Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:17]([NH2:18])=[N:16][NH:15][C:12]2=[CH:13][N:14]=1.[C:19](Cl)(=[O:23])[CH:20]([CH3:22])[CH3:21]>N1C=CC=CC=1.CO.ClCCl>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:17]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])=[N:16][NH:15][C:12]2=[CH:13][N:14]=1
Reactant: CC(C)C(=O)Cl
Reactant: Nc1n[nH]c2cnc(-c3cccc(F)c3F)cc12
Solvent: CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)C(=O)Nc1n[nH]c2cnc(-c3cccc(F)c3F)cc12

Procedure:
5-(2,3-Difluorophenyl)-1H-pyrazolo[3,4-c]pyridin-3-ylamine (Description 3; 100 mg, 0.41 mmol) was reacted with isobutyryl chloride (43 uL, 0.41 mmol) in pyridine (0.5 mL) in a manner analogous to that described in Example 1. Chromatography on silica gel using 4% v/v methanol in dichloromethane as eluent afforded the title compound as a solid.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)=O.C([O-])([O-])=O.[K+].[K+].Cl.[NH2:29][OH:30]>CCO.O>[OH:30]/[N:29]=[CH:1]/[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)cc2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(/C=N/O)cc2)CC1
Reaction time: 8 h

Procedure:
To a suspension of tert-butyl 4-(4-formylphenyl)piperazine-1-carboxylate (3.89 g, 13.41 mmol, prepared as described in Example 10) and K2CO3 (1.02 g, 7.38 mmol) in EtOH (50 mL) was added hydroxylamine hydrochloride (1.4 g, 20.1 mmol) in water (saturated, approx. 2 mL) and the reaction mixture stirred overnight. The reaction was filtered, concentrated in vacuo, water was added and the product filtered to afford tert-butyl 4-{4-[(E)-(hydroxyimino)methyl]phenyl}piperazine-1-carboxylate.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][O:20][C:21](=[O:60])[CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH2:57][CH3:58])([C:38]3[CH:43]=[CH:42][C:41]([C:44]#[C:45][C:46]([CH2:54][CH3:55])([O:49][Si](C)(C)C)[CH2:47][CH3:48])=[C:40]([CH3:56])[CH:39]=3)[CH2:36][CH3:37])=[CH:31][C:30]=2[CH3:59])[CH:28]=1>O1CCCC1.C(OCC)(=O)C>[CH3:19][O:20][C:21](=[O:60])[CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH2:36][CH3:37])([C:38]3[CH:43]=[CH:42][C:41]([C:44]#[C:45][C:46]([CH2:54][CH3:55])([OH:49])[CH2:47][CH3:48])=[C:40]([CH3:56])[CH:39]=3)[CH2:57][CH3:58])=[CH:31][C:30]=2[CH3:59])[CH:28]=1
Reactant: CCC(C#Cc1ccc(C(CC)(CC)c2ccc(-c3cncc(CC(=O)OC)c3)c(C)c2)cc1C)(CC)O[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(O)(C#Cc1ccc(C(CC)(CC)c2ccc(-c3cncc(CC(=O)OC)c3)c(C)c2)cc1C)CC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.8 %

Procedure:
Tetrabutylammonium fluoride (1 M solution in tetrahydrofuran, 0.316 mL, 0.316 mmol) was added to a solution of [5-(4-{1-ethyl-1-[4-(3-ethyl-3-trimethylsilanyloxy-1-pentynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester (Example 151-(1); 36.9 mg, 0.063 mmol) in tetrahydrofuran (3 mL), and the mixture was stirred at room temperature for 30 minutes. Then, the reaction mixture was diluted with ethyl acetate and was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to give the target compound as a colorless oil (16.7 mg, 52%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)=[N:10][C:9]([Br:26])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N([O-])=O.[Na+].[N-:31]=[N+:32]=[N-].[Na+].CCOCC>C(O)(C(F)(F)F)=O.O>[N:1]([C:2]1[C:11]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:17]=2)=[N:10][C:9]([Br:26])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[N+:31]=[N-:32]
Reactant: COC(=O)c1cc(Br)nc(-c2ccc(OCc3ccccc3)cc2)c1N
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCOCC
Product: COC(=O)c1cc(Br)nc(-c2ccc(OCc3ccccc3)cc2)c1N=[N+]=[N-]
Reaction time: 0.33 h
Yield: 64 %

Procedure:
Methyl 3-amino-2-(4-(benzyloxy)phenyl)-6-bromoisonicotinate (3.28 g, 7.94 mmol) was dissolved in TFA (40 mL) and the yellow solution was cooled in an ice bath. Solid sodium nitrite (1.1 g, 15.9 mmol) was added with stirring to give a red mixture with gas evolution. After 20 min, solid sodium azide (5.16 g, 79 mmol) was added over 5 min followed immediately by Et2O (40 mL). After 20 minutes water was added and the mixture was extracted with EtOAc. The combined organic phases were washed with water (3×), and saturated Na2CO3 solution (until the aqueous phase was basic) and brine. After drying the solvent with sodium sulfate, the solvent was removed. Flash chromatography (step gradient elution with hexane containing 10 to 40% DCM) afforded methyl 3-azido-2-(4-(benzyloxy)phenyl)-6-bromoisonicotinate (2.23 g, 5.08 mmol, 64% yield). 1H NMR (500 MHz, chloroform-d) δ ppm 7.68-7.79 (3H, m), 7.29-7.49 (5H, m), 7.06 (2H, d, J=8.55 Hz), 4.00 (3H, s).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][CH:8]=2)=[O:4].O1CCCC1.[OH-].[Na+].Cl>CO>[F:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][N:6]2[C:7]3[C:12](=[CH:11][C:10]([S:14]([CH3:17])(=[O:15])=[O:16])=[CH:9][CH:8]=3)[CH:13]=[C:5]2[C:3]([OH:4])=[O:2])=[CH:24][CH:23]=1
Reactant: COC(=O)c1cc2cc(S(C)(=O)=O)ccc2n1Cc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc2c(c1)cc(C(=O)O)n2Cc1ccc(F)cc1
Reaction time: 2 h

Procedure:
To a mixture of the compound obtained in Example 22 (3) (0.26,g), tetrahydrofuran (5 ml) and methanol (10 ml), a 1N aqueous sodium hydroxide solution (5 ml) was added at 15 to 30° C. and the mixture was stirred for 2 hours. 1N hydrochloric acid was added thereto and the mixture was extracted with dichloromethane. The organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure to obtain 0.25 g of the desired product as a white crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[CH:7][CH:8]=1.C([Li])CCC.CN(C)[C:17](=[O:19])[CH3:18].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH3:1][O:2][C:3]1[C:4]([CH2:9][C:17](=[O:19])[CH3:18])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)N(C)C
Reactant: COc1cccnc1C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cccnc1CC(C)=O
Temperature: 0 °C

Procedure:
To a stirred solution of 3-methoxy-2-methylpyridine (844 mg) in tetrahydrofuran (10 ml) was added a solution of n-butyllithium in n-hexane (1.59M, 5.6 ml) dropwise at −50° C. under a nitrogen atmosphere, and the mixture was warmed to 0° C. The mixture was cooled to −50° C., and N,N-dimethylacetamide (0.955 ml) was added dropwise. Then the mixture was warmed to room temperature, poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate (100 ml). The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 50 g, 25% ethyl acetate in n-hexane) to give 1-(3-methoxypyridin-2-yl)propan-2-one (1.12 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:8]([O:11]COC)=[CH:9][N:10]=1)[CH:6]=[O:7].Cl.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[OH:11][C:8]1[C:5]([CH:6]=[O:7])=[CH:4][C:3]([O:2][CH3:1])=[N:10][CH:9]=1
Reactant: COCOc1cnc(OC)cc1C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C=O)c(O)cn1
Temperature: 50 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
To a solution of 2-methoxy-5-(methoxymethoxy)isonicotinaldehyde (33.5 g, 0.17 mol) in THF (150 mL) was added HCl (3 N, 250 mL). The reaction was stirred at 50° C. for 1 h, cooled to RT and diluted with water (500 mL). The mixture was neutralized to pH 7-8 with solid K2CO3. The pale yellow solid was collected, washed with water, and dried in vacuum oven (40° C.) overnight to give 5-hydroxy-2-methoxyisonicotinaldehyde (17.9 g, 74.6%). 1H NMR (400 MHz; DMSO)=10.31 (s, 1H), 8.03 (s, 1H), 6.89 (s, 1H), 3.80 (s, 3H); MS (ESI) m/z 154.0 [M+H]+.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)=[CH:22][CH:21]=1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Reactant: OB(O)c1ccc(F)cc1
Product: N#Cc1cc(-c2ccc(F)cc2)c2c(c1)cc1n2CCCNC1=O

Procedure:
The title compound, light grey solid (75 mg, 94%), MS (ISP) m/z=320.4 [(M+H)+], mp 230° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available 4-fluoro-phenylboronic acid (45.5 mg, 0.325 mmol).
Reaction SMILES: C[C:2]1[C:3]([O:13][CH3:14])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[C:15]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:34]1[CH:39]=[CH:38][C:37]([C@@H:40](O)[CH3:41])=[CH:36][CH:35]=1>C1COCC1>[F:12][C:9]1[C:10]([O:11][C@H:40]([C:37]2[CH:38]=[CH:39][N:34]=[CH:35][CH:36]=2)[CH3:41])=[CH:2][C:3]([O:13][CH3:14])=[C:4]([CH:8]=1)[C:5]([O:7][CH3:15])=[O:6]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COc1c(C(=O)O)cc(F)c(O)c1C
Reactant: C[C@H](O)c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(F)c(O[C@@H](C)c2ccncc2)cc1OC
Temperature: 0 °C

Procedure:
A stirred solution of methyl 5-fluoro-2-methoxy-4-hydroxybenzoic acid (250 mg, 1.25 mmol, see Scheme II) in THF (15 mL) was treated with triphenylphosphine (494 mg, 1.88 mmol) and cooled to 0° C. under Argon. To this was added, dropwise over a period of 1 h, a solution of (S)-(-)-1-(4-pyridyl)-ethanol (232 mg, 1.88 mmol) and N,N'-diethylazodicarboxylate (300 μL, 1.88 mmol) in THF (5 mL). The reaction was allowed to warm to ambient temperature overnight with stirring. The reaction was filtered and the solvent was removed under reduced pressure. The residue was chromatographed on a silica gel column packed in 1:1 CH2Cl2 :EtOAc and elated with same. The appropriate fractions were combined and the solvent removed under reduced pressure to afford an impure mixture of 5-fluoro-2-methoxy-4-[1-(S)-(4-pyridyl)ethoxylbenzoate. The residue was rechromatographed on a preparative HPLC using a gradient of 95:5 to 5:95 water:acetonitrile (0.1% TFA added). The appropriate fractions were combined and the solvent removed under reduced pressure to afford the methyl 5-fluoro-2-methoxy-4-[1-(S)-(4-pyridyl)ethoxy]benzoate.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([O:12][CH3:13])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH2:6]2.C(O)(=[O:16])C>[Cr].O>[Cl:11][C:10]1[C:2]([Cl:1])=[C:3]2[C:7]([CH2:6][CH2:5][C:4]2=[O:16])=[CH:8][C:9]=1[O:12][CH3:13]
Reactant: CC(=O)O
Reactant: COc1cc2c(c(Cl)c1Cl)CCC2
Agent: [Cr]
Solvent: O
Product: COc1cc2c(c(Cl)c1Cl)C(=O)CC2
Reaction time: 1 h

Procedure:
4,5-Dichloro-6-methoxy-2,3-dihydro-1H-indene (21 gm., 0.097 mole) is dissolved in acetic acid (280 ml.) and chromium, trioxide (14 gm., 0.14 mole) in a mixture of water (15 ml.) and acetic acid (40 ml.) is added dropwise with stirring over a period of one hour. The mixture is poured, with stirring into cold water (1200 ml.) and the solid that separates is removed by filtration, washed with water and dried. The product, which consists of a mixture of the desired material and the isomer described in Step D, is subjected to column chromatographic separation using 225 gm. of silica gel and chloroform is used for elution. Evaporation of the solvent gives 6,7-dichloro-5-methoxy-2,3-dihydro-1H-inden-1-one, 5.2 gm., m.p. 154°-156° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3[F:35])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[C:18]=3[CH3:26])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[OH:36].[CH3:37][O:38][C:39](=[O:43])[C@@H:40]([CH3:42])O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3[F:35])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[C:18]=3[CH3:26])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[O:36][C@H:40]([CH3:42])[C:39]([O:38][CH3:37])=[O:43]
Reactant: COC(=O)[C@@H](C)O
Reactant: Cc1c(N(Cc2ccc(Oc3ccc(Cl)c(O)c3)cc2)Cc2ccc(F)cc2F)cccc1[N+](=O)[O-]
Product: COC(=O)[C@@H](C)Oc1cc(Oc2ccc(CN(Cc3ccc(F)cc3F)c3cccc([N+](=O)[O-])c3C)cc2)ccc1Cl

Procedure:
The product from Example 91F and methyl-(R)-lactate was processed as described in Example 62A to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([CH3:9])[CH:5]=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20].[Br:21]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(OCC)(=O)C>C(Cl)(Cl)(Cl)Cl>[Br:21][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([N:10]2[C:11](=[O:20])[C:12]3=[CH:19][CH:18]=[CH:17][CH:16]=[C:13]3[C:14]2=[O:15])=[C:2]([Cl:1])[C:7]=1[Cl:8]
Reactant: Cc1ccc(N2C(=O)c3ccccc3C2=O)c(Cl)c1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1c2ccccc2C(=O)N1c1ccc(CBr)c(Cl)c1Cl
Yield: 87.9 %

Procedure:
A solution of 4.0 grams (0.013 mole) of N-(2,3-dichloro-4-methylphenyl)phthalimide, 2.3 grams (0.013 mole) of N-bromosuccinimide and 0.3 gram of benzoyl peroxide in 200 ml of carbon tetrachloride was heated under reflux for 22 hours. The cooled reaction mixture was poured into 500 ml of ethyl acetate. The solution was washed with three 100 ml portions of water. The organic layer was dried with magnesium sulfate and was filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished using ethyl acetate:heptane (1:4). The appropriate fractions were combined and concentrated under reduced pressure to yield 4.4 grams of N-(4-bromomethyl-2,3-dichlorophenyl)phthalimide as a solid.
Reaction SMILES: C([C:4]1[NH:5][C:6]2[C:11]([C:12]=1[CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])=[CH:10][C:9]([CH2:18][S:19]([N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)(=[O:21])=[O:20])=[CH:8][CH:7]=2)(O)=O.Cl.C(OCC)(=O)C>N1C2C(=CC=CC=2)C=CC=1>[CH3:17][N:15]([CH3:16])[CH2:14][CH2:13][C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:18][S:19]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)(=[O:21])=[O:20])[CH:10]=2)[NH:5][CH:4]=1
Reactant: CN(C)CCc1c(C(=O)O)[nH]c2ccc(CS(=O)(=O)N3CCCC3)cc12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccc2ncccc2c1
Product: CN(C)CCc1c[nH]c2ccc(CS(=O)(=O)N3CCCC3)cc12
Temperature: 190 °C
Yield: 5.4 %

Procedure:
To a solution of previously dried 1-[[2-carboxy-3-(2-dimethylaminoethyl)-5-indolyl]methanesulphonyl]pyrrolidine (1.6 g; 0.0442 moles) in anhydrous quinoline (75 ml) and under atmosphere of nitrogen, cuprous oxide (160 mg; 0.0011 moles) was added. The reaction mixture was heated to 190° C. for 15 minutes, stirred to room temperature, poured into a mixture of 1N hydrochloric acid (150 ml) and ethyl acetate (50 ml), shaken and decanted. The aqueous solution was washed several times with ethyl acetate, then solid sodium bicarbonate was added until pH=7.8, and washed with n-hexane to eliminate the quinoline. The aqueous solution was made alkaline with solid potassium carbonate and extracted with ethyl acetate. The organic solution was dried (Na2SO4), the solvent removed under reduced pressure when a dark oil was obtained (1.3 g; yield 92%). This product was purified by column chromatography with silica gel and methylene chloride:ethanol:ammonium hydroxide (60:8:1) as eluent and a white foam (0.8 g) of 1-[[3-(2-dimethylaminoethyl)-5-indolyl]methanesulphonyl]pyrrolidine was obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[F:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([Cl:23])=[O:22])=[CH:19][CH:18]=1>>[ClH:23].[F:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:15][C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([O:8][CH:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)[N:14]=2)=[O:22])=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CN1CCC(Oc2cccc(N)n2)CC1
Product: CN1CCC(Oc2cccc(NC(=O)c3ccc(F)cc3)n2)CC1
Product: Cl
Yield: 96.7 %

Procedure:
Using a method similar to example 160, starting with 6-(1-methyl-piperidin-4-yloxy)-pyridin-2-ylamine (preparation 60, 150 mg, 0.724 mmol) and 4-fluorobenzoyl chloride (128 μL, 1.08 mmol) yields the title compound (256 mg, 97%). Mass spectrum (ion spray): m/z 330.1 (M+1); Analysis calculated for C18H21N3O2FCl.0.5H2O. The C, 57.68; H, 5.92; N, 11.21. Found: C, 57.76; H, 6.17; N, 11.44. mp=203-205° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[N:20]=[C:19]([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[N:18]=[C:17]([O:27][CH2:28][CH2:29][OH:30])[C:16]=2[O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[O:38][CH3:39])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CS(C)=[O:42]>>[OH:30][CH2:29][CH2:28][O:27][C:17]1[C:16]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[O:38][CH3:39])=[C:15]([NH:14][S:11]([C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH2:3][OH:42])=[CH:10][CH:9]=2)(=[O:12])=[O:13])[N:20]=[C:19]([C:21]2[N:22]=[CH:23][CH:24]=[CH:25][N:26]=2)[N:18]=1
Reactant: CS(C)=O
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(-c2ncccn2)nc1OCCO
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)CO)cc2)nc(-c2ncccn2)nc1OCCO
Reaction time: 48 h

Procedure:
Streptomyces rimosus subsp. rimosus ATCC10970 maintained on a quarter strength ATCC172 agar slope was inoculated as a loopful of spores into a 300 ml Erlenmeyer flask containing 50 ml of AS-7H 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 one 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 1 mg of 4-tert butyl-N-[4-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)pyrimidin-6-yl]benzenesulphonamide (CA 2071193) dissolved in 0.5 ml of dimethylsulfoxide was added to each of the flasks and the fermentation allowed to continue under the same conditions for a further 24 hours. The 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[C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][CH2:8][N:9]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][N:16]=3)=[O:13])[C:10]=2[N:11]=1.[Li]CCCC.CN([CH:30]=[O:31])C>C1COCC1>[CH:30]([C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][CH2:8][N:9]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][N:16]=3)=[O:13])[C:10]=2[N:11]=1)=[O:31]
Reactant: CN(C)C=O
Reactant: Cc1ccc(NC(=O)N2CCOc3ccc(Br)nc32)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)N2CCOc3ccc(C=O)nc32)nc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
6-Bromo-N-(5-methylpyridin-2-yl)-2H-pyrido[3,2-b][1,4]oxazine-4(3H)-carboxamide (intermediate 1A, 110 mg, 0.284 mmol) was dissolved in THF (3 ml). The solution was flushed with argon and cooled to −78° C. Subsequently, n-BuLi (1.4 M in hexanes, 0.506 ml, 0.709 mmol) was added drop wise and the mixture was stirred for 1 h at −78° C. before DMF (200 μl, 2.58 mmol) was added. The reaction mixture was stirred for 1 h at −78° C. and then slowly warmed up to room temperature. The reaction mixture was quenched with sat. aq. NH4Cl and diluted with EtOAc. The org. layer was separated, washed with water, dried over Na2SO4, filtered and concentrated. The crude material was purified by normal phase chromatography (4 g silica gel cartridge, heptanes/EtOAc 80:20 to 0:100) followed by preparative supercritical fluid chromatography (SFC 1, Hilic column) to obtain the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])=[C:12]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[C:32](OC(=O)C)(=[O:34])[CH3:33].C(N(CC)CC)C>CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])=[C:12]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([NH:31][C:32](=[O:34])[CH3:33])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(O)COc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: CC(=O)NS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(F)c3)c(=O)c2OCC(C)(C)O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-(3,4-difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(aminosulfonyl)phenyl]-3(2H)-pyridazinone (Example 459, 1 equivalent), acetic anhydride (3 equivalents), 4-(dimethylamino)pyridine (0.3 equivalents), and triethylamine (1.2 equivalents) is stirred at room temperature for 16 hours. The reaction mixture is partitioned between ethyl acetate and water. The organic layer is washed with brine then dried over MgSO4 and filtered. The filtrate is concentrated in vacuo to give the title compound.
Reaction SMILES: C([C:3](CC)([C:7]([C:9]([O-:11])=[O:10])=O)[C:4]([O-])=[O:5])C.[Na+].[Na+].C(O)(=O)C.[CH:20]([NH2:22])=[NH:21].[OH-].[Na+].C>O>[OH:5][C:4]1[N:22]=[CH:20][N:21]=[C:7]([C:9]([OH:11])=[O:10])[CH:3]=1
Reactant: CCC(CC)(C(=O)[O-])C(=O)C(=O)[O-]
Reactant: N=CN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cc(O)ncn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
63.5 g (287 mmol) sodium diethyl-oxalacetate and 30.2 g (287 mmol) formamidine acetate were added to 24.1 g (0.597 mol) NaOH in 3.6 L water. The mixture was stirred overnight at RT. Then activated charcoal was added and the mixture was refluxed for 1 h. It was filtered while hot and after cooling acidified with aqueous HCl. The solution was concentrated to dryness by rotary evaporation. The residue contained the desired product and was used in the next step without any further purification.