Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10]([OH:12])=O)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[F:24][C@H:25]1[CH2:27][C@@H:26]1[C:28]1[O:32][N:31]=[C:30]([C:33]2[CH:34]=[CH:35][C:36]([CH3:40])=[C:37]([CH:39]=2)[NH2:38])[N:29]=1>ClCCl.N1C=CC=CC=1>[F:24][C@H:25]1[CH2:27][C@@H:26]1[C:28]1[O:32][N:31]=[C:30]([C:33]2[CH:34]=[CH:35][C:36]([CH3:40])=[C:37]([NH:38][C:10]([C:3]3[N:4]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]4=[N:1][CH:2]=3)=[O:12])[CH:39]=2)[N:29]=1
Reactant: O=C(O)c1cnc2ccccn12
Reactant: Cc1ccc(-c2noc([C@H]3C[C@@H]3F)n2)cc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(-c2noc([C@H]3C[C@@H]3F)n2)cc1NC(=O)c1cnc2ccccn12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirring suspension of imidazo[1,2-a]pyridine-3-carboxylic acid (1) (52 mg, 0.32 mmol) in anhydrous dichloromethane (2 mL) at 0° C. under Argon was added dropwise oxalyl chloride (56 μL, 0.64 mmol). Then, a drop of anhydrous DMF was added and the reaction mixture was stirred at room temperature for 1.5 hours. The solvent was concentrated and the crude solid was added portion-wise to a stirring solution of 5-(5-((1R,2S)-2-fluorocyclopropyl)-1,2,4-oxadiazol-3-yl)-2-methylaniline (131) (62 mg, 0.27 mmol) in anhydrous pyridine (1 mL) at 0° C. The reaction was stirred at room temperature under Argon for 30 minutes and quenched with water. The crude product was purified by preparative HPLC to yield N-(5-(5-((1R,2S)-2-fluorocyclopropyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (F110). MS m/z 378.1 (M+1)+.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Br:16].Cl[Si:18]([CH3:21])([CH3:20])[CH3:19].Cl>C1COCC1>[Br:9][C:10]1[C:11]([Br:16])=[C:12]([Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:13]=[CH:14][C:15]=1[Si:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: C[Si](C)(C)Cl
Reactant: Brc1ccccc1Br
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)c1ccc([Si](C)(C)C)c(Br)c1Br
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
LDA (2 M, 70 mL, 140 mmol) was added dropwise to a solution of 1,2-dibromobenzene (15.0 g, 64 mmol) and chlorotrimethylsilane (20 mL, 153 mmol) in THF (90 mL) at −78° C. The resultant brown suspension was stirred at −78° C. for 30 min and then gradually warmed to room temperature. The reaction mixture was stirred for 18 h and then cooled to −78° C. again and chlorotrimethylsilane (20 mL, 153 mmol) was added. LDA (2M, 70 mL, 140 mmol) was added dropwise and the resultant brown suspension was stirred at −78° C. for 30 mins and then gradually warmed to room temperature. The reaction mixture was stirred for a further 18 h and then hydrolyzed with 1 N HCl (100 mL). The resultant mixture was extracted with diethyl ether (3×200 mL) and the combined organic layers was concentrated to give brown oil, which was used directly in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 7.34 (s, 2H), 0.40 (18H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.Cl.[O:14]([NH2:16])[CH3:15]>>[CH3:15][O:14][N:16]=[CH:7][C:6]1[CH:9]=[CH:10][C:3]([C:2]([F:12])([F:11])[F:1])=[CH:4][CH:5]=1
Reactant: CON
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: Cl
Product: CON=Cc1ccc(C(F)(F)F)cc1
Yield: 100 %

Procedure:
Reaction of 4-trifluoromethylbenzaldehyde with methoxylamine hydrochloride as described in the preparation of compound 3-A gave the title oxime ether as a clear oil (100% yield). 1HNMR indicated a 9:1 mixture of E- and Z-isomers. 1HNMR 400 MHz (CDCl3) δ (ppm): (E-isomer) 4.00 (3H, s, OCH3), 7.62 (2H, m, aromatics), 7.69 (2H, m, aromatics), 8.08 (1H, s, CH).
Reaction SMILES: [CH3:1][C:2]([CH3:22])([O:4][C:5]([NH:7][C:8]1[CH:20]=[CH:19][C:11]([O:12][CH2:13][C:14](OCC)=[O:15])=[CH:10][C:9]=1[CH3:21])=[O:6])[CH3:3].C(=O)=O.CC(O)C.[CH3:30][NH:31][CH3:32]>C(Cl)(Cl)Cl>[CH3:30][N:31]([CH3:32])[C:14](=[O:15])[CH2:13][O:12][C:11]1[CH:19]=[CH:20][C:8]([NH:7][C:5]([O:4][C:2]([CH3:22])([CH3:3])[CH3:1])=[O:6])=[C:9]([CH3:21])[CH:10]=1
Reactant: CNC
Reactant: CCOC(=O)COc1ccc(NC(=O)OC(C)(C)C)c(C)c1
Agent: O=C=O
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: Cc1cc(OCC(=O)N(C)C)ccc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 312 h
Yield: 100 %

Procedure:
To a 100 mL pressure vessel with a stirring bar was added ethyl 4-(1,1-dimethylethoxycarbonyl)amino-3-methylphenoxyacetate (1.00 g, 3.24 mmol). The vessel was cooled in a Dry Ice®/2-propanol bath to -78° C. and dimethylamine was condensed onto the solid to a final volume of ~30 mL. The reaction vessel was sealed, allowed to warm to ambient temperature and stirred for 13 days. The excess dimethylamine was vented and the residue was dissolved in CHCl3 and concentrated, twice to remove the last traces of dimethylamine. The crude product was chromatographed on 75 g of silica gel using 75/25 EtOAC-hexane as eluant to provide 1 g (100% yield) N,N-dimethyl-4-(1,1-dimethylethoxycarbonyl)amino-3-methylphenoxyacetamide as a white, crystalline solid. 1H NMR (CDCl3): d 1.50 (s, 9H), 2.22 (s, 3H), 2.96 (s, 3H), 3.07 (s, 3H), 4.63 (s, 2H), 6.09 (br s, 1H), 6.77, (s, 2H), 7.52 (br s, 1H). ##STR51## N,N-Dimethyl 4-amino-3-methylphenoxyacetamide (5-3)
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([CH2:27][O:28][CH2:29][CH3:30])[N:14]([CH2:15][CH2:16][N:17]3[C:21]4([CH2:25][CH2:24][CH2:23][CH2:22]4)[O:20][N:19]=[C:18]3[CH3:26])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:31]>CO>[CH2:29]([O:28][CH2:27][C:13]1[N:14]([CH2:15][CH2:16][N:17]2[C:21]3([CH2:25][CH2:24][CH2:23][CH2:22]3)[O:20][N:19]=[C:18]2[CH3:26])[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:31])[C:11]=2[N:12]=1)[CH3:30]
Reactant: CCOCc1nc2c(Cl)nc3ccccc3c2n1CCN1C(C)=NOC12CCCC2
Reactant: N
Solvent: CO
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCN1C(C)=NOC12CCCC2

Procedure:
The methods described in Part H of Example 10 were used to treat 4-chloro-2-(ethoxymethyl)-1-[2-(3-methyl-1-oxa-2,4-diazaspiro[4,4]non-2-en-4-yl)ethyl]-1H-imidazo[4,5-c]quinoline (770 mg, 1.80 mmol) with a solution of 7 M ammonia in methanol (20 mL) and isolate and purify the final product to provide 700 mg of 2-(ethoxymethyl)-1-[2-(3-methyl-1-oxa-2,4-diazaspiro[4,4]non-2-en-4-yl)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine as white needles, mp 211-213° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](/[CH:10]=[CH:11]\[C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C([NH:41][C@H:42]([C:44]([NH2:46])=[O:45])[CH3:43])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.[OH-].[Na+].[Cl-].[Na+]>CO>[NH2:1][C:2]1[CH:3]=[C:4](/[CH:10]=[CH:11]\[C:12]2[CH:13]=[C:14]([O:22][CH3:23])[C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[NH2:41][C@H:42]([C:44]([NH2:46])=[O:45])[CH3:43]
Reactant: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(N)=O
Agent: COc1ccc(/C=C\c2cc(OC)c(OC)c(OC)c2)cc1N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: C[C@H](N)C(N)=O
Reaction time: 3 h

Procedure:
One gram (1.6 mmols) of (Z)-1-(3-amino-4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-ethene-Fmoc-L-alanineamide was dissolved in 10 ml of methanol, and 0.9 ml (1.76 mmols) of an aqueous solution of 2-N sodium hydroxide were added thereto. The mixture was stirred for 3 hours. A saturated aqueous solution of sodium chloride was added thereto, and the resulting mixture was extracted three times with dichloromethane. The extract was dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The product was purified using a silica-gel plate (mixture of 5-% by volume methanol and dichloromethane) to produce 543 mg of the final compound in a yield of 87.9%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][CH:11]=[C:10]([C:13](=[N:15][NH:16][C:17]([N:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][C:27]([O:29]C)=[O:28])[CH2:21][CH2:20]3)=[S:18])[CH3:14])[C:9]=2[OH:31])=[CH:4][CH:3]=1>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][CH:11]=[C:10]([C:13](=[N:15][NH:16][C:17]([N:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH2:21][CH2:20]3)=[S:18])[CH3:14])[C:9]=2[OH:31])=[CH:4][CH:3]=1
Reactant: COC(=O)CCN1CCN(C(=S)NN=C(C)c2csc(-c3ccc(Br)cc3)c2O)CC1
Solvent: CCO
Product: CC(=NNC(=S)N1CCN(CCC(=O)O)CC1)c1csc(-c2ccc(Br)cc2)c1O
Yield: 55 %

Procedure:
The hydrolysis procedure in Synthetic Example 2 was followed using methyl 3-[4-{1-[5-(4-bromophenyl)-4-hydroxythiophen-3-yl]-ethylidene-hydrazinothiocarbonyl}-piperazin-1-yl]propionate and ethanol as the solvent to give the desired product (yield 55%).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:5]2[N:6]([CH:10]=[C:11]([CH3:13])[N:12]=2)[CH:7]=[CH:8][CH:9]=1.[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17]Cl.O>CS(C)=O>[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][O:3][C:4]1[C:5]2[N:6]([CH:10]=[C:11]([CH3:13])[N:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: ClCc1ccccc1Cl
Reactant: Cc1cn2cccc(O)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cn2cccc(OCc3ccccc3Cl)c2n1
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
A 60% dispersion of sodium hydride in mineral oil (1.87 g) was added portionwise to a suspension of 8-hydroxy-2-methylimidazo[1,2-a]pyridine (6.3 g) in dimethyl sulfoxide (63 ml) at room temperature over a period of 15 minutes. After being stirred for 30 minutes, 2-chlorobenzyl chloride (7.54 g) was added in one portion to the mixture and then the resultant mixture was stirred for 24 hours at room temperature. The mixture was poured into water and the resulting precipitate was collected by filtration. The crude product was purified by column chromatography on silica gel (30 g) with methylene chloride as an eluent to afford a solid, which was recrystallized from a mixture of diethyl ether and n-hexane to give 8-(2-chlorobenzyloxy)-2-methylimidazo[1,2-a]pyridine (7.75 g).
Reaction SMILES: C[N:2]([C:11]1[O:12][C:13]2[CH:19]=[CH:18][C:17]([CH:20]([CH3:24])[C:21]([OH:23])=[O:22])=[CH:16][C:14]=2[N:15]=1)[C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5](Cl)[CH:4]=1.COC1C=CC(NC2OC3C=C(C(C)C#N)C=CC=3N=2)=CC=1.ClC1C=CC(NC2OC3C=CC(C(C)C(OCC)=O)=CC=3N=2)=CC=1.[I-].[Li+].[C-]#N.[Na+].C(=O)(O)[O-].[Na+]>O.C(C(C)=O)C>[Cl:9][C:6]1[CH:5]=[CH:4][C:3]([NH:2][C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([CH:20]([CH3:24])[C:21]([OH:23])=[O:22])=[CH:16][C:14]=3[N:15]=2)=[CH:8][CH:7]=1
Reactant: CC(C(=O)O)c1ccc2oc(N(C)c3ccc(Cl)c(Cl)c3)nc2c1
Agent: CCOC(=O)C(C)c1ccc2oc(Nc3ccc(Cl)cc3)nc2c1
Agent: COc1ccc(Nc2nc3ccc(C(C)C#N)cc3o2)cc1
Agent: O=C([O-])O
Solvent: CCC(C)=O
Solvent: O
Product: CC(C(=O)O)c1ccc2oc(Nc3ccc(Cl)cc3)nc2c1

Procedure:
2-[2-(N-methyl-3,4-dichloroanilino)-5-benzoxazolyl]propionic acid (h) 2-[2-(4-methoxyanilino)-6-benzoxazolyl]propionic acid. Production of the acids was confirmed by thin-layer chromatography. (i) A stirred mixture of ethyl 2-[2-(4-chloroanilino)-5-benzoxazolyl]propionate (2.9g.), dry lithium iodide (10g.), sodium cyanide (0.4g.) and methyl ethyl ketone (35 ml.) was heated under reflux for 18 hours. The solution was diluted with water and made alkaline with sodium bicarbonate. The solution was washed several times with chloroform, filtered through a `Supercel` pad and acidified with concentrated hydrochloric acid. The solid obtained was filtered off, washed with water and recrystallised from aqueous methanol to give 2-[2-(4-chloroanilino)-5-benzoxazolyl]propionic acid as a buff powder, mpt 206°-8° C, which was characterised by ir, uv and NMR spectroscopy and by micro analysis which gave: C 60.45% H 4.31% N 8.75%. C16H13ClN2O3 requires C 60.66% H 4.11% N 8.85%
Reaction SMILES: C(C[CH2:4][NH:5][C:6](=[O:32])[C@@H:7]([NH:12][C:13]([N:15]1[C:19]2[CH2:20][CH2:21][O:22][CH2:23][C:18]=2[C:17]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[CH:25]=2)=[N:16]1)=[O:14])[C:8]([CH3:11])([CH3:10])[CH3:9])#N.[N:33]1([C:39]2[N:44]=[CH:43][CH:42]=[CH:41][N:40]=2)[CH2:38]CN[CH2:35][CH2:34]1>>[F:31][C:26]1[CH:25]=[C:24]([C:17]2[C:18]3[CH2:23][O:22][CH2:21][CH2:20][C:19]=3[N:15]([C:13]([NH:12][C@@H:7]([C:8]([CH3:9])([CH3:10])[CH3:11])[C:6](=[O:32])[N:5]3[CH2:4][CH2:38][N:33]([C:39]4[N:44]=[CH:43][CH:42]=[CH:41][N:40]=4)[CH2:34][CH2:35]3)=[O:14])[N:16]=2)[CH:29]=[CH:28][C:27]=1[F:30]
Reactant: CC(C)(C)[C@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCOC2)C(=O)NCCC#N
Reactant: c1cnc(N2CCNCC2)nc1
Product: CC(C)(C)[C@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCOC2)C(=O)N1CCN(c2ncccn2)CC1

Procedure:
Compound 107 was prepared by the procedure described for the synthesis of compound 104 by replacing 2-cyanoethylamine with 2-(piperazin-1-yl)pyrimidine. LCMS (+ESI) m/z=540.4 [M+H]+. 1H NMR (CDCl3) δ 8.33 (d, J=4.8 Hz, 2H), 8.00 (d, J=9.6 Hz, 1H), 7.47-7.52 (m, 1H), 7.30-7.33 (m, 1H), 7.19-7.26 (m, 1H), 6.56 (t, J=4.8 Hz, 1H), 4.90 (d, J=9.6 Hz, 1H), 4.82 (s, 2H), 4.00-4.06 (m, 1H), 3.63-3.96 (m, 9H), 3.18 (br, 2H), 1.11 (s, 9H).
Reaction SMILES: [S:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:18]=[C:17]([CH3:19])[N:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:29])([F:28])[F:27])[C:15]=2[CH3:30])=[O:13])=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].C([O-])([O-])=O.[K+].[K+].[CH2:37](I)[CH3:38]>CN(C=O)C>[CH2:37]([NH:2][S:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:18]=[C:17]([CH3:19])[N:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:28])([F:27])[F:29])[C:15]=2[CH3:30])=[O:13])=[CH:7][CH:6]=1)(=[O:3])=[O:4])[CH3:38]
Reactant: CCI
Reactant: Cc1cc(C(=O)Nc2ccc(S(N)(=O)=O)cc2)c(C)n1-c1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCNS(=O)(=O)c1ccc(NC(=O)c2cc(C)n(-c3ccccc3C(F)(F)F)c2C)cc1
Reaction time: 23 h
Yield: 19.2 %

Procedure:
To a suspension of 2,5-dimethyl-1-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylic acid (4-sulfamoyl-phenyl)-amide (83 mg, 0.19 mmol) and K2CO3 (34 mg) in anhyd DMF (0.5 mL) was added ethyl iodide (15 μL, 0.19 mmol). After 19 h additional ethyl iodide (10 μL) was added. After 23 h total the reaction mixture was concentrated to dryness in vacuo. The residue was purified by reverse-phase HPLC to yield 2,5-dimethyl-1-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylic acid (4-ethylsulfamoyl-phenyl)-amide (17 mg, 19%) as a colorless powder; 1H NMR (DMSO-d6): δ 9.7 (s, 1H), 7.90 (d, J=8 Hz, 1H), 7.85 (d, J=8 Hz, 2H), 7.81 (t, J=8 Hz, 1H), 7.70 (t, J=8 Hz, 1H), 7.60 (d, J=8 Hz, 2H), 7.39 (d, J=8 Hz, 1H), 7.28 (d, J=8 Hz, 1H), 6.54 (s, 1H), 2.66 (quintet, J=7 Hz, 2H), 2.03 (s, 3H), 1.77 (s, 3H), 0.86 (t, J=7 Hz, 3H); MS (ESI) m/z 466 [M+H]+. Also recovered from the reaction was dimethyl-1-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylic acid (4-diethylsulfamoyl-phenyl)-amide (12 mg, 13%) as a colorless solid; 1H NMR (DMSO-d6): δ 9.9 (s, 1H), 8.11 (d, J=8 Hz, 1H), 8.08 (d, J=7 Hz, 2H), J=8 Hz, 1H), 7.92 (t, J=8 Hz, 1H), 7.82 (d, J=7 Hz, 2H), 7.60 (d, J=8 Hz, 1H), 6.77 (s, 1H), 3.25 (q, J=7 Hz, 4H), 2.24 (s, 3H), 1.99 (s, 3H), 1.45 (t, J=7 Hz, 6H); MS (ESI) m/z 494 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:12][C:13]1[NH:14][O:15][C:16](=[O:18])[CH:17]=1>C(=O)(O)[O-].[Na+]>[CH3:12][C:13]1[N:14]([C:4](=[O:5])[C:3]2[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:2]=2[Cl:1])[O:15][C:16](=[O:18])[CH:17]=1
Reactant: Cc1cc(=O)o[nH]1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(=O)on1C(=O)c1ccc(Cl)cc1Cl
Temperature: 150 °C
Yield: 237.4 %

Procedure:
20.9 gm of 2,4-dichlorobenzoyl chloride was added to 5 gm of 3-methyl-3-isoxazolin-5-one. The reaction mixture was heated at 150° C. for 3 hours. The reaction was neutralized with 100 ml of saturated sodium bicarbonate solution and extracted with methylene chloride. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate and filtered. The solvent was stripped to yield 32.6 gm of the crude product. The product was recrystallized from methylene chloride-hexane yielding 6.4 gm, m.p. 137°-139° C.
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH:7]([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1.O.[OH-].[Na+].[CH:20](O)=[O:21]>>[N:1]1([CH:6]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][CH:20]=[O:21])=[CH:14][CH:15]=2)[CH:7]([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=CO
Reactant: CC(C)C(c1ccc(N)cc1)n1ccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)C(c1ccc(NC=O)cc1)n1ccnc1
Temperature: 120 °C
Yield: 86.6 %

Procedure:
A mixture of 4-[1-(1H-imidazol-1-yl)-2-methylpropyl]benzenamine (0.0185 mol) in formic acid (20 ml) was stirred and heated at 120° C. for 15 minutes. The mixture was poured into water, basified with NaOH 3N and extracted with EtOAc. The organic layer was dried, filtered off and the solvent evaporated, yielding 3.9 g (86.6%) of (±)-N-[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]phenyl]formamide (compound 177).
Reaction SMILES: [C:1]([C:4]1[CH:24]=[CH:23][C:7]2[S:8](=[O:22])(=[O:21])[C:9]3[CH:16]=[C:15]([C:17](OC)=[O:18])[CH:14]=[CH:13][C:10]=3[CH2:11][CH2:12][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[CH3:25][N:26]([Al](C)C)[CH3:27]>C1(C)C=CC=CC=1>[CH3:25][N:26]([CH3:27])[C:17]([C:15]1[CH:14]=[CH:13][C:10]2[CH2:11][CH2:12][C:6]3[CH:5]=[C:4]([C:1](=[O:3])[CH3:2])[CH:24]=[CH:23][C:7]=3[S:8](=[O:22])(=[O:21])[C:9]=2[CH:16]=1)=[O:18]
Reactant: COC(=O)c1ccc2c(c1)S(=O)(=O)c1ccc(C(C)=O)cc1CC2
Reactant: CN(C)[Al](C)C
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc2c(c1)CCc1ccc(C(=O)N(C)C)cc1S2(=O)=O
Temperature: 70 °C

Procedure:
To a solution of the ester from Step 1 (440 mg, 1.28 mmol) in dry toluene (5 mL) was added dropwise at room temperature a solution of N,N-dimethylamino dimethyl aluminum 0.8M in toluene (16 mL, 12.8 mmol). The resulting solution was heated to 70° C. for 2 hours. The reaction mixture was then cooled to 0° C. and quenched with excess ethyl acetate followed by addition of lN aqueous HCl. The solvents were removed under reduced pressure and the resulting solid was filtered, washed with ethyl acetate to afford the title product which was used as such for the next step.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][OH:10])[CH2:5][CH2:4]1.Cl[C:12]1[C:17]2[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:19][O:20][C:16]=2[CH:15]=[N:14][N:13]=1>CN(C)C=O>[C:21]1([C:18]2[C:17]3[C:12]([O:10][CH2:9][CH:6]4[CH2:7][CH2:8][NH:3][CH2:4][CH2:5]4)=[N:13][N:14]=[CH:15][C:16]=3[O:20][N:19]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Clc1nncc2onc(-c3ccccc3)c12
Reactant: OCC1CCNCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(-c2noc3cnnc(OCC4CCNCC4)c23)cc1
Reaction time: 0.5 h

Procedure:
To sodium hydride (95% dispersion in mineral oil, 0.043 g) in N,N-dimethylformamide (6 mL) at 0° C. was added piperidin-4-ylmethanol (0.206 g). After stirring for 30 minutes, the compound prepared in Example 82 was added. The ice bath was removed and the reaction mixture was stirred at room temperature for two hours. The reaction mixture was then diluted with saturated a sodium bicarbonate solution and extracted with dichloromethane. The organics were dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (methanol:concentrated aqueous ammonia:dichloromethane=6:1:94) to obtain the title compound (0.20 g) having the following physical data.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][C:29](O)=[O:30])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH:32]1([NH2:35])[CH2:34][CH2:33]1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:16]=[CH:17][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][C:29](=[O:30])[NH:35][CH:32]4[CH2:34][CH2:33]4)=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCC(=O)O)cc3)cc2)CC1
Reactant: NC1CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCC(=O)NC4CC4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using 1-{4′-[4-(2-carboxy-ethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and cyclopropylamine.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:24][C:25]1[CH:33]=[C:32]([C:34]#[C:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH3:41])[C:28]2[O:29][CH2:30][O:31][C:27]=2[C:26]=1[NH2:42].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CN(C=O)C>[Cl:24][C:25]1[CH:33]=[C:32]([C:34]#[C:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH3:41])[C:28]2[O:29][CH2:30][O:31][C:27]=2[C:26]=1[NH:42][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COCCOCC#Cc1cc(Cl)c(N)c2c1OCO2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN4CCOCC4)c(OC)cc23)c2c1OCO2
Yield: 77.6 %

Procedure:
This was prepared using the method described in example 4 using 4-chloro-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazoline (200 mg, 0.59 mmol), 5-chloro-7-[3-(2-methoxyethoxy)prop-1-yn-1-yl]-1,3-benzodioxol-4-amine (185 mg, 0.65 mmol) and a solution of sodium bis(trimethylsilyl)amide (1.0M in THF, 1.24 ml) in DMF (3 ml). The crude product was purified by column chromatography on silica using increasing concentrations of methanol in dichloromethane as eluent. There was thus obtained the title compound (268 mg, 77%) as a pale yellow solid; NMR Spectrum: (DMSOd6) 1.99 (quintet, 2H), 2.40 (m, 4H), 2.49 (t, 2H), 3.30 (s,3H), 3.52 (m, 2H), 3.59 (m, 4H), 3.65 (m, 2H), 3.93 (s, 3H), 4.20 (t, 2H), 4.44 (s, 2H), 6.16 (s, 2H), 7.16 (s, 1H), 7.19 (s, 1H), 7.82 (s, 1H), 8.32 (s, 1H), 9.5 (s, 1H); Mass Spectrum: M+H+ 585/587.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[C:8]([NH2:12])([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C.O>C(OCC)C>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([NH:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: O=C(Cl)CCCCl
Reactant: CC(C)(C)N
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)NC(=O)CCCCl

Procedure:
A solution of 35 g 4-chlorobutyrylchloride in 100 ml of diethylether is added dropwise to a stirred solution of 19 g tert-butylamine and 28 g triethylamine in 400 ml of diethylether. After reflux for one hour the mixture is poured into water, the organic phase is separated and the water layer is extracted with diethylether. The combined organic phase is successively washed with water and saturated NaCl solution, and then dried. After evaporating the solvent, 4-chloro-N-tert-butylbutyric amide is obtained in a yield of 40.8 g. The product can be purified by recrystallization from methanol: m.p. 62.5°-64° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:24](F)[C:21]=1[C:22]#[N:23]>>[NH2:19][C:20]1[C:21]([C:22]#[N:23])=[C:24]([CH:25]=[CH:26][CH:27]=1)[O:15][CH2:14][C:13]([CH3:16])([CH3:17])[C:12]([NH:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:18]
Reactant: N#Cc1c(N)cccc1F
Reactant: CC(C)(CO)C(=O)NCCOCc1ccccc1
Product: CC(C)(COc1cccc(N)c1C#N)C(=O)NCCOCc1ccccc1
Yield: 82 %

Procedure:
Prepared as in Example 215b (Method B) from N-(2-(benzyloxy)ethyl)-3-hydroxy-2,2-dimethylpropanamide (Example 218c) and 2-amino-6-fluorobenzonitrile in 82% yield. MS 368 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([S:13](=[O:16])(=[O:15])[NH2:14])=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].[OH-].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([S:13](=[O:16])(=[O:15])[NH2:14])=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(S(N)(=O)=O)ccc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(S(N)(=O)=O)cc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
Methyl 2-methoxy-5-sulfamoylbenzoate (4.91 g, 20 mmol) was dissolved in methanol (30 mL). 2N Aqueous sodium hydroxide (30 mL, 60 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 2N hydrochloric acid, and the separated solid was filtered to give the title compound (4.55 g, 98.3%) as a white solid.