Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13](S(C)=O)[N:14]=[CH:15][C:10]=3[C:9]([CH3:19])=[CH:8][C:7]2=[O:20])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[N:36][C:37]([NH2:40])=[CH:38][CH:39]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>C1(C)C=CC=CC=1>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[N:36][C:37]([NH:40][C:13]3[N:14]=[CH:15][C:10]4[C:9]([CH3:19])=[CH:8][C:7](=[O:20])[N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:11]=4[N:12]=3)=[CH:38][CH:39]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: Cc1cc(=O)n(C2CCCC2)c2nc(S(C)=O)ncc12
Solvent: Cc1ccccc1
Product: Cc1cc(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)ncc12
Temperature: 25 °C
Yield: 14.4 %

Procedure:
8-Cyclopentyl-2-methanesulfinyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (0.40 g, 1.37 mmol) and 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.497 g, 1.78 mmol) were heated to reflux in toluene (4 mL) for 16 hours. The reaction mixture was cooled to room temperature and the precipitate that formed was collected by filtration and washed on the funnel with toluene (3×10 mL) to give 4-[6-(8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester as a dark brown-gray solid (0.100 g, 16.2%). 1H NMR δ (400 MHz, DMSO-d6) 9.92 (s, 1H), 8.78 (s, 1H), 8.02 (d, J=2.9 Hz, 1H), 7.87 (d, J=9.3 Hz, 1H), 7.50 (dd, J=2.9, 9.0 Hz, 1H), 6.18 (s, 1H), 5.77 (m, 1H), 3.44 (m, 4H), 3.07 (m, 4H), 2.39 (s, 3H), 2.20 (m, 2H), 1.85 (m, 2H), 1.71 (m, 2H), 1.55 (m, 2H), 1.39 (s, 9H).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:4]1.[N+:18]([C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Br)([O-:20])=[O:19]>CN(C)C=O>[N+:18]([C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:4]1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: O=C(O)CCCc1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)CCCc1cn(Cc2cccc([N+](=O)[O-])c2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.3 %

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil) (0.59 g) in N,N-dimethylformamide (10 ml) was added a solution of 4-(3-indolyl)butyric acid (1.0 g) in N,N-dimethylformamide (5 ml). The mixture was stirred at room temperature for 30 minutes and cooled at -40° C. To the mixture was added a solution of 3-nitrobenzyl bromide (1.06 g) in N,N-dimethylformamide (5 ml). The mixture was stirred at -40° C. for 20 minutes and partitioned between ethyl acetate and 7% hydrochloric acid. The organic layer was washed with water, dried over magnesium sulfate and evaporated. The residue was washed with diisopropyl ether to give 4-[1-(3-nitrobenzyl)indol-3-yl]butyric acid as a white powder (1.20 g).
Reaction SMILES: [C:1]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([NH:16][C:17]3[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=3)[N:14]=2)[N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:8]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.[O:40]=[CH:41][CH2:42][C:43]#[N:44].C(O)(=O)C.N1CCCCC1>C(O)C>[CH3:33][N:34]1[CH2:39][CH2:38][N:37]([C:41]([C:42](=[CH:21][C:20]2[CH:23]=[CH:24][C:17]([NH:16][C:13]3[N:14]=[C:15]4[C:7]([C:1](=[O:6])[C:2]([CH3:4])([CH3:3])[CH3:5])=[CH:8][N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:30])[CH3:31])[C:10]4=[N:11][CH:12]=3)=[CH:18][CH:19]=2)[C:43]#[N:44])=[O:40])[CH2:36][CH2:35]1
Reactant: N#CCC=O
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=O)cc3)nc12
Reactant: CN1CCNCC1
Solvent: C1CCNCC1
Solvent: CCO
Solvent: CC(=O)O
Product: CN1CCN(C(=O)C(C#N)=Cc2ccc(Nc3cnc4c(n3)c(C(=O)C(C)(C)C)cn4COCC[Si](C)(C)C)cc2)CC1
Temperature: 80 °C
Yield: 103.9 %

Procedure:
To a 35 ml reaction vial, 4-(7-pivaloyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)benzaldehyde (0.200 g, 0.0004 mole) and 3-(4-methylpiperazin-3-oxopropanenitrile (0.211 g, 0.0013 mole) was taken in ethanol (10 ml). To this, piperidine acetate (3.3 M solution in water) (3 ml, 0.0099 mole) was added at RT and the reaction mixture was heated to 80° C. for 16 hr. After completion of the reaction, ethanol was evaporated under reduced pressure from the reaction mixture and then diluted with EtOAc (20 ml). The organic layer was washed with water, dried over Na2SO4 and evaporated to get product which was subjected for the column purification. The crude compound was purified using column purification using 60-120 mesh size neutral silica by eluting the compound with 2% MeOH in CH2Cl2 to yield 0.25 g of 2-(4-methylpiperazine-1-carbonyl)-3-(4-(7-pivaloyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)phenyl)acrylonitrile.
Reaction SMILES: CS(C)=O.[OH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH3:13])=[CH:8][CH:7]=1.[OH-].[K+].Br[C:31]([F:37])([F:36])[C:32]([F:35])([F:34])[Br:33]>O.C1(C)C=CC=CC=1>[Br:33][C:32]([F:35])([F:34])[C:31]([F:37])([F:36])[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:31]([F:37])([F:36])[C:32]([F:35])([F:34])[Br:33])=[CH:16][CH:15]=2)([C:21]2[CH:22]=[CH:23][C:24]([O:27][C:31]([F:37])([F:36])[C:32]([F:35])([F:34])[Br:33])=[CH:25][CH:26]=2)[CH3:13])=[CH:8][CH:7]=1
Reactant: CC(c1ccc(O)cc1)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: FC(F)(Br)C(F)(F)Br
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(c1ccc(OC(F)(F)C(F)(F)Br)cc1)(c1ccc(OC(F)(F)C(F)(F)Br)cc1)c1ccc(OC(F)(F)C(F)(F)Br)cc1
Temperature: 35 °C
Reaction time: 0.25 h
Yield: 12.2 %

Procedure:
A 1 liter 5-necked round bottom flask is fitted with a mechanical stirrer, a Dean Stark trap topped with a nitrogen padded reflux condenser, and a thermocouple attached to a temperature controller. A mixture of DMSO (450 ml), toluene (150 ml), and 1,1,1-tris(4-hydroxyphenyl)ethane (55.1 g, 0.18 mole) is added to the flask under nitrogen purge. After stirring for 15 minutes under a vigorous nitrogen purge, potassium hydroxide (85% pellets, 80.0 g, 1.2 mole) is slowly added to the reaction flask. The mixture is then stirred at reflux for 48 hours with azeotropic removal of water. The resulting suspension is cooled to 35° C. in an ice bath and 1,2-dibromotetrafluoroethane (155 g, 0.60 mole) is added at a rate that maintains a temperature of 30°-35° C. When the addition is complete, the mixture is heated to 50° C. with continuous stirring for 3 hours. After filtration, the solvents are removed by heating under vacuum on a rotary evaporator. The brown residue is purified by column chromatography on neutral alumina using hexane as eluent to provide as product 1,1,1-tris(4-[2-bromotetrafluoroethoxy]phenyl)ethane (18.3 g, 0.022 mole, 12% yield).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:10][C:11]1[CH:15]=[CH:14][NH:13][N:12]=1.O=[C:17]([CH2:24][CH2:25][CH3:26])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:17]([CH2:24][CH2:25][CH3:26])[NH:10][C:11]2=[N:12][NH:13][CH:14]=[C:15]12
Reactant: CCCC(=O)CC(=O)OCC
Reactant: O=Cc1ccccc1Br
Reactant: Nc1cc[nH]n1
Product: CCCC1=C(C(=O)OCC)C(c2ccccc2Br)c2c[nH]nc2N1

Procedure:
The title compound was prepared from 2-bromobenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)=[N:7][CH:8]=1.[OH:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH:24]=[CH:23]2.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[Cl:18][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=1[Cl:17])[CH2:10][NH:9][C:6]1[N:7]=[CH:8][C:3]([CH2:2][O:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[NH:26][C:25](=[O:30])[CH:24]=[CH:23]3)=[CH:4][CH:5]=1
Reactant: ClCc1ccc(NCc2ccc(Cl)c(Cl)c2)nc1
Reactant: O=c1ccc2cc(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1ccc2cc(OCc3ccc(NCc4ccc(Cl)c(Cl)c4)nc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 26 %

Procedure:
A mixture of 5-(chloromethyl)-N-(3,4-dichlorobenzyl)pyridin-2-amine (0.1 g, 0.332 mmol), 6-hydroxyquinolin-2(1H)-one (0.048 g, 0.298 mmol) and Cs2CO3 (0.864 g, 2.65 mmol) in DMF (3.3 mL) was stirred at room temperature for 18 h. The reaction was diluted with water and the resulting suspension was filtered. The filter cake was stirred in methanol for 1 h, filtered, washed with methanol, and dried to yield 6-((6-(3,4-dichlorobenzylamino)pyridin-3-yl)methoxy)quinolin-2(1H)-one as a beige solid (0.033 g, 22%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.65 (1H, s), 8.06 (1H, d, J=2.01 Hz), 7.85 (1H, d, J=9.54 Hz), 7.46-7.63 (3H, m), 7.08-7.37 (5H, m), 6.39-6.62 (2H, m), 4.91 (2H, s), 4.49 (2H, d, J=6.02 Hz). LCMS: R.T.=3.15; [M+H]+=426.00.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[C:10]([O:13]C(C2CC2)=O)[C:9]2[C:4](=[CH:5][C:6]([Cl:20])=[C:7]([F:19])[CH:8]=2)[N:3]=1.[OH-].[Na+].O.Cl>CO>[CH3:1][C:2]1[C:11]([CH3:12])=[C:10]([OH:13])[C:9]2[C:4](=[CH:5][C:6]([Cl:20])=[C:7]([F:19])[CH:8]=2)[N:3]=1
Reactant: Cc1nc2cc(Cl)c(F)cc2c(OC(=O)C2CC2)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1nc2cc(Cl)c(F)cc2c(O)c1C
Temperature: 50 °C
Reaction time: 3 h
Yield: 88.2 %

Procedure:
2,3-Dimethyl-4-cyclopropanecarbonyloxy-6-fluoro-7-chloroquinoline (590 mg) prepared as described in Example 9 was dissolved in 5 ml of methanol, and 5 ml of a 10% aqueous sodium hydroxide solution was added to this solution. The mixture was stirred at 50° C. for 3 hr. The reaction mixture was allowed to stand for cooling, was then poured into 50 ml of water, and was neutralized with 1 N hydrochloric acid, and the precipitate was then collected by filtration to give 400 mg of 2,3-dimethyl-4-hydroxy-6-fluoro-7-chloroquinoline. In 3 ml of tetrahydrofuran was suspended 26.4 mg of 60% sodium hydride. Separately, 100 mg of 2,3-dimethyl-4-hydroxy-6-fluoro-7-chloroquinoline (starting material 1) prepared above was suspended in 2 ml of tetrahydrofuran, and this suspension was added dropwise to the above suspension under ice cooling. After stirring for one hr, 0.1 ml of methyl chloroformate (starting material 2) was added thereto, and the mixture was stirred at room temperature for 3 hr. The reaction solution was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine and was then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under the reduced pressure. The crude product thus obtained was purified on Wako Gel C-200 (100 ml; elution solvent=n-hexane-ethyl acetate (10:1)) to give 48 mg of 2,3-dimethyl-4-methoxycarbonyloxy-6-fluoro-7-chloroquinoline (compound 28). 1H-NMR data are shown in Table 3.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:21]=[CH:20][C:12]([C:13]([NH:15][CH2:16][CH2:17][CH2:18]Cl)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([C:29]1([OH:35])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].CC(=O)CC>O>[CH2:22]([C:29]1([OH:35])[CH2:34][CH2:33][N:32]([CH2:18][CH2:17][CH2:16][NH:15][C:13](=[O:14])[C:12]2[CH:20]=[CH:21][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)[CH2:31][CH2:30]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: OC1(Cc2ccccc2)CCNCC1
Reactant: O=C(NCCCCl)c1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: O=C(NCCCN1CCC(O)(Cc2ccccc2)CC1)c1ccc(OCc2ccccc2)cc1
Yield: 24.6 %

Procedure:
A mixture of 4-benzyloxy-N-(3-chloro-propyl)-benzamide (0.5 g, 1.64 mmol), ), 4-benzyl-4-hydroxy-piperidine (0.315 g, 1.65 mmol), potassium carbonate (0.45 g, 3.29 mmol) and 2-butanone (10 ml) was stirred at 60° C. for 48 h. After the addition of water, the mixture was extracted with ethyl acetate. The organic layer was dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (silica gel, methylene chloride-methanol from 95:5 to 9:1) to give N-[3-(4-benzyl-4-hydroxy-piperidin-1-yl)-propyl]-4-benzyloxy-benzamide (185 mg, 25%) as a light yellow solid. MS: me/e=459 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[C:13](=[C:14]([S:19](Cl)=[O:20])[N:15]([CH3:18])[N:16]=2)[CH:12]=[CH:11][CH:10]=1.C[O:23][CH2:24][CH2:25][NH2:26].CNC.CN.N1CC[O:35]CC1.CN1CCNCC1.N(CCO)CCO>>[OH:23][CH2:24][CH2:25][NH:26][S:19]([C:14]1[N:15]([CH3:18])[N:16]=[C:17]2[C:13]=1[CH:12]=[CH:11][CH:10]=[C:9]2[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])(=[O:20])=[O:35]
Reactant: C1COCCN1
Reactant: Cn1nc2c(-c3ccc(Cl)cc3Cl)cccc2c1S(=O)Cl
Reactant: COCCN
Agent: CN
Agent: CN1CCNCC1
Agent: CNC
Solvent: OCCNCCO
Product: Cn1nc2c(-c3ccc(Cl)cc3Cl)cccc2c1S(=O)(=O)NCCO

Procedure:
The following compounds were prepared from 7-(2,4-dichloro-phenyl)-2-methyl-2H -indazole-3-sulfinyl chloride in a similar fashion by replacing ethanolamine with 2-methoxyethylamine, dimethylamine, methylamine, morpholine, N-methylpiperazine and diethanolamine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:5]=[CH:4][N:3]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[NH2:24].O.C([O-])(O)=O.[Na+]>CC(C)=O.Cl.CCOC(C)=O>[N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:18]=[C:9]([NH:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:24][C:23]3[CH:25]=[C:26]([O:30][CH3:31])[C:27]([O:28][CH3:29])=[C:21]([O:20][CH3:19])[CH:22]=3)[N:7]=2)[CH:10]=1
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: Clc1nccc(Nc2cnc3ccccc3c2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COc1cc(Nc2nccc(Nc3cnc4ccccc4c3)n2)cc(OC)c1OC

Procedure:
A mixture of (2-chloro-pyrimidin-4-yl)-quinolin-3-yl-amine (100 mg, 0.39 mmol) and 3,4,5-trimethoxyaniline was suspended in acetone (7 mL) and water (2 mL) with 2 drops of conc. HCl. The mixture was heated in a sealed tube to reflux overnight. The mixture was poured into EtOAc (100 mL) and sat. aq. NaHCO3. The organics were separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified via preparative HPLC. MS m/z=404. Calc'd for C22H21N5O3: 403.16.
Reaction SMILES: I[CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:4]1.[C:19]([C:23]1[CH:28]=[C:27]([SH:29])[CH:26]=[C:25]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]=1[OH:34])([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C.C(Cl)Cl>[C:30]([C:25]1[CH:26]=[C:27]([S:29][CH2:2][C@H:3]2[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:4]2)[CH:28]=[C:23]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:24]=1[OH:34])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CI)OC(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CSc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)OC(C)(C)O1
Yield: 91.8 %

Procedure:
A mixture of 0.12 g (0.324 mmol) of tert-butyl [(4R,6S)-6-(iodomethyl)-2,2-dimethyl-1,3-dioxane-4-yl]acetate, 0.0925 g (0.388 mmol) of 2,6-di-tert-butyl-4-mercaptophenol (See R. J. Laufer, U.S. Pat. No. 3,129,262), 0.067 g (0.49 mmol) of powderly anhydrous potassium carbonate and 0.5 ml of dry N,N-dimethylformamide was stirred for 16 hours at room temperature. The reaction solution was distilled away under reduced pressure. The residue was dissolved in ether, washed with saturated brine solution, dried and distilled away under reduced pressure. The residue was purified by subjecting to silica gel column chromatography [eluent: ethyl acetate-methylene chloride (1:19)]]to give 0.143 g of tert-butyl [(4R,6S)-6-[[(3,5-di-tert-butyl-4-hydroxyphenyl)thio]methyl]-2,2-dimethyl-1,3-dioxane-4-yl]acetate as crystals (yield: 92%). The desired compound was recrystallized from hexane.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH2:13][N:14]([CH2:17][CH2:18][O:19][CH3:20])[C:15](=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1.[CH:21]([N:24]1[CH2:29][CH2:28][CH:27](O)[CH2:26][CH2:25]1)([CH3:23])[CH3:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>>[CH:21]([N:24]1[CH2:29][CH2:28][CH:27]([O:1][C:2]2[CH:10]=[CH:9][C:8]3[N:7]4[CH2:11][CH2:12][CH2:13][N:14]([CH2:17][CH2:18][O:19][CH3:20])[C:15](=[O:16])[C:6]4=[CH:5][C:4]=3[CH:3]=2)[CH2:26][CH2:25]1)([CH3:23])[CH3:22]
Reactant: COCCN1CCCn2c(cc3cc(O)ccc32)C1=O
Reactant: CC(C)N1CCC(O)CC1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COCCN1CCCn2c(cc3cc(OC4CCN(C(C)C)CC4)ccc32)C1=O
Yield: 2 %

Procedure:
The title compound was synthesized in analogy to example 1, from 9-hydroxy-2-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one, 1-isopropyl-piperidin-4-ol (commercially available), triphenylphosphine and di-tert-butylazodicarboxylate, to give the desired product as a light yellow oil (2%).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[NH:9][N:8]=2)=[CH:4][C:3]=1[N:20]=[C:21]=[O:22].[NH2:23][C@@H:24]([C:29]([OH:31])=[O:30])[CH2:25]C(O)=O.C(N(CC)CC)C.C(OCC)(=O)C>C(Cl)Cl>[F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[NH:9][N:8]=2)=[CH:4][C:3]=1[NH:20][C:21](=[O:22])[NH:23][CH:24]([CH3:25])[C:29]([OH:31])=[O:30]
Reactant: O=C=Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: N[C@H](CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(NC(=O)Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)C(=O)O
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a suspension of 4-(3-isocyanato-benzyl)-2H-phthalazin-1-one (2)(1.4 g, 4.7 mmol) in dry DCM (40 ml) was added D-aspartic acid (0.455 g, 5.0 mmol), followed by triethylamine (1.4 ml, 10.0 mmol). The reaction was stirred at room temperature for 4 days. The reaction mixture was then filtered. The filtrate was then diluted with water (20 ml) and washed twice with DCM (2×20 ml). The combined DCM layers were dried over sodium sulfate and then concentrated in vacuo to afford a crude oil which was subjected to flash chromatography eluent neat ethyl acetate to remove impurity and the then 1:1 ethyl acetate/methanol to remove the desired component. (Rf of 0.2 in 1:1 ethyl acetate methanol). Single peak in LC-MS analysis, (0.79 g) requiring no further purification; m/z (LC-MS, ESP), RT=2.70 (M+H) 384;
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([C:10]([OH:12])=O)=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:14][NH:15][O:16][CH3:17].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>O.C(N(CC)CC)C.CN(C)C=O>[C:1]([C:5]1[S:9][C:8]([C:10]([N:15]([O:16][CH3:17])[CH3:14])=[O:12])=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cnc(C(=O)O)s1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CON(C)C(=O)c1ncc(C(C)(C)C)s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100.6 %

Procedure:
To a N,N-dimethylformamide (25 mL) solution of 5-tert-butyl-1,3-thiazole-2-carboxylic acid (2.5 g), N,O-dimethylhydroxylamine hydrochloride (2.0 g), WSC.HCl (3.9 g), HOBt.H2O (3.1 g) and triethylamine (7.1 g) were added, and the resultant was stirred at room temperature for 1 day. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over magnesium sulfate, and the desiccant was filtered off. Then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH-type silica gel; hexane/ethyl acetate-gradient elution=100/0→50/50) to obtain the title compound (3.1 g) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16]Br)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[CH:20]=[C:21]([C:30]2[N:35]=[C:34]([C:36]#[N:37])[C:33]3[N:38]=[CH:39][N:40]([CH3:41])[C:32]=3[CH:31]=2)[CH:22]=[C:23]([C:26]([F:29])([F:28])[F:27])[C:24]=1[OH:25].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][O:25][C:24]2[C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][C:21]([C:30]3[N:35]=[C:34]([C:36]#[N:37])[C:33]4[N:38]=[CH:39][N:40]([CH3:41])[C:32]=4[CH:31]=3)=[CH:20][C:19]=2[Cl:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(CCCBr)CC1
Reactant: Cn1cnc2c(C#N)nc(-c3cc(Cl)c(O)c(C(F)(F)F)c3)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: Cn1cnc2c(C#N)nc(-c3cc(Cl)c(OCCCN4CCN(C(=O)OC(C)(C)C)CC4)c(C(F)(F)F)c3)cc21

Procedure:
4-(3-Bromo-propyl)-piperazine-1-carboxylic acid tert-butyl ester (172 mg) was added to a mixture of 6-(3-chloro-4-hydroxy-5-trifluoromethyl-phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (165 mg) and potassium carbonate (130 mg) in acetonitrile (15 ml). The mixture was refluxed for 4 hours, then ethyl acetate (50 ml) and water (30 ml) were added and the organic layer was washed with brine, then dried over sodium sulfate, filtered and concentrated under reduced pressure to afford a crude product, 4-{3-[2-chloro-4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridin-6-yl)-6-trifluoromethyl-phenoxy]-propyl}-piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:19])[NH:4][C:5]2[N:10]([C:11]3[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=3[F:18])[N:9]=[CH:8][C:6]=2[N:7]=1.[H-].[Li+].I[CH3:23]>COCCOC.CN(C=O)C>[Br:1][C:2]1[N:7]=[C:6]2[CH:8]=[N:9][N:10]([C:11]3[C:12]([F:18])=[CH:13][CH:14]=[CH:15][C:16]=3[F:17])[C:5]2=[N:4][C:3]=1[O:19][CH3:23]
Reactant: CI
Reactant: O=c1[nH]c2c(cnn2-c2c(F)cccc2F)nc1Br
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: COCCOC
Product: COc1nc2c(cnn2-c2c(F)cccc2F)nc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 6.4 %

Procedure:
A mixture of 5-bromo-1-(2,6-difluorophenyl)-1H-pyrazolo[4,3-b]pyrazin-6(7H)-one (981 mg, 3.0 mmol) in 10 mL of DME and 1 mL of DMF at RT was treated with lithium hydride (119 mg, 15 mmol) in small portions. Iodomethane (0.62 mL, 9.9 mmol) was added 30 min later. The mixture was stirred at RT for 18 h, and poured into an ice cold sat. NH4Cl solution, then extracted twice with EtOAc. The combined EtOAc layes were washed with brine, dried and concentrated. Purification of the crude material on a silical gel column (25-85% EtOAc in Hexanes) provided: (1) 5-bromo-1-(2,6-difluorophenyl)-6-methoxy-1H-pyrazolo[3,4-b]pyrazine (65 mg, 6.4% yield) as an off white crystalline solid. MS (ES+): 341.0/343.0 (M+H)+; and (2) 5-bromo-1-(2,6-difluorophenyl)-7-methyl-1H-pyrazolo[4,3-b]pyrazin-6(7H)-one (616 mg, 60% yield) as an off white amorphous solid. MS (ES+): 341.0/343.0 (M+H)+.