Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[OH-].[K+].[CH3:12]I>CS(C)=O>[Br:1][C:2]1[C:7]([O:8][CH3:12])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Oc1cc(Cl)cnc1Br
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1cc(Cl)cnc1Br

Procedure:
To a stirred mixture of 2-bromo-5-chloro-3-pyridinol (15.66 g) and pulverized KOH (16.79 g) in DMSO (100 mL) at 55-60° C. was added dropwise a solution of CH3I (13.27 g) in DMSO (35 mL) while under nitrogen atmosphere. After the addition was complete, the reaction was maintained at 55°-60° C. for 1 h. The reaction was extracted with Et2O (3×150 mL) and the combined Et2O extracts were treated in turn with 1N NaOH (150 mL), water (150 mL), 1N HCl (150 mL), water (150 mL), and a saturated NaCl solution (150 mL). The organic phase was dried with MgSO4, filtered, and concentrated under reduced pressure to yield a solid material. Recrystallization of the solid from hexane afforded b) (3.52 g, 21%).
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].CC([O-])(C)C.[K+].C(C1[C:16](F)=[C:17]([F:33])[C:18]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])=[C:19]([CH:24]=1)[C:20]([O:22][CH3:23])=[O:21])(=O)C>C1COCC1>[F:33][C:17]1[C:16]2[O:5][N:4]=[C:2]([CH3:3])[C:1]=2[CH:24]=[C:19]([C:20]([O:22][CH3:23])=[O:21])[C:18]=1[NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32]
Reactant: CC(C)=NO
Reactant: COC(=O)c1cc(C(C)=O)c(F)c(F)c1Nc1ccccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1cc2c(C)noc2c(F)c1Nc1ccccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a solution of acetone oxime (3.17 g, 43.3 mmol) in THF (40 ml) was added t-BuOK (43.3 ml, 1 M in THF, 43.3 mmol). After stirring at room temperature for 30 min, the mixture was cooled to −78° C. To the mixture was added a solution of methyl 5-acetyl-3,4-difluoro-2-(2-fluorophenylamino)benzoate (4.0 g, 12.4 mmol) in THF (70 ml) dropwise. After stirring at −78° C. for 15 min, the reaction was warmed to 0° C. and stirred at the temperature for 4 h. The reaction was quenched with saturated aqueous NH4Cl solution (200 ml) and extracted with EtOAc (2×200 ml). The organic solution was washed with brine (100 ml), dried over MgSO4 and concentrated. To the resulting oil was added a mixture of 5% HCl solution (100 ml) and MeOH (100 ml). The resulting suspension was heated at reflux for 1.5 h. The reaction was cooled to room temperature, concentrated to half volume, and diluted with EtOAc (200 ml). The organic solution was washed with brine (100 ml), dried over Na2SO4 and concentrated. Silica gel chromatography (EtOAc:Hexanes=25:75) yielded 2.84 g (72%) of methyl 7-fluoro-6-(2-fluorophenylamino)-3-methylbenzo[d]isoxazole-5-carboxylate as a white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[CH2:9]([N:16]1[C:25]2[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=2)[C:19]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[C:18]([C:33]#[N:34])[C:17]1=[O:35])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>N1C=CC=CC=1>[CH2:9]([N:16]1[C:25]2[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=2)[C:19]([N:27]2[CH2:32][CH2:31][N:30]([C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[O:7])[CH2:29][CH2:28]2)=[C:18]([C:33]#[N:34])[C:17]1=[O:35])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)c1cccs1
Reactant: N#Cc1c(N2CCNCC2)c2cc(Cl)ccc2n(Cc2ccccc2)c1=O
Solvent: c1ccncc1
Product: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(Cl)ccc2n(Cc2ccccc2)c1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
2-Thiophene carbonyl chloride (160 μL, 1.5 mmol) was added to a stirred solution of Compound 71 (379 mg, 1.0 mmol) in pyridine (5 mL) under argon at 0° C. The solution was allowed to come to room temperature and further stirred overnight. The solution was poured into ice water and the solids formed were filtered. The solids were washed by excess water, dried, and recrystallized by ethyl acetate to yield 398 mg (82%) of white solids. M.P. 266° C. 1H NMR (DMSO-d6): δ 3.70 (m, 4H), 3.93 (m, 4H), 5.48 (s, 2H), 7.15 (m, 1H), 7.19-7.26 (m, 3H), 7.32 (m, 2H), 7.42 (d, J=8.9 Hz, 1H), 7.51 (d, J=4.0 Hz, 1H), 7.68 (dd, J=2.6, 8.9 Hz, 1H), 7.80 (d, J=4.0 Hz, 1H), 7.88 (s, 1H). EIMS m/z 512 (M+23). Anal. (C26H21ClN4O2S) C, H, N.
Reaction SMILES: C([O:4][C:5]1[C:10]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([S:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:8]=[CH:7][CH:6]=1)(=O)C.N>C(O)C>[OH:4][C:5]1[C:10]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([S:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(=O)CSc1cccc(OC(C)=O)c1CC(=O)OCC
Agent: N
Solvent: CCO
Product: CCOC(=O)CSc1cccc(O)c1CC(=O)OCC
Reaction time: 2 h

Procedure:
Ethyl 6-acetoxy-2-(ethoxycarbonylmethylthio)-phenylacetate (132 g) is added at room temperature to a solution of ammonia (34 g) in anhydrous ethanol (1.0L). After standing for 2 hours the solvent is evaporated in vacuo and the residue is mixed with methylene chloride and 1N hydrochloric acid. The layers are separated and the organic layer is washed with water to neutrality, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated in vacuo to obtain (as shown by NMR) ethyl 6-hydroxy-2-(ethoxycarbonylmethylthio)-phenylacetate as an oil.
Reaction SMILES: [H-].[Na+].[C:3](OC(C)C)(=[O:7])[C:4]([CH3:6])=O.[S:12]([CH:21](O)[C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[CH:13](O)[C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15].Cl>C(O)(C)C>[CH3:6][C:4]1[C:3]([OH:7])=[C:21]([C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[S:12][C:13]=1[C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15]
Reactant: CC(=O)C(=O)OC(C)C
Reactant: CC(C)OC(=O)C(O)SC(O)C(=O)OC(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1c(C(=O)OC(C)C)sc(C(=O)OC(C)C)c1O
Temperature: 0 °C
Reaction time: 2 h
Yield: 34.2 %

Procedure:
Sodium hydride (132 g, 5.52 mol) was added gradually into isopropyl alcohol (2-3 l) with cooling. To the resulting solution was then added a mixture of isopropyl pyruvate (360 g, 2.76 mol) and di-isopropyl 2,2'-thiodiglycolate (648 g, 2.76 mol) over 20-30 minutes with ice-cooling so that the solution was kept at 60°-80° C. The solution was stirred further for 2 hours at a temperature of 60°-40° C. The solution was poured into an ice-cooled dilute hydrochloric acid solution to form a white crystalline mass, which was recovered by filtration and then washed with water. It was recrystallized from methanol (3 l) to give pure di-isopropyl 3-methyl-4-hydroxy-2,5-thiophene-dicarboxylate (270 g, 34%), m.p. 87°-89° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].[CH2:15](O)[CH2:16][OH:17].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH2:16]1[O:17][C:12]([CH3:13])([CH2:11][C:8]2[CH:9]=[CH:10][C:5]([C:1]([O:3][CH3:4])=[O:2])=[CH:6][CH:7]=2)[O:14][CH2:15]1
Reactant: COC(=O)c1ccc(CC(C)=O)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)c1ccc(CC2(C)OCCO2)cc1

Procedure:
A mixture of 1-(4-carbomethoxyphenyl)propan-2-one (17.3 g), ethan-1,2-diol (5.6 g) and p-toluenesulphonic acid (200 ml) in benzene (150 ml) was refluxed under a Dean and Stark head until the theoretical amount of water had been collected (ca. 4 hours). The solvent was evaporated and the residue was partitioned between sodium bicarbonate solution and ether. The ethereal extract was washed with water, dried, evaporated and distilled to give 15.7 g (74%), bp 136-140/1.5 mm.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([Cl:10])=[N:8][CH:9]=1)(=[O:3])[CH3:2].C(O[CH:14](OCC)[N:15]([CH3:17])[CH3:16])C>>[CH3:14][N:15]([CH3:17])[CH:16]=[CH:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([Cl:10])=[N:8][CH:9]=1)=[O:3]
Reactant: CCOC(OCC)N(C)C
Reactant: CC(=O)c1ccc(Cl)nc1
Product: CN(C)C=CC(=O)c1ccc(Cl)nc1

Procedure:
15.4 g (98.7 mmol) of 5-acetyl-2-chloro-pyridine are stirred for 1 h at 110° with 100 ml of dimethylformamide diethylacetal. After cooling to 0° filtering and drying at 60°, under HV, 3-dimethylamino-1-(2-chloro-5-pyridyl)-2-propen-1-one is obtained; 1H-NMR (DMSO): 2.98 (3H,s), 3.2 (3H,s), 5.9 (1H,d), 7.6 (1H,d), 7.8 (1H,d), 8.3 (1H, m), 8.9 (1H,m).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)=[O:3].[Br:16]Br>>[CH:10]1([C:7]2[CH:6]=[CH:5][C:4]([C:2](=[O:3])[CH2:1][Br:16])=[CH:9][CH:8]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CC(=O)c1ccc(C2CCCCC2)cc1
Reactant: BrBr
Product: O=C(CBr)c1ccc(C2CCCCC2)cc1

Procedure:
p-cyclohexylphenyl methyl ketone is reacted with bromine in a non-polar solvent to produce the corresponding p-cyclohexylphenacyl bromide. Reaction of this reactive alpha-bromo ketone with commercially available thioacetamide in an protic solvent such as methanol with heat affords the corresponding 2-methyl-4-(4-cyclohexylphenylthiazole. N-Alkylation of this thiazole with [methoxy(polyethylene)n-1]ethyl chloride (where n is from 19 to 24) in aprotic solvents such as dimethylformamide and heat readily forms the corresponding methochioride product, which is also named either N-[methoxy(polyethylene)n-1]ethyl-2-methyl-4-(4-cyclohexylphenypthiazolium chloride or 3-[methoxy(polyethylene)n-1]ethyl-2-methyl-4-(4-cyclohexylphenyl)thiazolium chloride. Reaction of this thiazolium chloride with (N,N-dimethyl)amino benzaldehyde in a protic solvent such as methanol with a basic catalyst such as piperidine and heat then produces the desired 4-(4-cyclohexylphenyl)-2-(N,N-diethylaminostyryl)-3-[methoxy(polyethylene)n-1]ethylthiazolinm chloride, which can also be named 4-(4-cyclohexylphenyl)-2-[2-(4-dimethylaminophenyl)vinyl]-3-[methoxy(polyethylene)n-1]ethylthiazol-3-ium chloride. In all of the above reactions n is from 19 to 24.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].C(N(CC)CC)C.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[C:14]=1[CH2:21][C:22](=O)[CH3:23]>CO>[CH3:2][O:3][N:4]=[C:22]([CH3:23])[CH2:21][C:14]1[C:15]([Cl:20])=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=1[Cl:12]
Reactant: CON
Reactant: CC(=O)Cc1c(Cl)cc(Cl)cc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CON=C(C)Cc1c(Cl)cc(Cl)cc1Cl
Temperature: 60 °C
Reaction time: 3 h
Yield: 71.3 %

Procedure:
A solution of O-methyl-hydroxylamine hydrochloride (0.79 g, 9.4 mmol) in methanol (20 ml) was treated with triethylamine (1.32 ml, 9.4 mmol) followed by 1-(2,4,6-trichlorophenyl)-propan-2-one (1.5 g, 6.31 mmole). The resulting mixture was stirred at 60° C. for 3 hours. The reaction mixture was quenched with water and methanol was evaporated off. The resulting aqueous medium was extracted with ethylacetate (3×50 ml). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure (100 mbar; 45° C.). The resulting crude mass was purified by column chromatography using 60-120μ mesh silica gel and product collected at 2% ethyl acetate in hexane as elution system to give 1-(2,4,6-Trichloro-phenyl)-propan-2-one O-methyl-oxime (1.2 g, 76%), which was taken up for further reduction.
Reaction SMILES: CC([O:7][C:8]([C:10]1[N:15]2[C:16]([C@@H:18]([NH:19][C:20](/[C:22](/[C:26]3[O:30][CH:29]=[CH:28][CH:27]=3)=[N:23]\[O:24][CH3:25])=[O:21])[C@H:14]2[S:13][CH2:12][C:11]=1[CH2:31][O:32][C:33]([NH2:35])=[O:34])=[O:17])=[O:9])OC(C)=O.C[O-].[Na+].Cl>O1CCCC1.CO>[CH3:25][O:24]/[N:23]=[C:22](\[C:20]([NH:19][C@@H:18]1[C:16](=[O:17])[N:15]2[C:10]([C:8]([OH:9])=[O:7])=[C:11]([CH2:31][O:32][C:33]([NH2:35])=[O:34])[CH2:12][S:13][C@H:14]12)=[O:21])/[C:26]1[O:30][CH:29]=[CH:28][CH:27]=1
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(C)OC(C)=O)=C(COC(N)=O)CS[C@H]12)c1ccco1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1ccco1
Temperature: -60 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
Cefuroxime axetil (20.4 gm, S-isomer >90%, R-isomer <10%) was dissolved in a mixture of tetrahydrofuran (204 ml) and methanol (39 ml). This clear solution was cooled to -60° C., and sodium methoxide (5 gm) was added. The reaction mixture was stirred at −55 to −60° C. for 1 hour. Hydrochloric acid was added and the procedure described in Example 2 was followed to obtain cefuroxime (15.19 gm).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][C:23]2[N:24]=[N:25][N:26]([CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[N:27]=2)=[C:10]1[C:36]([O:38][CH2:39][CH3:40])=[O:37].[CH3:41][N:42]=[C:43]=[O:44]>ClCCl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][C:23]2[N:24]=[N:25][N:26]([CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][N:33]([C:43](=[O:44])[NH:42][CH3:41])[CH2:32][CH2:31]3)[N:27]=2)=[C:10]1[C:36]([O:38][CH2:39][CH3:40])=[O:37]
Reactant: CCOC(=O)C1=C(COCc2nnn(CCN3CCNCC3)n2)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Reactant: CN=C=O
Solvent: ClCCl
Product: CCOC(=O)C1=C(COCc2nnn(CCN3CCN(C(=O)NC)CC3)n2)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl

Procedure:
A solution of 5-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxymethyl}-2-[2-(1-piperazinyl)ethyl]tetrazole (321 mg) and methyl isocyanate (0.5 ml) in dichloromethane (10 ml) was stirred at room temperature for 30 minutes and evaporated. The residual oil was triturated with diethyl ether and the resulting solid collected, washed with diethyl ether and dried to give the title compound as a hemihydrate (383 mg), m.p. 112°-114° C. Found: C,50.78; H,5.59; N,16.89. C26H33Cl2N7O5.0.5H2O requires: C,50.91; H,5.60; N,16.96%.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)([OH:3])=[O:2].Cl.Br[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+:25].[Na+]>C(#N)C>[N:18]1[CH:19]=[CH:20][C:15]([C:7]2[CH:8]=[CH:9][C:4]([C:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:16][CH:17]=1.[Na+:25]
Reactant: Brc1ccncc1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: O=C([O-])c1ccc(-c2ccncc2)cc1
Temperature: 90 °C
Yield: 18 %

Procedure:
To a suspension of 4-carboxybenzeneboronic acid (0.660 g, 3.98 mmol) and 4-bromopyridine hydrochloride (0.770 g, 3.98 mmol) in dry acetonitrile (20 mL) was added 0.4 M aqueous sodium carbonate (20 mL) and the mixture was purged with nitrogen for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.240 g) was then added and the reaction mixture heated to 90° C. for 22 hours. The precipitated sodium salt was filtered, washed with acetonitrile and then dried in vacuo at 50° C. overnight to give the title compound (0.162 g, 18%) as a grey solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([NH:10][C:11]2[C:16]([C:17]#[N:18])=[CH:15][N:14]=[C:13]3[C:19]4[CH:25]=[C:24]([N+:26]([O-])=O)[CH:23]=[CH:22][C:20]=4[S:21][C:12]=23)=[C:4]([CH3:29])[CH:3]=1.[Cl-].[NH4+]>CO.[Fe]>[NH2:26][C:24]1[CH:23]=[CH:22][C:20]2[S:21][C:12]3[C:13](=[N:14][CH:15]=[C:16]([C:17]#[N:18])[C:11]=3[NH:10][C:5]3[CH:6]=[C:7]([O:8][CH3:9])[C:2]([Cl:1])=[CH:3][C:4]=3[CH3:29])[C:19]=2[CH:25]=1
Reactant: COc1cc(Nc2c(C#N)cnc3c2sc2ccc([N+](=O)[O-])cc23)c(C)cc1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: COc1cc(Nc2c(C#N)cnc3c2sc2ccc(N)cc23)c(C)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.3 %

Procedure:
A mixture of 476 mg (1.12 mmol) of 4-(4-chloro-5-methoxy-2-methylphenylamino)-8-nitrobenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile, 180 mg (3.22 mmol) of iron powder and 180 mg (3.36 mmol) of ammonium chloride in 20 mL of 50% aqueous methanol is heated at reflux temperature for 2 hours. An additional 80 mg (1.42 mmol) of iron powder and 100 mg (1.87 mmol) of ammonium chloride are added and the reaction mixture is heated at reflux temperature for 2 hours, then stirred at room temperature overnight. The reaction mixture is heated at reflux for 4 hours then cooled slightly and filtered. The solid residue is extracted with several portions of hot ethyl acetate followed by hot methanol. All the organic layers are combined and washed with water. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash chromatography eluting with a gradient of 1:1 hexane/ethyl acetate to only ethyl acetate to give 165 mg (37%) of a tan solid, mp 266–268° C. dec.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1.S(Cl)([Cl:15])=O>C(OCC)(=O)C>[CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:15])=[O:8])=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: CN(C)c1ccc(C(=O)Cl)cc1
Yield: 77.9 %

Procedure:
4-Dimethylaminobenzoic acid (250 g, 1.51 moles) was suspended in 2 L of ethyl acetate and thionyl chloride (359.3 g, 3.02 moles) was added. After the completion, the solvent was evaporated. Crystallization from ethyl acetate gave 216 g of 4-dimethylaminobenzoyl chloride (78%).
Reaction SMILES: [CH3:1][CH:2]([CH3:59])[C@H:3]([NH:54][C:55](=[O:58])[O:56][CH3:57])[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11]1[NH:12][CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[N:29]=[C:30]([CH:33]5[CH2:37][C:36]6([CH2:42][CH2:41][NH:40][CH2:39][CH2:38]6)[CH2:35][N:34]5[C:43](=[O:53])[C@@H:44]([NH:48][C:49]([O:51][CH3:52])=[O:50])[CH:45]([CH3:47])[CH3:46])[NH:31][CH:32]=4)=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)[N:15]=1)=[O:5].C(N(CC)CC)C.[C:67](Cl)(=[O:69])[CH3:68].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[C:67]([N:40]1[CH2:39][CH2:38][C:36]2([CH2:35][N:34]([C:43](=[O:53])[C@@H:44]([NH:48][C:49]([O:51][CH3:52])=[O:50])[CH:45]([CH3:46])[CH3:47])[CH:33]([C:30]3[NH:31][CH:32]=[C:28]([C:25]4[CH:24]=[CH:23][C:22]([C:19]5[CH:20]=[CH:21][C:16]([C:14]6[N:15]=[C:11]([C@@H:7]7[CH2:8][CH2:9][CH2:10][N:6]7[C:4]([C@@H:3]([NH:54][C:55](=[O:58])[O:56][CH3:57])[CH:2]([CH3:59])[CH3:1])=[O:5])[NH:12][CH:13]=6)=[CH:17][CH:18]=5)=[CH:27][CH:26]=4)[N:29]=3)[CH2:37]2)[CH2:42][CH2:41]1)(=[O:69])[CH3:68]
Reactant: CC(=O)Cl
Reactant: COC(=O)N[C@H](C(=O)N1CC2(CCNCC2)CC1c1nc(-c2ccc(-c3ccc(-c4c[nH]c([C@@H]5CCCN5C(=O)[C@@H](NC(=O)OC)C(C)C)n4)cc3)cc2)c[nH]1)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N1CC2(CCN(C(C)=O)CC2)CC1c1nc(-c2ccc(-c3ccc(-c4c[nH]c([C@@H]5CCCN5C(=O)[C@@H](NC(=O)OC)C(C)C)n4)cc3)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.9 %

Procedure:
To a solution of methyl [(1S)-2-methyl-1-({(2S)-2-[4-(4′-{2-[2-((2S)-3-methyl-2-{[(methyloxy)carbonyl]amino}butanoyl)-2,8-diazaspiro[4.5]dec-3-yl}-1H-imidazol-4-yl]-4-biphenylyl)-1H-imidazol-2-yl]-1-pyrrolidinyl}carbonyl)propyl]carbamate (Example 20) (19 mg, 0.02 mmol) in anhydrous CH2Cl2 (0.5 mL) was added triethylamine (0.016 mL, 0.12 mmol) followed by acetyl chloride (0.01 mL, 0.14 mmol) and the reaction stirred at room temperature for 1 h. The reaction is concentrated in vacuo and dissolved in methanol (0.7 mL) to which was added potassium carbonate (30 mg, 0.22 mmol) and the reaction was stirred at room temperature for 2 h. The reaction was concentrated in vacuo and partitioned between CH2Cl2 and water (3 mL each) and the aqueous layer extracted with CH2Cl2 (3 mL) and the organic layers combined and dried (MgSO4) and concentrated in vacuo to afford the title compound as a yellow solid (18 mg, 90% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.54-7.88 (m, 10H) 7.32 (br. s., 2H) 5.05-5.23 (m, 2H) 4.03-4.34 (m, 2H) 3.71-4.03 (m, 3H) 3.56-3.71 (m, 8H) 3.34-3.56 (m, 2H) 2.14-2.46 (m, 4H) 1.89-2.14 (m, 6H) 1.46-1.83 (m, 4H) 1.19-1.32 (m, 2H) 0.78-1.07 (m, 14H). HRMS for C46H60N9O7 (M+H)+ calc: 850.4616. found: 850.4617. Purity (LC-MS): 94%.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[C:17]([CH2:18][C:19]([OH:21])=O)=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C([N:24](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.N>CCCCCC.ClCCl>[C:1]1([C:7]2[O:8][C:9]3[C:17]([CH2:18][C:19]([NH2:24])=[O:21])=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: O=C(O)Cc1cccc2c(=O)cc(C3=CCCCC3)oc12
Reactant: CCN(CC)CC
Agent: N
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCCCCC
Product: NC(=O)Cc1cccc2c(=O)cc(C3=CCCCC3)oc12
Reaction time: 1 h

Procedure:
[2-(1-cyclohexenyl)-4-oxo-4H-[1]-benzopyran-8-yl]acetic acid (100 mg) and triethylamine (53 mg) were added to dichloromethane (2ml). After addition of diphenylphosphoryl azide (145 mg) with stirring under ice cooling, the mixture was stirred at room temperature for 1 hour. Conc. aqueous ammonia (5 ml) was added to the reaction mixture and stirring was further continued for 1 hour. Hexane (5 ml) was added and crystals deposited were filtered off. The crystals were recrystallized from dichloromethane and methanol to obtain the title compound as needles, m.p. 244°-245° C., yield 64 mg (64.6%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].N12CCCN=C1CCCCC2.[NH2:17][C:18]1[N:41]=[C:40](Cl)[CH:39]=[CH:38][C:19]=1[C:20]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:26][CH:25]=1)=[O:21]>CS(C)=O>[NH2:17][C:18]1[N:41]=[C:40]([NH:1][CH2:2][C:3]([OH:5])=[O:4])[CH:39]=[CH:38][C:19]=1[C:20](=[O:21])[NH:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:26][CH:25]=1
Reactant: Nc1nc(Cl)ccc1C(=O)NCc1ccc(OCc2ccccc2)cc1
Reactant: NCC(=O)O
Solvent: CS(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1nc(NCC(=O)O)ccc1C(=O)NCc1ccc(OCc2ccccc2)cc1
Temperature: 130 °C
Reaction time: 6 h
Yield: 44 %

Procedure:
Glycine (935 mg, 12.5 mmol) and 1,8-diazabicyclo[5,4,0]undec-7-ene (1.86 mL, 12.5 mmol) were added to 2-amino-N-(4-benzyloxy-benzyl)-6-chloro-nicotinamide described in Preparation Example A+-18 (454 mg, 1.25 mmol) under nitrogen atmosphere, and the solution was stirred for 6 hours at 130° C. Dimethylsulfoxide (35 mL) was added to the reaction mixture, which was then filtered with polytetrafluoroethylene membrane filter (Whatman Inc), the filtrate was purified by reverse phase high performance liquid chromatography (acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid) was used), and the title compound (287 mg, 0.551 mmol, 44%) was obtained.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([C:28]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=2[F:35])[O:7][C:8]=1[C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)=[N:13][CH:14]=1)(=[O:3])[NH2:2].O1CCOCC1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C(Cl)Cl.Cl>[F:35][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]([F:34])[C:28]=1[C:6]1[O:7][C:8]([C:9]2[CH:14]=[N:13][C:12]([N:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]3)=[CH:11][CH:10]=2)=[C:4]([C:1]([NH2:2])=[O:3])[N:5]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3oc(-c4c(F)cccc4F)nc3C(N)=O)cn2)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(N2CCNCC2)nc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 97.9 %

Procedure:
A mixture of tert-butyl 4-(5-(4-carbamoyl-2-(2,6-difluorophenyl)oxazol-5-yl)pyridin-2-yl)piperazine-1-carboxylate (0.227 g, 0.47 mmol) in DCM (3 mL) and 4N HCl in dioxane (2 mL, 8.0 mmol) was stirred at room temperature for 48 hours. The solvent was removed in vacuo to give 2-(2,6-difluorophenyl)-5-(6-(piperazin-1-yl)pyridin-3-yl)oxazole-4-carboxamide (0.211 g, 0.46 mmol, 98%) as a white solid as the dihydrochloride salt. 1H NMR (DMSO) 3.20 (4H, m), 3.90 (4H, t), 7.11 (1H, d), 7.39 (2H, t), 7.73 (3H, m), 8.44 (1H, dd), 9.0 (1H, d), 9.24 (1H, br. s), 9.30 (1H, br. s). LCMS (2) Rt: 2.38 min; m/z (ES+) 386.