Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[O:16]([CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCCCCC.O1CCCC1>[OH:4][C:3]1[CH2:5][C:24]([CH2:23][O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[O:25][C:1](=[O:6])[CH:2]=1
Reactant: O=C(COc1ccccc1)c1ccccc1
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1C=C(O)CC(COc2ccccc2)(c2ccccc2)O1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The title compound was prepared as described in General Method 1 using 0.85 mL of methyl acetoacetate, 350 mg of NaH 60% dispersion in oil, 5 mL of 1.6M n-butyl lithium in hexane, 2.0 g of 2-phenoxy-1-phenyl ethanone and 60 mL of tetrahydrofuran. After addition of the ketone, the reaction was stirred for 15 minutes at 0° C. then allowed to warm to room temperature and stirred for 1 hour. The crude product was triturated from diethyl ether to afford a solid (m.p. 133°-135° C.). 1 H NMR (DMSO-d6) δ 3.03 (d, 1 H), 3.35 (d, 1 H), 4.18 (dd, 2 H), 4.90 (s, 1 H), 6.92-6.95 (m, 3 H), 7.24-7.49 (m, 7 H), 11.56 (s, 1 H).
Reaction SMILES: [N:1]1[C:2]2[C:14](=[O:15])[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:3]=2[NH:4][C:5](=[O:7])[CH:6]=1.[OH:16]O>C(O)(=O)C.C(OC(=O)C)(=O)C>[NH:1]1[C:6](=[O:16])[C:5](=[O:7])[NH:4][C:3]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14](=[O:15])[C:2]1=2
Reactant: OO
Reactant: O=C1c2ccccc2-c2[nH]c(=O)cnc21
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C1c2ccccc2-c2[nH]c(=O)c(=O)[nH]c21
Yield: 79.6 %

Procedure:
9H-Indeno[1,2-b]pyrazine-3,9(4H)-dione (20 g, 100.9 mmol), recrystallized from acetic acid, was suspended in a mixture of 135 ml acetic acid and 135 ml acetic anhydride and hydrogen peroxide (9.8 ml, 35%) was added. After stirring overnight another portion (9.8 ml, 35%) of hydrogen peroxide was added. This was repeated five times over a week. The red precipitate was filtered off, washed with acetic acid and water and dried to give 18.5 g (79.6%) of the title compound, which could be further purified by dissolving in aqueous sodium hydroxide and precipitation by hydrochloric acid. M.p.>300° C. 1H-NMR (DMSO-d6, δ): 7.15-7.45 (m, 4H), 12 (s, 1H), 12.8 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8](O)[C:9]1[S:13][C:12]([NH:14][C:15]([C:17]2([C:20]3[CH:28]=[CH:27][C:23]4[O:24][CH2:25][O:26][C:22]=4[CH:21]=3)[CH2:19][CH2:18]2)=[O:16])=[N:11][CH:10]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[NH:42]1[CH2:46][CH2:45][C@@H:44]([OH:47])[CH2:43]1>ClCCl>[O:24]1[C:23]2[CH:27]=[CH:28][C:20]([C:17]3([C:15]([NH:14][C:12]4[S:13][C:9]([CH:8]([C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=5[Cl:1])[N:42]5[CH2:46][CH2:45][C@@H:44]([OH:47])[CH2:43]5)=[CH:10][N:11]=4)=[O:16])[CH2:18][CH2:19]3)=[CH:21][C:22]=2[O:26][CH2:25]1
Reactant: O[C@@H]1CCNC1
Reactant: O=C(Nc1ncc(C(O)c2ccccc2Cl)s1)C1(c2ccc3c(c2)OCO3)CC1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ncc(C(c2ccccc2Cl)N2CC[C@@H](O)C2)s1)C1(c2ccc3c(c2)OCO3)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 33333.3 %

Procedure:
1-Benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid [5-[(2-chloro-phenyl)-hydroxy-methyl]-thiazol-2-yl]-amide (0.500 g, 1.17 mmol) was placed in 10 mL of anhydrous dichloromethane containing trieihylamine (984 μL, 7.02 mmol). The mixture was cooled to 0° C. and methanesulfonyl chloride (364 μL, 4.68 mmol) was added, immediately followed by (R)-pyrrolidin-3-ol (945 μL, 11.7 mmol) and the solution was allowed to stir for 10 minutes at room temperature. The crude product was washed three times with an equal volume of a saturated aqueous solution of sodium bicarbonate, followed by a saturated aqueous solution of sodium chloride. The organic layer was then dried over sodium sulfate and evaporated to dryness. The crude mixture was purified by column, chromatography (20-90% ethyl acetate in hexanes on silica gel) to yield the product as a white solid (194.2 mg, 0.390 mol, 33.3%). 1H NMR (400 MHz, DMSO-d6) δ 1.09-1.15 (m, 2H), 1.41-1.44 (m, 2H), 1.54-1.63 (m, 1H), 1.93-2.77 (m, 5H), 4.20 (S, 1H), 4.72-4.77 (m, 1H), 4.96 (d, J=7.0 Hz, 1H), 6.00 (s, 2H), 6.85 (d, J=0.9 Hz, 2H), 6.95 (s, 1H), 7.24-7.29 (m, 1H), 7.37-7.43 (m, 3H), 7.76-7.80 (m, 1H), 11.03 (s, 1H. ESI-MS m/z calc. 497.1, found; 498.1 (M+1)+; Retention time 2.36 minutes.
Reaction SMILES: [CH3:1][CH:2]([SH:4])[CH3:3].[Na].Br[CH2:7][C:8](=[O:30])[C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([C:24](=[O:28])[CH2:25]2)[C@:21]2([CH3:22])[C@H:16]([CH2:17][C@H:18]([OH:29])[CH2:19][CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1>CC(O)C.C1(C)C=CC=CC=1>[OH:29][C@@H:18]1[CH2:19][CH2:20][C@@:21]2([CH3:22])[C@@H:16]([CH2:15][CH2:14][C@@H:13]3[C@@H:23]2[C:24](=[O:28])[CH2:25][C@@:26]2([CH3:27])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C:8](=[O:30])[CH2:7][S:4][CH:2]([CH3:3])[CH3:1])[CH2:17]1
Reactant: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CBr)[C@@]3(C)CC(=O)[C@@H]12
Reactant: CC(C)S
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: CC(C)SCC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C

Procedure:
Propane-2-thiol (1.3 ml.) was added to a warm solution of sodium (0.6 g.) in a mixture of propan-2-ol (25 ml.) and toluene (30 ml.). 21-Bromo-3α-hydroxy-5α-pregnane-11,20 -dione (0.7 g.) was then added and the mixture was gently refluxed for 2 hr. The mixture was then partitioned between water and ether and the organic layer was washed with water, dried (Na2SO4) and evaporated. The residual foam was purified by preparative t.l.c. (CHCl3) to give title compound (0.2 g.) as a white foam, [α]D + 67° (c 1.3).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5]Br.[C:7]1([CH2:13][SiH:14]([Cl:16])Cl)[CH:12]=[CH:11]C=CC=1.[Mg].O1CC[CH2:20][CH2:19]1>>[C:2]1([Si:14]2([Cl:16])[CH2:11][CH2:12][CH2:7][CH2:13]2)[CH:20]=[CH:19][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: BrCCCCBr
Reactant: Cl[SiH](Cl)Cc1ccccc1
Agent: [Mg]
Product: Cl[Si]1(c2ccccc2)CCCC1

Procedure:
A mixture of 25 parts of 1,4-dibromobutane and 50 parts of tetrahydrofuran was added dropwise over a period of 2 hours to a mixture of 200 parts of tetrahydrofuran, 80 parts phenylmethyldichlorosilane, and 25 parts of magnesium turnings. The reaction solution was heated under reflux for 1 hour, and the magnesium salt was then removed by filtration. Vacuum distillation of the filtrate subsequently yielded 20 parts 1-phenyl-1-chlorosilacyclopentane.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:9]=[C:8]([NH:10][N:11]=[C:12]2[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:13]2)[CH:7]=[CH:6][CH:5]=1.[CH3:26]I>CN(C=O)C.CCOC(C)=O>[Br:3][C:4]1[N:9]=[C:8]([N:10]([CH3:26])[N:11]=[C:12]2[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:13]2)[CH:7]=[CH:6][CH:5]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCCC(=NNc2cccc(Br)n2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(N=C1CCCN(C(=O)OC(C)(C)C)CC1)c1cccc(Br)n1
Reaction time: 0.33 h
Yield: 103.6 %

Procedure:
Sodium hydride (60% dispersion in oil, 0.83 g, 21 mmol) was added to a solution of tert-butyl 4-(2-(6-bromopyridin-2-yl)hydrazono)azepane-1-carboxylate (6.4 g, 17 mmol) in DMF (54 mL) at room temperature under N2 and stirred for 20 min. Methyl iodide (1.1 mL, 18 mmol) was added to the solution, and the resulting solution was stirred for 2 h at ambient temperature. The mixture was quenched with H2O (100 mL). The solution was extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine (4×30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford a dark orange oil. The oil was diluted with EtOAc (100 mL) and washed with brine (6×50 mL), dried over Na2SO4, filtered and concentrated to dryness under reduced pressure to provide the title compound (7.00 g, quant.) as an amber oil: 1H NMR (300 MHz, DMSO-d6) δ 7.44-7.36 (m, 1H), 6.88 (d, J=7.2 Hz, 1H), 6.49-6.38 (m, 1H), 3.56-3.35 (m, 4H), 3.06-3.04 (m, 3H), 2.75-2.50 (m, 4H, overlaps with H2O), 1.72-1.51 (m, 2H), 1.43-1.15 (m, 9H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:12])([CH3:11])[C:3]1=[CH2:13].[OH:14][CH2:15][C:16]1[C:17]([OH:28])=[C:18]([N:26]=O)[C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2>C(O)C>[CH3:1][N:2]1[C:3]2([O:28][C:17]3[C:16]([CH2:15][OH:14])=[CH:25][C:24]4[C:19]([C:18]=3[N:26]=[CH:13]2)=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:4]([CH3:11])([CH3:12])[C:5]2[C:10]1=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=Nc1c(O)c(CO)cc2ccccc12
Reactant: C=C1N(C)c2ccccc2C1(C)C
Solvent: CCO
Product: CN1c2ccccc2C(C)(C)C12C=Nc1c(c(CO)cc3ccccc13)O2
Yield: 20.9 %

Procedure:
In 100 ml of ethanol, 7.0 g (40 mmol) of 1,3,3-trimethyl-2-methyleneindoline and 8.0 g (40 mmol) of 3-hydroxymethyl-1-nitroso-2-naphthol were dissolved and the solution was heated to reflux for 3 hours. After removal of the solvent, purification was conducted by column chromatography and recrystallization from hexane to obtain 3.0 g of 1,3,3-trimethyl-5'-hydroxymethylspiro [indoline-2,3'-[3H]-naphtho[2,1-b](1,4)oxazine] as a white solid. In 50 ml of methylene dichloride, 1.1 g (3 mmol) of the thus obtained spirooxazine compound was dissolved and 4 ml of triethylamine was added thereto, and then 0.5 g (5 mmol) of methacrylic acid chloride was added dropwise thereto at room temperature and the mixture was allowed to react. After removal of solvent, purification was conducted by column chromatography and recrystallization from hexane to obtain 1.0 g of 1,3,3-trimethyl-5'-methacryloxymethylspiro[indoline-2,3'-[3H]-naphtho[2,1 -b](1,4)oxazine] as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][C:7](F)=[CH:8][CH:9]=2)[N:4]([CH:12]2[CH2:14][CH2:13]2)[CH:3]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][OH:22].[H-].[Na+]>CS(C)=O.CO>[Br:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([O:22][CH2:21][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=3)=[CH:8][CH:9]=2)[N:4]([CH:12]2[CH2:14][CH2:13]2)[CH:3]=1
Reactant: Fc1ccc2c(Br)cn(C3CC3)c2n1
Reactant: OCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: Brc1cn(C2CC2)c2nc(OCc3ccccn3)ccc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 77.6 %

Procedure:
To a solution of 3-bromo-1-cyclopropyl-6-fluoro-1H-pyrrolo[2,3-b]pyridine (0.249 g, 0.98 mmol) in dimethyl sulfoxide (5 mL) is added 2-pyridinemethanol (188 μL, 1.95 mmol), followed by portionwise addition of sodium hydride (97.6 mg, 2.44 mmol). The mixture is stirred at room temperature for 5 min., then poured onto brine and extracted with EtOAc. The organic layers are combined, dried (magnesium sulphate) and concentrated in vacuo to give a brown oil. This is taken up in methanol and poured onto a SCX-2 ion-exchange column. This is washed with 3 column volumes of MeOH, and then the product collected in the subsequent one column volume flush with 7 M methanolic ammonia. The solution is then concentrated in vacuo to give the title compound as a yellow oil (0.263 g, 0.76 mmol). MS (m/z): 344/346 (M+1).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:28](O)=[O:29])[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].[F:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38](=[N:40]O)[NH2:39]>>[F:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]1[N:40]=[C:28]([CH:13]2[CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:26])([F:25])[F:27])=[CH:19][CH:18]=3)[CH2:16][N:11]([C:9]([N:6]3[CH2:7][CH2:8][CH:3]([C:1]#[N:2])[CH2:4][CH2:5]3)=[O:10])[CH2:12]2)[O:29][N:39]=1
Reactant: NC(=NO)c1ccccc1F
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(OC(F)(F)F)cc3)C2)CC1
Product: N#CC1CCN(C(=O)N2CC(c3ccc(OC(F)(F)F)cc3)CC(c3nc(-c4ccccc4F)no3)C2)CC1

Procedure:
85 mg (0.2 mmol) of 1-[(4-cyanopiperidin-1-yl)carbonyl]-5-[4-(trifluoromethoxy)phenyl]-piperidine-3-carboxylic acid (Example 108A) and 46 mg (0.3 mmol) of 2-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 2. Yield: 69 mg (63% of theory).
Reaction SMILES: [I:1][C:2]1[C:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:4][NH:5][C:6]=1[CH3:7].[H-].[Na+].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20](Cl)=[CH:19][CH:18]=1.[CH3:24]N(C=O)C>>[I:1][C:2]1[C:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:4][N:5]([CH2:24][C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)[C:6]=1[CH3:7]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1n[nH]c(C)c1I
Reactant: COc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1nn(Cc2ccc(OC)cc2)c(C)c1I
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57 %

Procedure:
To a stirred solution of ethyl 4-iodo-5-methyl-1H-pyrazole-3-carboxylate (Step 1.1) (7.60 g, 27.1 mmol) in DMF (50 mL) under Ar was added NaH (1.302 g, 32.6 mmol) at 0° C. After 15 min, 4-methoxyphenyl chloride (3.70 mL, 27.1 mmol) was added. The reaction mixture was stirred for 1 hr at rt, quenched with a saturated aqueous solution of NaHCO3 (100 mL) and extracted with EtOAc (100 mL). The combined organic layers were washed with a saturated aqueous solution of NaHCO3 (100 mL), dried over Na2SO4 and the solvent was evaporated off under reduced pressure. The crude material was purified by silica gel column chromatography (hexane/EtOAc 5-40%) to afford the title product (6.23 g, 15.57 mmol, 57% yield) as a colorless oil. tR: 5.24 min (HPLC 1); tR: 1.12 min (LC-MS 2); ESI-MS: 401 [M+H]+ (LC-MS 2); Rf=0.66 (hexane/EtOAc 1:1).
Reaction SMILES: [C:1]1(=[O:17])[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[Br:18]Br>C(Cl)(Cl)Cl>[Br:18][CH:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:6]=2)[C:1]1=[O:17]
Reactant: BrBr
Reactant: COC(=O)COc1ccc2c(c1)CCCC2=O
Solvent: ClC(Cl)Cl
Product: COC(=O)COc1ccc2c(c1)CCC(Br)C2=O
Reaction time: 4 h

Procedure:
To a solution of the product from step (ii) (1.3 g) in chloroform (15 ml) was added dropwise a solution of bromine (0.29 ml) in chloroform (1 ml) and the resulting mixture was stirred for 4 hours. The solvent was evaporated to give an oil. Purification by flash column chromatography on silica, eluting with ethyl acetate/hexane (30:70 v/v) gave methyl 2-bromotetralone-6-oxyacetate (1.55 g) as an oil: NMR (d6DMSO) δ2.3-2.6(m,2H), 2.9-3.1(m,2H), 3.7(s,3H), 4.9(s,2H), 4.9-5.0(m,1H), 6.9-7.0(m,2H), 7.9(d,1H); m/e 313/315(M+H)+Br pattern.
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]OS(C)(=O)=O)[CH2:5][CH2:4]1.FC(F)(F)C(O)=O.[F:26][C:27]([F:39])([F:38])[C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1.[OH:40][CH2:41][CH2:42][NH:43][CH2:44][CH2:45][OH:46]>>[OH:40][CH2:41][CH2:42][N:43]([CH2:44][CH2:45][OH:46])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C@H:6]1[CH2:5][CH2:4][C@H:3]([N:2]([CH3:1])[S:34]([C:31]2[CH:32]=[CH:33][C:28]([C:27]([F:39])([F:38])[F:26])=[CH:29][CH:30]=2)(=[O:36])=[O:35])[CH2:8][CH2:7]1
Reactant: CN[C@H]1CC[C@H](CCCCCOS(C)(=O)=O)CC1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: OCCNCCO
Solvent: O=C(O)C(F)(F)F
Product: CN([C@H]1CC[C@H](CCCCCN(CCO)CCO)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to examples 29.10 and 29.11, trans-Methansulfonic acid 5-(4-methyl amino-cyclohexyl)-pentyl ester.Trifluoroacetic acid salt and 4-trifluoromethyl-phenyl sulfonylchloride were reacted, followed by treatment with 2-(2-Hydroxy-ethylamino)-ethanol to give trans-N-(4-{5-[Bis-(2-hydroxy-ethyl)-amino]-pentyl}-cyclohexyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide. MS: 495 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH3:35])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]2=[O:33])[CH:7]=1.[O:36]1[CH:40]=[CH:39][C:38]([NH2:41])=[N:37]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH3:35])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:41][C:38]4[CH:39]=[CH:40][O:36][N:37]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]2=[O:33])[CH:7]=1
Reactant: Nc1ccon1
Reactant: COc1ccc(Br)cc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(Br)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Temperature: 0 °C
Yield: 86.8 %

Procedure:
To a RBF was added perfluorophenyl 1-(5-bromo-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (5.92 g, 10.27 mmol) and THF (103 ml). Isoxazol-3-amine (0.950 g, 11.36 mmol) was added, and the reaction was cooled to 0° C. Lithium bis(trimethylsilyl)amide (1.0M in THF) (21.57 ml, 21.57 mmol) was added drop wise (reaction turned from clear solution to bright yellow suspension) and the reaction was allowed to stir in the ice bath for 1 h. The reaction was warmed to RT, and 1N HCl was added. The product was extracted with EtOAc (×3), and the resulting organics were dried with MgSO4 and concentrated in vacuo. The resulting light yellow solid was triturated in diethyl ether and filtered over a fine frit, rinsing with minimal ether, to yield 1-(5-bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (4.245 g, 8.91 mmol, 87% yield) as an off-white solid. MS (ESI, pos. ion) m/z: [M+1] 476.1
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([NH:12][C:13](=O)[C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:23]#[N:24].[OH2:25].[NH2:26][NH2:27].O>CN1CCCC1=O>[NH2:24][C:23]1[C:3]2[CH:4]=[N:5][C:6]3[C:7]([NH:12][C:13](=[O:25])[C:14]4[C:15]([Cl:21])=[CH:16][CH:17]=[CH:18][C:19]=4[Cl:20])=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:27][N:26]=1
Reactant: O
Reactant: N#Cc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1Cl
Reactant: NN
Solvent: CN1CCCC1=O
Product: Nc1n[nH]c2c1cnc1c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Temperature: 90 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
To a solution of 4-chloro-8-(2,6-dichlorobenzoylamino)-3-cyanoquinoline (300 mg) in N-methylpyrrolidone (6 ml) was dropwise added hydrazine monohydrate (399 mg), and the mixture was stirred for 2 hours at 90° C. Water (15 ml) was added thereto, the resulting precipitates were collected by filtration to give 3-amino-6-(2,6-dichlorobenzoylamino)-1H-pyrazolo[4,3-c]quinoline (260 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[C:9]2[S:21][CH:20]=[CH:19][C:10]=2[N:11]=[C:12]([C:14]([O:16]CC)=[O:15])[N:13]=1)=[O:7].[OH-].[Na+].Cl>CO.O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[C:9]2[S:21][CH:20]=[CH:19][C:10]=2[N:11]=[C:12]([C:14]([OH:16])=[O:15])[N:13]=1)=[O:7]
Reactant: CCOC(=O)c1nc(C(=O)c2cccs2)c2sccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1nc(C(=O)c2cccs2)c2sccc2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 49.6 %

Procedure:
A solution of ethyl 4-(2-thienylcarbonyl)thieno[3,2-d]pyrimidine-2-carboxylate (80 mg, 0.25 mmol) in MeOH (3 mL) was treated with 2M-NaOH (1 mL), stirred at room temperature for 20 min, acidified with 1M-HCl, diluted with water and filtered to give the title compound (36 mg, 50%) as a pale yellow solid.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5]CC)=O.[O-]CC.[Na+].[Na].[C:17](Cl)(=O)[C:18](C)([CH3:20])[CH3:19]>C1(C)C(C)=CC=CC=1.C(O)C>[C:3]([CH2:2][C:1]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[C:18]([CH3:20])([CH3:19])[CH3:17]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: Cc1ccccc1C
Solvent: CCO
Product: CCOC(=O)CC(=O)C(C)(C)C
Temperature: 25 °C

Procedure:
Ethyl pivaloylacetate was prepared from diethyl malonate in the following manner. Diethyl malonate (64 g, 0.4 mol) was dissolved in 350 ml of a mixture of xylene isomers. A solution of sodium ethoxide, prepared by dissolving sodium (9.66 g, 0.42 g at) in absolute ethanol (150 ml), was then added with stirring at ambient temperature. Ethanol was removed by distillation. After the mixture was cooled to 50° C., pivaloylchloride (53 g, 0.4 mol) was added with stirring over a period of one hour and the resulting slurry stirred for a further hour. The mixture obtained was then filtered to remove sodium chloride and the filtrate added to dry sodium ethoxide, which had been prepared by dissolving sodium (9.29 g; 0.4 g at) in 250 ml of absolute ethanol and evaporating to dryness. After stirring for 90 minutes at 50° C., the mixture was acidified with dilute hydrochloric acid and the organic phase separated and dried over anhydrous magnesium sulphate. Evaporation of the solvent in a rotary evaporator followed by vacuum distillation afforded essentially pure ethyl pivaloylacetate product as a colorless liquid (b.p. 167° C. at 65 mbar). Structure of the product was confirmed with NMR analysis. The product yield, determined by GLC, was 0.343 mol (86%).
Reaction SMILES: C[O-].[Na+].[CH3:4][N:5]1[CH2:10][CH2:9][CH:8]([SH:11])[CH2:7][CH2:6]1.Cl[CH2:13][C:14](=[O:16])[CH3:15]>O1CCCC1>[CH3:4][N:5]1[CH2:10][CH2:9][CH:8]([S:11][CH2:13][C:14](=[O:16])[CH3:15])[CH2:7][CH2:6]1
Reactant: CC(=O)CCl
Reactant: CN1CCC(S)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)CSC1CCN(C)CC1
Reaction time: 24 h

Procedure:
Sodium methylate (5.9 g) is added in portions to a solution of 1-methylpiperidine-4-thiol (14 g) in anhydrous tetrahydrofuran (100 ml) at room temperature. After 2 hours at this temperature, chloroacetone (8.8 ml) is added dropwise. After 24 hours, the precipitate is filtered off and the filtrate is concentrated and chromatographed on silica gel (eluent: ethyl acetate, then ethanol) to give 1-methyl-4-[(2-oxopropyl)thio]-piperidine (11.5 g) in the form of an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]2[O:11][C:12]3[N:13]=[C:14]([S:20][CH3:21])[N:15]=[C:16]([OH:19])[C:17]=3[N:18]=2)=[CH:5][C:4]=1[CH3:22].C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH3:32].O>CN(C)C=O>[CH3:1][O:2][C:3]1[C:4]([CH3:22])=[CH:5][C:6]([C:10]2[O:11][C:12]3[N:13]=[C:14]([S:20][CH3:21])[N:15]([CH2:30][CH2:31][CH3:32])[C:16](=[O:19])[C:17]=3[N:18]=2)=[CH:7][C:8]=1[CH3:9].[CH3:1][O:2][C:3]1[C:4]([CH3:22])=[CH:5][C:6]([C:10]2[O:11][C:12]3[N:13]=[C:14]([S:20][CH3:21])[N:15]=[C:16]([O:19][CH2:30][CH2:31][CH3:32])[C:17]=3[N:18]=2)=[CH:7][C:8]=1[CH3:9]
Reactant: CCCBr
Reactant: COc1c(C)cc(-c2nc3c(O)nc(SC)nc3o2)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1nc(SC)nc2oc(-c3cc(C)c(OC)c(C)c3)nc12
Product: CCCn1c(SC)nc2oc(-c3cc(C)c(OC)c(C)c3)nc2c1=O
Temperature: 60 °C
Reaction time: 5 h

Procedure:
5.9 g of 2-(4-methoxy-3,5-dimethyl-phenyl)-5-methylsulfanyl-oxazolo[5,4-d]pyrimidin-7-ol were dissolved in 150 ml of N,N-dimethylformamide, and 7.7 g of potassium carbonate and then 2.7 g of 1-bromo-propane were added. The solution was stirred at 60° C. for 5 h and then, after cooling, poured onto 150 ml of water. The precipitate was filtered off with suction. The obtained mixture of regioisomers was purified by silica gel chromatography (50 g silica (solute cartridge, heptane/ethyl acetate 9/1). Besides 1.4 g of 2-(4-methoxy-3,5-dimethyl-phenyl)-5-methylsulfanyl-6-propyl-6H-oxazolo[5,4-d]pyrimidin-7-one (LC/MS (method LC1): Rt=1.43 min; m/z=360.13 [M+H]+), 2.5 g of the title compound were obtained.