Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])SCCCS1.BrN1C(=[O:24])CCC1=O.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CC(C)=O.O>[CH3:1][O:2][CH2:3][CH2:4][C:5](=[O:24])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: COCCC1(C(=O)OC(C)(C)C)SCCCS1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COCCC(=O)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 71.4 %

Procedure:
To a solution of tert-butyl 2-(2-methoxy-ethyl)-[1,3]dithiane-2-carboxylate (1.14 g, 4.09 mmol) in acetone (23 mL) was then added water (1.14 mL), and subsequently the solution was cooled to −15° C., to which N-bromosuccinimide (NBS, 4.37 g, 24.6 mmol) was gradually added. After stirring for 30 minutes and confirming the consumption of the starting materials by TLC, to the solution was added a solution of sodium bicarbonate (1.71 g, 20.35 mmol) in water (9.0 mL), and subsequently, an aqueous solution (8 mL) of 5% sodium thiosulfate. After extraction with dichloromethane, the organic layer was washed with water, and dried over anhydrous sodium sulfate. The organic layer was filtered and the solvent was distilled off. The resulting residue was purified with SP1 (SiO2 cartridge, 10% ethyl acetate/n-hexane, Rf=0.4) to obtain tert-butyl 4-methoxy-2-oxo-butyrate (550 mg, 72% yield).
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:18])[NH:7][C:8]1[N:12]([CH3:13])[N:11]=[C:10]([C:14]([O:16]C)=[O:15])[CH:9]=1)[CH:2]([CH3:4])[CH3:3].[Li+].[OH-].O>CO>[CH2:1]([NH:5][C:6](=[O:18])[NH:7][C:8]1[N:12]([CH3:13])[N:11]=[C:10]([C:14]([OH:16])=[O:15])[CH:9]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)c1cc(NC(=O)NCC(C)C)n(C)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)CNC(=O)Nc1cc(C(=O)O)nn1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.4 %

Procedure:
To a solution of methyl 5-(3-isobutylureido)-1-methyl-1H-pyrazole-3-carboxylate (compound 351.5, 0.12 g, 0.47 mmol) in MeOH (5 ml) was added 1 M LiOH in H2O (1.42 ml, 1.42 mmol). The mixture was stirred at room temperature for 5 hours. TLC showed the reaction was complete. The mixture was acidified to pH 3-4 at 0° C. and then was extracted with EcOAc (2×50 ml). The combined organic layers were dried with Na2SO4, filtered, and concentrated to give 110 mg (100%) of a clear oil. m/z (ES+) 241 (M+H)+.
Reaction SMILES: CS([O:5][CH2:6][CH:7]1[CH2:12][CH2:11][C:10]([F:14])([F:13])[CH2:9][CH2:8]1)(=O)=O.O[C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=[O:20].C([O-])([O-])=O.[K+].[K+].CN1C(=O)CCC1>O>[F:13][C:10]1([F:14])[CH2:11][CH2:12][CH:7]([CH2:6][O:5][C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=2)[CH:19]=[O:20])[CH2:8][CH2:9]1
Reactant: O=Cc1cccc(O)c1
Reactant: CS(=O)(=O)OCC1CCC(F)(F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=Cc1cccc(OCC2CCC(F)(F)CC2)c1
Reaction time: 1 h

Procedure:
Mesylate 142 (0.9 g, 3.94 mmole), 3-hydroxybenzaldehyde (0.577 g, 4.73 mmole), K2CO3 (0.817 g, 5.91 mmole) and NMP (5 ml) were heated at 70° C. overnight. H2O (30 ml) and hexanes (50 ml) was added and stirred for 1 hr. The organic layer was dried over Na2SO4 and evaporated. Purfication by flash chromatography (20% ether/hexanes gradient) gave 3-((4,4-difluorocyclohexyl)methoxy)benzaldehyde (143) as ah oil. Yield (0.559 g, 56%): 1H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 7.51-7.46 (m, 21H), 7.41-7.40 (m, 1H), 7.25 (dt, J=6.8, 2.8 Hz, 1H), 3.91 (d, J=6.0 Hz, 2H), 2.06-1.98 (m, 5H), 1.89-1.73 (m, 5H), 1.37-1.27 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([CH2:8][OH:9])=[N:6][CH:7]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([CH2:8][O:9][C:19](=[O:21])[CH3:20])=[N:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: COc1cc(Br)cnc1CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(Br)cnc1COC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of (5-bromo-3-methoxy-pyridin-2-yl)-methanol (Stage 194.1.3, 2.79 mmol) and triethylamine (4.18 mmol) in dichloromethane was added slowly acetyl chloride (3.35 mmol) and the RM was stirred for 1 h at rt. The RM was diluted with dichloromethane, washed with saturated aqueous NaHCO3, with brine, dried over Na2SO4, filtered and evaporated. The residue was absorbed on silica gel and purified by flash chromatography (heptane/EtOAc 0% to 60%). The fractions containing product were evaporated together to give the title compound as a white solid. (HPLC: tR 2.72 min (Method A); M+H=260, 262 MS-ES)
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=2)[CH:11]=[C:10]([NH2:20])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:19][O:18][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[N:8]=[CH:9][C:10]([NH2:20])=[CH:11]2
Reactant: COc1ccc2c(c1)C=C(N)CN2C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2ncc(N)cc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of N-tert-butyloxycarbonyl-6-methoxy-3-aminoquinoline (Step F, 3 g, 0.011 mol) in CH2Cl2 (50 mL) cooled at 0° C. was added TFA (8.4 mL, 0.11 mL). The reaction mixture was warmed to RT and stirred for 8 h. The reaction mixture was concentrated under vacuum. The residue was suspended into MTBE. The yellow solid was filtered off and washed with MTBE. The dry yellow solid was suspended in NaOH 1N and the suspension was stirred for 15 min. The resulting slurry was filtered. The solid was washed with water and dried over P2O5 to give 6-methoxy-3-aminoquinoline as a white solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10](N(OC)C)=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([Mg]Br)=[CH:19][C:18]=1[F:25].[NH4+].[Cl-]>C1COCC1>[Si:1]([O:8][CH2:9][C:10]([C:20]1[CH:21]=[CH:22][C:17]([Cl:16])=[C:18]([F:25])[CH:19]=1)=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Fc1cc([Mg]Br)ccc1Cl
Reactant: CON(C)C(=O)CO[Si](C)(C)C(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC(=O)c1ccc(Cl)c(F)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
To a solution of 60 (15.12 g, 64.79 mmol) and THF (50 mL) cooled to 0° C. was added dropwise (4-chloro-3-fluorophenyl)magnesium bromide (226.8 mL, 113.4 mmol) and the solution was stirred at 0° C. for 2 h. Saturated NH4Cl was added and the reaction was extracted with DCM. The organic layer was separated, dried, filtered and concentrated. The crude product was purified by passage through a SiO2 plug eluting with 5% EtOAc/hexane to afford 18.36 g (93.6%) of 2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethanone (62).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[O-:24][C:25]#[N:26].[K+].O>C(O)(=O)C>[NH2:26][C:25]([N:6]([CH2:5][C:4]1[CH:20]=[CH:21][CH:22]=[CH:23][C:3]=1[O:2][CH3:1])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:24]
Reactant: N#C[O-]
Reactant: COc1ccccc1CNc1ccccc1Oc1ccccc1
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccccc1CN(C(N)=O)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 96.2 %

Procedure:
In 20 ml of acetic acid was dissolved 1.54 g of N-(2-methoxybenzyl)-2-phenoxyaniline synthesized in the same manner as in Example 1(1), and then an aqueous potassium cyanate solution (1.23 g of potassium cyanate and 10 ml of water) was added dropwise to the solution, followed by stirring at room temperature for 2.5 hours. The reaction mixture was poured into water and extracted with ethyl acetate, and the extract was washed with a saturated aqueous sodium bicarbonate solution and a saturated sodium chloride solution and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate−hexane=1:3) to give 1.69 g of N-aminocarbonyl-N-(2-methoxybenzyl)-2-phenoxyaniline as an oil.
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH:17]=[O:18])[CH:15]=3)[N:10]([C:19]([NH:21][C:22]3[S:23][C:24]([Cl:27])=[CH:25][N:26]=3)=[O:20])[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2].[CH3:28][Mg]Br>O1CCCC1.[Cl-].[NH4+]>[C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH:17]([OH:18])[CH3:28])[CH:15]=3)[N:10]([C:19]([NH:21][C:22]3[S:23][C:24]([Cl:27])=[CH:25][N:26]=3)=[O:20])[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: C[Mg]Br
Reactant: CC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(C=O)cc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(C(C)O)cc12
Reaction time: 1 h
Yield: 91 %

Procedure:
The 1′-acetyl-N-(5-chlorothiazol-2-yl)-5-formylspiro[indoline-3,3′-pyrrolidine]-1-carboxamide (30.0 mg, 0.074 mmol) obtained in Step 2 of Example 401 was dissolved in tetrahydrofuran (1.4 mL). Thereafter, methyl magnesium bromide (1 M tetrahydrofuran solution, 224 μL) was added to the above obtained solution under cooling on ice, and the thus obtained mixture was then stirred at the same temperature as above for 1 hour. Thereafter, the reaction solution was diluted with a saturated aqueous solution of ammonium chloride, and was then extracted with chloroform. The organic layer was washed with brine, and was then dried over anhydrous sodium sulfate, followed by concentration in vacuo. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=10:1) to obtain the captioned compound (28.1 mg, 91%) in the form of a white solid.
Reaction SMILES: [NH:1]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].C(OCC)(=O)C>CC(C)=O>[CH2:9]([O:8][C:6]([C:5]1[CH:4]=[C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:2]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[N:1]=1)=[O:7])[CH3:10]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCOC(=O)c1cc(C(=O)OCC)[nH]n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCOC(=O)c1cc(C(=O)OCC)n(CC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6.25 g (29.5 mmol) of diethyl 3,5-pyrazoledicarboxylate (1) in 225 mL of acetone was added 11.7 g (36 mmol) of cesium carbonate, followed after 10 min by the addition of 5.3 mL (36 mmol) of t-butyl bromoacetate and the mixture was stirred overnight at room temperature. Since TLC analysis confirmed that the reaction was complete (Rf product=0.6 (7:3 hexanes:ethyl acetate)), the mixture was filtered and concentrated to give quantitatively 1-tert-butoxycarbonylmethyl-1H-pyrazole-3,5-dicarboxylic acid diethyl ester (2) as a clear oil as indicated by 1H NMR (containing a trace of t-butyl bromoacetate). (δ(300 MHz, CDCl3) 7.14 (s, 1H), 5.15 (s, 2H), 4.29 (q, J=7.1 Hz, 2H), 4.24 (q, J=7.1 Hz, 2H), 1.30 (s, 9 H), 1.27 (t, J=7.1 Hz, 3H), 1.25 (t, J=7.1 Hz, 3H)). This material was used without further purification in the next reaction.
Reaction SMILES: [F:1][C:2]1[C:24]([S:25]([CH:27]2[CH2:32][CH2:31][N:30]([C:33]([CH3:37])([CH3:36])[CH2:34][OH:35])[CH2:29][CH2:28]2)=[O:26])=[CH:23][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([CH3:22])[N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.C(O)(C(F)(F)F)=[O:39].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl>[F:1][C:2]1[C:24]([S:25]([CH:27]2[CH2:32][CH2:31][N:30]([C:33]([CH3:37])([CH3:36])[CH2:34][OH:35])[CH2:29][CH2:28]2)(=[O:39])=[O:26])=[CH:23][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:20])[CH3:21])[N:17]=[C:16]([CH3:22])[N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(S(=O)C4CCN(C(C)(C)CO)CC4)c(F)cc2OCC3)n(C(C)C)n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1nc(-c2cn3c(n2)-c2cc(S(=O)(=O)C4CCN(C(C)(C)CO)CC4)c(F)cc2OCC3)n(C(C)C)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 38.2 %

Procedure:
To an ice-cooled solution of 2-{4-[8-fluoro-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene-9-sulfinyl]piperidin-1-yl}-2-methylpropan-1-ol 212 (41 mg, 0.0767 mmol) in DCM (8 mL) was added TFA (30 μL, 0.383 mmol) followed by a slow addition of a solution of m-CPBA (17 mg, 0.10 mmol) in DCM (1.5 mL) and the resulting mixture was stirred for 3 h at 0° C. Volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (C18, gradient 10-45% MeOH in 0.5% TFA/H2O) and then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 0.5M NH3 in MeOH. Further purification by column chromatography (Si-PCC, gradient 3-15% MeOH in DCM) afforded 219 as a white solid (16 mg, 38%). LCMS: RT 2.72 min [M+H]+ 547.1. 1H NMR (DMSO, 400 MHz): δ 8.87 (1H, d, J=8.22 Hz), 7.93 (1H, s), 7.24 (1H, d, J=11.15 Hz), 5.66-5.55 (1H, m), 4.70-4.52 (4H, m), 4.21 (1H, t, J=5.47 Hz), 3.24-3.14 (3H, m), 3.08-2.99 (2H, m), 2.25 (3H, s), 2.12 (2H, bt, J=11.72 Hz), 1.86 (2H, bd, J=11.95 Hz), 1.55-1.43 (8H, d, J=6.62 Hz), 0.88 (6H, s)
Reaction SMILES: Cl[CH2:2][C:3]#[C:4][CH2:5][NH:6][C:7](=[O:22])[C:8]([OH:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:23]([NH2:25])[CH3:24]>CO>[CH2:23]([NH:25][CH2:2][C:3]#[C:4][CH2:5][NH:6][C:7](=[O:22])[C:8]([OH:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:24]
Reactant: CCN
Reactant: O=C(NCC#CCCl)C(O)(c1ccccc1)c1ccccc1
Solvent: CO
Product: CCNCC#CCNC(=O)C(O)(c1ccccc1)c1ccccc1
Yield: 77.9 %

Procedure:
A solution of N-(4-chloro-2-butynyl)-2-hydroxy-2,2-diphenylacetamide (1.0 g) and 70% aqueous ethylamine (4.32 g) in methanol (3 ml) was stirred at room temperature for 30 minutes and then evaporated in vacuo. The residue was dissolved in chloroform (30 ml) and the solution was washed with sodium chloride aqueous solution, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of chloroform and methanol (5:1) as an eluent to give N-(4-ethylamino-2-butynyl)-2-hydroxy-2,2-diphenylacetamide (0.8 g), which was treated with 4N methanolic hydrogen chloride to give N-(4-ethylamino-2-butynyl)-2-hydroxy-2,2-diphenylacetamide hydrochloride (0.65 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:19])[C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1.[CH3:29][N:30]1[CH2:35][CH2:34][CH2:33][CH:32](O)[CH2:31]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:19])[C:12]3[CH:13]=[CH:14][C:15]([O:18][CH:32]4[CH2:33][CH2:34][CH2:35][N:30]([CH3:29])[CH2:31]4)=[CH:16][CH:17]=3)=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1
Reactant: CN1CCCC(O)C1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(O)cc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OC3CCCN(C)C3)cc2)cc1
Yield: 21 %

Procedure:
6-Methoxy-2-(4-methoxyphenyl)-3-(4-hydroxybenzoyl)benzo[b]thiophene (1.17 g, 3.00 mmol), 1-methyl-3-hydroxypiperidine (691 mg, 6.00 mmol), triphenylphosphine (1.57 g, 6.00 mmol), and DEAD (6.0 mmol) were converted to product by the procedure of Example 11 to give 307 mg of the title compound. Yield: 21%. MS(FD) 487(M+). IR (CHCl3) ν max 3010, 2947, 2840, 2795, 1646, 1599, 1476, 1254, 1167.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([CH3:14])([CH3:13])[CH2:11][OH:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:15](N(CC)CC)[CH3:16].CS(Cl)(=O)=O.C(=O)(O)[O-].[Na+]>C1COCC1>[C:4]([Si:1]([O:8][CH2:9][C:10]([CH3:14])([CH3:13])[CH2:11][O:12][CH2:15][CH3:16])([CH3:3])[CH3:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(CO)CO[Si](C)(C)C(C)(C)C
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOCC(C)(C)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropan-1-ol (Registry No. 117932-70-4) (2.18 g, 10 mmol) in THF (30 ml) were added triethylamine (1.67 ml, 12 mmol) and methanesulfonyl chloride (0.85 ml, 11 mmol) under ice cooling. The reaction liquid was stirred at room temperature for 30 minutes, and to the reaction liquid was added an aqueous solution of sodium bicarbonate. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (2.98 g, quant.) as colorless oily substance.
Reaction SMILES: [NH2:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].[C:14](OC(=O)C)(=[O:16])C>C(O)=O>[CH3:13][O:12][C:3]1[CH:4]=[C:5]([CH:6]=[O:7])[CH:8]=[C:9]([O:10][CH3:11])[C:2]=1[NH:1][CH:14]=[O:16]
Reactant: COc1cc(C=O)cc(OC)c1N
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: COc1cc(C=O)cc(OC)c1NC=O
Temperature: 10 °C
Reaction time: 2 h

Procedure:
A solution (cooled to 10° C.) of 18.1 g. of 4-amino-3,5-dimethoxy-benzaldehyde in 210 ml. of 98% formic acid was treated dropwise with 70 ml. of acetic anhydride with stirring and the temperature was maintained below 15° C. The solution was then stirred for 2 hours at room temperature, treated with 80 ml. of water and evaporated to dryness under vacuum. The residue was washed with water, recrystallized from alcohol and there was obtained 2',6'-dimethoxy-4'-formyl-formanilide having a melting point of 159°-160° C.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([N:5]=C=O)=[O:4].[NH2:10][C:11]1[NH:12][C:13]2[C:18]([C:19]=1[C:20]([NH2:22])=[O:21])=[CH:17][CH:16]=[C:15]([O:23][CH3:24])[CH:14]=2.N.CO>O1CCCC1>[NH2:5][C:3]([NH:10][C:11]1[NH:12][C:13]2[C:18]([C:19]=1[C:20]([NH2:22])=[O:21])=[CH:17][CH:16]=[C:15]([O:23][CH3:24])[CH:14]=2)=[O:4]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: COc1ccc2c(C(N)=O)c(N)[nH]c2c1
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(C(N)=O)c(NC(N)=O)[nH]c2c1
Reaction time: 2.5 h
Yield: 89.2 %

Procedure:
Trichloroacetyl isocyanate (1.7 mL, 14 mmol) was added dropwide to a solution of 2-amino-6-methoxyindole-3-carboxamide (Reference compound No.2-1, 2.9 g, 14 mmol) in anhydrous tetrahydrofuran (50 mL) at −40° C. over a period of 10 minutes and the mixture was stirred for 2.5 hours. Moreover, 2.0 M ammonia in methanol solution (40 mL, 80 mmol) was added thereto and the mixture was stirred overnight at room temperature. The reaction solution was concentrated in vacuo, and the obtained solid was filtered off and washed with a mixed solvent of chloroform-methanol (50 mL). The solid was dried at 40° C. under reduced pressure to give the title compound (3.1 g) as a gray solid (88%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O>>[CH3:25][N:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:27]([F:38])([F:37])[F:26])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1C(F)(F)F

Procedure:
The title compound was prepared in analogy to example 25, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 2-trifluoromethylphenylboronic acid (CAS RN 1423-27-4). Off-white solid (60%). MS (ESI): m/z=493.4 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]4[N:24]([S:27]([C:30]5[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=5)(=[O:29])=[O:28])[CH:25]=[CH:26][C:19]=34)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.[CH3:37][C@@H:38]1[CH2:43][NH:42][CH2:41][CH2:40][NH:39]1.C(N(CC)CC)C>C(O)CCCC.Cl>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([N:42]4[CH2:41][CH2:40][NH:39][C@H:38]([CH3:37])[CH2:43]4)=[N:7][N:6]3[C:8]=2[C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[N:24]([S:27]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)(=[O:29])=[O:28])[CH:25]=[CH:26][C:19]=23)=[CH:12][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4c(-c5ccc(F)cc5)nc5ccc(Cl)nn45)ccnc32)cc1
Reactant: C[C@@H]1CNCCN1
Agent: Cl
Solvent: CCCCCO
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4c(-c5ccc(F)cc5)nc5ccc(N6CCN[C@H](C)C6)nn45)ccnc32)cc1
Yield: 68.8 %

Procedure:
A mixture of 0.330 g (0.58 mmol) of 6-chloro-2(4-fluorophenyl)-3-{1-[(4-methylphenyl)sulphonyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}imidazo[1,2-b]pyridazine, 0.116 g (1.16 mmol) of (2R)-2-methylpiperazine and 0.08 ml (0.6 mmol) of triethylamine in 5 ml of pentanol is heated under reflux for 24 hours. The reaction medium is diluted with 100 ml of an aqueous solution of hydrochloric acid and the solution is washed with ethyl acetate. The aqueous phase is then basified by addition of aqueous ammonia and the product is extracted with dichloromethane. The organic phase is separated, dried over sodium sulphate and the solvent is removed by evaporation under reduced pressure. The chestnut brown solid obtained is then purified by chromatography on a silica gel column (35 g) by eluting with a mixture of dichloromethane, methanol and aqueous ammonia (95/5/0.5) in order to give 0.232 g of 2-(4-fluorophenyl)-6-[(3R)-3-methylpiperazin-1-yl]-3-{1-[(4-methylphenyl)sulphonyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}imidazo[1,2-b]pyridazine in the form of a yellow powder after drying.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:7][NH:8][O:9][CH3:10].N1C=CC=CC=1.Cl>C(Cl)Cl>[CH3:7][N:8]([O:9][CH3:10])[C:1](=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CNOC
Reactant: CCCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC(=O)N(C)OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.8 %

Procedure:
To a stirred solution of butanoyl chloride (5.33 g, 50 mmol) and N,O-dimethylhydroxylamine (5.36 g, 55.0 mmol) in DCM (100 mL) at 0° C., was added dropwise pyridine (8.90 mL, 110 mmol). The resulting mixture was stirred for 1.5 h at RT, followed by work-up using aqueous HCl (2.0M) (100 mL) and DCM (200 mL), to afford the title compound (6.02 g) which was carried over to next step without further purification. LCMS (B) m/z: 132 [M+1]+, Rt 1.74 min.
Reaction SMILES: [C:1]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:6])[CH2:2][C:3]([CH3:5])=O.[Br:14]Br.S(=O)(=O)(O)O>C(Cl)(Cl)Cl>[Br:14][CH2:5][C:3]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:1](=[O:6])[CH:2]=1
Reactant: BrBr
Reactant: CC(=O)CC(=O)Nc1ccccc1
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: O=c1cc(CBr)c2ccccc2[nH]1
Temperature: 25 °C

Procedure:
30 Grams of acetoacetanilide was dissolved in 30 ml of chloroform, then a solution containing 27 g of bromine in 30 ml of chloroform was added dropwise thereto at a room temperature with stirring. After completion of the addition of bromine, the reaction mixture was refluxed for 30 minutes. The reaction mixture was concentrated under a reduced pressure, the residue obtained was added to 70 ml of a concentrated sulfuric acid with stirring. The addition operation was conducted by keeping the inside of the vessel within 70°-75° C., then the whole mixture was poured into ice-water and the crystals precipitated were collected by filtration. Recrystallized from methanol-chloroform to obtain 20 g of 4-bromomethylcarbostyril in the form of colorless needel-like crystals.