Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[C:13]2[O:12][CH2:11][CH2:10][NH:9][CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.C(O)(=O)C.C(OCC)C.[BrH:23]>>[BrH:23].[O:12]1[C:13]2[C:3]([OH:2])=[CH:4][CH:5]=[CH:6][C:7]=2[CH2:8][NH:9][CH2:10][CH2:11]1
Reactant: COc1cccc2c1OCCNC2
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: Oc1cccc2c1OCCNC2
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A suspension of 9-(methyloxy)-2,3,4,5-tetrahydro-1,4-benzoxazepine (Preparation 84) (43.4 g, 242 mmol) in 33% HBr in acetic acid (300 ml, 1823 mmol) was heated at 80° C. overnight. The mixture was allowed to cool to room temperature then treated with diethyl ether (300 ml) and stirred for 30 minutes. The resulting solid was collected by filtration, washed with diethyl ether (300 ml) and dried under vacuum at 40° C. to give the title compound as a pale brown powder (55.1 g)
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][CH:10]([S:13]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][N:20]=[CH:19]3)(=[O:15])=[O:14])[CH2:9]1.[C:25]1([CH2:31][CH2:32][CH2:33][CH:34]=O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:25]1([CH2:31][CH2:32][CH2:33][CH2:34][N:8]2[CH2:12][CH2:11][CH:10]([S:13]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][N:20]=[CH:19]4)(=[O:15])=[O:14])[CH2:9]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=CCCCc1ccccc1
Reactant: O=S(=O)(c1ccc2[nH]ncc2c1)C1CCNC1
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccc2[nH]ncc2c1)C1CCN(CCCCc2ccccc2)C1

Procedure:
The title compound, MS: m/e=384.2(M+H+) was prepared from (RS)-5-(pyrrolidine-3-sulfonyl)-1H-indazole trifluoroacetic acid and 4-phenyl-butyraldehyde.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:25][CH3:26])=[C:21]([OH:24])[CH:22]=2)[N:17]=[CH:16][N:15]=1.[C:27]([N:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][CH2:38]O)[CH2:32][CH2:31]1)(=[O:29])[CH3:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[C:27]([N:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][CH2:38][O:24][C:21]2[CH:22]=[C:23]3[C:18](=[CH:19][C:20]=2[O:25][CH3:26])[N:17]=[CH:16][N:15]=[C:14]3[Cl:13])[CH2:32][CH2:31]1)(=[O:29])[CH3:28]
Reactant: COc1cc2ncnc(Cl)c2cc1O
Reactant: CC(=O)N1CCN(CCCO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2ncnc(Cl)c2cc1OCCCN1CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.2 %

Procedure:
Diethyl azodicarboxylate (991 mg, 5.7 mmol) was added dropwise to a solution of 4-chloro-6-hydroxy-7-methoxyquinazoline (1 g, 4.75 mmol), 3-(4-acetylpiperazin-1-yl)propan-1-ol (972 mg, 5.22 mmol), (prepared as described for the starting material in Example 1 or Example 7), and triphenylphosphine (1.74 g, 6.65 mmol) in methylene chloride (25 ml). The mixture was stirred at ambient temperature for 2 hours. The solution was poured onto silica and eluted with methylene chloride, followed by methylene chloride/methanol (97/3 followed by 92/8). The fractions containing the expected product were combined and evaporated to give 6-[3-(4-acetylpiperazin-1-yl)propoxy]-4-chloro-7-methoxyquinazoline (1.3 g, 72%).
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11]O)[OH:10])[OH:8])[OH:6])=[O:4].[CH3:13][N:14](C)C=O>>[CH3:13][NH:14][CH2:11][C@@H:9]([C@H:7]([C@@H:5]([C@@H:3]([CH2:2][OH:1])[OH:4])[OH:6])[OH:8])[OH:10]
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CN(C)C=O
Product: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
5 g of polifungin and 1.5 g of fructose were suspended in 50 ml of dimethyl formamide and next the procedure was carried out as in the Example IV. 4.4 g of N-methylglucamine salt of N-glycosyl polifungin of E1 cm1% =562 at 304 nm and IC50 =0.46 mcg/ml were obtained. Original antibiotic: E1 cm1% =660 at 304 nm and IC50 =0.16 mcg/ml.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[C:5]([N:7]([CH2:19][CH3:20])[C@@H:8]([C:16](O)=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6].COC(=O)[C@@H](CC1C=CC=CC=1)NC(=O)C1C=C(C)C=C(C)C=1.C(I)C.[H-].[Na+].Cl.C[O:55][C:56](=[O:69])[C@H:57]([CH2:59][C:60]1[C:68]2[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=2)[NH:62][CH:61]=1)[NH2:58]>>[CH3:24][C:22]1[CH:21]=[C:4]([CH:3]=[C:2]([CH3:1])[CH:23]=1)[C:5]([N:7]([CH2:19][CH3:20])[C@@H:8]([C:16]([NH:58][C@H:57]([C:56]([OH:55])=[O:69])[CH2:59][C:60]1[C:68]2[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=2)[NH:62][CH:61]=1)=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: CCN(C(=O)c1cc(C)cc(C)c1)[C@H](Cc1ccccc1)C(=O)O
Agent: COC(=O)[C@@H](Cc1ccccc1)NC(=O)c1cc(C)cc(C)c1
Agent: Cl
Agent: [H-]
Solvent: CCI
Product: CCN(C(=O)c1cc(C)cc(C)c1)[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
Following the procedure described in example 12 and starting from N-(3,5-dimethylbenzoyl)-N-ethyl-(D)-phenylalanine (prepared by alkylation of N-(3,5-dimethylbenzoyl)-(D)-phenylalanine methyl ester with ethyl iodide in the presence of sodium hydride followed by hydrolysis of the methyl ester moiety according to example 1 and (L)-tryptophan methyl ester hydrochloride gives N-(3,5-dimethylbenzoyl)-N-ethyl-(D)-phenylalanyl-(L)-tryptophan; FAB-MS m/e 510 (M-H)-.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[C:7](/[CH:10]=[CH:11]\[C:12]([O:14]CC)=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].N1C=CN=C1>>[CH2:1]([C:5]1[N:6]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[C:7](/[CH:10]=[CH:11]\[C:12]([OH:14])=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(/C=C\C(=O)OCC)n1Cc1ccccc1Cl
Agent: c1c[nH]cn1
Product: CCCCc1ncc(/C=C\C(=O)O)n1Cc1ccccc1Cl

Procedure:
The title compound was prepared according to the procedure described in Example 11 Method A by using ethyl (Z)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-propenoate in place of methyl (E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-propenoate. The title compound had a mp 183°-184° C. The NMR was consistent with a cis or (Z) relationship of the imidazole and carboxyl groups.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=3)=[CH:11][C:10]([C:22]([O:24]CC)=[O:23])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[K+]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=3)=[CH:11][C:10]([C:22]([OH:24])=[O:23])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2cccc([N+](=O)[O-])c2)n(-c2cccc(Cl)c2)n1
Agent: [K+]
Agent: [OH-]
Product: O=C(O)c1cc(-c2cccc([N+](=O)[O-])c2)n(-c2cccc(Cl)c2)n1
Yield: 92 %

Procedure:
Starting from 400 mg (1.1 mmol) of ethyl 1-(3-chlorophenyl)-5-(3-nitrophenyl)-1H-pyrazole-3-carboxylate from example 20A and 603 mg (10.7 mmol) of potassium hydroxide, 340.5 mg (0.99 mmol, 92% yield of theory) are obtained as crystals according to the method described in example 7A.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C@@H:13]([OH:41])[C@@H:14]([N:24](CC1C=CC=CC=1C)CC1C=CC=CC=1C)[CH2:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C@@H:13]([OH:41])[C@@H:14]([NH2:24])[CH2:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: Cc1ccccc1CN(Cc1ccccc1C)[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1CCCN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1[C@@H](O)[C@@H](N)Cc1cc(F)cc(F)c1

Procedure:
Add 2-(R)-[2-(S)-[bis-(2-methylbenzyl)-amino]-3-(3,5-difluorophenyl)-1-(S)-hydroxypropyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.116 g, 0.205 mmol), 20% palladium on carbon (0.069 g) and methanol (3 mL) and hydrogenate at one atmosphere hydrogen gas for 18 h. Add filter agent and filter and concentrate to give the title compound as a residue (0.069 g, 94%).
Reaction SMILES: Cl.[CH3:2][C:3]1[NH:4][C:5]([CH3:9])=[C:6]([CH3:8])[N:7]=1.[H-].[Na+].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].O>CN(C)C=O>[CH2:12]([N:4]1[C:5]([CH3:9])=[C:6]([CH3:8])[N:7]=[C:3]1[CH3:2])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: Cc1nc(C)c(C)[nH]1
Reactant: CCCCCCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCn1c(C)nc(C)c1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Dissolve 16.0 g (0.019 mole) of 2,4,5-trimethyl-1H-imidazole hydrochloride in 125 ml dry N,N-dimethylformamide and cool to 0° C. Add 8.75 g (0.218 mole) of sodium hydride (60%), stir at 0° C. for 30 minutes and then heat reaction mixture to 100° C. for one hour. Cool to 0° C. and then add 18.0 ml (0.114 mole) of n-heptyl bromide to reaction mixture. Upon completion of addition, heat to 100° C. for four hours, following the progress of the reaction by thin-layer chromatography on silica gel (methanol:1M sodium chloride, 95:5). At the completion of the reaction, cool to room temperature and add 2 ml water. Filter precipitated salts and evaporate solvent.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8][N:9]=[C:10]([N:17]2[C:21]([CH3:22])=[N:20][N:19]=[N:18]2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=1.N#N.[CH:25]1([C:28]#[CH:29])[CH2:27][CH2:26]1.C(N(CC)CC)C>C1COCC1.CCOC(C)=O.[Cu](I)I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:25]1([C:28]#[C:29][C:2]2[S:3][CH:4]=[C:5]([CH2:7][O:8][N:9]=[C:10]([N:17]3[C:21]([CH3:22])=[N:20][N:19]=[N:18]3)[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:6]=2)[CH2:27][CH2:26]1
Reactant: C#CC1CC1
Reactant: Cc1nnnn1C(=NOCc1csc(Br)n1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1nnnn1C(=NOCc1csc(C#CC2CC2)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 56.2 %

Procedure:
To a stirred solution of N-[(2-bromo-1,3-thiazol-4-yl)methoxy]-1-(5-methyl-1H-tetrazol-1-yl)-1-phenylmethanimine (0.2 g, 0.527 mmol, 1 eq.) in 3 ml dry THF “degassed” with N2, was added cyclopropylacetylene (0.069 g, 1.05 mmol, 2 eq.) followed by triethylamine (0.213 g, 2.1 mmol, 4 eq.), Copper Iodide (0.015 g, 0.079 mmol, 0.15 eq.) and Tetrakis(triphenylphosphine)palladium (0.030 g, 0.026 mmol, 0.05 eq.). The reaction was stirred for 20 hrs at room temperature for complete conversion. The reaction was diluted with EtOAc (50 ml), filtered through “Chem Elut” cartridge, washed with fresh EtOAc (2×20 ml) and the filtrate was concentrated. The residue was chromatographed on silica gel to give N-{[2-(cyclopropylethynyl)-1,3-thiazol-4-yl]methoxy}-1-(5-methyl-1H-tetrazol-1-yl)-1-phenylmethanimine (0.108 g, 56% yield) as a brown gum.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]([N:17]2[CH:21]=[N:20][N:19]=[CH:18]2)[C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[H][H]>[Ni].C(O)C>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]([N:7]([N:17]2[CH:18]=[N:19][N:20]=[CH:21]2)[CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:23][CH:22]=2)=[CH:9][CH:10]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(N(Cc2ccc(Br)cc2)n2cnnc2)cc1
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc(N(Cc2ccc(Br)cc2)n2cnnc2)cc1
Yield: 32 %

Procedure:
A catalytic amount of Raney nickel was added to 50 ml of an ethanol solution containing 3.74 g of 4-[N-(4-bromobenzyl)-N-(4-nitrophenyl) amino]-4H-1,2,4-triazole, and the mixture was stirred for about 2 hours in the presence of hydrogen gas at room temperature. After the catalyst was removed by filtration, the resulting filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give 1.1 g of 4-[N-(4-aminophenyl)-N-(4-bromobenzyl)amino]-4H-1,2,4-triazole from the chloroform/methanol (50:1) eluate.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([CH3:13])=[C:10]([CH2:14][C:15]([NH2:17])=[O:16])[C:9]=2[CH:18]=1)[CH3:3].C[O:20][C:21](=O)[C:22]([C:24]1[C:32]2[C:27](=[C:28]([CH3:33])[CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1)=O.CC([O-])(C)C.[K+]>C1COCC1.CCOC(C)=O>[CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([CH3:13])=[C:10]([C:14]3[C:15](=[O:16])[NH:17][C:21](=[O:20])[C:22]=3[C:24]3[C:32]4[C:27](=[C:28]([CH3:33])[CH:29]=[CH:30][CH:31]=4)[NH:26][CH:25]=3)[C:9]=2[CH:18]=1)[CH3:3]
Reactant: Cc1oc2ccc(CN(C)C)cc2c1CC(N)=O
Reactant: COC(=O)C(=O)c1c[nH]c2c(C)cccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1oc2ccc(CN(C)C)cc2c1C1=C(c2c[nH]c3c(C)cccc23)C(=O)NC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
To a solution of 2-(5-dimethylaminomethyl-2-methyl-benzofuran-3-yl)-acetamide (111 mg, 0.406 mmol) and (7-methyl-1H-indol-3-yl)-oxo-acetic acid methyl ester (132 mg, 0.608 mmol) in anhydrous THF (4.0 mL) is added dropwise a 1 M solution of t-BuOK in THF (2.0 mL) at 0° C. under an argon atmosphere. The resulting deep red reaction mixture is stirred for 1 h at 0° C., diluted with EtOAc, washed with a saturated aqueous NH4Cl solution and washed with brine. The combined aqueous phases are extracted with EtOAc and the combined organic phases are dried over Na2SO4, filtered and concentrated at reduced pressure to afford an orange solid. Purification by flash column chromatography (silica gel, EtOAc/acetic acid/water 7:1:1) affords the title compound as an orange solid (122 mg, 0.295 mmol, 73%). 1H NMR (400 MHz, DMSO-d6, 298 K): δ=11.88 (bs, 1H), 11.07 (bs, 1H), 7.91 (s, 1H), 7.38 (d, J=8.3 Hz, 1H), 7.04 (d, J=8.3 Hz, 1H), 6.93 (s, 1H), 6.75 (d, J=6.8 Hz, 1H), 6.50 (t, J=7.5 Hz, 1H), 6.42 (d, J=7.8 Hz, 1H), 3.40-3.16 (m, 2H), 2.40 (s, 2H), 2.12 (s, 2H), 1.84 (s, 6H). MS (ES+): 414 (M(C26H23N3O3)+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1.[Br:11]NC(=O)CCC(N)=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH2:10][Br:11])[CH:3]=1
Reactant: NC(=O)CCC(=O)NBr
Reactant: Cc1cc(Br)ccc1C#N
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(Br)cc1CBr
Temperature: 85 °C
Yield: 102.7 %

Procedure:
To a stirred mixture of 4-Bromo-2-methyl-benzonitrile (5.00 g, 25.5 mmol) in CCl4 (40 mL) under argon was added N-bromosuccinamide (5.00 g, 28.1 mmol) and a catalytic amount of benzoyl peroxide. This mixture was heated at 85° C. for 2 days and cooled to room temperature. The precipitate was filtered off and the cake was rinsed with CCl4 (2×10 mL). The filtrate was concentrated in vacuo to give 7.2 g crude 4-Bromo-2-bromomethyl-benzonitrile (quantitative yield) which was used without further purification.
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]=[C:7]([C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:27])[C:15]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][N:17]3[CH2:20][CH3:21])=[CH:12][C:11]=2[F:28])[S:8][CH:9]=1)=[N+]=[N-].[H][H]>C(O)(=O)C.[Pd]>[NH2:1][CH2:4][C:5]1[N:6]=[C:7]([C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:27])[C:15]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][N:17]3[CH2:20][CH3:21])=[CH:12][C:11]=2[F:28])[S:8][CH:9]=1
Reactant: CCOC(=O)c1cn(CC)c2cc(-c3nc(CN=[N+]=[N-])cs3)c(F)cc2c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)c1cn(CC)c2cc(-c3nc(CN)cs3)c(F)cc2c1=O
Yield: 94.5 %

Procedure:
A solution of 0.87 g (2.17 mmol) ethyl 7-[4-(azidomethyl)-2-thiazolyl]-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate in 125 ml acetic acid was stirred with 0.10 g 10% palladium on carbon catalyst and hydrogen gas bubbled through for 1.5 hours. After filtration, evaporation of solvent and trituration with ether gave 0.77 g of ethyl 7-[4-(aminomethyl)-2-thiazolyl]-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:8]([N:10]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:11]([CH3:14])(=[O:13])=[O:12])[CH:9]=1)(=[O:3])[CH3:2].[Br-:30].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>C1COCC1>[Br:30][CH2:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:8]([N:10]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:11]([CH3:14])(=[O:13])=[O:12])[CH:9]=1)=[O:3]
Reactant: [Br-]
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(N(Cc2ccccc2)S(C)(=O)=O)c1
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: CS(=O)(=O)N(Cc1ccccc1)c1cc(C(=O)CBr)ccc1OCc1ccccc1
Reaction time: 6 h

Procedure:
A solution of N-{5-acetyl-2-[(phenylmethyl)oxy]phenyl}-N-(phenylmethyl) methanesulfonamide (J. Med Chem 1977, 20, 687-92) (1.18 g) in THF (50 ml) was treated with phenyltrimethylammonium tribromide (1.08 g) at <10° and stirred for 6 h. The reaction mixture was quenched with chilled water and then filtered. The filtrate was partitioned between diethyl ether and water, the organic phase was dried (MgSO4) and the solvent was removed in vacuo. The mixture was purified by column chromatography on silica (SPE bond elut, gradient 0 to 45% EtOAc-cyclohexane) to afford the title compound. LCMS RT=3.48 min
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:27])=[C:21]([CH:23]=[CH:24][C:25]=2[F:26])[NH2:22])[CH:5]=[CH:4][N:3]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=1[S:36](Cl)(=[O:38])=[O:37]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[N:10][C:9]=2[C:19]2[C:20]([F:27])=[C:21]([NH:22][S:36]([C:30]3[CH:31]=[C:32]([F:35])[CH:33]=[CH:34][C:29]=3[F:28])(=[O:38])=[O:37])[CH:23]=[CH:24][C:25]=2[F:26])[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Reactant: Nc1ccc(F)c(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F
Product: O=S(=O)(Nc1ccc(F)c(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1cc(F)ccc1F

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2,4-difluoroaniline (900 mg, 2.196 mmol) and 2,5-difluorobenzenesulfonyl chloride (0.355 mL, 2.64 mmol) the title compound of Step H was obtained as a light yellow solid (774 mg, 60% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.41 (d, J=5.5 Hz, 1H), 7.48-7.57 (m, 4H), 7.29 (t, J=8.8 Hz, 1H), 6.57 (d, J=5.5 Hz, 1H), 3.70-3.74 (m, 4H), 3.52-3.55 (m, 4H). MS (ESI): 585 [M+H]+.
Reaction SMILES: [C:1]([N:4]1[C@H:8]([CH2:9]O)[C@@H:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[O:6][C:5]1([CH3:22])[CH3:21])(=[O:3])[CH3:2].C(N(CC)C(F)(F)C(F)C(F)(F)[F:29])C>C(Cl)Cl>[C:1]([N:4]1[C@H:8]([CH2:9][F:29])[C@@H:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[O:6][C:5]1([CH3:22])[CH3:21])(=[O:3])[CH3:2]
Reactant: CCN(CC)C(F)(F)C(F)C(F)(F)F
Reactant: CC(=O)N1[C@H](CO)[C@@H](c2ccc(S(C)(=O)=O)cc2)OC1(C)C
Solvent: ClCCl
Product: CC(=O)N1[C@H](CF)[C@@H](c2ccc(S(C)(=O)=O)cc2)OC1(C)C
Temperature: 22.5 °C

Procedure:
(4R,5R)-3-acetyl-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine (Compound II) (75 g, 0.2291 moles) in methylene chloride (525 ml) reacts with N,N-diethyl-1,1,2,3,3,3-hexafluoro-1-propanamine (Ishikawa Reagent) (76.7 g, 0.3437 moles) at 95-105° C. for about 4 hours. Cooling to 20-25° C., addition to sodium hydroxide (6 g) in water (2500 mL), separation of the methylene chloride layer, distillation and replacement of methylene chloride by isopropanol (750 mL), precipitates the desired product. Filtration, washing with water (100 mL) and isopropanol (75 mL), then drying yields (4S,5R)-3-acetyl-2,2-dimethyl-4-fluoromethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine (Compound IX: R1 is methylsulfonyl; R2, R3 and R4 are methyl).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[C:12]1[CH:11]=[C:10]([O:18][CH3:19])[CH:9]=[CH:8][C:7]=1[O:6]2)#[N:2].[N-:20]=[N+:21]=[N-:22].[Na+].[Cl-].[NH4+].Cl>CN(C)C=O.O>[CH3:19][O:18][C:10]1[CH:9]=[CH:8][C:7]2[O:6][C:5]3[C:14](=[CH:15][CH:16]=[C:3]([C:1]4[NH:22][N:21]=[N:20][N:2]=4)[CH:4]=3)[C:13](=[O:17])[C:12]=2[CH:11]=1
Reactant: COc1ccc2oc3cc(C#N)ccc3c(=O)c2c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2oc3cc(-c4nnn[nH]4)ccc3c(=O)c2c1

Procedure:
6-Cyano-2-methoxyxanthone (12.6 g) was heated with sodium azide (3.41 g) and ammonium chloride (2.95 g) in dimethylformamide (100 ml) at 125° for 6 h. The reaction mixture was diluted with water and acidified with excess hydrochloric acid. The precipitated 2-methoxy-6-(5-tetrazolyl)xanthone was filtered off, washed with water, and recrystallised from dimethylformamide, decomposes above 300°.
Reaction SMILES: [O:1]([CH:8]([CH3:11])[C:9]#[N:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>CCOCC>[O:1]([CH:8]([CH3:11])[CH2:9][NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C#N)Oc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CC(CN)Oc1ccccc1
Reaction time: 0.33 h

Procedure:
A solution of 2-phenoxypropionitrile (11.0 s.) in dry ether (50 ml.) was added dropwise to a stirred suspension of lithium aluminium hydride (3.8 g.) in dry ether (50 ml.). The mixture was then heated to reflux for 3 hours, cooled and treated cautiously (vigorous stirring) with water (3.8 ml.) then with 15% aqueous sodium hydroxide (3.8 ml.) and finally with water (11.4 ml.). The mixture was stirred for 20 minutes and filtered. The filtrate was dried over anhydrous potassium carbonate and evaporated. The residue was distilled under water-pump vacuum to give pure 2-phenoxypropylamine, b.p. 115°-116°/15 mm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][O:9][CH3:10])[C:3]=1[Cl:11].[Cl:12][C:13]1[CH:29]=[CH:28][C:16]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25](Cl)=[O:26])=[CH:20][CH:19]=2)=[CH:15][CH:14]=1>C1(C)C(C)=CC=CC=1>[Cl:11][C:3]1[C:4]([CH2:8][O:9][CH3:10])=[N:5][CH:6]=[CH:7][C:2]=1[NH:1][C:25](=[O:26])[CH2:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][C:16]2[CH:28]=[CH:29][C:13]([Cl:12])=[CH:14][CH:15]=2)=[CH:19][CH:20]=1
Reactant: O=C(Cl)Cc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: COCc1nccc(N)c1Cl
Solvent: Cc1ccccc1C
Product: COCc1nccc(NC(=O)Cc2ccc(Oc3ccc(Cl)cc3)cc2)c1Cl
Yield: 28.5 %

Procedure:
0.58 g (3.36 mmol) of 4-amino-3-chloro-2-methoxymethylpyridine was added to 0.94 g (3.36 mmol) of 4-(4-chloro-phenoxy)phenylacetyl chloride in 40 ml of xylene, and the mixture was refluxed for 8 hours. After the xylene had been removed in vacuo, the residue was taken up in methylene chloride. The mixture was washed with water and 0.1N aqueous sodium hydroxide solution, the combined aqueous phases were rendered neutral and extracted three times using ethyl acetate, and the ethyl acetate phase was dried over sodium sulfate. After the solvent had been removed in vacuo and the residue purified by column chromatography (silica gel, ethyl acetate:petroleum ether=80:20), 0.40 g of a yellow oil were obtained.