Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([O:7][C:8](=[O:34])[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH2:32])=[C:28]([F:33])[CH:27]=3)[CH:22]=[CH:21][N:20]=2)[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:35][C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=1[NH:43][C:44]([C:46]1([C:49](O)=[O:50])[CH2:48][CH2:47]1)=[O:45].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[C:1]1([O:7][C:8](=[O:34])[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:49]([C:46]4([C:44](=[O:45])[NH:43][C:37]5[CH:38]=[CH:39][C:40]([F:42])=[CH:41][C:36]=5[F:35])[CH2:48][CH2:47]4)=[O:50])=[C:28]([F:33])[CH:27]=3)[CH:22]=[CH:21][N:20]=2)[C:10]([O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccc(Oc2ccnc(N(C(=O)Oc3ccccc3)C(=O)Oc3ccccc3)c2)cc1F
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2F)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4F)CC3)c(F)c2)ccn1
Reaction time: 8 h
Yield: 19.6 %

Procedure:
A crude product of [4-(4-amino-3-fluorophenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (400 mg) was dissolved in N,N-dimethylformamide (5 ml). 1-(2,4-Difluorophenylcarbamoyl)cyclopropanecarboxylic acid (241 mg), triethylamine (0.139 ml) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (442 mg) were added under a nitrogen atmosphere at room temperature and stirred overnight. Liquid-liquid separation was carried out after addition of ethyl acetate and water to the reaction mixture. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (3 times) and brine in this order, and dried over anhydrous sodium sulfate. The solvent was removed and the residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=3:2 to 1:1) to provide the titled compound as white powder (116.2 mg).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[C:9]([N:13]1[CH2:16][CH:15]([OH:17])[CH2:14]1)([CH3:12])([CH3:11])[CH3:10].[OH-].[K+].[ClH:20]>>[ClH:20].[OH:2][C:1]1[CH:8]=[CH:7][C:5]([O:6][CH2:16][CH:15]([OH:17])[CH2:14][NH:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C)N1CC(O)C1
Reactant: Oc1ccc(O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CC(C)(C)NCC(O)COc1ccc(O)cc1
Temperature: 140 °C
Yield: 58 %

Procedure:
A mixture of 11 parts of hydroquinone, 6.5 parts of 1-(tert.-butyl)-3-azetidinol and 0.3 part of potassium hydroxide was heated under nitrogen gas at 140° C. for 8 hours with agitation. The reaction mixture was cooled and dissolved into 50 parts of 4N-hydrochloric acid aqueous solution. The resulting solution was washed with 50 parts of chloroform. The water layer was acidified with concentrated hydrochloric acid, evaporated and solidified. The residue was dissolved in isopropyl alcohol and filtered. The filtrate was decolored with active carbon and allowed to cool. As a result 6.9 parts of 1-(p-hydroxyphenoxy)-3-(tert.-butylamino)-2-propanol hydrochloride melting at 201° - 203° C were obtained. The yield was 58%. The results of infra-red spectrum analysis and nuclear magnetic resonance analysis of the resulting hydrochloride are as follows:
Reaction SMILES: [Cl-].[Li+].[CH2:3]([C:7]1[CH:12]=[CH:11][C:10]([N:13]=[C:14]=[O:15])=[CH:9][CH:8]=1)[CH2:4][CH2:5][CH3:6].[CH3:16][O:17][C:18]1[CH:26]=[CH:25][C:21]([CH:22]2[O:24][CH2:23]2)=[CH:20][CH:19]=1.O>CN(C=O)C>[CH2:3]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:23][CH:22]([C:21]3[CH:20]=[CH:19][C:18]([O:17][CH3:16])=[CH:26][CH:25]=3)[O:24][C:14]2=[O:15])=[CH:9][CH:8]=1)[CH2:4][CH2:5][CH3:6]
Reactant: COc1ccc(C2CO2)cc1
Reactant: CCCCc1ccc(N=C=O)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1ccc(N2CC(c3ccc(OC)cc3)OC2=O)cc1
Yield: 14.5 %

Procedure:
In a 20 ml-three necked flask, 0.013 g of lithium chloride and 3.8 ml of DMF were placed. To the mixture, a solution of 1.09 g (6.22 mM) of 4-butylphenyl isocyanate and 6.20 mM of optically active 4-methoxystyrene oxide in 1.3 ml of DMF was added dropwise in 12 minutes under refluxing and stirring in nitrogen atmosphere, followed by refluxing for 50 minutes under stirring. After the reaction, the reaction mixture was left standing for cooling, then poured into water, and subjected to extraction with ethyl acetate. The organic layer was washed with water, dried with anhydrous sodium sulfate and evaporated under reduced pressure to obtain a residue The residue was purified by silica gel column chromatography (eluent: toluene/ethyl acetate=10/1) and recrystallized from methanol to obtain 0.29 g of optically active 3-(4-butylphenyl)-5-(4-methoxyphenyl)-2-oxazolidinone (Yield: 14.5%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10](B(O)O)[CH:11]=[CH:12][CH:13]=2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH:3]=1.Br[C:28]1[C:29]([F:39])=[CH:30][C:31]([F:38])=[C:32]([S:34]([NH2:37])(=[O:36])=[O:35])[CH:33]=1>>[F:38][C:31]1[CH:30]=[C:29]([F:39])[C:28]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([C:6]3[CH:5]=[C:4]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:19][CH:18]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:9]=2)=[CH:33][C:32]=1[S:34]([NH2:37])(=[O:36])=[O:35]
Reactant: NS(=O)(=O)c1cc(Br)c(F)cc1F
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(B(O)O)c2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cc(S(N)(=O)=O)c(F)cc3F)c2)n1

Procedure:
The title compound was prepared from 3-[6-methyl-4-(4-trifluoromethyl-phenyl)pyridin-2-yl]-benzeneboronic acid (example G.9) (0.40 g, 1.1 mmol) and commercially available 5-bromo-2,4-difluoro-benzenesulfonamide (0.635 g, 2.3 mmol) according to the general procedure VI. Obtained as a white solid (0.150 g, 27%). MS (ISP) 505.1 [(M+H)+]; mp 227° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[O:11][CH3:12]>C(O)C.Cl.[Fe]>[Br:1][C:2]1[C:3]([O:11][CH3:12])=[CH:4][CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: COc1cccc([N+](=O)[O-])c1Br
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: COc1cccc(N)c1Br
Temperature: 25 °C

Procedure:
Iron (1.94 g, 34 mmol) was added to a solution of 2-bromo-1-methoxy-3-nitrobenzene (2.50 g, 10.77 mmol) in ethanol (18 mL) and concentrated hydrochloric acid (1 mL), and the reaction was heated at reflux for 1.5 hours. The mixture was cooled to room temperature, filtered through Celite and concentrated in vacuo to afford the title compound as a solid. Yield: 2.57 g, 10.77 mmol, 100%. LCMS m/z 202.1 (M+1). 1H NMR (400 MHz, CD3OD) δ 3.77 (s, 3H), 6.30 (d, J=8.0 Hz, 1H), 6.43 (d, J=8.0 Hz, 1H), 6.98 (dd, J=8.0, 8.0 Hz, 1H).
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2[N:10]=[C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:12]=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1.[I:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[S:32])[CH:27]=[CH:28][CH:29]=1>>[I:23][C:24]1[CH:25]=[C:26]([NH:30][C:31]([N:17]2[CH2:18][CH2:19][N:14]([C:11]3[N:12]=[CH:13][C:8]4[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4][N:3]([CH2:2][CH3:1])[C:9]=4[N:10]=3)[CH2:15][CH2:16]2)=[S:32])[CH:27]=[CH:28][CH:29]=1
Reactant: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCNCC3)nc21
Reactant: S=C=Nc1cccc(I)c1
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(C(=S)Nc4cccc(I)c4)CC3)nc21

Procedure:
Pipemidic acid (40 mg, 0.133 mmol) and 3-iodophenyl isothiocyanate (29 mg, 0.111 mmol) were used. Purification on silica yielded compound 29 in Table 1, below (57 mg, 90%). 1H NMR (250 MHz, CDCl3) δ 9.33 (s, 1H), 8.73 (s, 1H), 7.66-7.64 (m, 1H), 7.54-7.51 (m, 1H), 7.40-7.24 (m, 1H), 7.12-7.06 (m, 1H), 4.48-4.31 (m, 2H), 4.27-3.93 (m, 8H), 1.34-1.17 (m, 3H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=O)[CH:8]2[CH2:13][C:14]([O:16]CC)=O.[C:20]1([CH2:26][CH2:27][CH2:28][NH2:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]2[CH2:5][CH2:6][C@H:7]3[C@H:8]([CH2:13][C:14](=[O:16])[N:29]3[CH2:28][CH2:27][CH2:26][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)CC1C(=O)CCc2c(OC)cccc21
Reactant: NCCCc1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc2c1CC[C@H]1[C@@H]2CC(=O)N1CCCc1ccccc1
Reaction time: 10 h
Yield: 78.6 %

Procedure:
4.0 g (0.01525 mol) of ethyl 1,2,3,4-tetrahydro-5-methoxy-2-oxo-1-naphthylacetate were dissolved in 80 ml of toluene, 2.29 ml (0.016 mol) of 3-phenylpropylamine were added thereto and the mixture was boiled for 20 hours on a water separator. After concentration the residue was hydrogenated with 1.5 g of Raney-nickel in 150 ml of ethanol at 70° and 80 bar for 10 hours. The product was chromatographed over silica gel with cyclohexane/ethyl acetate 1:1. There were obtained 4.02 g (76%) of oily rac-cis-1,3,3a,4,5,9b-hexahydro-6-methoxy-3-(3-phenyl-propyl)-2H-benzo[e]indol-2-one.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([OH:9])=[O:8].[C:10](Cl)(=O)C(Cl)=O>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccsc1Br
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccsc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.1 %

Procedure:
2-bromo-3-thiophene carboxylic acid (1.0 eq, 12.56 g, 60.66 mmol) was suspended in CH2Cl2 (200 ml). Oxalyl chloride (1.1 eq, 5.9 ml, 67.16 mmol) and 5 drops of DMF were added, inducing formation of gas. The mixture was stirred overnight at room temperature and the volatiles were removed in vacuo. The resulting solid was suspended in dry methanol (150 ml) and the mixture heated to ebullition. Evaporation of the solvents afforded methyl 2-bromo-3-thiophene carboxylate (13.16 g, 98% yield) as a crude brown oil. LCMS (ES): 99% pure, m/z not detected; 1H NMR (CDCl3, 400 MHz) δ 3.88 (s, 3H), 7.23 (d, J=5.6, 1H), 7.56 (d, J=5.6, 1H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]([C:15]1[S:16][C:17](I)=[CH:18][C:19]=1[N:20]([C:28]([C@H:30]1[CH2:35][CH2:34][C@H:33]([CH3:36])[CH2:32][CH2:31]1)=[O:29])[CH:21]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1)=[O:14].C1(C)C=CC=CC=1.CO.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[CH3:11][O:12][C:13]([C:15]1[S:16][C:17]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:18][C:19]=1[N:20]([C:28]([C@H:30]1[CH2:31][CH2:32][C@H:33]([CH3:36])[CH2:34][CH2:35]1)=[O:29])[CH:21]1[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]1)=[O:14]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COC(=O)c1sc(I)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCN(C)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCN(C)CC1
Temperature: 70 °C

Procedure:
To the mixture of 4-chlorophenylboronic acid (46.9 mg, 0.3 mmol) and 5-iodo-3-[(trans-4-methyl-cyclohexanecarbonyl)-(1-methyl-piperidin-4-yl)-amino]-thiophene-2-carboxylic acid methyl ester (50 mg, 0.099 mmol), from step 5, in 5:1 mixture of toluene/MeOH (2.0 mL) was added a solution of Pd(PPh3) 4 (12.0 mg, 0.01 mmol, 10 mol %) in toluene (1.0 mL) followed by aqueous 2M Na2CO3 solution (0.1 mL, 0.2 mmol). The resultant reaction mixture was heated at 70° C. for 16 h, cooled to room temperature, filtered off through MgSO4 and washed with EtOAc. Evaporation of the solvent and purification of the residue over preparative TLC (1 mm, 60A°) using DCM/CHCl3/MeOH/Et3N (100:90:16:1) as an eluent furnished 5-(4-chloro-phenyl)-3-[(trans-4-methyl-cyclohexanecarbonyl)-(1-methyl-piperidin-4-yl)-amino-]-thiopene-2-carboxylic acid methyl ester (35.0 mg, 71.5% yield). NMR 1H (CDCl3, 400 MHz): 7.53 (d, J=8.3, 2H), 7.4 (d, J=8.5, 2H), 7.0 (s, 1H), 4.67-4.58 (m, 1H), 3.84 (s, 3H), 2.82-2.64 (m, 1H), 2.2 (s, 3H), 2.14-1.35 (m), 0.763 (d, J=6.6, 3H), 0.76-0.56 (m, 2H).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([OH:19])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:23]2)=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:38][C:39]1([CH3:47])[C:41]([CH3:43])([CH3:42])[CH:40]1[C:44](Cl)=[O:45]>>[Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:44]([CH:40]2[C:41]([CH3:43])([CH3:42])[C:39]2([CH3:47])[CH3:38])=[O:45])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])[CH2:23]2)=[CH:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Product: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](OC(=O)C3C(C)(C)C3(C)C)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Yield: 68.5 %

Procedure:
A procedure similar to that described in Example 4, above, was followed, but using 1.0 g (1.8 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], and 1.17 g of 2,2,3,3-tetramethylcyclopropanecarbonyl chloride, to provide 833 mg of the title compound.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH2:10]([NH:17][CH2:18][CH2:19][OH:20])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>CN(C)C=O>[C:6]([O:5][C:3](=[O:4])[CH2:2][N:17]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:18][CH2:19][OH:20])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: OCCNCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN(CCO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
tert-Butyl bromoacetate (32.3 ml; 0.2 mol) is slowly added dropwise, while cooling in ice, to a solution of N-benzylethanolamine (30.2 g; 0.2 mol) and triethylamine (27.9 ml; 0.2 mol) in anhydrous N,N-dimethylformamide (200 ml). The mixture is stirred at room temperature for 22 h and is then concentrated in vacuo. The residue is subsequently distilled repeatedly with toluene. The resulting oil is taken up in dichloromethane (400 ml) and extracted twice by shaking with water (160 ml on each occasion). The organic phase is dried (magnesium sulphate) and concentrated. Yield: 47.8 g (90%), colourless oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]([O:29][CH2:30][CH2:31][O:32][C:33]4[N:38]=[CH:37][C:36]([Cl:39])=[CH:35][N:34]=4)=[N:12][N:13]([CH3:28])[C:14]=3[NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][N:20]=3)(=[O:18])=[O:17])=[CH:9][C:4]=2[O:3][CH2:2]1.C[OH:41]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]([O:29][CH2:30][CH2:31][O:32][C:33]4[N:38]=[CH:37][C:36]([Cl:39])=[CH:35][N:34]=4)=[N:12][N:13]([CH3:28])[C:14]=3[NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH2:26][OH:41])=[CH:21][N:20]=3)(=[O:18])=[O:17])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)c1ccc(S(=O)(=O)Nc2c(-c3ccc4c(c3)OCO4)c(OCCOc3ncc(Cl)cn3)nn2C)nc1
Reactant: CO
Product: CC(CO)c1ccc(S(=O)(=O)Nc2c(-c3ccc4c(c3)OCO4)c(OCCOc3ncc(Cl)cn3)nn2C)nc1
Reaction time: 48 h

Procedure:
Streptomyces rimosus subsp. rimosus ATCC10970 maintained on a ¼ strength ATCC172 agar slope was inoculated as a loopful of spores into a 300 ml Erlenmeyer flask containing 50 ml of AS7-H inoculum medium. This was allowed to incubate for 2 days at 28° C., 200 rpm on an Infors Multitron Shaker™ with 1″ throw. 2 mls of this inoculum medium was then transferred to each of twenty 300 ml Erlenmeyer flask containing 50 ml of AP-5H production medium and incubated under the same conditions for a further 24 hours. At this point 5 mg of N-(4-(1,3-benzodioxol-5-yl)-3-{2-[(5-chloro-2-pyrimidinyl)oxy]ethoxy}-1-methyl-1H-pyrazol-5-yl)-5-isopropyl-2-pyridinesulfonamide (Example 103) dissolved in 0.5 ml of methanol was added to each of the flasks and the fermentation allowed to continue under the same conditions for a further 96 hours. Each flask was then extracted with 200 mls of ethyl acetate and the combined ethyl acetate solubles concentrated to dryness to give a gum solid.
Reaction SMILES: [Br:1][C:2]1[C:14]([F:15])=[CH:13][C:5]2[S:6][C:7]([C:9]([O:11]C)=[O:10])=[CH:8][C:4]=2[CH:3]=1.[Li+].[OH-].O>C1COCC1>[Br:1][C:2]1[C:14]([F:15])=[CH:13][C:5]2[S:6][C:7]([C:9]([OH:11])=[O:10])=[CH:8][C:4]=2[CH:3]=1
Reactant: COC(=O)c1cc2cc(Br)c(F)cc2s1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc2cc(Br)c(F)cc2s1
Yield: 84 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 25 for the preparation of I-25b above, methyl 5-bromo-6-fluorobenzo[b]thiophene-2-carboxylate (I-28b: 0.3 g, 1.038 mmol) in THF (10 mL) was hydrolyzed with LiOH (300 mg, 1.038 mmol) and water (2 mL) to afford 240 mg of the product (85% yield)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[O:11][CH3:12]>[Fe].CC(O)=O.O>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1ccc([N+](=O)[O-])cc1Br
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(N)cc1Br
Temperature: 80 °C
Yield: 86 %

Procedure:
A mixture of 670 mg (2.9 mmol) of 2-bromo-4-nitroanisole and 1.20 g (21.1. mmol) of iron powder in 10 mL of 1:1 v/v HOAc/H2O was heated at 80° C. for 1.5 h. The mixture was cooled and filtered onto a pad of Celite. The flask and filtered solids were rinsed with 100 mL of EtOAc and 100 mL of H2O. The filtrate was transfered to a separatory fumel and the layers were separated. The organic layer was washed with 50 mL of sat'd NaHCO3, 50 mL sat'd NaCl, dried over MgSO4 and concentrated in vacuo. Flash chromatography on 25 g of silica gel using 3:2 v/v hexanes/ether as the eluant afforded 504 mg (86%) of the title compound as an oil.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([CH2:22][O:23][CH2:24][CH3:25])[N:14]([CH2:15][CH:16]3[O:20][N:19]=[C:18]([CH3:21])[CH2:17]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:26]>CO>[CH2:24]([O:23][CH2:22][C:13]1[N:14]([CH2:15][CH:16]2[O:20][N:19]=[C:18]([CH3:21])[CH2:17]2)[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:26])[C:11]=2[N:12]=1)[CH3:25]
Reactant: CCOCc1nc2c(Cl)nc3ccccc3c2n1CC1CC(C)=NO1
Reactant: N
Solvent: CO
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC1CC(C)=NO1
Temperature: 150 °C

Procedure:
4-Chloro-2-(ethoxymethyl)-1-[(3-methyl-4,5-dihydroisoxazol-5-yl)methyl]-1H-imidazo[4,5-c]quinoline (1.30 g, 3.62 mmol) was treated with a solution of 7 M ammonia in methanol (60 mL), and the mixture was sealed in a pressure vessel and heated at 150° C. for 24 hours. The volatiles were removed under reduced pressure, and the residue was partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The aqueous layer was extracted with two additional portions of dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, gradient elution using 98:2 to 96:4 dichloromethane/methanol) to afford 2-(ethoxymethyl)-1-[(3-methyl-4,5-dihydroisoxazol-5-yl)methyl]-1H-imidazo[4,5-c]quinolin-4-amine (1.10 g) as a white solid that was crystallized from acetonitrile to provide white needles, mp 204-205° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](=[S:9])[NH2:8])([O-:3])=[O:2].Cl[CH2:14][CH:15]=O.C(O)(=O)C.[OH-].[Na+]>C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([C:7]2[S:9][CH:14]=[CH:15][N:8]=2)[CH:10]=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: O=CCCl
Reactant: NC(=S)c1cccc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccc(-c2nccs2)c1
Temperature: 25 °C
Yield: 93.1 %

Procedure:
A yellow suspension of 3-nitrobenzothioamide (2.0 g, 10.98 mmol), 2-chloroacetaldehyde (45% in H2O) (2.01 g, 11.53 mmol), and acetic acid (7.32 mL) was heated to reflux for 1 hour. The mixture was cooled to room temperature, poured into ice water, and rendered alkaline using 30 mL of 12 N NaOH solution. Ethyl acetate was then added, and the resulting emulsion was filtered through CELITE®. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layers were dried over magnesium sulfate. Filtration and concentration under reduced pressure afforded Intermediate 57A (2.107 g, 91% yield) as a brown solid. HPLC: Rt=3.331 min. (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min. gradient, monitored at 220 nm). MS (ES): m/z=207.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.68 (1H, t, J=1.89 Hz), 8.34-8.41 (1H, m), 8.28-8.34 (1H, m), 8.00-8.05 (1H, m), 7.94 (1H, d, J=3.27 Hz), 7.80 (1H, t, J=8.06 Hz).
Reaction SMILES: [NH:1]([C:3]([C@@H:5]1[CH2:9][C:8](=[N:10][O:11][CH3:12])[CH2:7][N:6]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:4])[NH2:2].[C:20](=S)=[S:21].[OH-].[K+]>C(O)C>[CH3:12][O:11][N:10]=[C:8]1[CH2:7][N:6]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:5]([C:3]2[O:4][C:20](=[S:21])[NH:2][N:1]=2)[CH2:9]1
Reactant: S=C=S
Reactant: CON=C1C[C@@H](C(=O)NN)N(C(=O)OC(C)(C)C)C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CON=C1C[C@@H](c2n[nH]c(=S)o2)N(C(=O)OC(C)(C)C)C1

Procedure:
To a solution of tert-butyl (2S,4EZ)-2-(hydrazinocarbonyl)-4-(methoxyimino)-1-pyrrolidinecarboxylate (Intermediate 9, 2.86 mmoles; 780 mg) in ethanol (25 mL) at 0° C. was added carbon disulfide (6.86 mmoles; 522 mg) and potassium hydroxide (3 mmoles; 168 mg). The mixture was refluxed for 7 h. The solvent was evaporated and the residue re-dissolved in EtOAc and washed with NH4Cl sat and 10% NaHCO3 and brine. The organic layer was dried over Na2SO4 and evaporated to give the desired N-protected intermediate, tert-butyl (2S,4EZ)-4-(methoxyimino)-2-(5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-1-pyrrolidine-carboxylate, as a yellowish oil (200 mg, 23%).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].Cl[C:6]1[N:11]=[C:10]([C:12]2[C:13]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)=[N:14][N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:17][C:16]=23)[CH:9]=[CH:8][N:7]=1>>[F:37][C:34]1[CH:35]=[CH:36][C:31]([C:13]2[C:12]([C:10]3[CH:9]=[CH:8][N:7]=[C:6]([NH:4][CH:1]([CH3:3])[CH3:2])[N:11]=3)=[C:16]3[CH2:17][N:18]([C:21]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:19][CH2:20][N:15]3[N:14]=2)=[CH:32][CH:33]=1
Reactant: CC(C)N
Reactant: O=C(OCc1ccccc1)N1CCn2nc(-c3ccc(F)cc3)c(-c3ccnc(Cl)n3)c2C1
Product: CC(C)Nc1nccc(-c2c(-c3ccc(F)cc3)nn3c2CN(C(=O)OCc2ccccc2)CC3)n1

Procedure:
A solution of isopropylamine (2.0 mL) and phenylmethyl 3-(2-chloro-4-pyrimidinyl)-2-(4-fluorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (i.e. the product of Step C) (1.00 g, 2.05 mmol) was heated in a sealed tube at 80° C. in a microwave reactor for 8 h. The reaction mixture was concentrated under reduced pressure to remove the excess amine. The residue was diluted with dichloromethane (50 mL) and treated with silica gel (10.0 g). The silica gel suspension was concentrated to leave a mixture of silica gel and crude product, which was purified by silica gel chromatography using a gradient of ethyl acetate/hexanes (0:1 to 7:1) as eluant to give 0.5 g of the title compound as a white solid.