Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[O:16][C:17]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)[CH3:2].[C:30](Cl)(=[O:32])[CH3:31].C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:7][N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[O:16][C:17]3[CH:23]=[CH:22][C:21]([NH:24][C:30](=[O:32])[CH3:31])=[CH:20][C:18]=3[N:19]=2)[CH2:12][CH2:13]1)[CH3:2]
Reactant: CCOc1cc(CN2CCC(Nc3nc4cc(N)ccc4o3)CC2)ccc1OC
Reactant: CC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(CN2CCC(Nc3nc4cc(NC(C)=O)ccc4o3)CC2)ccc1OC
Temperature: 100 °C
Yield: 18.5 %

Procedure:
To a solution of N2-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-benzooxazole-2,5-diamine (39.8 mg, 0.1 mmol, 1.0 equiv) and acetyl chloride (0.009 mL, 7.9 mg, 0.1 mmol, 1.0 equiv) in anhydrous DMF (1 mL) was added diisopropylethylamine (23.4 μL, 25.9 mg, 0.2 mmol, 2.0 equiv) and the mixture stirred at 100° C. over night. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 8.1 mg (19%) of the title compound. MS (ESI): 439.5 [M+H]+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.O.ON1C2C=CC=CC=2N=N1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][NH2:31]>CN(C=O)C>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][NH:31][C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[N:7][CH:6]=2)[N:1]=1)=[O:13]
Reactant: COc1cccc(CN)c1
Reactant: O=C(O)c1ccc2cnccc2n1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(CNC(=O)c2ccc3cnccc3n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a stirring mixture of 2-[1,6]naphthyridinecarboxylic acid (50 mg, 0.287 mmol) in anhydrous DMF (1.0 mL) at room temperature was added sequentially 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol), 3-methoxybenzylamine (56.6 μL, 0.431 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarboiimide hydrochloride (61.8 mg, 0.316 mmol). The resulting mixture was allowed to stir at room temperature overnight and it was found to be clear. The solvent was removed under vacuum. Flash column chromatography of the residue (50% hexane/ethyl acetate to 100% ethyl acetate) afforded the desired product as a clear oil (79.1 mg, 94%).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:29][C:30]1[CH:31]=[CH:32][C:33]([F:38])=[C:34]([CH:37]=1)[CH:35]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:35][C:34]3[CH:37]=[C:30]([Br:29])[CH:31]=[CH:32][C:33]=3[F:38])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: Fc1ccc(Br)cc1CNc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 5-bromo-2-fluorobenz aldehyde. MS (ESI) m/z 565.
Reaction SMILES: C([O:8][C:9](=[O:25])[C@H:10]([CH2:19][C:20]1[N:24]=[CH:23][NH:22][CH:21]=1)[NH:11][C:12]([C@H:14]1[NH:17][C:16](=[O:18])[CH2:15]1)=[O:13])C1C=CC=CC=1>CO.[C].[Pd]>[NH:17]1[C@H:14]([C:12]([NH:11][C@H:10]([C:9]([OH:25])=[O:8])[CH2:19][C:20]2[N:24]=[CH:23][NH:22][CH:21]=2)=[O:13])[CH2:15][C:16]1=[O:18]
Reactant: O=C1C[C@@H](C(=O)N[C@@H](Cc2c[nH]cn2)C(=O)OCc2ccccc2)N1
Agent: [Pd]
Solvent: CO
Product: O=C1C[C@@H](C(=O)N[C@@H](Cc2c[nH]cn2)C(=O)O)N1
Yield: 91.3 %

Procedure:
In 20 ml of methanol was suspended 342 mg of compound (60-1) and the compound was catalytically reduced with the addition of 20 mg of 10% palladium-carbon at ambient temperature and ordinary pressure. After the absorption of hydrogen had stopped, the catalyst was filtered off and methanol was distilled off under reduced pressure to provide 230 mg of Nα -[(S)-2-azetidinone-4-carbonyl]-L-histidine (61) having a melting point of 213° to 215° C. (dec.) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([NH2:18])[CH3:17])=[CH:12][CH:11]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:26][N:27]1[CH:31]=[C:30]([S:32](Cl)(=[O:34])=[O:33])[C:29]([C:36]([F:39])([F:38])[F:37])=[N:28]1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([NH:18][S:32]([C:30]3[C:29]([C:36]([F:39])([F:37])[F:38])=[N:28][N:27]([CH3:26])[CH:31]=3)(=[O:34])=[O:33])[CH3:17])=[CH:12][CH:11]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: Cn1cc(S(=O)(=O)Cl)c(C(F)(F)F)n1
Reactant: COc1ncc(F)cc1-c1ccc(C(C)N)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ncc(F)cc1-c1ccc(C(C)NS(=O)(=O)c2cn(C)nc2C(F)(F)F)cc1
Reaction time: 16 h
Yield: 25 %

Procedure:
The organic phase was washed with water, brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue chromatographed on silica gel to give to give 2-{1-[4-(5-fluoro-2-methoxy-pyridin-3-yl)-phenyl]-ethyl}-isoindole-1,3-dione (0.31 g, 0.82 mmol, 41%). To a solution of 2-{1-[4-(5-fluoro-2-methoxy-pyridin-3-yl)-phenyl]-ethyl}-isoindole-1,3-dione (0.31 g, 0.8 mmol) in dioxan/methanol (1:1, 10 ml) was added hydrazine hydrate (0.83 g, 46.5 mmol). The reaction was stirred at room temperature for 24 h. The solvent was evaporated and dichloromethane added. The resultant white solid was filtered off and dried to give 1-[4-(5-fluoro-2-methoxy-pyridin-3-yl)-phenyl]-ethylamine (0.21 g, 0.8 mmol, 100%) as a clear oil. To a solution of 1-[4-(5-fluoro-2-methoxy-pyridin-3-yl)-phenyl]-ethylamine (0.1 g, 0.4 mmol) in dichloromethane (2 ml) was added triethylamine (123 mg, 1.2 mmol) and 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-sulfonylchloride (111 mg, 0.45 mmol). The reaction mixture was agitated for 16 h and quenched with saturated aqueuos sodium bicarbonate solution. The organic phase was washed with water, brine and dried over anhydrous magneium sulfate. The residue was chromatographed on silica gel to give the title compound (42 mg, 0.1 mmol, 25%). 1H NMR (400 MHz, CDCl3): δ 8.00 (d, 1H), 7.45 (m, 3H), 7.35 (dd, 1H), 7.21 (d, 2H), 4.86 (d, 1H), 4.60 (q, 1H), 3.96 (s, 3H), 3.75 (s, 3H), 1.50 (b, 3H) ppm; MS (ESI) m/z: 459.3 [M+H]+.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([CH3:34])=[C:22]([C:27]2[CH:31]=[CH:30][S:29][C:28]=2[C:32]#[N:33])[CH:23]=[CH:24][C:25]=1[CH3:26])([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.Cl>>[NH2:33][CH2:32][C:28]1[S:29][CH:30]=[CH:31][C:27]=1[C:22]1[CH:23]=[CH:24][C:25]([CH3:26])=[C:20]([CH2:19][O:18][Si:1]([C:14]([CH3:16])([CH3:15])[CH3:17])([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:21]=1[CH3:34]
Reactant: Cc1ccc(-c2ccsc2C#N)c(C)c1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: Cl
Product: Cc1ccc(-c2ccsc2CN)c(C)c1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
A mixture of 3-(3-tert-butyldiphenylsilyloxymethyl-2,4-dimethylphenyl)-2-cyanothiophene (471 mg) and 1M boranetetrahydrofuran complex (3 ml) was stirred for 30 minutes at 0° C. under nitrogen atmosphere and allowed to stand at ambient temperature overnight. To the mixture was added 4N hydrochloric acid (1.5 ml) under ice-cooling, and the mixture was stirred for 1 hour. The mixture was partitioned between ethyl acetate and water, and the separated organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform:methanol=50:1, V/V) to give 2-aminomethyl-3-(3-tert-butyldiphenylsilyloxymethyl-2,4-dimethylphenyl)thiophene (415 mg) as oil.
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:7])[CH2:6][CH2:5][CH2:4]1.Cl[C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][N:10]=1.O>C1COCC1>[Cl:15][C:14]1[C:9]([O:7][CH:3]2[CH2:6][CH2:5][CH2:4]2)=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: OC1CCC1
Reactant: Clc1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Clc1cccnc1OC1CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
Sodium hydride dispersion (60%, 1.22 g, 30.5 mmol) was suspended in anhydrous THF (40 mL) under a nitrogen atmosphere. A solution of cyclobutanol (2.0 g, 27.7 mmol) in THF (10 mL) was added dropwise at room temperature then the reaction was stirred 1 hour at room temperature. 2,3-dichloropyridine (5.0 g, 33.8 mmol) was added and the reaction mixture was stirred at 60° C. under nitrogen for 16 hours. Water (50 mL) was added and the reaction mixture was concentrated in vacuo. The aqueous layer was extracted with EtOAc (3×30 mL). The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with 3% EtOAc in heptane to afford the title compound as a clear oil (3.7 g, 72%):
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([NH2:18])=[C:13]([CH:17]=2)C(O)=O)[CH:6]=[CH:7][CH:8]=1.C[N:20]1CCC[C:21]1=[O:25].C(N(CC)CC)C>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]3[NH:18][C:21](=[O:25])[NH:20][C:13]=3[CH:17]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2ccc(N)c(C(=O)O)c2)c1
Reactant: CN1CCCC1=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1cccc(-c2ccc3[nH]c(=O)[nH]c3c2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 5-(3-methoxyphenyl)-2-aminobenzoic acid (2.0 g) in 1,4-dioxane (20 mL) add N-methylpyrolidinone (NMP, 5 mL) and triethylamine (1.4 mL), followed by diphenyl phosphoric azide (DPPA, 2.5 g). After stirring at ambient temperature for 30 minutes, heat the mixture to 100° C. for 2 hours, until gas evolution fully subsided. Cool the mixture to ambient temperature and concentrate in vacuo. Dissolve the residue in MeOH and leave to stand for 18 hours. Filter the precipitate and air dry to obtain 5-(3-methoxyphenyl)benzimidazolidin-2-one as a pale yellow solid. C. 2-Chloro-5-(3-methoxyphenyl)benzimidazole
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][C:3]=1[NH2:11].S(=O)(=O)(O)[OH:13].[OH-].[Na+]>O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:13])[NH2:10])=[CH:4][C:3]=1[NH2:11]
Reactant: N#CCc1ccc(N)c(N)c1
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=O)Cc1ccc(N)c(N)c1

Procedure:
To 1.03 g. of 1,2-diamino-4-cyanomethylbenzene (1.03 g.) was slowly added concentrated sulphuric acid (7 ml.). The mixture was heated at 90° for 90 minutes, then poured onto 50 ml. of water and ice and adjusted to pH 8 with NaOH. The precipitate which formed on cooling was discarded and the aqueous phase was concentrated to drynes. The residue was extracted with acetone, the extracts were concentrated and chromatographed on silica gel using CH2Cl2 /MeOH 9:1 to 8:2 v/v to give 1,2-diamino-4-carbamoylmethylbenzene (0.65 g.) which was used without further purification.
Reaction SMILES: [NH2:1][C@H:2]([C:9]([OH:11])=[O:10])[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.N.[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:15]=1[CH2:16]Cl>C1COCC1>[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:15]=1[CH2:16][N:6]1[CH:7]=[N:8][C:4]([CH2:3][C@@H:2]([C:9]([OH:11])=[O:10])[NH2:1])=[CH:5]1
Reactant: ClCc1c(Cl)cccc1Cl
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: N
Solvent: C1CCOC1
Product: N[C@@H](Cc1cn(Cc2c(Cl)cccc2Cl)cn1)C(=O)O
Reaction time: 3 h
Yield: 56.5 %

Procedure:
L-histidine (3.13 g) was added to a solution of NaNH2 in liquid ammonia prepared from Na (0.93 g) and FeCl3 (catalytic amount) in liquid ammonia (50 ml) After 15 min., a solution of 2,6-dichlorobenzylchloride (3.96 g) in THF (5 ml) was added and the mixture was stirred for 3 hr. The reaction mixture was quenched with H2O and ether. The pH of the aqueous layer was adjusted to pH 8 with 5% HCl followed by cooling. The resulting precipitate was collected by filtration, washed with H2O, and dried to give 1-[(2,6-dichlorophenyl)methyl]-L-histidine (3.58 g). The obtained compound (0.80 g) was dissolved in MeOH (30 ml) and HCl gas was bubbled for 10 min. at 0° C. The reaction mixture was stirred for 15 hr. at room temperature and the solvent was removed in vacuo to give 1-[(2,6-Dichlorophenyl)methyl]-L-histidine methyl ester, dihydrochloride salt.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22](C2C=NC=CC=2)[NH:21][C:20]1=[O:35]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][N:21]([CH2:10][CH2:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=3)[C:20]2=[O:35])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: NC1C(=O)NC(c2cccnc2)c2ccccc21
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1C(=O)N(CCc2ccccc2)Cc2ccccc21

Procedure:
Following General Procedure D above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 4-amino-2-phenethyl-1,2,3,4-tetrahydroisoquinoline-3-one (General Procedure 5-D), the title compound was prepared as a solid having a melting point of 75-76° C. C28H27N3O3F2 (MW=491); mass spectroscopy: 491.2.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[C:4]([F:24])[CH:3]=1.[CH3:25][C@@H:26]1[CH2:30][O:29][C:28](=[O:31])[NH:27]1>>[F:24][C:4]1[CH:3]=[C:2]([N:27]2[C@H:26]([CH3:25])[CH2:30][O:29][C:28]2=[O:31])[CH:7]=[C:6]([F:8])[C:5]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=[O:10]
Reactant: Cc1ccc(N2CCN(C(=O)c3c(F)cc(Br)cc3F)CC2)nc1
Reactant: C[C@@H]1COC(=O)N1
Product: Cc1ccc(N2CCN(C(=O)c3c(F)cc(N4C(=O)OC[C@H]4C)cc3F)CC2)nc1
Yield: 67.1 %

Procedure:
By reaction and treatment in the same manner as in Example 110 and using (4-bromo-2,6-difluorophenyl)[4-(5-methylpyridin-2-yl)piperazin-1-yl]methanone (393 mg) described in Preparation Example 185 and (R)-4-methyloxazolidin-2-one (132 mg) described in Preparation Example 25, the title compound (277 mg) was obtained.
Reaction SMILES: [Br-:1].[Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCN(C(C)C)C(C)C.[Cl:31][C:32]1[CH:48]=[C:47]([CH3:49])[CH:46]=[C:45]([Cl:50])[C:33]=1[O:34][CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43]O)=[CH:39][CH:38]=1>ClCCl>[Br:1][CH2:43][C:40]1[CH:41]=[CH:42][C:37]([CH2:36][CH2:35][O:34][C:33]2[C:32]([Cl:31])=[CH:48][C:47]([CH3:49])=[CH:46][C:45]=2[Cl:50])=[CH:38][CH:39]=1
Reactant: Cc1cc(Cl)c(OCCc2ccc(CO)cc2)c(Cl)c1
Reactant: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(Cl)c(OCCc2ccc(CBr)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of triphenylphosphine dibromide (1.2 eq.) and Hunig's base (2 eq.) in dichloromethane (0.09 M) was added, dropwise over 5 min, {4-[2-(2,6-dichloro-4-methylphenoxy)ethyl]phenyl}methanol prepared in the previous step (1 eq.). The resulting mixture was stirred at RT for 2 h and then concentrated in vacuo. The residue was suspended in a 10:1 (v/v) Hex:ether solution and filtered through a pad of SiO2. The filtrate was concentrated in vacuo to afford the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][N:5]([CH2:8][CH3:9])[C:4](=[O:10])[CH:3]=1.[I:11][C:12]1[N:13]=[C:14]([CH3:17])[NH:15][CH:16]=1>>[CH2:8]([N:5]1[C:4](=[O:10])[CH:3]=[C:2]([N:15]2[CH:16]=[C:12]([I:11])[N:13]=[C:14]2[CH3:17])[CH:7]=[N:6]1)[CH3:9]
Reactant: CCn1ncc(Cl)cc1=O
Reactant: Cc1nc(I)c[nH]1
Product: CCn1ncc(-n2cc(I)nc2C)cc1=O

Procedure:
The title compound, white crystalline solid, MS: m/e=331.0 (M+H+), was prepared in accordance with the general method of example 23b from 5-chloro-2-ethyl-2H-pyridazin-3-one and 4-Iodo-2-methyl-1H-imidazole.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]23[CH2:17][CH2:16][O:15][CH2:14][CH:13]2[CH2:12][S:11][C:10]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[N:9]3)[CH:5]=[CH:6][CH:7]=1.CO>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([C@:8]23[CH2:17][CH2:16][O:15][CH2:14][CH:13]2[CH2:12][S:11][C:10]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[N:9]3)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC1=NC2(c3cccc(Br)c3)CCOCC2CS1
Solvent: CC#N
Solvent: CO
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cccc(Br)c3)CCOCC2CS1
Yield: 46.8 %

Procedure:
Racemic tert-butyl (4aSR,8aSR)-8a-(3-bromophenyl)-4,4a,5,7,8,8a-hexahydropyrano[4,3-d][1,3]thiazin-2-ylcarbamate (2.80 g, 6.55 mmol) is purified by chiral HPLC: Column: Chiralcel OJ 8×35 cm; eluent: 75:25 (methanol:acetonitrile); flow: 400 mL/min at UV 260 nm. The second eluting isomer is isolated to provide the enantiomerically enriched title compound (1.31 g, 47%). ES/MS m/e (79Br/81Br) 427, 429 (M+1).
Reaction SMILES: [F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14](O)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.O=S(Cl)[Cl:20]>C1(C)C=CC=CC=1>[F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([Cl:20])=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Solvent: Cc1ccccc1
Product: O=C(Cl)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Temperature: 60 °C

Procedure:
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid (1.2 eq) is slurried in toluene (2.5 vol) and the mixture heated to 60° C. SOCl2 (1.4 eq) is added via addition funnel. The toluene and SOCl2 are distilled from the reaction mixture after 30 minutes. Additional toluene (2.5 vol) is added and distilled again.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[C:7]([N+:15]([O-:17])=[O:16])[CH:8]=[C:9]([O:13][CH3:14])[C:10]=2O)[N:5]=[CH:4][CH:3]=1.[OH-].[NH4+].P(Cl)(Cl)([Cl:22])=O>>[CH3:1][C:2]1[C:11]2[C:6](=[C:7]([N+:15]([O-:17])=[O:16])[CH:8]=[C:9]([O:13][CH3:14])[C:10]=2[Cl:22])[N:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc([N+](=O)[O-])c2nccc(C)c2c1O
Agent: [NH4+]
Agent: [OH-]
Product: COc1cc([N+](=O)[O-])c2nccc(C)c2c1Cl
Yield: 69 %

Procedure:
A solution of the 5-hydroxyquinoline IV (5.25 g, 0.022 mol) in phosphorus oxychloride (75 mL) was heated at 80° for 2 hours. The reaction mixture was poured onto ice and basified with excess ammonium hydroxide. The tan solid was filtered to give 5.8 g of crude product. This material was purified via column chromatography over silica gel and elution with chloroform. The fast-moving yellow band was collected and concentrated to give 3.9 g (69%) of the title compound, mp 167°-169°. Crystallization from ethanol did not raise the melting point. The crude material can also be purified by sublimation.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH2:6][CH2:7][C:8](=[O:30])[C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([C:24](=[O:28])[CH2:25]2)[C@:21]2([CH3:22])[C@H:16]([CH2:17][C@H:18]([OH:29])[CH2:19][CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)=[O:4].[I-:31].[Na+]>CC(C)=O>[OH:29][C@@H:18]1[CH2:19][CH2:20][C@@:21]2([CH3:22])[C@@H:16]([CH2:15][CH2:14][C@@H:13]3[C@@H:23]2[C:24](=[O:28])[CH2:25][C@@:26]2([CH3:27])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C:8](=[O:30])[CH2:7][CH2:6][O:5][C:3](=[O:4])[CH2:2][I:31])[CH2:17]1
Reactant: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CCOC(=O)CCl)[C@@]3(C)CC(=O)[C@@H]12
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CCOC(=O)CI)[C@@]3(C)CC(=O)[C@@H]12
Yield: 103.4 %

Procedure:
21-Chloroacetoxymethyl-3α-hydroxy-5α-pregnane-11,20-dione (400 mg.) in acetone (40 ml) was treated with sodium iodide (420 mg.) and the mixture was refluxed for 40 mins. The filtered solution was evaporated to a yellow solid which was partitioned between water and ether/ethyl acetate 1:1. The organic layer was washed with water, dried over sodium sulphate and evaporated to give title compound (500 mg) as a yellow foam.
Reaction SMILES: [CH2:1]([P:5]([O:10][CH2:11][CH3:12])(=[O:9])[O:6][CH2:7][CH3:8])[CH:2]=[CH:3][CH3:4].O1CCCC1.C([Li])CCC.[CH2:23](Cl)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>Cl.CCCCCC>[CH2:23]([CH:1]([P:5]([O:6][CH2:7][CH3:8])(=[O:9])[O:10][CH2:11][CH3:12])[CH:2]=[CH:3][CH3:4])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC=CCP(=O)(OCC)OCC
Reactant: ClCc1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC=CC(Cc1ccccc1)P(=O)(OCC)OCC
Temperature: -70 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
1.92 g of diethyl 2-butenephosphonate was placed in 10 ml. of dry tetrahydrofuran, and the solution was cooled to -70° C. in an atmosphere of argon. 7 ml. of n-butyl lithium (as a 15% by weight n-hexane solution) was gradually added, and the mixture was stirred at -70° C. for 1 hour. The reaction mixture was turbid assuming a pale yellow color. When 1.7 g of benzyl chloride was added to this mixture, it became clear. The temperature of the reaction mixture was gradually elevated to room temperature, and it was stirred for an additional 2 hours. The reaction mixture was then diluted with dilute hydrochloric acid, and extracted with ether. The extract was washed with a solution of sodium hydrogen carbonate, washed with water, and dried. The solution was concentrated, and then the residue was distilled at reduced pressure to afford 2.33 g of diethyl 1-benzyl-2-butenephosphonate having a boiling point of 144° C. (0.3 mmHg) in a yield of 93%. The analysis values of the product were as follows:
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([NH2:7])=[N:4][CH:3]=1.[CH:8]([O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=1)[C:15](O)=[O:16])([CH3:10])[CH3:9]>>[CH:8]([O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=1)[C:15]([NH:7][C:5]1[S:6][C:2]([Br:1])=[CH:3][N:4]=1)=[O:16])([CH3:10])[CH3:9]
Reactant: CC(C)Oc1cc(Oc2ccccc2)cc(C(=O)O)c1
Reactant: Nc1ncc(Br)s1
Product: CC(C)Oc1cc(Oc2ccccc2)cc(C(=O)Nc2ncc(Br)s2)c1
Yield: 81.9 %

Procedure:
3-Isopropyloxy-5-phenoxy-N-(5-bromothiazol-2-yl)-benzamide (1.1 g, 82%) was prepared from 5-bromo-2-aminothiazole (830 mg, 4.6 mmol) and 3-isopropyloxy-5-phenoxybenzoic acid (835 mg, 3.1 mmol) following the general procedure A.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([OH:14])=O)[C:6]=2[CH:15]=1.[Cl:16][C:17]1[CH:28]=[CH:27][C:20]2[NH:21][C:22]([CH2:24][NH:25][CH3:26])=[N:23][C:19]=2[CH:18]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>O.CN(C=O)C>[Cl:16][C:17]1[CH:28]=[CH:27][C:20]2[NH:21][C:22]([CH2:24][N:25]([CH3:26])[C:12](=[O:14])[CH2:11][N:7]3[C:6]4[CH:15]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[S:9][C:8]3=[O:10])=[N:23][C:19]=2[CH:18]=1
Reactant: O=C(O)Cn1c(=O)sc2ccc(Cl)cc21
Reactant: CNCc1nc2cc(Cl)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1nc2cc(Cl)ccc2[nH]1)C(=O)Cn1c(=O)sc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
To a mixture of (5-chloro-2-oxo-1,3-benzothiazol-3(2H)-yl)acetic acid (300 mg), 1-(5-chloro-1H-benzimidazol-2-yl)-N-methylmethanamine (265 mg) and DMF (20 mL) were added TEA (687 μL), HOBt (200 mg), and WSC.HCl (283 mg), followed by stirring at room temperature overnight. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was washed with water, a saturated aqueous NaHCO3 solution, and brine in this order, dried over Na2SO4, and then concentrated under reduced pressure. The obtained solid was washed with EtOAc to obtain N-[(5-chloro-1H-benzimidazol-2-yl)methyl]-2-(5-chloro-2-oxo-1,3-benzothiazol-3(2H)-yl)-N-methylacetamide (339 mg).