Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].C(Br)C.[C:5]1([C@H:11]([CH3:20])[CH2:12][C:13]2[CH:18]=[CH:17][C:16](Cl)=[CH:15][CH:14]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.COB(OC)OC.Cl.Br[C:30]1[CH:35]=[CH:34][C:33]([C@H:36]2[CH2:41][CH2:40][C@H:39]([CH2:42][CH2:43][CH3:44])[CH2:38][CH2:37]2)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.C1(C)C=CC=CC=1.COCCOC>[CH2:42]([C@H:39]1[CH2:40][CH2:41][C@H:36]([C:33]2[CH:34]=[CH:35][C:30]([C:16]3[CH:17]=[CH:18][C:13]([CH2:12][C@H:11]([C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH3:20])=[CH:14][CH:15]=3)=[CH:31][CH:32]=2)[CH2:37][CH2:38]1)[CH2:43][CH3:44]
Reactant: CCC[C@H]1CC[C@H](c2ccc(Br)cc2)CC1
Reactant: C[C@H](Cc1ccc(Cl)cc1)c1ccccc1
Agent: COB(OC)OC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCBr
Solvent: C1CCOC1
Solvent: COCCOC
Product: CCC[C@H]1CC[C@H](c2ccc(-c3ccc(C[C@@H](C)c4ccccc4)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
70 ml of tetrahydrofuran was added to 25.3 g (1.04 mol) of magnesium, and a solution having 9.45 g (0.087 mol) of ethyl bromide and 200 g (0.867 mol) of (R)-2-phenyl-1-(4-chlorophenyl)propane dissolved in 250 ml of tetrahydrofuran was dropwise added thereto over a period of 30 minutes at room temperature with stirring, followed by stirring for 6 hours under reflux. After the mixture was cooled to room temperature, 650 ml of tetrahydrofuran was added thereto. The above reaction liquid was dropwise added to a solution having 112 g (0.44 mol) of trimethoxyboron dissolved in 300 ml of tetrahydrofuran over a period of 1 hour at −20° C., followed by stirring for 1 hour. The temperature was raised to 0° C., 700 ml of 3M hydrochloric acid was dropwise added, followed by stirring for 1 hour at the same temperature. After extraction with toluene from the reaction liquid, washing with water and drying were carried out to distill off the solvent. To a 1,2-dimethoxyethane 800 ml solution of the obtained residue and 238 g (0.845 mol) of 1-bromo-4-(trans-4-propylcyclohexyl)benzene, 1160 ml of an aqueous solution of 19.5 g (16.9 mmol) of tetrakistriphenylphosphine palladium and 260 g (2.45 mol) of sodium carbonate was added, followed by stirring for 3 hours under reflux. The mixture was cooled to room temperature, toluene was added thereto for liquid separation, and the obtained organic layer was washed with water and dried, the solvent was distilled off, and recrystallization and purification by silica gel column chromatography were carried out to obtain 240 g of aimed (R)-1-[4-[4-(trans-4-propylcyclohexyl)phenyl]phenyl]-2-pheynylpropane. Melting point: 93.8° C., TSI: 130.8° C., MS m/e: 396 (M+)
Reaction SMILES: [C:1]([N:4]1[CH2:21][CH2:20][C:7]2([NH:11][C:10](=[O:12])[C@H:9]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:8]2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+].[CH2:24](Cl)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>C1COCC1>[C:1]([N:4]1[CH2:5][CH2:6][C:7]2([N:11]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:10](=[O:12])[C@H:9]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:8]2)[CH2:20][CH2:21]1)(=[O:3])[CH3:2]
Reactant: ClCc1ccccc1
Reactant: CC(=O)N1CCC2(CC1)NC(=O)[C@H](Cc1ccccc1)N2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N1CCC2(CC1)N[C@@H](Cc1ccccc1)C(=O)N2Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 8-acetyl-3-(S)-benzyl-1,4,8-triazaspiro[4,5]decan-2-one (2.8 g, 9.7 mmol) in 20 mL of dry THF there was added sodium hydride (350 mg, 14.6 mmol) at 0° C. and under a blanket of nitrogen. Following stirring over a period of 1 h at 0° C., benzyl chloride (1.36 g, 10.7 mmol) was slowly added dropwise, and the mixture was allowed to warm up to RT and then heated under reflux over a period of 24 h. Following the addition of an aqueous saturated HCl solution (25 mL), the reaction mixture was isolated by filtration and the filtrate was extracted with EE (3×20 mL), and the combined organic phases were dried over Na2SO4. Following removal, by distillation, of the solvent, there was obtained the crude product as a yellow oil. Further purification was carried out by column chromatography. The product 8-acetyl-1,3-(S)-dibenzyl-1,4,8-triazaspiro[4,5]decan-2-one was obtained in a yield of 1.25 g (34%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[CH2:8][O:9][C:10]3[CH:33]=[C:32]4[C:13]([CH:14]=[CH:15][C:16]5[N:20]=[C:19]([C@@H:21]6[CH2:25][C@H:24]([O:26][CH2:27][CH3:28])[CH2:23][N:22]6C([O-])=O)[NH:18][C:17]=54)=[CH:12][C:11]=3[C:5]2=[CH:4][CH:3]=1.Cl.[CH3:35][O:36][C:37]([NH:39][C@@H:40]([CH:44]([CH3:46])[CH3:45])[C:41](O)=[O:42])=[O:38].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[C:6]2[CH2:8][O:9][C:10]3[CH:33]=[C:32]4[C:13]([CH:14]=[CH:15][C:16]5[N:20]=[C:19]([C@@H:21]6[CH2:25][C@H:24]([O:26][CH2:27][CH3:28])[CH2:23][N:22]6[C:41](=[O:42])[C@@H:40]([NH:39][C:37](=[O:38])[O:36][CH3:35])[CH:44]([CH3:46])[CH3:45])[NH:18][C:17]=54)=[CH:12][C:11]=3[C:5]2=[CH:4][CH:3]=1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: CCO[C@H]1C[C@@H](c2nc3ccc4cc5c(cc4c3[nH]2)OCc2cc(Cl)ccc2-5)N(C(=O)[O-])C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: CCO[C@H]1C[C@@H](c2nc3ccc4cc5c(cc4c3[nH]2)OCc2cc(Cl)ccc2-5)N(C(=O)[C@@H](NC(=O)OC)C(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
To a solution of (2S,4S)-2-(9-chloro-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-ethoxypyrrolidine-1-carboxylate (0.46 g, 0.9 mmol) in a mixture of CH2Cl2 (9.0 mL) and MeOH (1.5 mL) was added HCl (in dioxanes, 4M, 6.5 mL, 26.0 mmol). The resulting solution was stirred at room temperature for 2 h. The solution was concentrated to dryness under reduced pressure. To the crude intermediate in CH2Cl2 (10.0 mL) was added (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (0.17 g, 0.9 mmol), HATU (0.41 g, 1.1 mmol), and DIPEA (0.5 mL, 2.9 mmol). The resulting solution was stirred at room temperature for 48 h and diluted with CH2Cl2. The solution was washed with aqueous HCl (1N) and brine. The aqueous layers were back extracted with CH2Cl2 (2×). The resulting organic layers were combined, dried (Na2SO4), and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (20% to 100% EtOAc (w/5% MeOH)/Hexanes to 80% MeOH/EtOAc) to afford methyl {(2S)-1-[(2S,4S)-2-(9-chloro-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-ethoxypyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate (0.46 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[ClH:29]>O1CCOCC1>[ClH:1].[Cl:1][C:2]1[C:24]([C:25]([F:26])([F:27])[F:28])=[CH:23][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[ClH:29]
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(Cl)c(C(F)(F)F)cc32)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1[nH]c2cc(Cl)c(C(F)(F)F)cc2n1C1CCNCC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
1,1-Dimethylethyl 4-[5-chloro-2-oxo-6-(trifluoromethyl)-2,3-dihydro-1H-benzimidazol-1-yl]-1-piperidinecarboxylate D12 (0.27 mmol, 115 mg) was treated with HCl (315 microliters of a 4M solution in 1,4-dioxane) at room temperature; the mixture was stirred at room temperature for 2.5 hours. Solvent was evaporated to afford the title compound, mono hydrochloride salt, 82 mg, 96%, M++H=320.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[F:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:21]3[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:20]=3[F:19])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: Cc1ccc(B(O)O)c(F)c1
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3ccc(C)cc3F)cccc2c1N
Yield: 85.9 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (150 mg, 0.485 mmol) and 2-fluoro-4-methyl-phenylboronic acid (154 mg, 1.000 mmol) were reacted to afford the title compound (141 mg, 86% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.56 (br, 1H), 7.91 (m, 1H), 7.81-7.69 (m, 2H), 7.28 (m, 1H), 7.24-7.16 (m, 1H), 7.13-7.04 (m, 1H), 3.45 (apparent quartet, J=7.0 Hz, 2H), 2.39 (s, 3H), 1.65 (apparent sextet, J=7.0 Hz, 2H), 1.00 (t, J=7.0 Hz, 3H). MS APCI, m/z=339 (M+H). HPLC 1.86 min.
Reaction SMILES: Cl.Cl.[NH2:3][C@@H:4]([CH2:13]C)[C@H:5]([OH:12])[C:6]([NH:8][CH:9]1[CH2:11][CH2:10]1)=[O:7].O[CH2:16]C(NC(=O)OC(C)(C)C)(C)C>>[NH2:3][C:4]([CH3:13])([CH3:16])[CH:5]([OH:12])[C:6]([NH:8][CH:9]1[CH2:10][CH2:11]1)=[O:7]
Reactant: CC[C@H](N)[C@H](O)C(=O)NC1CC1
Reactant: CC(C)(CO)NC(=O)OC(C)(C)C
Agent: Cl
Product: CC(C)(N)C(O)C(=O)NC1CC1

Procedure:
The title compound was prepared in analogy to (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamide dihydrochloride, Representative Procedure A, starting with tert-butyl 1-hydroxy-2-methylpropan-2-ylcarbamate in the second step (A2).
Reaction SMILES: [NH2:1][C:2](=[O:34])[C:3]([C:5]1[C:9]2[C:10]([O:14][CH2:15][C:16]([OH:18])=[O:17])=[N:11][CH:12]=[CH:13][C:8]=2[N:7]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2C2C=CC=CC=2)[C:6]=1[CH2:32][CH3:33])=[O:4].[OH-].[K+].O.[OH-].[Li+]>CO.O>[NH2:1][C:2](=[O:34])[C:3]([C:5]1[C:9]2[C:10]([O:14][CH2:15][C:16]([OH:18])=[O:17])=[N:11][CH:12]=[CH:13][C:8]=2[N:7]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:6]=1[CH2:32][CH3:33])=[O:4]
Reactant: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)O)nccc2n1Cc1ccccc1-c1ccccc1
Agent: [K+]
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)O)nccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-(3-(2-amino-2-oxoacetyl)-1-(biphenyl-2-ylmethyl)-2-ethyl-1H-pyrrolo[3,2-c]pyridin-4-yloxy)acetic acid, Ily-II-10: Compound 21 (0.227 mmol) is dissolved in methanol (20 mL). To the mixture the solution of KOH (1M, 0.25 mL) is added at room temperature. After addition the mixture was stirred at room temperature for 18 h. Then solution of lithium hydroxide monohydrate (90 mg) in H2O (5 mL) is added. After another hour stirring the mixture was concentrated and the residue is redissolved in methanol (10 mL) and ethanol (10 mL). The mixture is filtered and the filtrate was acidified by hydrogen chloride in ether (1.0 M) to pH=3-4. Solvent is evaporated and the residue is washed with a mixture of dichloromethane: ether (1:1), then water (5 mL) and ether to afford 2-(3-(2-amino-2-oxoacetyl)-1-benzyl-2-ethyl-1H-pyrrolo[3,2-c]pyridin-4-yloxy)acetic acid, Ily-II-10.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:20]=[CH:19][C:18]3[O:17][C:16]4[CH:15]=[CH:14][NH:13][C:12](=[O:21])[C:11]=4[C:10](=O)[C:9]=3[CH:8]=2)[CH:2]=1.[CH3:23][Mg]Br.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1COCC1.ClCCCl>[CH2:23]=[C:10]1[C:11]2[C:12](=[O:21])[NH:13][CH:14]=[CH:15][C:16]=2[O:17][C:18]2[CH:19]=[CH:20][C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:8][C:9]1=2
Reactant: C[Mg]Br
Reactant: O=c1[nH]ccc2oc3ccc(-c4cccnc4)cc3c(=O)c12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: ClCCCl
Product: C=C1c2cc(-c3cccnc3)ccc2Oc2cc[nH]c(=O)c21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 8-(pyridin-3-yl)-1H-chromeno[3,2-c]pyridine-1,10(2H)-dione (0.100 g, 0.345 mmol) in THF (3.00 mL) was cooled to 0° C. and methylmagnesium bromide (3.0 M in diethyl ether) (0.345 mL, 1.034 mmol) was added dropwise. The mixture stirred at 0° C. for 1 h. The mixture was quenched at 0° C. with saturated aqueous ammonium chloride solution and diluted with ethyl acetate. The aqueous phase was separated and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a tan solid. The material was dissolved in 1,2-dichloroethane (3.00 mL), pyridinium p-toluenesulfonate (8.66 mg, 0.034 mmol) was added, and the mixture was heated at reflux for 2 h to afford a tan suspension. This mixture was filtered, and the solids were washed with 1,2 dichloroethane and dried to afford 10-methylene-8-(pyridin-3-yl)-2,10-dihydro-1H-chromeno[3,2-c]pyridin-1-one as a tan solid. MS m/z=289.0 [M+H]+. Calcd for C18H12N2O2: 288.1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:11]3[O:26][C@H:25]([CH2:27][O:28]CC4C=CC(Cl)=CC=4Cl)[C@@H:14]([O:15]CC4C=CC(Cl)=CC=4Cl)[C@@:12]3([CH3:38])[OH:13])[N:9]=[CH:10][C:3]=12.B(Cl)(Cl)Cl>ClCCl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:11]3[O:26][C@H:25]([CH2:27][OH:28])[C@@H:14]([OH:15])[C@@:12]3([CH3:38])[OH:13])[N:9]=[CH:10][C:3]=12
Reactant: C[C@@]1(O)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1ncc2c(N)ncnc21
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ncc2c(N)ncnc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
To a solution of the compound from Step A (0.20 g, 0.33 mmol) in dichloromethane (10 mL) at −78° C. was added boron trichloride (1M in dichloromethane) (3 mL, 3 mmol) dropwise. The mixture was stirred at −78° C. for 0.5 h, then at −45° C. to −30° C. for 2 h. The reaction was quenched by addition of sodium acetate (1.0 g) and methanol (10 mL). The solution was evaporated and the residue was purified by flash chromatography over silica gel using CH2Cl2 and CH2Cl2/MeOH (95:5-90:10) gradient as the eluent to furnish the desired compound (60 mg) as a solid, which was recrystallized from methanol and acetonitrile to give the title compound as an off-white solid (40 mg).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([OH:22])=O)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[N:25]1[CH:30]=[CH:29][N:28]=[CH:27][C:26]=1[CH2:31][C:32]([NH:34][NH2:35])=[O:33].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>CCOC(C)=O.C1COCC1>[F:10][C:9]([F:11])([F:12])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:34]([C:32](=[O:33])[CH2:31][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][N:25]=3)[NH2:35])=[O:22])[N:14]=2)[CH:4]=[C:3]([C:2]([F:24])([F:1])[F:23])[CH:8]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: NNC(=O)Cc1cnccn1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NN(C(=O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)C(=O)Cc1cnccn1
Temperature: -60 °C
Reaction time: 1 h
Yield: 6.1 %

Procedure:
In a 50 mL, 3-neck round-bottom flask, (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.3 g, 1.0 eq.) was dissolved in EtOAc:THF (15 mL; 2:1) and cooled to −60° C. where 2-(pyrazin-2-yl)acetohydrazide (0.129 g, 1.1 eq.) was introduced. T3P (50% in EtOAc) (1.01 mL, 2 eq.) was added dropwise followed by DIPEA (0.35 mL, 2.5 eq.) and the reaction mixture was stirred for 1 h at −60° C. The reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product that was purified by column chromatography (60/120 silica gel) using methanol/dichloromethane gradient (the column was packed in dichloromethane and the desired compound started eluting from 3% methanol/dichloromethane). Fractions containing the desired compounds were combined to afford (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N-(2-(pyrazin-2-yl)acetyl)acrylohydrazide (0.025 g, yield: 5%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([O:8][CH2:9][CH2:10][O:11][C:12]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[C:15]([NH:24][S:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[N:14]([CH3:38])[N:13]=2)=[N:6][CH:7]=1.C[OH:40]>>[Br:1][C:2]1[CH:7]=[N:6][C:5]([O:8][CH2:9][CH2:10][O:11][C:12]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[C:15]([NH:24][S:25]([C:28]3[CH:29]=[CH:30][C:31]([C:34]([CH3:35])([CH3:37])[CH2:36][OH:40])=[CH:32][CH:33]=3)(=[O:26])=[O:27])[N:14]([CH3:38])[N:13]=2)=[N:4][CH:3]=1
Reactant: CO
Reactant: Cc1ccc(-c2c(OCCOc3ncc(Br)cn3)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Product: Cc1ccc(-c2c(OCCOc3ncc(Br)cn3)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)CO)cc2)cc1
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 sixteen 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 20 mg of N-[3-{2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy}-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]-4-(tert-butyl)benzenesulfonamide (Example 3) 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 6 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, 1.4 g.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[C:6]([CH3:20])=[N:7][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18]O)=[CH:14][CH:13]=2)[C:9]=1[CH3:10].C(N(CC)CC)C.CS([Cl:33])(=O)=O>ClCCl>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[C:6]([CH3:20])=[N:7][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][Cl:33])=[CH:14][CH:13]=2)[C:9]=1[CH3:10]
Reactant: COC(=O)Cc1c(C)nn(Cc2ccc(CO)cc2)c1C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Cc1c(C)nn(Cc2ccc(CCl)cc2)c1C
Reaction time: 12 h

Procedure:
[1-(4-Hydroxymethyl-benzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-acetic acid methyl ester (intermediate 16.1.1, 4.8 g, 16.7 mmol) was dissolved in 60 ml dichloromethane. Triethylamine (3.5 ml, 25 mmol) was added, followed by dropwise addition of methanesulfonyl chloride (1.29 ml, 16.7 mmol). After 12 h at room temperature, the mixture was washed with water, aqueous KHSO4 solution, water, aqueous NaHCO3 solution and with water. The organic layer was dried over MgSO4 and the solvent was evaporated under reduced pressure.
Reaction SMILES: Cl.Cl.C([O:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([NH:21][C:22]3[C:27]([Cl:28])=[CH:26][CH:25]=[C:24]4[O:29][CH2:30][O:31][C:23]=34)=[N:16][CH:17]=[N:18]2)=[C:13]([O:32][CH:33]2[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]2)[CH:12]=1)C1C=CC=CC=1.FC(F)(F)C(O)=O>>[Cl:28][C:27]1[C:22]([NH:21][C:15]2[C:14]3[C:19](=[CH:20][C:11]([OH:10])=[CH:12][C:13]=3[O:32][CH:33]3[CH2:34][CH2:35][NH:36][CH2:37][CH2:38]3)[N:18]=[CH:17][N:16]=2)=[C:23]2[O:31][CH2:30][O:29][C:24]2=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(OCc3ccccc3)cc3ncnc(Nc4c(Cl)ccc5c4OCO5)c23)CC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: Oc1cc(OC2CCNCC2)c2c(Nc3c(Cl)ccc4c3OCO4)ncnc2c1
Temperature: 80 °C
Yield: 78.2 %

Procedure:
A mixture of 7-benzyloxy-5-[N-(tert-butoxycarbonyl)piperidin-4-yloxy]-4-(6-chloro-2,3-methylenedioxyanilino)quinazoline dihydrochloride (2.3 g) and trifluoroacetic acid (28 ml) was stirred and heated to 80° C. for 6 hours. The mixture was evaporated and the residue was dissolved in water and the solution was basified to pH10 by the addition of 1N aqueous sodium hydroxide solution. The mixture was stirred at ambient temperature for 1 hour. The solid was isolated, washed with water and dried under vacuum. There was thus obtained the title compound (1.1 g); NMR Spectrum: (DMSOd6) 1.6–1.8 (m, 2H), 2.0–2.15 (m, 2H), 2.65–2.75 (m, 2H), 2.9–3.05 (m, 2H), 4.8 (m, 1H), 6.1 (s, 2H), 6.62 (s, 1H), 6.7 (s, 1H), 6.92 (d, 1H), 7.05 (d, 1H), 8.25 (s, 1H), 9.2 (s, 1H); Mass Spectrum: M+H+ 415 and 417.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[O:24]1[C:29]2[CH:30]=[CH:31][CH:32]=[C:33]([C:34](O)=[O:35])[C:28]=2[O:27][CH2:26][CH2:25]1>>[Cl:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:34]([C:33]2[C:28]3[O:27][CH2:26][CH2:25][O:24][C:29]=3[CH:30]=[CH:31][CH:32]=2)=[O:35])=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c(-c2cccc(Cl)c2)s1
Reactant: O=C(O)c1cccc2c1OCCO2
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3c2OCCO3)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-[5-(3-chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 2,3-Dihydro-benzo[1,4]dioxine-5-carboxylic acid. LC-MS (basic): tR=0.89 min; [M+H]+=510.3.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][CH:10]=1.[OH-].[K+].C(O)C.Cl>O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1
Reactant: CCOC(=O)c1ccc(NCCc2cccs2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(NCCc2cccs2)cc1

Procedure:
A mixture of 29.7 g. of crude ethyl 4-[2-(2-thienyl)ethylamino]benzoate, 29 g. of potassium hydroxide and 200 ml. of 95% ethanol is refluxed for 3 hours. The solution is diluted with 100 ml. of water and adjusted to pH 6 with concentrated hydrochloric acid. The mixture is cooled, filtered and the solid washed with ethanol-water (1:1) to give a solid. The solid is heated with 200 ml. of ethanol, filtered and the filtrate concentrated. Purification gives the product, m.p. 163°-165° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][OH:26])=[CH:21][CH:20]=3)[N:15]=2)=[CH:10][C:9]=1[C:27]([F:30])([F:29])[F:28]>O1CCOCC1.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:24]=[CH:23][C:22]([CH:25]=[O:26])=[CH:21][CH:20]=3)[N:15]=2)=[CH:10][C:9]=1[C:27]([F:30])([F:28])[F:29]
Reactant: Cc1ccccc1-c1ccc(-c2nc(-c3ccc(CO)cc3)no2)cc1C(F)(F)F
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: Cc1ccccc1-c1ccc(-c2nc(-c3ccc(C=O)cc3)no2)cc1C(F)(F)F
Temperature: 70 °C
Yield: 97.3 %

Procedure:
(4-(5-(2′-methyl-2-(trifluoromethyl)biphenyl-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)methanol (5.89 g, 14.4 mmol) was dissolved in dioxane (100 mL) and manganese dioxide (10 g, 116.0 mmol) was added. The mixture was heated at 70° C. overnight and then the solvent was removed in vacuo. The residue was triturated with a mixture of petrol/diethyl ether to give the title compound as a white solid (5.72 g, 97%). 1H NMR (CDCl3, 400 MHz) δ 10.13 (1H, s), 8.64 (1H, s), 8.43-8.36 (3H, m), 8.06 (2H, d, J=8.0 Hz), 7.49 (1H, d, J=8.0 Hz), 7.38-7.21 (3H, m), 7.15 (1H, d, J=7.6 Hz), 2.07 (3H, s). LC/MS (Method A): 409 (M+H)+. HPLC (Method G) Rt 4.89 min (Purity: 95.7%).