Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C([O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH:15]([CH3:17])[CH3:16])[C:10]([CH3:18])=[C:9]2[C:19]([NH:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:24][CH2:23]1)=[O:20])(=O)C.[OH-].[Na+]>CO.O>[ClH:1].[OH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH:15]([CH3:16])[CH3:17])[C:10]([CH3:18])=[C:9]2[C:19]([NH:21][CH:22]1[CH2:23][CH2:24][N:25]([CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][CH2:27]1)=[O:20]
Reactant: CC(=O)Oc1ccc2c(c1)c(C(=O)NC1CCN(CCc3ccccc3)CC1)c(C)n2C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c(C(=O)NC2CCN(CCc3ccccc3)CC2)c2cc(O)ccc2n1C(C)C
Reaction time: 0.17 h

Procedure:
To a solution of a total amount of the hydrochloride in 80 ml of methanol was added a solution of 2 g of sodium hydroxide in 10 ml of water, and the mixture was stirred for 10 minutes. After the methanol was concentrated, water was added to the residue to separate oil. To the oil was added 3 ml of glacial acetic acid and ethyl acetate, and the mixture was shaken well. The organic layer was washed with water and an aqueous solution of sodium hydrogencarbonate and the precipitated crystals were filtered. The crystals were dissolved in acetone containing ethanol and treated with concentrated hydrochloric acid to precipitate the corresponding hydrochloride. The crystalline hydrochloride was filtered and recrystallized from aqueous ethanol to give 5-hydroxy-1-isopropyl-2-methyl-N-(1-(2-phenylethyl)-4-piperidyl)indole-3-carboxamide hydrochloride, melting at 271°-276° C. with decomposition.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=O.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][N:17]=1.C(=O)([O-])O.[Na+]>>[Br:22][C:19]1[CH:20]=[CH:21][C:16]2[N:17]([CH:2]=[C:3]([C:5]3[CH:14]=[CH:13][C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH:6]=3)[N:15]=2)[CH:18]=1
Reactant: O=C(CBr)c1ccc2ccccc2c1
Reactant: Nc1ccc(Br)cn1
Agent: O=C([O-])O
Agent: [Na+]
Product: Brc1ccc2nc(-c3ccc4ccccc4c3)cn2c1
Yield: 127.9 %

Procedure:
By carrying out the process as in Example 1, and starting from 0.5 g of 2-bromo-1-(naphthalen-2-yl)ethanone, 0.72 g of 2-amino-5-bromopyridine and 0.29 g of sodium hydrogen carbonate, 0.83 g of 6-bromo-2-(naphthalen-2-yl)imidazo[1,2-a]pyridine is obtained. Mp=226-228° C.
Reaction SMILES: CN1CCOCC1.[C:8]([O:12][C:13]([NH:15][C@H:16]([C:22]([O:24][CH3:25])=[O:23])[CH2:17][CH2:18][C:19]([OH:21])=O)=[O:14])([CH3:11])([CH3:10])[CH3:9].[C:26]([O:30][C:31]([NH:33][CH2:34][CH2:35][NH:36][CH2:37][CH2:38][NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:32])([CH3:29])([CH3:28])[CH3:27]>C(Cl)Cl>[C:42]([O:41][C:40]([NH:39][CH2:38][CH2:37][N:36]([CH2:35][CH2:34][NH:33][C:31]([O:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:32])[C:19]([CH2:18][CH2:17][C@H:16]([NH:15][C:13]([O:12][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:14])[C:22]([O:24][CH3:25])=[O:23])=[O:21])=[O:46])([CH3:45])([CH3:44])[CH3:43]
Reactant: COC(=O)[C@H](CCC(=O)O)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NCCNCCNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](CCC(=O)N(CCNC(=O)OC(C)(C)C)CCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 72 %

Procedure:
To a solution of CDMT (2.22 g, 12.62 mmol) in DCM (40 mL) and cooled to 0° C. was added N-methylmorpholine (1.38 mL, 12.63 mmol). The mixture was stirred for 10 min before adding (4S)-4-{[(tert-butoxy)carbonyl]amino}-5-methoxy-5-oxopentanoic acid (3.0 g, 11.48 mmol). The solution was stirred for 60 min at 0° C. The tert-butyl N-{2-[(2-{[(tert-butoxy)carbonyl]amino}ethyl)amino]ethyl}carbamate X was then added and the mixture stirred at r.t. overnight. The solution was washed with 1 M aq. K2CO3, 1 M aq. HCl, brine and dried over anhydrous MgSO4. The crude product was crystallized from DCM/hexane to give methyl (2S)-4-[bis(2-{[(tert-butoxy)carbonyl]amino}ethyl)carbamoyl]-2-{[(tert-butoxy)carbonyl]amino}butanoate XIV (4.91 g, 8.98 mmol, 72% yield). 1H NMR (DMSO-d6) 1.35-1.47 (m, 27H), 1.80-1.91 (m, 1H), 2.19-2.32 (m, 1H), 2.33-2.42 (m, 1H), 2.46-2.57 (m, 1H), 3.11-3.38 (m, 6H), 3.40-3.53 (m, 1H), 3.54-3.62 (m, 1H), 3.73 (s, 3H), 4.26-4.38 (m, 1H), 4.99-5.09 (brs, 1H), 5.31-5.46 (m, 2H); ESIMS found for C25H46N4O9 m/z 547 (M+H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[CH2:19]([N:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[C:29](=[O:36])[N:28]([CH2:37][CH2:38][CH2:39][Cl:40])[C:27]1=[O:41])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[ClH:40].[CH2:19]([N:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[C:29](=[O:36])[N:28]([CH2:37][CH2:38][CH2:39][N:14]2[CH2:15][CH2:16][N:11]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[O:4][CH2:3][C:2]([F:1])([F:17])[F:18])[CH2:12][CH2:13]2)[C:27]1=[O:41])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: FC(F)(F)COc1ccccc1N1CCNCC1
Reactant: O=c1c(C(F)(F)F)cn(Cc2ccccc2)c(=O)n1CCCCl
Product: Cl
Product: O=c1c(C(F)(F)F)cn(Cc2ccccc2)c(=O)n1CCCN1CCN(c2ccccc2OCC(F)(F)F)CC1

Procedure:
substituting 1-[2-(2,2,2-trifluoroethoxy)phenyl]piperazine and 1-benzyl-3-(3-chloropropyl)-5-trifluoromethyl-2,4(1H,3H)-pyrimidinedione gave 1-benzyl-3-(3-(4-[2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1-yl)propyl)-5-trifluoromethyl-2,4(1H,3H)-pyrimidinedione hydrochloride, m.p. 125°-127° C.; Anal.: Calcd. for C27H28F6N4O3.HCl: C, 52.65; H, 4.91; N, 9.10%; Found: C, 52.44; H, 4.79; N, 8.92%;
Reaction SMILES: [OH:1]S(C(F)(F)F)(=O)=O.[C:9](=[NH:32])([O:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=2)=[CH:16][CH:15]=1)[NH2:10].[CH:33]([CH:35]([CH2:41][C:42]1[C:47](F)=[CH:46][C:45]([F:49])=[CH:44][C:43]=1[F:50])[C:36](OCC)=O)=[O:34].C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][C:17]2[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][O:11][C:9]3[NH:10][CH:36]=[C:35]([CH2:41][C:42]4[C:47]([OH:1])=[CH:46][C:45]([F:49])=[CH:44][C:43]=4[F:50])[C:33](=[O:34])[N:32]=3)=[CH:19][CH:18]=2)=[CH:22][C:23]=1[C:28]([F:31])([F:30])[F:29]
Reactant: N=C(N)OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: CCOC(=O)C(C=O)Cc1c(F)cc(F)cc1F
Reactant: O=S(=O)(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=c1nc(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)[nH]cc1Cc1c(O)cc(F)cc1F
Temperature: 160 °C
Yield: 33.7 %

Procedure:
The mixture of 2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl imidocarbamate triflate (120 mg, 0.236 mmol), ethyl 2-formyl-3-(2,4,6-trifluorophenyl)propanoate (154 mg, 0.591 mmol) and K2CO3 (98 mg, 0.709 mmol) in DMA (5 mL) was heated with a microwave reactor at 160° C. for 1 hour. Purification via MDAP then afforded the title compound (44 mg, 32.0% yield). LCMS: rt=4.14 min, [M+H+]=553.2
Reaction SMILES: Br[C:2]1[C:3]([C:13]([O:15][CH3:16])=[O:14])=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([Sn](CCCC)(CCCC)[C:22]([O:24]CC)=[CH2:23])CCC.Cl.[F-].[K+]>O1CCOCC1.C(OCC)(=O)C.O>[C:22]([C:2]1[C:3]([C:13]([O:15][CH3:16])=[O:14])=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:24])[CH3:23]
Reactant: COC(=O)c1noc(-c2ccccc2)c1Br
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1noc(-c2ccccc2)c1C(C)=O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A solution of methyl 4-bromo-5-phenylisoxazole-3-carboxylate (358 mg, 1.269 mmol, prepared in a similar manner as described in step 9-B) and tributyl(1-ethoxyvinyl)tin (0.858 mL, 2.54 mmol) in dioxane (5 mL) was heated at 100° C. for 24 h. To the reaction mixture was added 1N aqueous hydrochloric acid (2.54 mL, 2.54 mmol), and the mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water (30 mL), washed with a saturated aqueous solution of sodium bicarbonate (30 mL), and washed with brine (30 mL). The mixture was concentrated to ˜5 mL, and potassium fluoride (0.059 mL, 2.54 mmol) in 2 mL of water was added, and the mixture was stirred for 10 minutes. The solid was filtered and washed with ethyl acetate, and the filtrate was washed with water (10 mL), washed with brine (10 mL), and dried over anhydrous sodium sulfate. Concentration followed by purification by silica gel chromatography with hexanes/ethyl acetate (10/1) afforded methyl 4-acetyl-5-phenylisoxazole-3-carboxylate (105 mg). The compound had an HPLC ret. time=2.69 min.−Column: YMC S5 COMBISCREEN® 4.6×50 mm; Gradient time: 4 min; Flow rate=4 ml/min; Solvent A=10% MeOH−90% Water−0.2% H3PO4; Solvent B=90% MeOH−10% water−0.2% H3PO4; Start % B=0; Final % B=100. LC-MS: M+1=246+.
Reaction SMILES: [C:1](=[S:3])=[O:2].[NH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH2:9]>O.C(O)C>[NH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:1](=[S:3])[OH:2]
Reactant: NCCCCN
Reactant: O=C=S
Solvent: CCO
Solvent: O
Product: NCCCCNC(O)=S

Procedure:
passing carbonyl sulfide gas into a solution of tetramethylene diamine dissolved in a mixture of water and ethanol in equal proportions by weight at a temperature of from about 30° C. to about 45° C. to form N-(4-aminobutyl)thiocarbamic acid or zwitterion thereof; and
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[CH2:16][CH2:15][CH2:14][CH2:13][N:12]2[CH:17]=1.C1C(=O)N([I:25])C(=O)C1>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[CH2:16][CH2:15][CH2:14][CH2:13][N:12]2[C:17]=1[I:25]
Reactant: O=C1CCC(=O)N1I
Reactant: Fc1ccc(-c2cn3c(n2)CCCC3)c(F)c1
Solvent: CN(C)C=O
Product: Fc1ccc(-c2nc3n(c2I)CCCC3)c(F)c1
Reaction time: 8 h
Yield: 68.7 %

Procedure:
A solution of 2-(2,4-difluorophenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (3.25 g, 13.9 mmol, prepared using General Procedure R from Example #8, Step A with 2-iminopiperidine hydrochloride), NIS (3.12 g, 13.9 mmol), and DMF (35 mL) was stirred at ambient temperature. After stirring overnight, the reaction mixture was partitioned between Et2O (400 mL) and water (200 mL). The organic phase was separated and dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography using heptane/EtOAc (gradient from 100:0 to 0:100) to give the title compound (3.44 g, 69%). LC/MS (Table 1, Method a) Rt=3.32 min; MS m/z: 361.0 (M+H)+.
Reaction SMILES: O=[C:2]1[CH:6]2[CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][N:5]2C(=O)[O:3]1.[NH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1>C1COCC1.O>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([NH:19][C:2]([CH:6]2[NH:5][CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:7]2)=[O:3])[CH:21]=1
Reactant: Nc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)OC(=O)C2C1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCNC(C(=O)Nc2cccnc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.3 %

Procedure:
tert-Butyl 1,3-dioxotetrahydro-1H-oxazolo[3,4-a]pyrazine-7(3H)-carboxylate (1.50 g, 5.85 mmol) and 3-aminopyridine (1.10 g, 11.7 mmol) were heated to reflux in THF (20 mL). After 4 h, the reaction mixture was cooled to rt, diluted with H2O (50 mL), and was extracted with EtOAc (3×75 mL). The combined extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was purified by column chromatography (0 to 8% MeOH in CH2Cl2 with 0.5% NH4OH gradient), yielding 0.740 g (44%) of the title compound. LC-MS: RT=4.14 min, [M+H]+=307.1.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21]#[C:22][CH2:23][OH:24])=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:34][CH2:35]Br.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]#[C:22][CH2:23][OH:24])[CH:17]=3)[N:12]([CH:34]=[CH2:35])[CH:11]=2)=[O:9])=[CH:25][CH:26]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(C#CCO)cc2c1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)ccc21
Temperature: 90 °C

Procedure:
A solution of N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide from Preparation No. 5 (1.83 g) is dissolved in DMF (25 mL), and K2CO3 (1.38 g) and 1,2-dibromoethane (4.3 mL) are added. The reaction mixture is heated to 90° C. for 2 h. Water is added and the mixture is extracted with ethyl acetate and then chloroform. The combined organic layers are concentrated in vacuo to give 2.5 g of a dark oil. Column chromatography (elution with 1-3% MeOH/CHCl3) gave 0.378 g of 1-(1-bromoethyl)-N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide as a solid which is used without further purification. 1-(1-bromoethyl)-N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide (0.347 g) is suspended in 1:1 THF/CH3CN (15 mL) and sodium carbonate (0.16 g) and ethylamine (0.4 mL) are added and the mixture is refluxed for 16 h. An additional amount of ethylamine (0.80 mL) is added and the mixture is refluxed for 16 h. An additional amount of ethylamine (0.80 mL) and DMF (5 mL) is added and the mixture is heated at 100° C. for 6 h, and then held at room temperature for 48 h. Potassium carbonate (0.193 g) is added and the mixture is heated at 100° C. for 3 h. The mixture is concentrated in vacuo and partitioned between ethyl acetate and water. The organic layer is concentrated in vacuo to give 0.60 g of an oil. Column chromatography (elution with 1-5% MeOH/CHCl3) gave 0.118 g of the title compound as a solid.
Reaction SMILES: Cl.Cl.[CH:3]1([N:6]2[CH2:11][CH2:10][CH:9]([NH2:12])[CH2:8][CH2:7]2)[CH2:5][CH2:4]1.C([O-])(O)=[O:14].[Na+].C[O:19][C:20]([C:22]1[CH:46]=[CH:45][C:25]2[N:26]([CH2:33][C:34]3[CH:38]=[C:37]([C:39]4[S:40][C:41]([Cl:44])=[CH:42][CH:43]=4)[O:36][N:35]=3)[C:27]([C:29](Cl)(Cl)Cl)=[N:28][C:24]=2[CH:23]=1)=[O:21]>CC#N.O>[Cl:44][C:41]1[S:40][C:39]([C:37]2[O:36][N:35]=[C:34]([CH2:33][N:26]3[C:25]4[CH:45]=[CH:46][C:22]([C:20]([OH:19])=[O:21])=[CH:23][C:24]=4[N:28]=[C:27]3[C:29](=[O:14])[NH:12][CH:9]3[CH2:10][CH2:11][N:6]([CH:3]4[CH2:5][CH2:4]4)[CH2:7][CH2:8]3)[CH:38]=2)=[CH:43][CH:42]=1
Reactant: NC1CCN(C2CC2)CC1
Reactant: COC(=O)c1ccc2c(c1)nc(C(Cl)(Cl)Cl)n2Cc1cc(-c2ccc(Cl)s2)on1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C(O)c1ccc2c(c1)nc(C(=O)NC1CCN(C3CC3)CC1)n2Cc1cc(-c2ccc(Cl)s2)on1
Reaction time: 3 h

Procedure:
21.0 mg (0.098 mmol) (1-Cyclopropyl-piperidin-4-ylamine-dihydrochloride were dissolved in 3 mL CH3CN and 3 mL water. 82.3 mg (0.98 mmol, 10 equivalents) NaHCO3 were added. Then, a solution of 48.1 mg (0.098 mmol) 1-[5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-trichloromethyl-1H-benzoimidazole-5-carboxylic acid methyl ester in 2 mL CH3CN was added and the resulting mixture was stirred vigorously for 3 h under reflux. The mixture was concentrated under reduced pressure. The residue was purified by preparative RP-HPLC (CH3CN/H2O gradient and 0.05% formic acid) to give pure 1-[5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-cyclopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-5-carboxylic acid in form of a colorless amorphous solid. (Under these conditions the methyl ester was hydrolyzed simultaneously!)
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH:13]1[CH:22]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:21](=O)[C:20]2[C:19]([C:31]([O:33]CC)=O)=[CH:18][CH:17]=[CH:16][C:15]=2[NH:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:37][NH2:38]>CO>[CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH:13]1[NH:14][C:15]2[C:20]3[C:21](=[N:37][NH:38][C:31](=[O:33])[C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH:22]1[C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1ccc(F)cc1)C(c1nccn1Cc1ccccc1)N2
Solvent: O
Solvent: CO
Product: O=c1[nH]nc2c3c(cccc13)NC(c1nccn1Cc1ccccc1)C2c1ccc(F)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
A mixture of ethyl 2-(1-benzyl-1H-imidazol-2-yl)-3-(4-fluorophenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (280 mg, 0.59 mmol) and hydrazine monohydrate (2 mL, 85%) in methanol (4 mL) was stirred at 40° C. for 2 hr, and then evaporated to half of the original volume. The mixture was filtrated and washed the solid with ethyl acetate to obtain the title compound (200 mg, yield 96%). LC-MS (ESI) m/z: 437 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][CH2:7][C:8]2[S:9][CH:10]=[CH:11][C:12]=2[S:13](Cl)(=[O:15])=[O:14])=[CH:4][CH:3]=1.[NH2:19][C:20]1[O:24][N:23]=[C:22]([CH3:25])[C:21]=1[Br:26]>>[Br:26][C:21]1[C:22]([CH3:25])=[N:23][O:24][C:20]=1[NH:19][S:13]([C:12]1[CH:11]=[CH:10][S:9][C:8]=1[CH2:7][CH2:6][C:5]1[CH:17]=[CH:18][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:15])=[O:14]
Reactant: Cc1ccc(CCc2sccc2S(=O)(=O)Cl)cc1
Reactant: Cc1noc(N)c1Br
Product: Cc1ccc(CCc2sccc2S(=O)(=O)Nc2onc(C)c2Br)cc1
Yield: 52 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methyl)phenethyl]thiophene-3-sulfonamide was prepared, as described in Example 10, using 2-[(4-methyl)-phenethyl]thiophene-3-sulfonylchloride and 5-amino-4-bromo-3-methylisoxazole in 52% yield.
Reaction SMILES: CS[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][C@H:10]3[N:21]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])[CH2:20][CH2:19][C@@:16]4([C:17]=2[CH:18]=1)[C@H:11]3[CH2:12][CH2:13][CH2:14][CH2:15]4.S(Cl)([Cl:35])(=O)=O>C(Cl)Cl>[CH2:25]([O:24][C:22]([N:21]1[CH2:20][CH2:19][C@@:16]23[C:17]4[CH:18]=[C:5]([O:4][CH2:3][Cl:35])[CH:6]=[CH:7][C:8]=4[CH2:9][C@@H:10]1[C@@H:11]2[CH2:12][CH2:13][CH2:14][CH2:15]3)=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: CSCOc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(C(=O)OCc1ccccc1)CC3
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(OCCl)cc13
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (+)[N-(Benzyloxycarbonyl)morphinan-3-yloxy]methyl methyl sulfide (1.78 g, 4.07 mmol) in DCM (40 mL) was added sulfuryl chloride (6.1 mL, 6.11 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight. After removal of excess reagent and DCM by rotary evaporation, the product was dried under vacuum to afford (+)-[N-(benzyloxycarbonyl)morphinan-3-yloxy]methyl chloride as a yellow gum. Then, it was added to a stirred suspension of cesium carbonate (1.59 g, 4.88 mmol) and isobutyric acid (0.45 mL, 4.88 mmol) in acetone (20 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was filtered and evaporated under vacuum to provide the crude product, which was further purified by prep reverse-phase HPLC to afford the title compound (0.844 g, 43%) as a yellow solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]([CH3:10])=C.C([OH:14])C=C.O1C=CCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH:10]=[O:14]
Reactant: C=CCO
Reactant: C=C(C)OC1CCCCO1
Agent: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=CCOC1CCCCO1

Procedure:
2-(Tetrahydro-2-pyranyloxy)-propene (20 g, 0.14 mole) was dissolved in dichloro-methane (250 ml). Ozone was bubbled into the solution at -78° C. for about 3 hours until the solution turned blue. Warmed to room temperature and zinc powder (20 g) was added. Acetic acid (20 ml) and water (3 ml) were added slowly with cooling in ice bath. The reaction mixture was further stirred for 2 hours at room temperature and then extracted with dichloromethane. The extract was washed with sodium bicarbonate aqueous solution (10 ml×2), dried over anhydrous magnesium sulfate, concentrated. The crude product was distilled under vacuum (62°-64° C./2 mmHg) gave colorless oil (13.72 g, 68%). 2-(Tetra-hydro-2-pyranyloxy)-propene was directly prepared from allyl alcohol and dihydropyran in the presence of a small amount of p-toluenesulfonic acid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.Cl.Cl.[O:34]1[CH:38]=[C:37]([CH:39]([NH2:41])[CH3:40])[N:36]=[CH:35]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O.CN(C=O)C>[O:34]1[CH:38]=[C:37]([CH:39]([NH:41][C:21]([C:20]2[C:14]3[C:15](=[N:16][CH:17]=[C:12]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=5)[N:8]([CH3:11])[N:7]=4)[N:13]=3)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:31])[CH3:29])[CH:19]=2)=[O:22])[CH3:40])[N:36]=[CH:35]1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Reactant: CC(N)c1cocn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1cocn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 91.7 %

Procedure:
A round-bottomed flask was charged with 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.23 mmol) and 1-oxazol-2-yl-ethylamine dihydrochloride (crude from Step 3, 90 mg, 0.41 mmol). DMF (1.1 ml) was added followed by N,N-diisopropylethylamine (0.26 ml, 1.49 mmol) and HATU (95 mg, 0.25 mmol). The light yellow solution was stirred at room temperature for 48 h. Water was added and the resulting suspension was filtered. The solid was washed with water and petroleum ether then dried under high vacuum to afford 113 mg (93%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-oxazol-4-yl-ethyl)-amide as an off-white powder.
Reaction SMILES: C1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=CC=CC=3)[C:6](=O)[C:5]=2C=CC=1.[NH2:17][C:18]1[C:31]2[C:30](=[O:32])[C:29]3[C:24](=[C:25]([NH2:35])[C:26]([Br:34])=[CH:27][C:28]=3[OH:33])[C:23](=[O:36])[C:22]=2[C:21]([OH:37])=[CH:20][C:19]=1Br>>[NH2:17][C:18]1[C:31]2[C:30](=[O:32])[C:29]3[C:24](=[C:25]([NH2:35])[C:26]([Br:34])=[CH:27][C:28]=3[OH:33])[C:23](=[O:36])[C:22]=2[C:21]([OH:37])=[CH:20][C:19]=1[O:15][C:13]1[CH:14]=[CH:5][CH:6]=[CH:7][CH:12]=1
Reactant: O=C1c2ccccc2C(=O)c2ccccc21
Reactant: Nc1c(Br)cc(O)c2c1C(=O)c1c(O)cc(Br)c(N)c1C2=O
Product: Nc1c(Br)cc(O)c2c1C(=O)c1c(O)cc(Oc3ccccc3)c(N)c1C2=O

Procedure:
When the process according to Example 190a is carried out and, instead of the anthraquinone component mentioned there, 11.7 g of 1,5-diamino-4,8-dihydroxy-2,6-dibromoanthraquinone, compare Example 348a, are used, then 3.8 g, corresponding to 31% of theory, of 1,5-diamino-4,8-dihydroxy-2-phenoxy-6-bromoanthraquinone are obtained.