Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([NH:11][C:12](=[O:24])[C:13]3[CH:18]=[CH:17][C:16](Cl)=[N:15][C:14]=3[S:20][CH2:21][CH2:22][CH3:23])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH:25]1[CH2:30][CH2:29][CH2:28][C@@H:27]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH2:26]1.Cl.C(=O)([O-])[O-].[K+].[K+]>C(#N)CCC.CCOC(C)=O>[C:1]12([NH:11][C:12]([C:13]3[CH:18]=[CH:17][C:16]([N:25]4[CH2:30][CH2:29][CH2:28][C@@H:27]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH2:26]4)=[N:15][C:14]=3[S:20][CH2:21][CH2:22][CH3:23])=[O:24])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: COC(=O)C[C@@H]1CCCNC1
Reactant: CCCSc1nc(Cl)ccc1C(=O)NC12CC3CC(CC(C3)C1)C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCC#N
Product: CCCSc1nc(N2CCC[C@@H](CC(=O)OC)C2)ccc1C(=O)NC12CC3CC(CC(C3)C1)C2
Yield: 44 %

Procedure:
N-adamantan-1-yl-6-chloro-2-(propylthio)nicotinamide (0.365 g, 1 mmol) was added to (S)-methyl 2-(piperidin-3-yl)acetate.HCl (0.194 g, 1 mmol) and potassium carbonate (0.415 g, 3 mmol) in butyronitrile (4 mL) was heated at 150° C. for 2 hours. The reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with water (20 mL) and brine (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in hexane. Pure fractions were evaporated to dryness to afford methyl {(3S)-1-[5-(adamantan-1-ylcarbamoyl)-6-(propylthio)pyridin-2-yl]piperidin-3-yl}acetate (0.215 g, 44%) as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][N:3]=[C:2]1[NH:7][CH2:8][CH2:9][CH:10](O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.S(=O)(=O)(O)O.[OH-].[Na+]>>[C:11]1([CH:10]2[N:3]3[CH2:4][CH2:5][CH2:6][N:1]=[C:2]3[NH:7][CH2:8][CH2:9]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OC(CCNC1=NCCCN1)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: c1ccc(C2CCNC3=NCCCN32)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2 parts of α-[2-(1,4,5,6-tetrahydro-2-pyrimidinylamino)ethyl]benzylalcohol and 27 parts of sulfuric acid 80% is stirred for 2 hours at room temperature. The reaction mixture is poured onto crushed ice and the whole is alkalized with sodium hydroxide solution. The product is extracted with toluene. The organic layer is separated, dried, filtered and evaporated. The solid residue is crystallized from acetone, yielding 3,4,6,7,8,9-hexahydro-6-phenyl-2H-pyrimido-[1,2-a]pyrimidine, m.p. 177°-179°C.
Reaction SMILES: C[CH2:2][OH:3].[O:4]=[CH:5][C@H:6]([C@@H:8]([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9])[OH:7]>OCC(CO)O>[O:4]=[CH:5][C@@H:6]([C@H:8]([C@@H:10]([C@@H:12]([CH2:2][OH:3])[OH:13])[OH:11])[OH:9])[OH:7]
Reactant: CCO
Reactant: O=C[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: OCC(O)CO
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 450 h

Procedure:
It was confirmed by 450 hours of cultivation in shake flasks on glucose that the hexokinase/glucokinase deletion strain IMK318 (hxk1Δ hxk2Δ glk1Δ) is unable to grow on glucose alone. Therefore the strain was cultivated in YP-EtOH/Glyc and subsequently stored at −80° C. after the addition of glycerol. Subsequently, IMK318 was cultivated in 100 ml MY containing 2% arabinose. After 3 days, at an OD660 of approximately 1, 2 ml of the culture was transferred to 100 ml fresh MY containing 2% arabinose. After approximately 12 days the OD660 of the culture was >5 and samples were stored at −80° C. as glycerol stocks. Strain IMK318 was cultivated at 30° C. for several days in MY-ara. At an OD660 of approximately 5, 2 ml of the culture was transferred to 6 separate shake flasks containing 100 ml MYurea supplemented with 2% arabinose and varying concentrations of glucose: 0, 0.11, 0.23, 0.65, 1.3 and 2.5 (w/v) %. Growth of these 6 parallel cultures was recorded by OD660 measurements (FIG. 3). It was observed that, in the presence of glucose, growth is delayed. An increasing amount of glucose resulted in an increasingly delayed growth on arabinose. Two of these parallel cultures (Line A which started at 0.65 w/v % glucose; Line B which started at 2.5 w/v % glucose) were transferred serially to 100 ml MY supplemented with arabinose and glucose according to the transfer-schemes shown in Table 4.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH2:7].[C:8]([C:12]1[CH:21]=[CH:20][C:15]([CH2:16][N:17]=[C:18]=[S:19])=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9]>ClCCl.C(OCC)(=O)C>[C:8]([C:12]1[CH:21]=[CH:20][C:15]([CH2:16][NH:17][C:18]([NH:7][CH2:6][C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[S:19])=[CH:14][CH:13]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)c1ccc(CN=C=S)cc1
Reactant: NCc1ccco1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CNC(=S)NCc2ccco2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
Furan-2-ylmethylamine (0.58 g) was dissolved in dichloromethane (50 ml) and to the solution was added 4-t-butylbenzylisothiocyanate (1.23 g), followed by stirring at room temperature for 8 hours. Then, the resulting mixture was diluted with ethyl acetate, washed with water, dried, and concentrated under reduced pressure. The residue was purified by column-chromatography (dichloromethane) to yield the compound 16-2 (1.57 g, 87%) as a liquid.
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]([CH2:19][O:20][CH2:21][CH:22]=[CH2:23])([CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:7][CH3:8])[CH:2]=[CH2:3].[Cl:24][SiH:25]([Cl:27])[Cl:26]>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[Cl:24][Si:25]([CH2:23][CH2:22][CH2:21][O:20][CH2:19][C:6]([CH2:5][O:4][CH2:1][CH2:2][CH2:3][Si:25]([Cl:27])([Cl:26])[Cl:24])([CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:7][CH3:8])([Cl:27])[Cl:26]
Reactant: C=CCOCC(CC)(COCC=C)COCCCCCCCC
Reactant: Cl[SiH](Cl)Cl
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Product: CCCCCCCCOCC(CC)(COCCC[Si](Cl)(Cl)Cl)COCCC[Si](Cl)(Cl)Cl
Temperature: 55 °C
Yield: 60 %

Procedure:
A 1 L, 3-neck flask equipped with magnetic stirrer, pot thermometer and condenser was charged with 3,3-diallyloxymethyl-5-oxa-tridecane (200 g) prepared in Example 4. After heating to 50-60° C., 30 ml of trichlorosilane was added followed by 1 ml of 2.5% chloroplatinic acid solution. Once initiation was observed, a total of 178.8 g of trichlorosilane was added at a rate to maintain reaction temperature at 70-100° C. After the addition was complete, the mixture was maintained at 80-90° C. for 2 hours. The mixture was distilled. The product was isolated in 60% yield, b.p. 220-222 C./0.9 mm; density 1.135; 1HNMR (C6D6): 0.90(m, 6H), 1.13(m, 4H), 1.26(m, 10H), 1.58(m, 8H), 3.10(t, 4H), 3.32(s, 2H), 3.38(t, 4H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8](Cl)=[O:9])([CH3:4])([CH3:3])[CH3:2].[NH2:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:23]([OH:25])=[O:24]>COCCOC>[C:23]([C:22]1[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:20]([NH:19][C:8](=[O:9])[C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:13]([OH:14])=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:11]=2)[CH:21]=1)([OH:25])=[O:24]
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Reactant: COc1ccc(C(=O)O)cc1N
Solvent: COCCOC
Product: COc1ccc(C(=O)O)cc1NC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 23.8 %

Procedure:
A solution of 5.06g (0.02 mole) of 3,5-di-t-butyl-4-hydroxybenzoyl chloride in 100 ml of 1,2-dimethoxyethane was mixed with a solution of 6.69g (0.04 mole) of 3-amino-4-methoxybenzoic acid in 125 ml of 1,2-dimethoxyethane, and the mixture was stirred at 25° C. for about 16 hours. The reaction mixture was heated gently for 30 minutes and then allowed to cool before being filtered to remove the hydrochloride salt of the excess starting amine. The filtrate was concentrated under vacuum and then diluted with water. The resulting precipitate was collected and was then recrystallized three times from a mixture of ethanol and water to give 1.9g of white solid N-(5-carboxy-2-methoxyphenyl)-3,5-di-t-butyl-4-hydroxybenzamide, m.p. 259°-261° C. Analysis: Calculated for C23H29NO5 : %C, 69.2; %H, 7.3; %N, 3.5; Found: %C, 69.3; %H, 7.3; %H, 3.6.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][CH:15]([C:18]4[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.[CH3:29][O:30][CH2:31][CH2:32][NH:33][CH3:34].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC(N(C)C)=O>[CH3:29][O:30][CH2:31][CH2:32][N:33]([CH3:34])[C:22](=[O:23])[C:21]1[CH:25]=[CH:26][C:18]([CH:15]2[CH2:14][CH2:13][N:12]([C:9]3[CH:10]=[CH:11][C:6]4[N:7]([C:3]([C:2]([F:27])([F:1])[F:28])=[N:4][N:5]=4)[N:8]=3)[CH2:17][CH2:16]2)=[CH:19][CH:20]=1
Reactant: O=C(O)c1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Reactant: CNCCOC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COCCN(C)C(=O)c1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.2 %

Procedure:
A mixture of 4-[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]benzoic acid (79 mg, 0.20 mmol), N-(2-methoxyethyl)methylamine (21 mg, 0.24 mmol), DIPEA (0.105 mL, 0.61 mmol) and HATU (92 mg, 0.24 mmol) in DMA (3 mL) was stirred at ambient temperature for 16 hours. The reaction mixture was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to give N-(2-methoxyethyl)-N-methyl-4-[1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]benzamide (77 mg, 82%) as a solid.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([OH:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:31][CH:32]1[CH2:34][CH2:33]1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:31][CH:32]3[CH2:34][CH2:33]3)=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(O)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: ClCC1CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC#N
Product: CC(=O)N1c2ccc(OCC3CC3)cc2C(C)(c2ccccc2)CC1(C)C
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A mixture of 1-acetyl-6-hydroxy-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (20 mg), cesium carbonate (63 mg), tetrabutylammonium bromide (29 mg) and chloromethylcyclopropane (8.4 l) in acetonitrile (1 ml) was stirred at 50° C. for 18 h. The reaction mixture was concentrated in vacuo and the residue was chromatographed on silicagel in heptane/ethyl acetate=1/0=>6/4 (v/v) as eluent.
Reaction SMILES: [C:1]1([CH3:23])[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1>[Cl-].[Cl-].[Cl-].[Ti+3]>[C:1]1([CH3:23])[CH:2]=[CH:3][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=3)[CH2:11][CH2:12]2)=[CH:5][CH:6]=1
Reactant: Cc1ccc(N2CCN(Cc3ccc([N+](=O)[O-])cc3)CC2)cc1
Agent: [Ti+3]
Agent: [Cl-]
Product: Cc1ccc(N2CCN(Cc3ccc(N)cc3)CC2)cc1

Procedure:
In the manner given in Example 1B, 1-(p-tolyl)-4-(p-nitrobenzyl)piperazine is reduced with aqueous titanium trichloride to give 1-(p-tolyl)-4-[(4-aminophenyl)methyl]piperazine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[N+:8]([C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=1)([O-:10])=[O:9]>>[N+:8]([C:11]1[CH:12]=[CH:13][C:14]([C:15]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[O:16])=[CH:18][CH:19]=1)([O-:10])=[O:9]
Reactant: Nc1cccnc1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Product: O=C(Nc1cccnc1)c1ccc([N+](=O)[O-])cc1
Yield: 49.6 %

Procedure:
Using 3-aminopyridine (1.55 g, 16.5 mmol) and 4-nitrobenzoic acid (2.5 g, 15.0 mmol), the procedure of Reference Example 16 was repeated to obtain 1.81 g (49.6%) of the title compound in the form of colorless powder.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([F:13])[CH:8]=2)[CH2:3][CH2:2]1.[H][H]>CCO.[OH-].[Pd+2].[OH-]>[F:13][C:9]1[CH:8]=[C:7]([CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH:12]=[CH:11][N:10]=1
Reactant: Fc1cc(C2=CCOCC2)ccn1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: Fc1cc(C2CCOCC2)ccn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.2 %

Procedure:
A suspension of palladium hydroxide, (20 wt % palladium dry basis on carbon, wet, degussa type e101 ne/w, 150 mg), and 4-(3,6-Dihydro-2H-pyran-4-yl)-2-fluoropyridine (0.90 g, 5.0 mmol) in EtOH (10 mL) was placed under 1 atm hydrogen (balloon) and stirred for 4 h at RT. The mixture was then placed back under argon atmosphere, the palladium was filtered off, and the filtrate was concentrated to give 2-fluoro-4-(tetrahydro-2H-pyran-4-yl)pyridine (0.86 g, 4.76 mmol, 95%) as a yellow oil.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].Cl[CH2:7][Si:8]([O:13][CH3:14])([O:11][CH3:12])[O:9][CH3:10].[SiH4]>[Br-].C([P+](CCCC)(CCCC)CCCC)CCC.C(OC)(=O)CCCCCCCCCCC>[C:1]([O:4][CH2:7][Si:8]([O:13][CH3:14])([O:11][CH3:12])[O:9][CH3:10])(=[O:3])[CH3:2]
Reactant: CO[Si](CCl)(OC)OC
Reactant: CC(=O)[O-]
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CCCCCCCCCCCC(=O)OC
Product: CO[Si](COC(C)=O)(OC)OC
Temperature: 120 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
Example 2 was repeated using sodium acetate (312 g, 3.81 mol) and (chloromethyl)trimethoxysilane (563 g, 3.30 mol) as starting materials, tetrabutylphosphonium bromide (22.46 g, 66.2 mmol) as catalyst and methyl laurate (525 mL) as solvent. Before the silane was added, the other components were mixed and incipiently stripped at 116° C./4 mbar (for drying, 16 g of distillate). The silane was metered in at 120° C. over 2 hours, the mixture was heated at 120° C. for a further 4 hours and then distilled at 10-11 mbar (head), 74-76° C. (head) and 88-122° C. (pot) through a packed column (20 cm) to obtain 608 g (3.13 mol, 95% of theory) of (acetoxymethyl)trimethoxysilane in the distillate; purity 98.6% (GC area %). The solvent then started to pass over at 3.1 mbar (head), 113° C. (head) and 128° C. (pot). By distilling over a small amount (about 10 g) of the solvent, the product (acetoxymethyl)trimethoxysilane was fully removed from the residue. The remaining solvent, sodium chloride, excess sodium acetate and the phase transfer catalyst (in the form of the bromide, chloride and acetate salt of tetrabutylphosphonium) remained in the residue.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[C:9](OS(C(F)(F)F)(=O)=O)=[N:10][C:11]2[C:16]([N:17]=1)=[CH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=2.[F:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:30][C:31]1[CH:36]=[CH:35][C:34]([C:9]2[C:8]([N:3]3[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]3[CH3:1])=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=3)[N:10]=2)=[CH:33][CH:32]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCCCC3C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCCC3C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 42.8 %

Procedure:
To a solution of methyl 3-(2-methylpiperidin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (880 mg, crude) in dioxane (25 ml) was added Pd(PPh3)4 (100 mg, 0.09 mmol), 4-fluorophenylboronic acid (485 mg, 3.47 mmol), K3PO4 (735 mg, 3.46 mmol) and water (3 ml). The resulting solution was stirred for 1 hour at 90° C. under an inert atmosphere of nitrogen, and then concentrated in vacuo to give a residue, which was purified via silica gel column chromatography (1%-10% ethyl acetate in petroleum ether) to afford methyl 2-(4-fluorophenyl)-3-(2-methylpiperidin-1-yl)quinoxaline-6-carboxylate as a yellow solid (330 mg).
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2].[Br:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][C:25](=[O:31])[NH:26]2>>[Br:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[C:24](=[CH:16][C:13]1[NH:12][C:9]3[CH2:10][CH2:11][N:6]([CH2:5][CH2:4][N:3]([CH2:19][CH3:20])[CH2:1][CH3:2])[C:7](=[O:18])[C:8]=3[C:14]=1[CH3:15])[C:25](=[O:31])[NH:26]2
Reactant: O=C1Cc2c(Br)cccc2N1
Reactant: CCN(CC)CCN1CCc2[nH]c(C=O)c(C)c2C1=O
Product: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4cccc(Br)c43)c(C)c2C1=O
Yield: 77.2 %

Procedure:
The title compound was prepared under the same conditions as described in Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-bromo-1,3-dihydro-indol-2-one (prepared according to US20030225127) as starting materials to give 2-(4-bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-diethylamino-ethyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (59 mg, 77.2%) as a bright yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:27][C:28]([O:30]C(C)(C)C)=[O:29])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:26])[NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:12][CH:11]=1)#[N:2].C(O)(C(F)(F)F)=O>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([CH2:27][C:28]([OH:30])=[O:29])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16](=[O:26])[NH:17][CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:14][CH:15]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccccc3)cc2)c(C#N)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(CC(=O)O)ccc1Oc1ccc(C(=O)NCCc2ccccc2)cc1
Temperature: 25 °C
Yield: 95 %

Procedure:
To a solution of tert-butyl 2-(3-cyano-4-(4-(phenethylcarbamoyl)phenoxy)phenyl)acetate 0.120 g) in 2 ml of dichloromethane was added 2 ml of TFA and the reaction was stirred at ambient temperature. After 1 hour the reaction was concentrated and dried under vacuum to give 2-(3-cyano-4-(4-(phenethylcarbamoyl)phenoxy)phenyl)acetic acid (0.100 g). MS −355.3 [M—CO2H].
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9](=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18].[OH-].[Na+]>O1CCCC1>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][CH2:9][OH:8]
Reactant: COC(=O)Cc1ccccc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccccc1CCO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
Lithium aluminum hydride (21 g, 0.55 mol) was added to a solution of (2-methoxy-phenyl)-acetic acid methyl ester (90 g, 0.50 mol) in anhydrous tetrahydrofuran (500 mL) at 0° C. After stirred at 0° C. for 30 minutes, the mixture was treated with sodium hydroxide (5% aqueous solution, 180 g). The mixture was extracted three times with ethyl acetate (400 mL) and the combined organic layers were washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered, and evaporated to dryness to give 2-(2-methoxy-phenyl)-ethanol (43 g, 0.28 mol, 57%), which was used directly in the next step.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[N:7]1[C:14]2[C@@H:13]3[CH2:15][C@@H:12]3[CH2:11][C:10]=2[C:9]([C:16]([OH:18])=O)=[N:8]1.[NH2:19][C@@H:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:21][OH:22]>>[OH:22][CH2:21][C@@H:20]([NH:19][C:16]([C:9]1[C:10]2[CH2:11][C@H:12]3[CH2:15][C@H:13]3[C:14]=2[N:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)[N:8]=1)=[O:18])[C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: O=C(O)c1nn(-c2cnccn2)c2c1C[C@H]1C[C@@H]21
Reactant: CC(C)(C)[C@H](N)CO
Product: CC(C)(C)[C@@H](CO)NC(=O)c1nn(-c2cnccn2)c2c1C[C@H]1C[C@@H]21

Procedure:
The title compound was prepared as described in Method G using Intermediate 2 and (S)-2-amino-3,3-dimethylbutan-1-ol. LCMS m/z=342.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.41 (td, J=4.4 and 3.3 Hz, 1H), 0.93 (s, 9H), 1.23-1.28 (m, 1H), 2.25-2.34 (m, 1H), 2.69-2.74 (m, 1H), 2.75 (d, J=16.0 Hz, 1H), 2.90 (dd, J=16.2 and 6.4 Hz, 1H), 3.50-3.58 (m, 1H), 3.62-3.67 (m, 1H), 3.76-3.82 (m, 1H), 4.52 (t, J=5.0 Hz, 1H), 7.54 (d, J=9.8 Hz, 1H), 8.58 (dd, J=2.5 and 1.5 Hz, 1H), 8.64 (d, J=2.6 Hz, 1H), 9.39 (d, J=1.4 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22]C3CCCCO3)[CH:17]=2)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:29][N:30]([CH3:38])[C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH:9]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)(=[O:14])=[O:15])[CH:11]=[C:10]([CH2:29][N:30]([CH3:38])[C:31](=[O:37])[O:32][C:33]([CH3:34])([CH3:35])[CH3:36])[CH:9]=1
Reactant: CN(Cc1cc(-c2ccccc2F)n(S(=O)(=O)c2cccc(OC3CCCCO3)c2)c1)C(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CN(Cc1cc(-c2ccccc2F)n(S(=O)(=O)c2cccc(O)c2)c1)C(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
tert-Butyl ((5-(2-fluorophenyl)-1-((3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 1g (0.45 g, 0.83 mmol) was dissolved in 5 mL of methanol, followed by addition of p-toluenesulfonic acid (16 mg, 0.08 mmol), and then the reaction solution was stirred for 3 h. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with elution system B to obtain the title product tert-butyl ((5-(2-fluorophenyl)-1-((3-hydroxyphenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 1h (0.35 g, a red oil) in 92% yield.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[F:11][C:12]1[CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1>>[Cl:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH:8][S:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([F:11])[CH:13]=2)(=[O:20])=[O:19])=[N:6][CH:7]=1
Reactant: COc1nc(Cl)cnc1N
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Product: COc1nc(Cl)cnc1NS(=O)(=O)c1cccc(F)c1

Procedure:
By the method outlined in Example 1 (reaction performed at room temperature) using 5-chloro-3-methoxy-2-pyrazinamine (0.798 g) and 3-fluorobenzenesulphonyl chloride (1.17 g). Yield 0.64 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19](O)=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23].[CH:37]1([S:40]([NH2:43])(=[O:42])=[O:41])[CH2:39][CH2:38]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:43][S:40]([CH:37]3[CH2:39][CH2:38]3)(=[O:42])=[O:41])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23]
Reactant: Cc1ccc(F)c(Nc2c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc3c(C(=O)O)cnn23)c1
Reactant: NS(=O)(=O)C1CC1
Product: Cc1ccc(F)c(Nc2c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc3c(C(=O)NS(=O)(=O)C4CC4)cnn23)c1
Yield: 54.1 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-fluoro-5-methylphenylamino)-6-[4-(4- fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (68 mg, 0.14 mmol) obtained in Example 81, step 4 and cyclopropanesulfonamide (84 mg, 0.69 mmol), the title compound (45 mg, 55%) was obtained.