:12]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([CH3:26])[CH2:22][CH2:23][CH2:24][OH:25])=[CH:17][CH:16]=1)([O:6]C)=[O:5]>C(O)C>[C:4]([C:8]1[S:9][CH:10]=[CH:11][C:12]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([CH3:26])[CH2:22][CH2:23][CH2:24][OH:25])=[CH:17][CH:16]=1)([OH:6])=[O:5]
Reactant: COC(=O)c1sccc1COc1ccc(C(C)CCCO)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(CCCO)c1ccc(OCc2ccsc2C(=O)O)cc1
Reaction time: 8 h
Yield: 82.9 %

Procedure:
To a stirred solution of 14.59 g of potassium hydroxide, 15 ml of water, and 60 ml of 95% ethanol was added a solution of 8.68 g of 4-[4-(2-carbomethoxy-3-thienylmethoxy)phenyl]pentanol and 30 ml of 95% ethanol. The stirred solution was heated under reflux for five hours, allowed to stand overnight at ambient temperature, and concentrated. The residue was diluted with 500 ml of water, and the solution was acidified with concentrated hydrochloric acid. An oil separated. The mixture was extracted with ether (2×250 ml) and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. A solution of the residue and toluene was filtered through anhydrous sodium sulfate and the filtrate was concentrated to afford 6.89 g (82.7%) of product as an oil, dried at 60° C. in vacuo.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[CH2:6][N:5]([CH:14]([CH3:16])[CH3:15])[C:4]=2[N:3]=1.[CH3:17][S:18]([C:21]1[CH:22]=[C:23]([NH2:30])[CH:24]=[C:25]([N+:27]([O-:29])=[O:28])[CH:26]=1)(=[O:20])=[O:19]>>[CH:14]([N:5]1[C:4]2[N:3]=[C:2]([NH:30][C:23]3[CH:24]=[C:25]([N+:27]([O-:29])=[O:28])[CH:26]=[C:21]([S:18]([CH3:17])(=[O:20])=[O:19])[CH:22]=3)[N:11]=[CH:10][C:9]=2[N:8]([CH3:12])[C:7](=[O:13])[CH2:6]1)([CH3:16])[CH3:15]
Reactant: CC(C)N1CC(=O)N(C)c2cnc(Cl)nc21
Reactant: CS(=O)(=O)c1cc(N)cc([N+](=O)[O-])c1
Product: CC(C)N1CC(=O)N(C)c2cnc(Nc3cc([N+](=O)[O-])cc(S(C)(=O)=O)c3)nc21
Yield: 58.1 %

Procedure:
Starting from 2-chloro-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one (9.35 g; 38.85 mmol) and 3-methansulfonyl-5-nitro-phenylamine (8.4 g; 38.5 mmol), 9.4 g (22.38 mmol; 57.5% yield) of the desired nitro-product were obtained as a powder.
Reaction SMILES: [O-]CC.[Na+].C(O)C.[C:8]([O:11][CH2:12][CH3:13])(=[O:10])[CH3:9].C([O:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=O)C>C1(C)C=CC=CC=1>[CH2:12]([O:11][C:8](=[O:10])[CH2:9][C:17](=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[CH3:13]
Reactant: CCOC(=O)c1ccccn1
Reactant: CCOC(C)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(=O)c1ccccn1
Temperature: 90 °C
Yield: 91 %

Procedure:
Stir a mixture of sodium ethoxide (360 g, 5.29 mol), toluene (4 L), ethanol (18 mL, 0.265 mol), and ethyl acetate (1.04 L, 10.6 mol) in a 22 L flask equipped with a reflux condenser, nitrogen inlet, and mechanical stirrer. Stir for 1 h as the mixture warms to 26° C. Add pyridine-2-carboxylic acid ethyl ester (Fluka; 400 g, 2.65 mol) and heat the mixture to reflux (90° C.) for 18 h. Cool the mixture to room temperature, dilute with toluene (8 L), wash with water (6 L), and separate the layers. Acidify the aqueous layer to pH 5 with glacial acetic acid. Extract with ethyl acetate (2×4 L), dry the combined organic layers (sodium sulfate), filter, and concentrate in vacuo to yield 466 g (91%) the subtitled compound as a dark oil in 93% purity by HPLC analysis. MS (ES) m/z=194 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:11](=[O:22])[C:12]2[C:17]([C:18](=[O:21])[C:19]=1[Cl:20])=[CH:16][CH:15]=[CH:14][CH:13]=2>C(O)C>[Cl:20][C:19]1[C:18](=[O:21])[C:17]2[C:12]([C:11](=[O:22])[C:10]=1[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1)=[CH:13][CH:14]=[CH:15][CH:16]=2
Reactant: O=C1C(Cl)=C(Cl)C(=O)c2ccccc21
Reactant: Cc1ccc(N)cc1
Solvent: CCO
Product: Cc1ccc(NC2=C(Cl)C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C

Procedure:
p-Toluidin (1.4 g, 13.2 mmol) was added to the solution of 2,3-dichloro-1,4-naphthoquinone (1.0 g, 4.4 mmol) in ethanol (300 ml). The reaction mixture was allowed to stir at room temperature for over night. The precipitated product was filtered off and washed with cold ethanol. The product was purified by recrystallization with ethanol/CHCl3 (1:5) to afford the fine reddish needles. Yield: 0.642 g (53.8%), Mp: 295° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][CH:6]=[CH2:7].I[C:21]1[CH:26]=[CH:25][C:24]([N:27]([CH2:34][CH2:35][CH3:36])[C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5]/[CH:6]=[CH:7]/[C:21]1[CH:26]=[CH:25][C:24]([N:27]([CH2:34][CH2:35][CH3:36])[C:28]2[N:29]=[CH:30][CH:31]=[CH:32][N:33]=2)=[CH:23][CH:22]=1
Reactant: CCCN(c1ccc(I)cc1)c1ncccn1
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Product: CCCN(c1ccc(/C=C/CC(NC(=O)c2c(Cl)cccc2Cl)C(=O)OC)cc1)c1ncccn1
Yield: 71.9 %

Procedure:
In the same manner as in Example 1, 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (171 mg) was reacted with N-(4-iodophenyl)-N-propylpyrimidin-2-amine (192 mg) to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-(propyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (209 mg). Column chromatography (silica gel, eluent: cyclohexane/chloroform=4/1-3/1) was used for purification.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][CH:11]([O:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([O:23][C:24]2[CH:36]=[CH:35][C:27]3[C:28](=[O:34])[N:29]([CH3:33])[CH2:30][CH2:31][O:32][C:26]=3[CH:25]=2)[CH:22]=1)[C:17](O)=[O:18])[CH3:12].[NH2:37][C:38]1[CH:42]=[CH:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[N:39]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:12][CH:11]([O:13][C:14]1[CH:15]=[C:16]([C:17]([NH:37][C:38]2[CH:42]=[CH:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[N:39]=2)=[O:18])[CH:20]=[C:21]([O:23][C:24]2[CH:36]=[CH:35][C:27]3[C:28](=[O:34])[N:29]([CH3:33])[CH2:30][CH2:31][O:32][C:26]=3[CH:25]=2)[CH:22]=1)[CH3:10]
Reactant: CC(C)Oc1cc(Oc2ccc3c(c2)OCCN(C)C3=O)cc(C(=O)O)c1
Reactant: CC(C)(C)OC(=O)n1ccc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1cc(Oc2ccc3c(c2)OCCN(C)C3=O)cc(C(=O)Nc2ccn(C(=O)OC(C)(C)C)n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 11.9 %

Procedure:
DIPEA (0.26 mL, 1.5 mmol) was added to a solution of 3-[(1-methylethyl)oxy]-5-[(4-methyl-5-oxo-2,3,4,5-tetrahydro-1,4-benzoxazepin-8-yl)oxy]benzoic acid (185 mg, 0.5 mmol), 1,1-dimethylethyl 3-amino-1H-pyrazole-1-carboxylate (110 mg, 0.6 mmol) and HATU (247 mg, 0.65 mmol) in DMF (2 mL) and the mixture stirred at RT for 16 hours. The mixture was poured onto water (30 mL), extracted with ethyl acetate (3×15 mL), the combined organic extracts washed with 1N citric acid, saturated sodium hydrogen carbonate, brine, dried (MgSO4) and evaporated in vacuo. The residue was chromatographed on silica, eluting with 60% ethyl acetate in isohexane, to give the desired compound (32 mg). 1H NMR δ (CDCl3): 1.3 (d, 6H), 1.55 (s, 9H), 3.15 (s, 3H), 3.5 (t, 2H), 4.3 (t, 2H), 4.5 (m, 1H), 6.5 (s, 1H), 6.7 (m, 2H), 7.1 (d, 1H), 7.8 (d, 1H), 7.95 (d, 1H), 8.7 (s, 1H); m/z 535 (M−H)−
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[OH:20])[N:7]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Br)=[CH:32][CH:31]=1>CN(C=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH2:34][C:33]2[CH:36]=[CH:37][C:30]([Cl:29])=[CH:31][CH:32]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: Clc1ccc(CBr)cc1
Reactant: CCOC(=O)c1cc(C)n(Cc2cc(Cl)ccc2O)n1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(C)n(Cc2cc(Cl)ccc2OCc2ccc(Cl)cc2)n1
Temperature: 100 °C
Yield: 66.8 %

Procedure:
To a solution of 1-(5-Chloro-2-hydroxy-benzyl)-5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester 2 (0.6 g, 2.0 mmol) in DMF (5 mL) were added potassium carbonate (0.84 g, 6.1 mmol), potassium iodide (0.34 g, 2.0 mmol) and 4-chlorobenzylbromide (0.38 g, 2.2 mmol). The resulting mixture was heated at 100° C. overnight. The mixture was poured into water (20 mL) and extracted with Et2O (3×15 mL). The organic layers were combined, washed with brine (30 mL), dried (Na2SO4) and the volatiles were removed in vacuo to give 0.56 g (71%) of 1-(2-Benzyloxy-5-chloro-benzyl)-5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester 3 as a white solid.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:35][CH2:36][CH2:37][OH:38])(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:26]3[CH:31]=[CH:30][C:29]([S:32]([NH:35][CH2:36][CH2:37][OH:38])(=[O:34])=[O:33])=[CH:28][CH:27]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: O=S(=O)(NCCO)c1ccc(Br)cc1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: O=S(=O)(NCCO)c1ccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1

Procedure:
The title compound was prepared from 7-difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (340 mg, 1.0 mmol) and 4-bromo-N-(2-hydroxy-ethyl)-benzenesulfonamide (example B.29) (276 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (360 mg, 66%). MS (ISP) 537.3 [(M+H)+]; mp 191–194° C.
Reaction SMILES: O=C1C2C(=CC=CC=2)N=C(C(OCC)=O)N1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:32]3[C:31](=[O:33])[NH:30][C:29]([C:34]([O:36]CC)=O)=[N:28][C:27]=3[S:26][CH:25]=2)=[CH:20][CH:19]=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)N2C=NC(CCCOC3C=C(CN)C=CN=3)=N2)C=CC=CC=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:82]2[CH:86]=[N:85][C:84]([O:87][CH2:88][CH2:89][O:90][C:91]3[CH:92]=[C:93]([CH2:97][NH2:98])[CH:94]=[CH:95][CH:96]=3)=[N:83]2)C=CC=CC=1>>[F:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[C:32]3[C:31](=[O:33])[NH:30][C:29]([C:34]([NH:98][CH2:97][C:93]4[CH:94]=[CH:95][CH:96]=[C:91]([O:90][CH2:89][CH2:88][O:87][C:84]5[N:85]=[CH:86][NH:82][N:83]=5)[CH:92]=4)=[O:36])=[N:28][C:27]=3[S:26][CH:25]=2)=[CH:22][CH:23]=1
Reactant: NCc1cccc(OCCOc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Reactant: CCOC(=O)c1nc2scc(-c3ccc(F)cc3)c2c(=O)[nH]1
Agent: CCOC(=O)c1nc2ccccc2c(=O)[nH]1
Agent: NCc1ccnc(OCCCc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Product: O=C(NCc1cccc(OCCOc2nc[nH]n2)c1)c1nc2scc(-c3ccc(F)cc3)c2c(=O)[nH]1

Procedure:
By a method similar to that in Example 22, and using, instead of ethyl 4-oxo-3,4-dihydro-2-quinazolinecarboxylate, ethyl 5-(4-fluorophenyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxylate obtained in Reference Example 77 and using, instead of 1-[2-({3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propyl}oxy)pyridin-4-yl]methaneamine, 1-{3-[(2-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]oxy}ethyl)oxy]phenyl}methanamine obtained in Reference Example 32, the title compound was obtained as a white powder (187.2 mg, 69%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([C:12](=O)[CH2:13][C:14](=O)[CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])=[C:4]([F:24])[CH:3]=1.O.[NH2:26][NH2:27]>C(O)C>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([C:12]2[CH:13]=[C:14]([CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])[NH:27][N:26]=2)=[C:4]([F:24])[CH:3]=1
Reactant: NN
Reactant: CCOC(OCC)C(=O)CC(=O)c1cc(OC(C)C)c(Cl)cc1F
Solvent: CCO
Solvent: O
Product: CCOC(OCC)c1cc(-c2cc(OC(C)C)c(Cl)cc2F)n[nH]1

Procedure:
The crude 1-(4-chloro-2-fluoro-5-isopropoxy-phenyl)-4,4-diethoxybutane-1,3-dione (Example H7) is initially introduced into 150 ml of dry ethanol. 2.90 g of hydrazine monohydrate are added dropwise at room temperature, while stirring. The mixture is then stirred for 4 hours, while heating under gentle reflux, and is subsequently cooled and the alcohol is removed on a rotary evaporator in vacuo. The residue obtained is partitioned between aqueous sodium bicarbonate solution and ethyl acetate. After extraction by shaking and separation of the phases, the organic phase is washed with water and then dried over sodium sulfate and concentrated. 17.5 g of a dark yellow oil are obtained.
Reaction SMILES: C(C1C=CC=CC=1CCC)CC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH3:22])=[C:16]([CH2:23][CH2:24][CH3:25])[CH:15]=1.CNN.[CH2:29]([NH:32]N)[CH2:30][CH3:31].C1(NN)CC1>>[Br:13][C:14]1[CH:19]=[CH:18][C:17]2[C:16](=[C:23]([CH2:24][CH3:25])[N:32]([CH2:29][CH2:30][CH3:31])[C:20]=2[CH2:21][CH3:22])[CH:15]=1
Reactant: CCCc1ccc(Br)cc1CCC
Reactant: CCCNN
Agent: CCCc1ccccc1CCC
Agent: CNN
Agent: NNC1CC1
Product: CCCn1c(CC)c2ccc(Br)cc2c1CC

Procedure:
Following the procedure of Example 3, Step A, except that the o-dipropylbenzene of Example 3 is replaced by an equivalent amount of: 4-chloro-; 4-iodo-; and 4-bromo-1,2-dipropylbenzene and the methylhydrazine is replaced by an equivalent amount of propylhydrazine; cyclopropylhydrazine; and γ-THP-oxy-propylhydrazine, there is obtained 5-chloro, 5-iodo, and 5-bromo-2-propyl-1,3-diethylisoindole; 5-chloro-; 5-iodo-; and 5-bromo-2-cyclopropyl-1,3-diethylisoindole; and 5-chloro-; 5-iodo-; and 5-bromo-2-γ-THP-oxy-propyl-1,3-diethylisoindole, respectively; wherein THP represents tetrahydropyranyloxy.
Reaction SMILES: [C:1]([C:3]1[S:7][CH:6]=[C:5]([N:8](C(OC(C)(C)C)=O)[NH:9]C(OC(C)(C)C)=O)[CH:4]=1)#[N:2].[ClH:24].O1CCOCC1>CC(O)C>[ClH:24].[NH:8]([C:5]1[CH:4]=[C:3]([C:1]#[N:2])[S:7][CH:6]=1)[NH2:9]
Reactant: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1csc(C#N)c1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: N#Cc1cc(NN)cs1
Yield: 97 %

Procedure:
To a stirring solution of compound 12 (1.38 g, 4.07 mmol) in 2-propanol (10 mL) was added 4M HCl in dioxane (10 mL, 40.0 mmol). The reaction heated to 80 degrees for 1 hour turning into a dark brown solution. The mixture was evaporated to dryness and the resulting the brown solid suspended and sonicated in diethyl ether. The suspension was filtered to afford compound 13 (0.701 g, 97%) as a brown solid. LRMS (ESI): calc. 139.0; found 140.1 (MH)+.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[C:3]#[C:4][CH:5]=[N:6][OH:7].[Cl:10]N1C(=O)CCC1=O.O>CN(C=O)C>[OH:7][N:6]=[C:5]([Cl:10])[C:4]#[C:3][Si:2]([CH3:9])([CH3:8])[CH3:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: C[Si](C)(C)C#CC=NO
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#CC(Cl)=NO
Reaction time: 4 h

Procedure:
To a solution of 3-trimethylsilylprop-2-ynal oxime (Carreira, Erick M.; Lohse-Fraefel, Nina, Organic Letters, Volume 7, Issue 10, 2005, Pages 2011-20141, 68 g, 11.9 mmol) in 11.9 mL of DMF stirred at r.t. was added N-chlorosuccinimide (1.99 g, 14.8 mmol). After 4 h stirring, the solution was poured into water and extracted with Et2O. After the usual work-up, the residue (2.09 g) was used as it was for the next step.
Reaction SMILES: [C:1]([NH:11][C:12]([CH3:16])([CH3:15])[CH2:13][OH:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[C:17](Cl)(=[O:19])[CH3:18].C(N(CC)CC)C>ClCCl>[C:17]([O:14][CH2:13][C:12]([NH:11][C:1]([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2])([CH3:16])[CH3:15])(=[O:19])[CH3:18]
Reactant: CC(C)(CO)NC(=O)OCc1ccccc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCC(C)(C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a dichloromethane solution containing 2.52 g (0.011 mol) 2-carbobenzoxyamino-2-methyl-1-propanol and 1.17 g (0.015 mol) acetyl chloride was added dropwise with stirring 1.11 g (0.011 mol) triethylamine. The reaction was stirred at ambient temperature overnight and the dichloromethane was removed under reduced pressure. The triethylamine hydrochloride residue was triturated in anhydrous ether. Following filtration, the ether was removed under reduced pressure to afford 2.38 g (0.009 mol), 82%, crude 2-carbobenzoxyamino-2-methyl-1-propyl acetate as a pale yellow liquid, pmr (CDCl3) δ 7.2 (s, 5H), 5.4 (bs, 1H), 5.0 (s, 2H), 2.0 (s, 3H) and 1.2 (s, 6H) ppm.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[C:42]3[N:41]=[CH:40][N:39]=[C:29]([NH:30][C:31](=[O:38])[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:28]=3[N:27]=[CH:26]2)[C@H:22]([O:43][CH2:44][CH:45]([OH:48])CO)[C@@H:21]1[OH:49])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>C(Cl)Cl>[Si:1]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[C:42]3[N:41]=[CH:40][N:39]=[C:29]([NH:30][C:31](=[O:38])[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:28]=3[N:27]=[CH:26]2)[C@H:22]([O:43][CH2:44][CH:45]=[O:48])[C@@H:21]1[OH:49])([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](OC[C@H]1O[C@@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)[C@H](OCC(O)CO)[C@@H]1O)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)[Si](OC[C@H]1O[C@@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)[C@H](OCC=O)[C@@H]1O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 105.2 %

Procedure:
Compound 112 (5.59 g, 8.17 mmol) was dissolved in dry CH2Cl2 (40.42 mL). To this NaIO4 adsorbed on silica gel (Ref. J. Org. Chem. 1997, 62, 2622-2624) (16.34 g, 2 g/mmol) was added and stirred at ambient temperature for 30 minutes. Reaction monitored by TLC (5% MeOH in CH2Cl2). Reaction mixture was filtered and the filtrate washed thoroughly with CH2Cl2. Dichloromethane layer evaporated to get the aldehyde 113 (5.60 g) that was used in the next step without purification. Rf 0.3 (5% MeOH in CH2Cl2)
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[F:11][C:12]([F:25])([F:24])[CH2:13][O:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1>>[F:10][C:4]1[CH:3]=[C:2]([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH2:13][C:12]([F:11])([F:24])[F:25])[CH:16]=2)[CH:8]=[C:7]([F:9])[C:5]=1[NH2:6]
Reactant: Nc1c(F)cc(Br)cc1F
Reactant: OB(O)c1cccc(OCC(F)(F)F)c1
Product: Nc1c(F)cc(-c2cccc(OCC(F)(F)F)c2)cc1F
Yield: 77.2 %

Procedure:
The title compound (89 mg) was prepared from 4-bromo-2,6-difluoroaniline (80 mg, 0.38 mmol) and 3-(2,2,2-trifluoroethoxy)phenylboronic acid (108 mg, 0.5 mmol) as a colourless liquid.
Reaction SMILES: [CH2:1]=[C:2]1[S:6]/[C:5](=[N:7]\[C:8](=[O:10])[CH3:9])/[N:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH2:3]1.[C:21]([OH:24])(=[O:23])[CH3:22].ICl.C([O-])(=O)C.[K+]>ClCCl>[C:21]([O:24][CH2:1][C:2]1[S:6]/[C:5](=[N:7]\[C:8](=[O:10])[CH3:9])/[N:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH:3]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)O
Reactant: C=C1CN(c2ccc(C(F)(F)F)cc2)/C(=N/C(C)=O)S1
Agent: CC(=O)[O-]
Agent: ClI
Agent: [K+]
Solvent: ClCCl
Product: CC(=O)/N=c1\sc(COC(C)=O)cn1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
N-{(2Z)-5-Methylene-3-[4-(trifluoromethyl)phenyl]-1,3-thiazolidin-2-ylidene}acetamide (4.51 g, 15.0 mmol, Intermediate A6) was dissolved into acetic acid (60 mL) and treated with 1 M iodine monochloride in dichloromethane (30 mL) over three minutes. After about 15 minutes more iodine monochloride solution (0.8 mL) was added, and after another ten minutes the solution was partially concentrated, and then concentrated twice from toluene. The residue was triturated with 20% ethyl acetate/toluene and the allyl chloride was collected by filtration. The filtrate was concentrated and redissolved into acetic acid (20 mL), treated with potassium acetate (2.95 g, 30 mmol), stirred 6 hours at room temperature, and concentrated thrice from ethyl acetate. The residue was mixed with a little ethyl acetate and filtered through basic alumina with a 2% methanol/ethyl acetate rinse. The filtrate was concentrated and chromatographed on silica (ethyl acetate/dichloromethane/hexanes) to give the title compound.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[CH2:16][C@@H:15]([OH:17])[CH2:14][N:13]2[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[O:19])(=O)=O)=CC=1.[N-:31]=[N+:32]=[N-:33].[Na+]>CN(C)C=O.O>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][O:20][C:18]([N:13]2[CH2:14][C@H:15]([OH:17])[CH2:16][C@H:12]2[CH2:11][N:31]=[N+:32]=[N-:33])=[O:19])=[CH:23][CH:24]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(COC(=O)N2C[C@H](O)C[C@H]2COS(=O)(=O)c2ccc(C)cc2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COC(=O)N2C[C@H](O)C[C@H]2CN=[N+]=[N-])cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
To a solution of (2S,4R)-1-p-methoxybenzyloxycarbonyl-4-hydroxypyrrolidine-2-methanol p-toluenesulfonate (8.7 g: 20 mmole) in dimethylformamide (60 ml), a solution of sodium azide (1.56 g) in water (6 ml) is added. The mixture is stirred at 80° C. overnight. The reaction mixture is poured into ice water and extracted with ethyl acetate. The extract is successively washed with water and brine, dried over magnesium sulfate, and concentrated in vacuo to give crude (2S,4R)-1-p-methoxybenzyloxycarbonyl-4-hydroxy-2-azidomethylpyrrolidine (5.6 g). Yield: 92%.
Reaction SMILES: [ClH:1].[CH2:2]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:16](=[O:17])[C:15]3=[CH:18][C:19]([N+:22]([O-])=O)=[CH:20][CH:21]=[C:14]3[C:13]2=[O:25])[CH2:8][CH2:7]1)[CH2:3][CH2:4][CH3:5].[H][H]>C(O)(=O)C.[Pd]>[NH2:22][C:19]1[CH:18]=[C:15]2[C:16](=[O:17])[N:12]([CH:9]3[CH2:10][CH2:11][N:6]([CH2:2][CH2:3][CH2:4][CH3:5])[CH2:7][CH2:8]3)[C:13](=[O:25])[C:14]2=[CH:21][CH:20]=1.[ClH:1]
Reactant: CCCCN1CCC(N2C(=O)c3ccc([N+](=O)[O-])cc3C2=O)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: CCCCN1CCC(N2C(=O)c3ccc(N)cc3C2=O)CC1

Procedure:
To a solution of 1.2 grams of 1-n-butyl-4-(4-nitrophthalimido) piperidine monohydrochloride in 50 milliliters of glacial acetic acid were added 0.3 grams of 5% palladium on carbon catalyst and the mixture hydrogenated at 40°-60° C. at 50 p.s.i. until the theoretical amount of hydrogen was taken up. The solution was cooled, filtered over kieselguhr and evaporated to a small volume, then triturated with ether to give the title compound as the monohydrochloride. Melting Point: 265°-270° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([NH:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: NCc1ccccc1
Reactant: N#Cc1c(N)nc2ccccc2c1Cl
Solvent: O
Product: N#Cc1c(N)nc2ccccc2c1NCc1ccccc1
Temperature: 130 °C

Procedure:
5 g of 2-amino-3-cyano4-chloroquinoline and 11 ml of benzylamine are heated under stirring at 130° C. The reaction mixture is poured onto 50 ml of water, the resulting precipitate is filtered off, washed with 50 ml of water. The pale-yellow precipitate is recrystallized from dimethylformamide to obtain 5.2 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:22][CH2:23][CH3:24].Cl>C(#N)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:22][CH2:23][CH3:24])[CH2:11][CH2:10]1
Reactant: CCCI
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCN1CCN(c2cccc(Cl)c2Cl)CC1

Procedure:
Preparation according to Example 1: 1-(2,3-dichlorophenyl)piperazine (1.0 g, 3.74 mmol), acetonitrile (40 ml), potassium carbonate (1.55 g, 11.2 mmol) and 1-iodopropane (0.293 ml, 3.74 mmol). Yield: 0.23 g (20%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 220-221° C. MS m/z (relative intensity, 70 eV) 274 (M+, 15), 272 (M+, 22), 245 (63), 243 (bp), 174 (22), 172 (27).