Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([NH:11][C:12]3[CH:22]=[CH:21][C:15]([C:16]([N:18]([CH3:20])[CH3:19])=[O:17])=[C:14]([CH3:23])[CH:13]=3)=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[F:24][C:25]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[C:36]([F:49])[C:26]=1[CH2:27][N:28]1[CH2:33][CH2:32][S:31](=[O:35])(=[O:34])[CH2:30][CH2:29]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:35]=[S:31]1(=[O:34])[CH2:32][CH2:33][N:28]([CH2:27][C:26]2[C:36]([F:49])=[CH:37][C:38]([C:2]3[C:10]4[O:9][C:8]([NH:11][C:12]5[CH:22]=[CH:21][C:15]([C:16]([N:18]([CH3:20])[CH3:19])=[O:17])=[C:14]([CH3:23])[CH:13]=5)=[N:7][C:6]=4[CH:5]=[CH:4][CH:3]=3)=[CH:39][C:25]=2[F:24])[CH2:29][CH2:30]1
Reactant: Cc1cc(Nc2nc3cccc(Br)c3o2)ccc1C(=O)N(C)C
Reactant: CC1(C)OB(c2cc(F)c(CN3CCS(=O)(=O)CC3)c(F)c2)OC1(C)C
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc(Nc2nc3cccc(-c4cc(F)c(CN5CCS(=O)(=O)CC5)c(F)c4)c3o2)ccc1C(=O)N(C)C
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of 0.1 g (0.267 mmol) 4-(7-bromo-benzooxazol-2-ylamino)-2,N,N-trimethyl-benzamide, 0.114 g (0.294 mmol) 4-[2,6-difluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-thiomorpholine 1,1-dioxid and 174 mg K3PO4 are dissolved in 5 ml 1,2-dimethoxy-ethane, water (0.1 ml) is added and a stream of argon is bubbled through the mixture in order to exclude oxygen from the reaction mixture. Tetrakis (triphenylphosphine) palladium (0.0095 g, 0.0082 mmol) is added and the reaction mixture is stirred at 100° C. for 8 h. After that the reaction mixture is poured on water and extracted 3× with EtOAc. The combined organic layers are washed with water and saturated NaCl solution, dried over MgSO4, filtered and the filtrate is concentrated in vacuo. The residue is purified by chromatography (silicagel, EtOAc), followed by recrystallisation diethylether/methanol to afford the title compound as white crystals. Rt=2.13 min (Waters Symmetry C8, 2.1×50 mm, detection 210-250 nM, 5% to 100% CH3CN in H2O in 2 min+0.05% TFA, flow rate 1.0 ml/min); MS: 555 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]1[N:14]([C:15]([N:17]([C@@H:19]([C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=2)[CH3:20])[CH3:18])=[O:16])[CH2:13][CH2:12][C@H:11]([N:35]2[CH2:40][C@@H:39]3[CH2:41][CH2:42][C:43](=[O:44])[N:38]3[CH2:37][CH2:36]2)[CH2:10]1.Cl.[OH2:46].N.[C:48]([O:51]CC)(=[O:50])[CH3:49]>>[CH3:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]1[N:14]([C:15]([N:17]([C@@H:19]([C:21]2[CH:22]=[C:23]([C:31]([F:32])([F:33])[F:34])[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=2)[CH3:20])[CH3:18])=[O:16])[CH2:13][CH2:12][C@H:11]([N:35]2[CH2:40][C@@H:39]3[CH2:41][CH2:42][C:43](=[O:44])[N:38]3[CH2:37][CH2:36]2)[CH2:10]1.[CH:49](/[C:48]([OH:51])=[O:50])=[CH:42]/[C:43]([OH:44])=[O:46]
Reactant: CCOC(C)=O
Reactant: O
Agent: Cc1cc(F)ccc1[C@H]1C[C@@H](N2CCN3C(=O)CC[C@H]3C2)CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Agent: N
Product: O=C(O)/C=C\C(=O)O
Reaction time: 8 h

Procedure:
Orvepitant Hydrochloride (1.00 G) Was Suspended In Ethyl Acetate (20 Ml) And Water (10 ml) and 25% w/w ammonia (10 ml) were added. The aqueous layer was separated and the organic layer was washed with 10% w/w sodium chloride solution (2×10 ml). The organic solution was separated, evaporated to dryness and isopropanol (20 ml) was added. The solution was evaporated to dryness. The material was diluted with isopropanol (6 ml) and a solution of maleic acid (0.174 g) in isopropanol (2.0 ml) was added. Iso-octane (a total of 8 ml) was added and the solution was stirred overnight. The solution was evaporated to an oil. Tert-butyl methyl ether (10 ml) was added and the solution was evaporated to dryness. Repeat the addition of tert-butyl methyl ether and evaporation a total of 4 times. On final evaporation, a foam forms that solidifies to give the title compound.
Reaction SMILES: [Cl-].C[Al+]C.[N+:5]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:16]=1[NH:15][CH:14]=[CH:13]2)([O-:7])=[O:6].[C:17](Cl)(=[O:19])[CH3:18].[Cl-].[NH4+]>CCCCCC.ClCCl>[C:17]([C:13]1[C:12]2[C:16](=[C:8]([N+:5]([O-:7])=[O:6])[CH:9]=[CH:10][CH:11]=2)[NH:15][CH:14]=1)(=[O:19])[CH3:18]
Reactant: O=[N+]([O-])c1cccc2cc[nH]c12
Reactant: CC(=O)Cl
Agent: C[Al+]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(=O)c1c[nH]c2c([N+](=O)[O-])cccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A 1.0M solution (11 ml) of dimethylaluminum chloride (11 mmol) in hexane was added to 50 ml of a solution of 1.2 g (7.5 mmol) of 7-nitro-1H-indole in dichloromethane at 0° C. in a nitrogen atmosphere, followed by the addition of 2.1 ml (29.5 mmol) of acetyl chloride at 0° C. The obtained mixture was stirred at room temperature for 4 hours, followed by the addition of a saturated aqueous solution of ammonium chloride. The precipitate thus formed was recovered by filtration and washed with hot ethanol sufficiently. The washings and the filtrate were combined and concentrated. Water was added to the residue and the resulting mixture was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous solution of common salt, dried over magnesium sulfate and distilled in a vacuum to remove the solvent. The residue was purified by silica gel column chromatography to give 3-acetyl-7-nitro-1H-indole. This product was dissolved in 100 ml of methanol and hydrogenated in the presence of palladium-carbon at ordinary temperature under normal pressure. After the removal of the catalyst by filtration, the filtrate was concentrated to dryness to give 790 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C([N:14]=C=NCCCN(C)C)C.[Cl-].[NH4+].C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:14])=[O:5]
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1cccc(C(=O)O)c1N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cccc(C(N)=O)c1N
Reaction time: 60 h
Yield: 86.6 %

Procedure:
To 2-amino-3-methylbenzoic acid (1.5 g, 10 mmol) in DMF (5 mL) at rt were added hydroxybenzatriazole (2.0 g, 13 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (2.3 g, 12 mmol), ammonium chloride (2.3 g, 42 mmol), and diisopropylethylamine (7.5 ml, 42 mmol). The mixture was purged with N2 and stirred for 60 h. The mixture was poured into water and extracte with EtOAc (50 mL×3), and the combined extracts were washed with brine (20 mL×2), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was dissolved in DCM and purified by silica gel chromatography eluting with 1:1 EtOAc/hexanes to afford 2-amino-3-methyl-benzamide as a white solid (1.3 g, 87%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5]P(OCC)(OCC)=O)C.C[O-].[Na+].CO.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][C:30](=O)[C:29]([CH3:35])([CH3:34])[CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>O1CCCC1>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH:31]=[C:30]([CH2:5][C:4]([O:3][CH3:1])=[O:14])[C:29]([CH3:35])([CH3:34])[CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(C)(C)C1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CC1=CCN(C(=O)OC(C)(C)C)CC1(C)C
Yield: 52.9 %

Procedure:
To a cooled (0° C.) solution of diethylphosphonoacetic acid ethyl ester (4.4 mL, 24.2 mmol) in tetrahydrofuran (50 mL) under an atmosphere of nitrogen were added a solution of 28% sodium methoxide in methanol (4.6 mL, 26.4 mmol), and then a solution of 3,3-dimethyl-4-oxopiperidine-1-carboxylic acid t-butyl ester (5.0 g, 22.0 mmol) in tetrahydrofuran (10 mL) and stirred for 3 hours at room temperature. After the reaction was completed, the solvent was removed under a reduced pressure and water was added to the residue. The mixture was extracted with ether, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After drying, the extract was filtered and the filtrate was concentrated under a reduced pressure. The residue was subjected to silica gel column chromatography (developing solvent, hexane:ethyl acetate=6:1) to obtain 1.8 g (yield 32.1%) of 4-methoxycarbonylmethylene-3,3-dimethylpiperidine-1-carbxylic acid t-butyl ester (A) and 3.3 g (yield 58.9%) of 4-methoxycarbonylmethyl-3,3-dimethyl-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (B). Each of their physical properties is shown below.
Reaction SMILES: [CH:1]([N:4]([C:18]([C:20]1[CH:28]=[C:27]2[C:23]([C:24]([CH3:37])([CH3:36])[C:25](=[O:35])[N:26]2[CH2:29][CH2:30][CH2:31][CH2:32][O:33][CH3:34])=[CH:22][CH:21]=1)=[O:19])[C@@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1)([CH3:3])[CH3:2].C1C(=O)N([Cl:45])C(=O)C1.CN(C=O)C>O>[Cl:45][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][C:20]=1[C:18]([N:4]([CH:1]([CH3:3])[CH3:2])[C@@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1)=[O:19])[N:26]([CH2:29][CH2:30][CH2:31][CH2:32][O:33][CH3:34])[C:25](=[O:35])[C:24]2([CH3:36])[CH3:37]
Reactant: COCCCCN1C(=O)C(C)(C)c2ccc(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc21
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: COCCCCN1C(=O)C(C)(C)c2cc(Cl)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc21
Temperature: 65 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
To tert-butyl (3R)-3-(isopropyl{[1-(4-methoxybutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl]carbonyl}amino)piperidine-1-carboxylate (220 mg) were added NCS (86 mg) and DMF (5 ml), and the mixture was stirred at 65° C. for one hour. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate solution. This ethyl acetate was washed with water and an aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to give the title compound (200 mg) as a colorless liquid.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:36])[N:8]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:9]=[CH:10][C:11]=1[CH2:12][N:13]([CH2:24][C:25]([O:27][CH3:28])=[O:26])S(C1C=CC(C)=CC=1)(=O)=O)=O)C.C[O-].[Na+].Cl>CO>[CH3:28][O:27][C:25]([C:24]1[N:13]=[CH:12][C:11]2[CH:10]=[CH:9][N:8]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:7](=[O:36])[C:6]=2[C:4]=1[OH:3])=[O:26]
Reactant: CCOC(=O)c1c(CN(CC(=O)OC)S(=O)(=O)c2ccc(C)cc2)ccn(Cc2ccccc2)c1=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ncc2ccn(Cc3ccccc3)c(=O)c2c1O
Reaction time: 8 h
Yield: 32.1 %

Procedure:
1-Benzyl-4-{[methoxycarbonylmethyl-(toluene-4-sulfonyl)-amino]-methyl}-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid ethyl ester (0.94 g, 1.84 mmol) was dissolved in MeOH (40 mL) and cooled in an ice bath. NaOMe solution (1.3 mL, 5.51 mmol, 25 wt % in MeOH) was added, and the mixture was stirred overnight. The mixture was placed in an ice bath, and 1 M HCl was added until pH was about 3-4. The resulting suspension was extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated. The residue was chromatographed (5-90% EtOAc/hexanes+2% AcOH) to give 183 mg of the title compound as an orange solid. MS: (−) m/z 309.01 (M−1).
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[Cl:32])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)C.[OH-].[Na+]>O1CCCC1>[Cl:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[O:25][C:22]1[CH:23]=[CH:24][C:19]([S:16]([NH:15][C@@H:10]2[CH2:11][CH2:12][CH2:13][C:14]3[N:6]([CH2:5][C:4]([OH:33])=[O:3])[N:7]=[CH:8][C:9]2=3)(=[O:17])=[O:18])=[CH:20][CH:21]=1
Reactant: CCOC(=O)Cn1ncc2c1CCC[C@H]2NS(=O)(=O)c1ccc(Oc2ccccc2Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cn1ncc2c1CCC[C@H]2NS(=O)(=O)c1ccc(Oc2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a solution of {(R)-4-[4-(2-chloro-phenoxy)-benzenesulfonylamino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid ethyl ester (example 1-1) (167 mg, 0.34 mmol) in tetrahydrofuran (3 mL) was added 1N sodium hydroxide (3 mL). The reaction mixture was stirred at room temperature for 2 hours, and then extracted with diethyl ether (10 mL). The organic layer was discarded. The aqueous layer was acidified with concentrated hydrochloric acid to pH 4 and stirred with diethyl ether (3 mL) and petroleum ether (9 mL) at room temperature for 2 hours. The resulting mixture was filtered through a glass funnel to afford {(R)-4-[4-(2-chloro-phenoxy)-benzenesulfonylamino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid (124 mg, 79%) as a white powder. 1H NMR (400 MHz, CD3OD) δ ppm 7.94 (d, 2 H), 7.60 (q, 1 H), 7.43 (m, 1 H), 7.26 (m, 2 H), 7.07 (d, 2 H), 6.70 (s, 1 H), 4.80 (s, 2 H), 4.37 (t, 1 H), 2.60-2.48 (m, 2 H), 1.94-1.75 (m, 4 H). MS cald. (calculated) for C21H20ClN3O5S 461, obsd. (observed) (ESI+) [(M+H)+] 462.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][N:4]=1.C([Li])CCC.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]=[O:22].[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=2)[OH:22])=[CH:5][N:4]=1
Reactant: COc1ccc(Br)cn1
Reactant: O=Cc1ccccn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2ccccn2)cn1
Temperature: -78 °C
Reaction time: 1 h
Yield: 44.6 %

Procedure:
50 ml of a tetrahydrofuran solution containing 3.00 g of 2-methoxy-5-bromopyridine was cooled to −78° C., followed by the dropwise addition of 10 ml of n-butyl lithium (1.6M hexane solution). After the completion of the dropwise addition, 1.70 g of picoline aldehyde was immediately added thereto, followed by stirring at −78° C. for 1 hour, to return the mixture slowly to room temperature. To the mixture was added a saturated aqueous solution of ammonium chloride, and then it was extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, and then dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel chromatography (ethyl acetate), to give 1.53 g of the title compound as a pale yellow solid.
Reaction SMILES: [CH3:1][C@@:2]1([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[CH:19]=[N:20][CH:21]=[N:22][CH:23]=3)[CH:13]=2)[CH2:7][CH2:6][S:5][C:4]([NH:8]C(=O)C)=[N:3]1.[ClH:24]>>[ClH:24].[ClH:24].[CH3:1][C@@:2]1([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[CH:19]=[N:20][CH:21]=[N:22][CH:23]=3)[CH:13]=2)[CH2:7][CH2:6][S:5][C:4]([NH2:8])=[N:3]1
Reactant: CC(=O)NC1=N[C@](C)(c2cccc(-c3cncnc3)c2)CCS1
Agent: Cl
Product: C[C@@]1(c2cccc(-c3cncnc3)c2)CCSC(N)=N1
Yield: 81 %

Procedure:
A solution of (S)-N-[4-Methyl-4-(3-pyrimidin-5-yl-phenyl)-5,6-dihydro-4H-[1,3]thiazin-2-yl]-acetamide (2.7 g, 8.3 mmoles, 1.0 equiv) is stirred in 5N hydrogen chloride (50 mL, 250 mmoles, 30 equiv) at 100° C. for 2 h. The reaction is cooled and the volatiles are removed under reduced pressure. The resulting residue is dissolved in water and extracted with ethyl acetate. The aqueous phase is neutralized with saturated aqueous sodium bicarbonate and extracted ethyl acetate. The organic phase is dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue is filtered through a silica gel plug and washed with ethyl acetate. The silica gel plug is further washed with ethyl acetate containing ethyl acetate and 10% isopropyl amine. The 10% isopropyl amine in ethyl acetate wash is collected and the solvent removed under reduced pressure. The resulting free amine is dissolved in a solution of 100 mL of water containing 14 mL of 1 N HCl. The resulting solution is freeze dried to give the title compound (81% yield): MS (m/z): 285 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[C:5]([N+:15]([O-:17])=[O:16])=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:3]=1.[F:24][CH:25]([F:37])[C:26]1[NH:30][C:29]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:28]=2[N:27]=1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl.CCOC(C)=O>CS(C)=O.O>[F:37][CH:25]([F:24])[C:26]1[N:30]([C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=3)[C:5]([N+:15]([O-:17])=[O:16])=[C:4]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:3]=2)[C:29]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:28]=2[N:27]=1
Reactant: COc1cccc2[nH]c(C(F)F)nc12
Reactant: O=[N+]([O-])c1c(Nc2cccnc2)nc(Cl)nc1N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(Nc2cccnc2)c([N+](=O)[O-])c(N2CCOCC2)n1
Temperature: 120 °C
Yield: 74.6 %

Procedure:
A mixture of 0.23 g of the above nitro compound (0.68 mmol), 0.147 g (0.74 mmol) of 2-difluoromethyl-4-methoxy-1H-benzimidazole (Example 2) and 0.38 g (2.75 mmol) of powdered K2CO3 in 4 mL of DMSO was heated at 120° C. for 4 hrs. The reaction mixture was diluted with water, and extracted with EtOAc (×4). The combined organic layers were washed with brine, dried, and concentrated. The residue was purified by chromatography on silica, eluting first with hexanes/EtOAc (1:1), and then with CH2Cl2/EtOAc (2:1), to give 0.253 g (75% yield) of 2-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-5-nitro-N-(3-pyridinyl)-4-pyrimidinamine, as a yellow powder: 1H NMR (CDCl3) δ 10.26 (s, 1H), 8.72 (d, J=2.4 Hz, 1H), 8.60 (dd, J=4.8, 1.4 Hz, 1H), 7.95 (ddd, J=8.3, 2.4, 1.6 Hz, 1H), 7.45 (dd, J=8.3, 0.6 Hz, 1H), 7.40 (dd, J=8.3, 4.8 Hz, 1H), 7.18 (t, J=8.3 Hz, 1H), 7.11 (t, JHF=53.5 Hz, 1H), 6.78 (d, J=7.8 Hz, 1H), 4.03 (s, 3H), 3.88 (t, J=4.5 Hz, 4H), 3.70 (t, J=4.5 Hz, 4H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([OH:13])(=O)[CH2:8][CH2:9][CH:10]=[CH2:11].C(Cl)(=O)CCC=C.[CH3:21][NH:22][O:23][CH3:24].C(=O)([O-])[O-].[K+].[K+].Cl.CNOC>ClCCl.O>[CH3:24][O:23][N:22]([CH3:21])[C:7](=[O:13])[CH2:8][CH2:9][CH:10]=[CH2:11]
Reactant: C=CCCC(=O)O
Reactant: CNOC
Agent: C=CCCC(=O)Cl
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Product: C=CCCC(=O)N(C)OC
Temperature: 0 °C
Reaction time: 45 h

Procedure:
Oxalyl chloride (25 g) was added dropwise at 0° C. under nitrogen to a stirred solution of pent-4-enoic acid (19 ml) in dichloromethane (400 ml), then the mixture was stirred at 0° C. for 45 minutes and at ambient temperature for 45 hours. The resulting solution of pent-4-enoyl chloride was added dropwise at 0-5° C. over 1.25 hours to a stirred aqueous solution of N,O-dimethylhydroxylamine prepared by addition of potassium carbonate (46.6 g) in portions at 0-5° C. over 30 minutes to a stirred solution of N,O-dimethylhydroxylamine hydrochloride (19.2 g) in water (200 ml). When the addition of the acid chloride solution was complete, the mixture was stirred at 0° C. for 30 minutes and at ambient temperature for 5 hours, then it was allowed to stand at ambient temperature for 65 hours. The organic phase was separated, washed with water (200 ml) and saturated aqueous sodium chloride solution (200 ml) and dried (MgSO4), then the solvent was removed in vacuo to leave N-methoxy-N-methylpent-4-enamide (30.7 g) as a colourless oil which was used without further purification.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[S:5][C:6]=1[C:7]1[N:11]2[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]2=[N:9][C:8]=1[CH3:22].[Li]CCCC.CCCCCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:50])(=O)=O)=CC=1.[NH4+].[Cl-]>C(OCC)C.C1(C)C=CC=CC=1>[CH2:17]([CH:16]([C:15]1[C:10]2[N:11]([C:7]([C:6]3[S:5][C:4]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[N:3][C:2]=3[F:50])=[C:8]([CH3:22])[N:9]=2)[N:12]=[C:13]([CH3:21])[CH:14]=1)[CH2:19][CH3:20])[CH3:18]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(N4CCOCC4)nc3Br)c(C)nc12
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCC(CC)c1cc(C)nn2c(-c3sc(N4CCOCC4)nc3F)c(C)nc12
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 9.2 %

Procedure:
50 mg of 3-(4-Bromo-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.11 mmol) is dissolved in 4 ml of diethylether and cooled to −78° C. and 0.1 ml of n-BuLi 1.6M in hexane (0.16 mmol) is added at −78° C. and stirred at −78° C. for 20 min. 104 mg of N-fluorobenzene sulfonimide (0.33 mmol) in 2 ml of toluene is added at −78° C. and stirred at room temperature for 1 h. sat. NH4Cl is added, and the mixture is extracted with Et2O, dried over Na2SO4 and evaporated. The crude product is applied onto a silica-gel chromatography column (Hexane:AcOEt=3:1) to give 4.1 mg of the title compound. Yield 10%. Mass spectrum (m/e): 404 (M+1). 6.71 (s, 1H), 3.87 (t, J=4.6 Hz, 4H), 3.55 (t, J=5.0 Hz, 4H), 3.34 (m, 1H), 2.58 (s, 3H), 2.54 (s, 3H), 1.84 (m, 4H), 0.88 (t, J=7.4 Hz, 6H).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16](Cl)=[O:17])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[C@@H:19]12[O:28][C@@H:23]([O:24][C@H:25]1[CH2:26][OH:27])[CH2:22][NH:21][CH2:20]2.C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[OH:27][CH2:26][C@H:25]1[C@H:19]2[O:28][C@H:23]([CH2:22][N:21]([C:16]([C:13]3[S:14][CH:15]=[C:11]([C:7]4[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=4[CH3:10])[N:12]=3)=[O:17])[CH2:20]2)[O:24]1
Reactant: CC(=O)Nc1nc(C)c(-c2csc(C(=O)Cl)n2)s1
Reactant: OC[C@@H]1O[C@H]2CNC[C@@H]1O2
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)c(-c2csc(C(=O)N3C[C@@H]4O[C@@H](CO)[C@H](C3)O4)n2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2′-Acetylamino-4′-methyl-[4,5′]bithiazolyl-2-carbonyl chloride, prepared as in Step I of Example 13, described above (200 mg, 0.66 mmol, 1 eq.), is dissolved in THF (8 ml) and DCM (4 ml). (1S,5S,7S)-6,8-dioxa-3-azabicyclo[3.2.1]oct-7-ylmethanol, synthesized according the literature (Guarna et al J. Org. Chem. 1999, 64, 7347) (96.2 mg; 0.66 mmol; 1 eq.), and triethylamine (0.37 ml; 2.65 mmol; 4 eq.) are added and the mixture is stirred 1 hour at rt. Solvents are evaporated and the crude product is purified by preparative HPLC, affording Compound (49) as a white-off powder (73 mg; 26%). M− (ESI): 409.16; M+ (ESI): 411.07. HPLC (method A), Rt: 2.16 min (purity: 95.46%).