Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3](=[O:18])[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:15])[CH2:12][CH2:13][OH:14])=[C:7]([CH:16]=[CH2:17])[CH:6]=1.C(N([CH2:25][CH3:26])CC)C.[C:27]([Si:31]([CH3:34])([CH3:33])Cl)([CH3:30])([CH3:29])[CH3:28].O>ClCCl.CN(C)C1C=CN=CC=1>[CH3:19][N:2]([CH3:1])[C:3](=[O:18])[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:15])[CH2:12][CH2:13][O:14][Si:31]([C:27]([CH3:30])([CH3:29])[CH3:28])([C:34]2[CH:26]=[CH:25][CH:12]=[CH:11][CH:8]=2)[C:33]2[CH:9]=[CH:10][CH:5]=[CH:6][CH:7]=2)=[C:7]([CH:16]=[CH2:17])[CH:6]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCN(CC)CC
Reactant: C=Cc1cc(OC(=O)N(C)C)ccc1C(O)CCO
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: C=Cc1cc(OC(=O)N(C)C)ccc1C(O)CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 139.6 %

Procedure:
To a solution of 4-(1,3-dihydroxy-propyl)-3-vinyl-phenyl dimethylcarbamate (4.44 g, 16.7 mmol) synthesized in step (e) of Example 192 in dichloromethane (40 ml) were added triethylamine (4.18 ml, 30.0 mmol), t-butyldimethylchlorosilane (4.67 g, 17.0 mmol) and a catalytic amount of 4-dimethylaminopyridine at −0° C. with stirring, and the resulting mixture was stirred for 5 hours at room temperature under a nitrogen atmosphere. After stirring, water (30 ml) was added to the reaction mixture, and the resulting mixture was extracted with dichloromethane (40 ml×2). The organic layer was washed successively with 1N hydrochloric acid (50 ml×1) and saturated aqueous sodium chloride solution (50 ml×1), dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to afford the crude product. The crude product was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (2:1-1:1) as the eluent to afford the title compound (5.87 g, yield: 70%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH2:11]([CH2:15][C:16](=O)[CH3:17])[C:12]([CH3:14])=O.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH3:17][C:16]1[N:1]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)[C:12]([CH3:14])=[CH:11][CH:15]=1
Reactant: CC(=O)CCC(C)=O
Reactant: Nc1ccc2[nH]ccc2c1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1-c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a 250 mL argon purged round bottom flask containing a magnetic stirbar and a solution of 5-aminoindole (91) (15.00 g, 113 mmol) in anhydrous toluene (50 mL) was added acetonylacetone (25.4 mL, 216 mmol, 1.9 eq). The flask was fitted with a Dean-Stark trap with a 10 mL reservoir filled with toluene. The uppermost portion of the flask and the condensing arm of the trap were wrapped with foil and the reaction vessel placed into an oil bath preheated to a temperature of 125° C. The dark brown solution was allowed to stir under a continuous flow of argon at this temperature for 45 minutes, followed by draining of the trap solvent reservoir. After a total of 4 hours, TLC (5% ethyl acetate, 95% hexanes) revealed the reaction was complete. The reaction was cooled gradually to room temperature overnight. The reaction was poured onto a plug of silica gel and the solvent pulled through by vacuum filtration. The silica was washed with hexanes (200 mL). A white precipitate started to form almost immediately in the filtrate. The silica was washed again with a solution of 6% diethyl ether, 94% hexanes (800 mL). Crystals were collected from both washes, and the filtrates combined. The plug was washed with ether (150 mL) and the filtrate combined with the washes. The combined filtrates were concentrate to afford a brown oil. The oil was purified on the Biotage SP-1 (0-8% ether in hexanes). TLC revealed that all products were identical (white solids) and all products were combined. (Yield: 17.10 g of white solid, compound 92 (72%). 1H NMR (CDCl3) δ: 8.26 (bs, NH), 7.48-7.48 (d, 1H, J=1.2 Hz), 7.46-7.43 (d, 1H, J=8.7 Hz), 7.31-7.29 (t, 1H, J=2.7), 7.04-7.00 (dd, 1H, J=2.1, 8.4), 6.61 (s, 1H), 5.92 (s, 2H), 2.05 (s, 6H). MS-ESI m/z (%): 211 (M+, 100).
Reaction SMILES: Br[C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7]([NH:11][CH3:12])[N:8]=[C:9]([CH3:10])[C:4]=2[CH:3]=1.[N:21]1[CH:26]=[C:25](B(O)O)[CH:24]=[N:23][CH:22]=1>>[CH:16]1([N:13]2[C:5]3[N:6]=[C:7]([NH:11][CH3:12])[N:8]=[C:9]([CH3:10])[C:4]=3[CH:3]=[C:2]([C:25]3[CH:26]=[N:21][CH:22]=[N:23][CH:24]=3)[C:14]2=[O:15])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CNc1nc(C)c2cc(Br)c(=O)n(C3CCCC3)c2n1
Reactant: OB(O)c1cncnc1
Product: CNc1nc(C)c2cc(-c3cncnc3)c(=O)n(C3CCCC3)c2n1
Yield: 10 %

Procedure:
Following the procedure described in Preparation of Example 14, using 6-bromo-8-cyclopentyl-4-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one in place of 6-bromo-8-cyclopentyl-2-(2-hydroxy-2-methylpropylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one, pyrimidin-5-ylboronic acid in place of 3-hydroxyphenylboronic acid, the title compound was obtained in 10% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([N:11]2[CH2:15][C@H:14]([C@H:16]([O:18][C:19]3[C:20]4[N:21]([N:34]=[CH:35][CH:36]=4)[CH:22]=[C:23](B4OC(C)(C)C(C)(C)O4)[CH:24]=3)[CH3:17])[CH2:13][C:12]2=[O:37])[CH3:10])=[CH:5][CH:4]=1.Br[C:39]1[N:44]=[CH:43][C:42]([N:45]2[CH2:50][CH2:49][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47][CH2:46]2)=[CH:41][CH:40]=1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.O.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([N:11]2[C:12](=[O:37])[CH2:13][C@@H:14]([C@H:16]([O:18][C:19]3[C:20]4[N:21]([N:34]=[CH:35][CH:36]=4)[CH:22]=[C:23]([C:39]4[N:44]=[CH:43][C:42]([N:45]5[CH2:50][CH2:49][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47][CH2:46]5)=[CH:41][CH:40]=4)[CH:24]=3)[CH3:17])[CH2:15]2)[CH3:10])=[CH:5][CH:4]=1
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(B4OC(C)(C)C(C)(C)O4)cn4nccc34)CC2=O)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)nc2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cn4)cn4nccc34)CC2=O)cc1
Temperature: 90 °C

Procedure:
(R)-1-((R)-1-(4-methoxyphenyl)ethyl)-4-((R)-1-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one 6.19 (55.0 mg, 0.109 mmol), tert-butyl 4-(6-bromopyridin-3-yl)piperazine-1-carboxylate 7.13 (65.2 mg, 0.190 mmol) and Cs2CO3 (106 mg, 0.326 mmol) were dissolved in 1,2-dimethoxyethane (3.0 mL) and water (1.5 mL). The mixture was degassed for 5 minutes. PEPPSI-IPr catalyst (7.42 mg, 0.0109 mmol) was added and the mixture was heated for 1 h at 90° C. The reaction was cooled and diluted with EtOAc and water. The layers were separated and the organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (50 to 100% EtOAc in hexanes) to provide tert-butyl 4-(6-(4-((R)-1-((R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)pyridin-3-yl)piperazine-1-carboxylate 6.20.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][CH2:11][Cl:12])[CH:6]=[CH:5][N:4]=1.[OH-].[NH4+].[CH:15](O)=[O:16]>>[CH:15]([NH:1][CH2:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][CH2:11][Cl:12])[CH:6]=[CH:5][N:4]=1)=[O:16]
Reactant: O=CO
Reactant: NCc1cc(CCCCl)ccn1
Agent: [NH4+]
Agent: [OH-]
Product: O=CNCc1cc(CCCCl)ccn1

Procedure:
A solution of 2-aminomethyl-4-(3-chloropropyl)pyridine (0.47 g) in 1 ml of formic acid is heated at 90° for 18 hours, cooled to 0° and made basic by the addition of saturated ammonium hydroxide solution. Extraction with methylene chloride (4×10 ml), drying over sodium sulfate and evaporation yields 2-(N-formylaminomethyl)-4-(3-chloropropyl)pyridine (IR 1674 cm-1) which is heated at 90° in phosphorus oxychloride (0.75 g) for 15 hours. Excess phosphorus oxychloride is evaporated with toluene and the residue is suspended in methylene chloride (15 ml), cooled to 0° and made basic with saturated ammonium hydroxide. Extraction with methylene chloride (4×15 ml), drying over sodium sulfate and preparative thin layer chromatography (silica gel, EtOAc) of the residue yields 7-(3-chloropropyl)-imidazo[1,5-a]pyridine (Rf=0.24, EtOAc) as a gum; NMR (CDCl3) 3.58 (t, 2 H), 6.42 (q, 1 H), 7.21 (s, 1 H), 7.32 (s, 1 H), 7.88 (d, 1 H), 8.07 (s, 1 H).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[S:7])[N:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[C:4](=[O:15])[NH:3]1.[H-].[Na+].[CH3:18][O:19][CH2:20]Br>CN(C=O)C.C(Cl)Cl>[CH3:1][N:2]1[C:6](=[S:7])[N:5]([C:8]2[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=2)[C:4](=[O:15])[N:3]1[CH2:18][O:19][CH3:20]
Reactant: Cn1[nH]c(=O)n(-c2ccc(Cl)cc2)c1=S
Reactant: COCBr
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COCn1c(=O)n(-c2ccc(Cl)cc2)c(=S)n1C
Reaction time: 0.5 h

Procedure:
To 1-methyl-4-(4-chlorophenyl)-1,2,4-triazolidin-3-one-5-thione (5 g) in 200 ml dry DMF was added 0.91 g sodium hydride. After stirring for 30 minutes, bromomethyl methyl ether (2.63 g) was added dropwise, then heated to reflux for 30 minutes, and stirred overnight at room temperature. The solvent was stripped and the residue was dissolved in methylene chloride, washed with water, and chromatographed on a silica gel column (200 g) by elution with methylene chloride, followed by 2.5% methanol in methylene chloride. Yield: 4.8 g.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:17]=[CH:16][C:15]=2[NH:26][C:27]([C:29]2[NH:30][CH:31]=[C:32]([C:34]#[N:35])[N:33]=2)=[O:28])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1.[N:36]1[CH:41]=[CH:40][C:39]([CH2:42][C:43](O)=[O:44])=[CH:38][CH:37]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:21][CH2:22][N:23]([C:43](=[O:44])[CH2:42][C:39]4[CH:40]=[CH:41][N:36]=[CH:37][CH:38]=4)[CH2:24][CH2:25]3)[CH:17]=[CH:16][C:15]=2[NH:26][C:27]([C:29]2[NH:30][CH:31]=[C:32]([C:34]#[N:35])[N:33]=2)=[O:28])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCNCC3)cc2C2=CCCCC2)n1
Reactant: O=C(O)Cc1ccncc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCN(C(=O)Cc4ccncc4)CC3)cc2C2=CCCCC2)n1

Procedure:
The title compound was prepared from 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (as prepared in Example 14, step (b)), according to the procedure in Example 29 using pyridin-4-yl-acetic acid. 1H-NMR (400 MHz, CD3OD): δ 8.78 (d, 2H), 8.12 (d, 1H), 8.00 (m, 3H), 7.18 (dd, 1H), 7.08 (d, 1H), 5.80 (m, 1H), 4.66 (m, 1H), 4.22 (s, 2H), 4.18 (m, 1H), 3.34 (m, 1H), 2.84 (m, 2H), 2.24 (m, 4H), 2.00-1.70 (m, 7H), 1.64 (m, 1H). Mass spectrum (ESI, m/z): Calcd. for C29H30N6O2, 495.2 (M+H), found 495.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:21](=[O:22])[N:20]([CH3:23])[C:11]3[N:12]([CH3:19])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:4][CH:3]=1.[Br:24][CH2:25][C:26](Cl)=[O:27]>>[Br:24][CH2:25][C:26]([C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:19])[C:11]1[N:20]([CH3:23])[C:21](=[O:22])[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[CH:9][C:10]2=1)=[O:27]
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2)cc2c3ccccc3n(C)c21
Reactant: O=C(Cl)CBr
Product: Cn1c(=O)c(-c2ccc(Cl)cc2)cc2c3cc(C(=O)CBr)ccc3n(C)c21

Procedure:
The process is carried out as in preparation 1.1 above, using compound from Example 104A, 3-(4-chlorophenyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and bromoacetyl chloride.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1.[I:12]I>CN(C)C=O.S([O-])([O-])(=O)=O.[Ag+2]>[F:11][C:2]([F:1])([F:10])[C:3]1[CH:4]=[C:5]([I:12])[C:6]([NH2:9])=[N:7][CH:8]=1
Reactant: II
Reactant: Nc1ccc(C(F)(F)F)cn1
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CN(C)C=O
Product: Nc1ncc(C(F)(F)F)cc1I
Reaction time: 14 h

Procedure:
A solution of 5-(trifluoromethyl)pyridin-2-amine (3-a with R4=CF3, 1.6 g, 9.87 mmol) (Maybridge Chemical company, Cornwall, England) in N,N-dimethylformamide (30 mL) was treated at room temperature with silver sulfate (3.1 g, 9.87 mmol) and iodine (2.5 g, 9.87 mol). The reaction mixture was stirred for 14 h and filtered. The filtrated solution was concentrated in vacuo. The residue was chromatographed (SiO2, 25% ethyl acetate in hexanes) to give 5-(trifluoromethyl)-3-iodopyridin-2-amine (3-b, with R4=CF3). The iodide (3-b, with R4=CF3, 1.0 g, 3.47 mmol) and cuprous cyanide (CuCN, 78 g, 8.68 mmol) was dissolved in N,N-dimethylformamide (6 mL) and heated under the microwave at 100 C for 30 min, cooled to ambient temperature, and diluted with ethyl acetate. The precipitates were removed by filtration. The filtrated solution was partitioned between ethyl acetate and water. The organic layer was washed with brine, separated, dried (MgSO4) and concentrated in vacuo. Trituration of the residue with hexanes afforded the desired product, 2-amino-5-(trifluoromethyl)pyridine-3-carbonitrile (3-c, with R4=CF3). 2-amino-5-(trifluoromethyl)pyridine-3-carbonitrile (3-c, with R4=CF3, 545 mg, 29.2 mmol) was stirred in methanol (10 mL, saturated with ammonia) under hydrogen atmosphere in the presence of Pd/C (200 mg) overnight. The reaction mixture was filtered and the filtrate solution was concentrated in vacuo to afford the crude amine (3-d, with R4=CF3). A solution of (S)-2-phenylbutanoic acid (300 mg, 18.3 mmol) and diisopropylethylamine (888 uL, 52.4 mmol) in N,N-dimethylformamide (5 mL) was treated at room temperature with benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBop, 953 mg, 18.3 mmol). After 15 min, 3-(aminomethyl)-5-(trifluoromethyl)pyridin-2-amine (500 mg, 26.2 mmol) was added. The reaction mixture was stirred for 2 h, partitioned between ethyl acetate and 0.5N—NaOH. The aqueous layer was removed and the organic layer was washed with brine. The organic layer was separated, dried (MgSO4) and concentrated in vacuo to give the desired product (3-g); HRMS (M+1)=338.1405.
Reaction SMILES: C[O:2][C:3](=[O:33])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([CH:18]([CH3:32])[C:19]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([Cl:31])[CH:26]=3)([OH:24])[C:20]([F:23])([F:22])[F:21])[CH:12]=2)=[N:6][CH:5]=1.[Li+].[OH-].O>C1COCC1>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:33])=[O:2])=[CH:5][N:6]=2)=[CH:12][C:13]=1[CH:18]([CH3:32])[C:19]([C:25]1[CH:30]=[CH:29][N:28]=[C:27]([Cl:31])[CH:26]=1)([OH:24])[C:20]([F:23])([F:21])[F:22]
Reactant: COC(=O)c1ccc(Oc2ccc(Cl)c(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(c1cc(Oc2ccc(C(=O)O)cn2)ccc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Temperature: 25 °C

Procedure:
6-{4-Chloro-3-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenoxy}-nicotinic acid methyl ester (14 mg, obtained in Example 132) was dissolved in THF (5 mL). The mixture was cooled in an ice bath and aqueous LiOH solution (1.0 M, 0.048 mL) was added. The mixture was stirred over night at r.t. The reaction mixture was poured into water and extracted with ethyl acetate. The aqueous phase was acidified with 2 M aqueous HCl to pH 1 and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4 and the solvent was evaporated. The title compound was obtained as an off-white solid (12 mg, 88%) and was used without further purification. MS (neg. ion, m/e)=485.0 [(M−H)−].
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].[BrH:20].S(=O)(=O)(O)O>C(O)(=O)C>[Br:20][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: Br
Reactant: O=C(O)CCCCCCCCCCCCCCCO
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C(O)CCCCCCCCCCCCCCCBr

Procedure:
A mixture of 18 g. of 16-hydroxyhexadecanoic acid and 160 g. of 30-32% hydrogen bromide in acetic acid is treated with 32 ml. of concentrated sulfuric acid and stirred at ambient temperature for 18 hours. The solution is stirred under reflux for 7 hours and then poured into 500 ml. of ice-water and filtered. A methylene chloride solution of the product is treated with charcoal, dried over magnesium sulfate, and evaporated. Crystallization of the residue from ether-petroleum ether and then acetonitrile affords 16-bromohexadecanoic acid as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8](O)=[O:9])=[CH:4][CH:3]=1.S(Cl)([Cl:17])=O>>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([Cl:17])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)(Oc1ccc(Cl)cc1)C(=O)O
Product: CC(C)(Oc1ccc(Cl)cc1)C(=O)Cl

Procedure:
A mixture of 2-(4-chlorophenoxy)-2-methylpropionic acid (15.0 g) and thionyl chloride (70 ml) was boiled under reflux for 1 hour. The thionyl chloride was distilled off and the residue distilled under vacuum to give 2-(4-chlorophenoxy)-2-methylpropionyl chloride, b.p. 84°-87° C. at 0.07 mbar. A solution of this chloride (14.17 g) in dichloromethane (50 ml) was added dropwise to a mixture of 1-(3-aminopropyl)imidazole (7.63 g), triethylamine (6.78 g) and dichloromethane (100 ml) at below 0° C. with stirring. After the addition, the mixture was allowed to warm up to ambient temperature and stirred at this temperature for 2 hours. Saturated aqueous sodium bicarbonate solution (100 ml) was added and the mixture stirred for 1 hour. The mixture was separated and the aqueous layer was washed with dichloromethane. The combined organic layers were dried and evaporated to give a solid which was recrystallised from ethyl acetate to give 2-(4-chlorophenoxy)-N-[3-(imidazol-1-yl)propyl]-2-methylpropionamide, m.p. 83°-84° C.
Reaction SMILES: Cl[CH2:2][C:3](=O)[C:4](=[N:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:22][C:23]([NH2:25])=[S:24].C([O-])(=O)C.[Na+].C(O)C>O>[NH2:25][C:23]1[S:24][CH:2]=[C:3]([C:4](=[N:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:22]=1
Reactant: CCOC(=O)C(=NOCc1ccc(Cl)cc1Cl)C(=O)CCl
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(=NOCc1ccc(Cl)cc1Cl)c1csc(N)n1
Yield: 32.1 %

Procedure:
Ethyl 4-chloro-2-(2,4-dichorobenzyloxyimino)-3-oxobutyrate (syn isomer, 37.3 g.), thiourea (8.1 g.), sodium acetate (8.7 g.), ethanol (100 ml.) and water (100 ml.) were treated in a similar manner to that of Example C-(3) to give ethyl 2-(2-aminothiazol-4-yl)-2-(2,4-dichlorobenzyloxyimino)acetate (syn isomer, 12.7 g.).
Reaction SMILES: C([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH:13]([N:18]=[N+:19]=[N-:20])[O:14][CH2:15][CH2:16][OH:17])[CH:6]=1)C.[OH-].[Na+]>C(O)C>[N:18]([CH:13]([O:14][CH2:15][CH2:16][OH:17])[CH2:12][O:11][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[C:4]([OH:21])=[O:3])=[N+:19]=[N-:20]
Reactant: CCOC(=O)c1cccc(OCC(N=[N+]=[N-])OCCO)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: [N-]=[N+]=NC(COc1cccc(C(=O)O)c1)OCCO
Reaction time: 3 h

Procedure:
3-[2-Azido-2-(2-hydroxyethoxy)ethoxy]benzoic acid ethyl ester (1.34 g, 4.55 mmol) was stirred with 4 M aqueous sodium hydroxide (11.4 ml, 45.5 mmol) and ethanol (11.4 ml) at room temperature. After 3 hrs, all the solvents were removed under reduced pressure and the residue was dissolved in 50 ml water. The solution was acidified with 1N HCl to pH 2 and then extracted with DCM (3×50 ml). All the DCM extracts were combined, dried over MgSO4 and evaporated under reduced pressure. The title compound was obtained as a colourless solid (1.2 g, 98.7%). ES-MS, m/z 265.85 (M−1).
Reaction SMILES: [NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]3)[O:8][C:4]=2[CH:3]=1.[CH2:19]([Br:22])[CH:20]=[CH2:21]>CN(C=O)C>[Br-:22].[CH2:19]([N+:12]1([CH3:15])[CH2:13][CH2:14][N:9]([C:7]2[O:8][C:4]3[CH:3]=[C:2]([NH2:1])[C:17]([Cl:18])=[CH:16][C:5]=3[N:6]=2)[CH2:10][CH2:11]1)[CH:20]=[CH2:21]
Reactant: CN1CCN(c2nc3cc(Cl)c(N)cc3o2)CC1
Reactant: C=CCBr
Solvent: CN(C)C=O
Product: C=CC[N+]1(C)CCN(c2nc3cc(Cl)c(N)cc3o2)CC1
Product: [Br-]
Temperature: 25 °C

Procedure:
A 50 mg portion of 6-amino-5-chloro-2-(4-methyl-1-piperazinyl)benzoxazole was dissolved in 5 ml of DMF, and the solution, while stirring at room temperature, was mixed with 135 mg of allyl bromide and stirred for additional 2 hours. Thereafter, the solvent was evaporated under a reduced pressure and the thus obtained mixture was purified by an LH-20 gel column chromatography (chloroform:methanol=1:1) to obtain the title compound (15 mg) in light yellow color.
Reaction SMILES: [S:1]([OH:11])(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=[O:2].Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[N:16]=[N:15][CH:14]=1>O.C(O)C>[Cl:23][C:19]1[CH:18]=[C:17]2[C:22]([C:13]([NH:9][C:6]3[CH:5]=[CH:4][C:3]([S:1]([OH:11])(=[O:10])=[O:2])=[CH:8][CH:7]=3)=[CH:14][N:15]=[N:16]2)=[CH:21][CH:20]=1
Reactant: Clc1ccc2c(Cl)cnnc2c1
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: O=S(=O)(O)c1ccc(Nc2cnnc3cc(Cl)ccc23)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
Sulphanilic acid (1.95 g) in water (75 ml) and ethanol (10 ml) at 70° C. was treated with 4,7-dichlorocinnoline (2.2 g) and ethanol (10 ml) was added. The resultant green suspension was stirred vigorously overnight at 70° C. The mixture was cooled, and the solid was filtered, washed with water and dried at room temperature to give 3.45 g of the title compound as the monohydrate, melting point greater than 280° C.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([CH3:18])=[CH:5][CH:6]([S:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=1)[CH3:7].[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1>C1COCC1>[CH3:17][N:15]([CH3:16])[C:12]1[CH:13]=[CH:14][C:9]([S:8][CH:6]([CH3:7])[CH:5]=[C:4]([CH3:18])[CH2:3][OH:2])=[CH:10][CH:11]=1
Reactant: COC(=O)C(C)=CC(C)Sc1ccc(N(C)C)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(=CC(C)Sc1ccc(N(C)C)cc1)CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
To a solution of 4-(4-dimethylaminophenylsulfanyl)-2-methylpent-2-enoic acid methyl ester (0.279 g, 1.0 mmol) in dry THF (4 mL) at 0° C. was added dropwise a solution of di-isobutylaluminium hydride in toluene (1M, 3.0 mL, 3.0 mmol), under an atmosphere of argon. After stirring at 0° C. for one hour (TLC monitoring), the mixture was quenched by addition of methanol (0.5 mL: CAUTION), then water (0.3 mL), 5% aqueous sodium hydroxide solution (0.3 mL) and lastly 30% aqueous sodium potassium tartrate (4 mL). The mixture was stirred for 2 hours at 20° C., then extracted with diethyl ether (3×10 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and evaporated to give the title compound (0.22 g, 88%) as a colourless oil.