Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([NH:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[C@@H:30]2[O:42][C@H:41]([CH2:43][O:44]C(=O)C)[C@@H:36]([O:37]C(=O)C)[C@H:31]2[O:32]C(=O)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>COCCOC>[OH:32][C@@H:31]1[C@H:36]([OH:37])[C@@H:41]([CH2:43][OH:44])[O:42][C@H:30]1[N:14]1[CH:13]=[N:12][C:11]2[C:15]1=[N:16][C:17]([C:19]([NH:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:20])=[N:18][C:10]=2[NH:9][CH2:8][CH:7]([C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCN4CCCCC4)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: O=C(NCCN1CCCCC1)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 52.5 °C
Yield: 79.2 %

Procedure:
To a stirred solution of 6-[(2,2-diphenylethyl)amino]-N-[2-(1-piperidinyl)ethyl]-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-9H-purine-2-carboxamide (assumed to be 310 g, 0.426 moles) (Preparation 24) and 1,2-dimethoxyethane (1600 ml) was added 5M aqueous sodium hydroxide solution (640 ml, 3.2 moles) over a 45 minute period with cooling in ice. The resultant mixture was stirred at ambient temperature for 3 hours, and then the layers were separated. The stirred organic phase was then diluted with deionised water (1800 ml) with cooling. When the addition was complete, the resultant mixture was heated to 50-55° C. whereupon crystallisation started. To this heated and stirred suspension was added further deionised water (1800 ml) over a period of 50 minutes. Once the addition was complete, the resultant slurry was cooled to 10° C. over a period of 45 minutes and the resulting solid was then collected by filtration. The solid was washed with a solution of 1,2-dimethoxyethane (400 ml) and deionised water (800 ml) and was then dried at 55° C. under reduced pressure to give the crude title compound as a brown solid (203 g).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.[CH3:43][C:44]1[CH:48]=[C:47]([NH2:49])[NH:46][N:45]=1.[ClH:50].[Cl:51][C:52]1[CH:53]=[C:54]([CH2:71][N:72]2[CH2:77][CH2:76][O:75][CH2:74][CH2:73]2)[C:55]2[N:56]([C:58]([CH2:62][C:63]3[CH:68]=[CH:67][C:66]([Cl:69])=[CH:65][C:64]=3[F:70])=[C:59]([CH3:61])[N:60]=2)[N:57]=1.C(=O)(O)[O-].[K+]>CN(C=O)C.[Pd](Cl)Cl>[ClH:51].[ClH:50].[Cl:69][C:66]1[CH:67]=[CH:68][C:63]([CH2:62][C:58]2[N:56]3[N:57]=[C:52]([NH:49][C:47]4[CH:48]=[C:44]([CH3:43])[NH:45][N:46]=4)[CH:53]=[C:54]([CH2:71][N:72]4[CH2:77][CH2:76][O:75][CH2:74][CH2:73]4)[C:55]3=[N:60][C:59]=2[CH3:61])=[C:64]([F:70])[CH:65]=1
Reactant: Cc1cc(N)[nH]n1
Reactant: Cc1nc2c(CN3CCOCC3)cc(Cl)nn2c1Cc1ccc(Cl)cc1F
Agent: Cl[Pd]Cl
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1cc(Nc2cc(CN3CCOCC3)c3nc(C)c(Cc4ccc(Cl)cc4F)n3n2)n[nH]1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
Prepare active catalyst by combining palladium chloride (160 mg, 0.90 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.10 g, 1.84 mmol) in DMF (25 mL) and warming to form a solution. Add the preformed catalyst to a solution of 3-methyl-1H-pyrazol-5-amine (3.0 g, 29.65 mmol), 4-((6-chloro-3-(4-chloro-2-fluorobenzyl)-2-methylimidazo[1,2-b]pyridazin-8-yl)methyl)morpholine hydrochloride (9.0 g, 20.19 mmol), potassium bicarbonate (6.0 g, 59.93 mmol) in DMF (65 mL) and heat to 150° C. for 1 h. Cool the reaction to 60° C. and add mercaptopropyl functionalized silica (500 mg) and stir for 1 h then filter to remove the silica. Cool to ambient temperature, add 2-methyltetrahydrofuran (125 mL) and extract with water to remove DMF. Add HCl to the organic solution to form the 3-(4-chloro-2-fluorobenzyl)-2-methyl-N-(5-methyl-1H-pyrazol-3-yl)-8-(morpholinomethyl)imidazo[1,2-b]pyridazin-6-amine hydrochloride salt. Add the HCl salt (1.1 g) to sodium hydroxide (10 mL, 1N) in n-butanol (10 mL) and stir. Filter the resulting mixture to obtain 0.22 g of the free base, imidazo[1,2-b]pyridazin-6-amine, 3-[(4-chloro-2-fluorophenyl)methyl]-2-methyl-N-(5-methyl-1H-pyrazol-3-yl)-8-(4-morpholinylmethyl), (22% yield, M+1.=470).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[C@@H:4]([NH:19][C:20](=[O:36])[C:21]1[CH:26]=[C:25]([Br:27])[CH:24]=[CH:23][C:22]=1[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])=[CH:8][CH:7]=1.[F:38][C:39]([F:50])([F:49])[C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1>>[CH3:1][O:2][C:3](=[O:37])[C@@H:4]([NH:19][C:20](=[O:36])[C:21]1[CH:26]=[C:25]([Br:27])[CH:24]=[CH:23][C:22]=1[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:43]2[CH:44]=[CH:45][C:40]([C:39]([F:50])([F:49])[F:38])=[CH:41][CH:42]=2)=[CH:10][CH:11]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCCCCCCOc1ccc(Br)cc1C(=O)N[C@@H](Cc1ccc(-c2ccccc2O)cc1)C(=O)OC
Product: CCCCCCCOc1ccc(Br)cc1C(=O)N[C@@H](Cc1ccc(-c2ccccc2Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)OC

Procedure:
The title compound was the prepared from (2S)-(5-bromo-2-heptyloxy-benzoylamino)-3-(2′-hydroxy-biphenyl-4-yl)-propionic acid methyl ester (0.080 g, 0.140 mmol) and 4-trifluoromethylphenylboronic acid (0.050 g, 0.281 mmol) as per general procedure G to give (2S)-(5-bromo-2-heptyloxy-benzoylamino)-3-[2′-(4-trifluoromethyl-phenoxy)-biphenyl-4-yl]-propionic acid methyl ester which was further hydrolyzed as per general procedure C to give the title compound (0.020 g, 30% yield).
Reaction SMILES: C1(N2CCNCC2)C=CC=CC=1.C([O:20][C:21]1[CH:41]=[CH:40][C:24]([O:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][N:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:30][CH2:29]2)=[CH:23][CH:22]=1)C1C=CC=CC=1.[ClH:42]>CCO>[OH:20][C:21]1[CH:22]=[CH:23][C:24]([O:25][CH2:26][CH2:27][N:28]2[CH2:29][CH2:30][N:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:32][CH2:33]2)=[CH:40][CH:41]=1.[ClH:42]
Reactant: c1ccc(COc2ccc(OCCN3CCN(c4ccccc4)CC3)cc2)cc1
Agent: Cl
Agent: c1ccc(N2CCNCC2)cc1
Solvent: CCO
Product: Oc1ccc(OCCN2CCN(c3ccccc3)CC2)cc1

Procedure:
35.75 g of 1-[2-(-4-benzyloxyphenoxy)ethyl]-4-phenylpiperazine phenylpiperazine was added rapidly with stirring to 75 ml concentrated HCl and the mixture was heated on a steam bath for 15 minutes. During this time starting material dissolved and then a white crystalline solid began to form and eventually the reaction mixture almost solidified. The reaction was cooled to ~5° and then was diluted with 100 ml EtOH. The solids were filtered off and were washed in EtOH and ether to give 1-[2-(4-hydroxyphenoxy)ethyl]-4-phenylpiperazine as its monohydrochloride. The salt was dissolved in 150 ml hot MeOH and 50 ml H2O and was then treated with 25 ml triethylamine. Water was then added to the refluxing mixture just to the cloud point whereupon the product began to crystallize from solution. The mixture was chilled and the solids were collected by filtration to give the end product, mp 142°-143°.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@H:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:26][C:27]([F:44])([F:43])[C@H:28]([O:30][C:31](=O)[O:32]C1C=CC([N+]([O-])=O)=CC=1)[CH3:29]>>[F:26][C:27]([F:44])([F:43])[C@H:28]([O:30][C:31]([N:23]1[CH2:24][CH2:25][CH:20]([C@@H:18]2[O:17][C:14]3=[CH:15][N:16]=[C:11]([C:8]4[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=4)[CH:12]=[C:13]3[CH2:19]2)[CH2:21][CH2:22]1)=[O:32])[CH3:29]
Reactant: CS(=O)(=O)c1ccc(-c2cc3c(cn2)O[C@@H](C2CCNCC2)C3)cc1
Reactant: C[C@@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Product: C[C@@H](OC(=O)N1CCC([C@H]2Cc3cc(-c4ccc(S(C)(=O)=O)cc4)ncc3O2)CC1)C(F)(F)F

Procedure:
The title compound is prepared from (R)-5-(4-methanesulfonyl-phenyl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine and carbonic acid 4-nitro-phenyl ester (R)-2,2,2-trifluoro-1-methyl-ethyl ester following a procedure analogous to that described for Example 1. LC (method 2): tR=1.07 min; Mass spectrum (ESI+): m/z=499 [M+H]+.
Reaction SMILES: [ClH:1].Cl.Cl.[Cl:4][C:5]1[CH:14]=[CH:13][C:12](Cl)=[C:11]2[C:6]=1[CH:7]=[C:8]([C:16]1[C:17]([NH2:33])=[N:18][CH:19]=[C:20]([C:22]3[CH:23]=[N:24][N:25]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH:26]=3)[CH:21]=1)[N:9]=[CH:10]2.[Cl:34]C1C=CC=C2C=1C=C(OS(C(F)(F)F)(=O)=O)N=C2>>[ClH:4].[ClH:34].[ClH:1].[Cl:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[C:8]([C:16]1[C:17]([NH2:33])=[N:18][CH:19]=[C:20]([C:22]3[CH:23]=[N:24][N:25]([CH:27]4[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]4)[CH:26]=3)[CH:21]=1)[N:9]=[CH:10]2
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1cc2c(Cl)ccc(Cl)c2cn1
Reactant: O=S(=O)(Oc1cc2c(Cl)cccc2cn1)C(F)(F)F
Agent: Cl
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1cc2c(Cl)cccc2cn1

Procedure:
The procedure for the preparation of 3-(5,8-dichloroisoquinolin-3-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine trihydrochloride was followed, except using trifluoromethanesulfonic acid 5-chloroisoquinolin-3-yl ester in place of trifluoromethanesulfonic acid 5,8-dichloroisoquinolin-3-yl ester. This afforded the title compound as a yellow solid. MS (ES+): m/z=405.05/407.03 [MH+]. HPLC: tR=1.91 min (ZQ2, polar—5 min).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:21][CH2:22][CH3:23])[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[F:20])=[O:12])=[CH:9][N:10]=2)[N:7]=1.[C@H:24]1([NH2:31])[CH2:29][CH2:28][C@H:27]([NH2:30])[CH2:26][CH2:25]1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1.O>[NH2:30][C@H:27]1[CH2:28][CH2:29][C@H:24]([NH:31][C:2]2[CH:3]=[C:4]([NH:21][CH2:22][CH3:23])[C:5]3[N:6]([C:8]([C:11]([NH:13][C:14]4[CH:19]=[CH:18][N:17]=[CH:16][C:15]=4[F:20])=[O:12])=[CH:9][N:10]=3)[N:7]=2)[CH2:25][CH2:26]1
Reactant: CCNc1cc(Cl)nn2c(C(=O)Nc3ccncc3F)cnc12
Reactant: N[C@H]1CC[C@H](N)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCNc1cc(N[C@H]2CC[C@H](N)CC2)nn2c(C(=O)Nc3ccncc3F)cnc12
Temperature: 120 °C

Procedure:
A mixture of 82A (62.7 mg, 0.187 mmol), trans-cyclohexane-1,4-diamine (214 mg, 1.873 mmol) and DIEA (0.033 mL, 0.187 mmol) in NMP (1 mL) was heated in a microwave reactor at 120° C. for 50 minutes. The resulting mixture was diluted with water and made basic with saturated aqueous NaHCO3. The resulting solid was collected by filtration and dried under vacuum to give 6-((trans)-4-aminocyclohexylamino)-8-(ethylamino)-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide as an off white solid (66.1 mg). HPLC Rt=2.122 minutes (Chromolith SpeedROD 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFA, 4 min gradient, monitored at 220 nm). [M+H]=413.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.O1CCOCC1>Cl>[CH:1]1([N:4]2[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CC2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: C1CN(C2CC2)CCN1
Yield: 59.8 %

Procedure:
A solution of tert-butyl 4-cyclopropylpiperazine-1-carboxylate (0.792 g, 3.50 mmol) in 4M HCl in 1,4-dioxane (4.37 mL, 17.50 mmol) was stirred at room temperature for 3 h under nitrogen. The reaction mixture was filtered and washed with ether to afford crude 1-cyclopropylpiperazine (0.659 g) as a white solid. The crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 3.5M NH3/MeOH and pure fractions were evaporated to dryness to afford 1-cyclopropylpiperazine (0.264 g, 59.7%) as a yellow oil.
Reaction SMILES: [CH:1]1([C:4]2[O:5][CH:6]=[N:7][N:8]=2)[CH2:3][CH2:2]1.[Li]CCCC.[Mg+2].[Br-].[Br-].O(CC)CC.[C:22]([O:26][C:27](=[O:34])[NH:28][CH:29]([CH:32]=[O:33])[CH2:30][CH3:31])([CH3:25])([CH3:24])[CH3:23]>C1COCC1>[C:22]([O:26][C:27](=[O:34])[NH:28][CH:29]([CH:32]([C:6]1[O:5][C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:8][N:7]=1)[OH:33])[CH2:30][CH3:31])([CH3:23])([CH3:24])[CH3:25]
Reactant: c1nnc(C2CC2)o1
Reactant: CCC(C=O)NC(=O)OC(C)(C)C
Agent: [Br-]
Agent: [Li]CCCC
Agent: [Mg+2]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(NC(=O)OC(C)(C)C)C(O)c1nnc(C2CC2)o1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 48.6 %

Procedure:
A solution of 2-cyclopropyl-[1,3,4]oxadiazole (2.16 g, 19.6 mmol) in dry THF (100 mL) is cooled to −78° C. nBuLi (1.6M in hexanes, 12.3 mL, 19.6 mmol) is added dropwise. The reaction mixture is stirred at −78° C. for 40 min. MgBr2.OEt2 (5.0692 g, 19.6 mmol) is added. The reaction mixture is allowed to warm up to −45° C. and stirred at that temperature for 1.5 hr. A solution of (1-formyl-propyl)-carbamic acid tert-butyl ester (3.7 g, 19.6 mmol) in THF (40 mL) is added. The reaction mixture is allowed to warm up to −20° C. and stirred at that temperature for 3.5 hrs. The reaction mixture is quenched with a solution of saturated NH4Cl solution and extracted with ethyl acetate. Combined organic extracts is washed with saturated NaCl solution and dried over MgSO4. The solvent is evaporated under reduced pressure and the crude is purified by column chromatography eluting with ethyl acetate and heptane mixture to give {1-[(5-cyclopropyl-[1,3,4]oxadiazol-2-yl)-hydroxy-methyl]-propyl}-carbamic acid tert-butyl ester (2.83 g, 49%).
Reaction SMILES: [OH:1][C:2]1([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4](=[O:11])N1CCCC.Cl.[OH2:24]>>[OH:24][C:2]1([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4](=[O:11])[O:1]1
Reactant: O
Reactant: CCCCN1C(=O)c2cccnc2C1(O)c1cccc(Cl)c1
Agent: Cl
Product: O=C1OC(O)(c2cccc(Cl)c2)c2ncccc21

Procedure:
To the 7-hydroxy-7-(3-chlorophenyl)-6-(n-butyl)-6,7-dihydropyrrolo[3,4-b]pyridin-5-one was added 500 mL of water, 250 mL of concentrated hydrochloric acid and the mixture was heated under reflux for 24 hours. The solution was then filtered, cooled and made basic with sodium hydroxide. An ethyl acetate extraction removed unhydrolyzed starting material and the pH of the resulting aqueous fraction was adjusted to pH 2 with hydrochloric acid. The resulting aqueous fraction was extracted twice with ethyl acetate (250 mL). The solvent was removed yielding 16 g of 7-hydroxy-7-(3-chlorophenyl)-7H-furo[3,4-b]pyridin-5-one, which was used without further purification.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:13][CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:9](=[O:12])[CH2:10][NH:11][C:5]2=[N:4][CH:3]=1.Br[C:22]1[N:23]=[C:24]([NH:35][CH2:36][CH2:37][CH:38]2[CH2:43][CH2:42]OCC2)C(NCC(OCC)=O)=NC=1.Cl>C(O)C>[NH:35]1[C:24]2=[N:23][CH:22]=[C:42]([C:2]3[N:7]=[C:6]4[N:8]([CH2:13][CH2:14][CH:15]5[CH2:20][CH2:19][O:18][CH2:17][CH2:16]5)[C:9](=[O:12])[CH2:10][NH:11][C:5]4=[N:4][CH:3]=3)[CH:43]=[C:38]2[CH:37]=[CH:36]1
Reactant: CCOC(=O)CNc1ncc(Br)nc1NCCC1CCOCC1
Reactant: O=C1CNc2ncc(Br)nc2N1CCC1CCOCC1
Agent: Cl
Solvent: CCO
Product: O=C1CNc2ncc(-c3cnc4[nH]ccc4c3)nc2N1CCC1CCOCC1
Temperature: 100 °C

Procedure:
7-Bromo-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one. Ethyl 2-(5-bromo-3-(2-(tetrahydro-2H-pyran-4-yl)ethylamino)pyrazin-2-ylamino)acetate (0.5 g, 1.291 mmol) and hydrochloric acid (6 M in water, 0.215 mL, 1.291 mmol) were combined in ethanol (2 mL) and the resulting mixture was heated in a Biotage Emrys Optimizer microwave reactor at 100° C. for 2400 s. The reaction mixture was concentrated and purified using silica gel chromatography (33% ethyl acetate in hexanes) to yield the title compound (quantitative yield). MS (ESI) m/z 341.1 [M]+, 343.1 [M+2]−.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:25][C:26]([NH2:28])=[O:27]>CN(C=O)C>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[O:16][CH2:25][C:26](=[O:27])[NH2:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1cc(Cl)ccc1O
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1cc(Cl)ccc1OCC(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
5-Chloro-2-hydroxy-benzyl)-carbamic acid tert-butyl ester 78 (210 mg, 0.8 mmol) was dissolved in DMF (6 mL) and to the stirred solution K2CO3 (13.8 mg, 1 mmol) and 2-bromoacetamide (138 mg, 1 mmol) were added. The mixture was stirred at room temperature overnight. The suspension was concentrated in vacuo, and the residue was partitioned between water (20 mL) and CH2Cl2 (10 mL). The aqueous phase was separated and extracted with CH2Cl2 (20 mL×2). The combined organic phases were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate 80/20), to give 79 as a white solid (226 mg, 90%). 1H NMR (CDCl3, 300 MHz) δ7.88 (br s, 1H), 7.27-7.18 (m, 2H), 6.76 (d, J=8.7 Hz, 1H), 5.54 (br s, 1H), 4.78( br s, 1H), 4.47 (s, 1H), 4.36 (d, J=6.3 Hz), 1.43 (s, 9H). MS (m/e) (API-ES) 337.0 (MNa)+. m.p 142-143° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[C:17]([CH:18]([C:20]3[C:25]([N:26]([S:30]([C:33]4[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([C:40]([F:43])([F:42])[F:41])[CH:34]=4)(=[O:32])=[O:31])[CH2:27][O:28][CH3:29])=[CH:24][C:23]([Cl:44])=[CH:22][N:21]=3)[OH:19])[C:12]=2[O:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCOCC1.O=[Mn]=O>[C:1]([O:5][C:6]([N:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[C:17]([C:18]([C:20]3[C:25]([N:26]([S:30]([C:33]4[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([C:40]([F:43])([F:41])[F:42])[CH:34]=4)(=[O:32])=[O:31])[CH2:27][O:28][CH3:29])=[CH:24][C:23]([Cl:44])=[CH:22][N:21]=3)=[O:19])[C:12]=2[O:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCN(c1cc(Cl)cnc1C(O)c1cccc2c1OCCN2C(=O)OC(C)(C)C)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: O=[Mn]=O
Solvent: C1COCCO1
Product: COCN(c1cc(Cl)cnc1C(=O)c1cccc2c1OCCN2C(=O)OC(C)(C)C)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 80 °C
Yield: 82.9 %

Procedure:
To a solution of 8-({5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridin-2-yl}-hydroxy-methyl)-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester (562.7 mg, 0.91 mmol) in dioxane (4 mL) was added preactivated MnO2 (932.9 mg, 9.12 mmol), and the resulted mixture was heated at 80° C. for two hour. The resulted mixture was cooled to r.t., and filtered. The solid was washed with EtOAc (20 mL×3). EtOAc washing solution was combined with dioxane filtrate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to provide 8-{5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carbonyl}-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester (510.2 mg) as yellow syrup. MS m/z: 676.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([NH:23][OH:24])=[NH:22])=[CH:16][CH:15]=3)[C:10]([CH2:25][CH3:26])=[C:9]([CH3:27])[N:8]=2)=[CH:4][CH:3]=1.Cl[C:29]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:30].CCN(CC)CC>ClCCl>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([CH2:20]/[C:21](=[N:22]\[C:29](=[O:30])[O:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)/[NH:23][OH:24])=[CH:18][CH:19]=3)[C:10]([CH2:25][CH3:26])=[C:9]([CH3:27])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Nc1ccc(CC(=N)NO)cc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Nc1ccc(C/C(=N\C(=O)Oc2ccccc2)NO)cc1
Temperature: 25 °C
Yield: 102.2 %

Procedure:
A 18-mL vial was charged with 2-[4-[[2-(5-Chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]phenyl]-N-hydroxy-acetamidine (61 mg, 0.15 mmol), phenyl chloroformate (29 mg, 0.18 mmol, 1.2 eq.), Et3N (20 mg, 0.2 mmol, 1.3 eq.) and dichloromethane (5 ml). The mixture was stirred at 0 C˜rt until starting material was consumed (4 hr). The mixture was poured into saturated sodium bicarbonate solution (10 ml) and extracted with dichloromethane (3×5 ml). The organic layers were combined and dried over Na2SO4. Removal of solvent under reduced pressure gave the title compound (80 mg, 100% yield). The product thus obtained was forwarded to the next step without any purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O>[C:14]1([S:20]([N:8]2[C:5]3=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:10]([I:11])=[CH:9]2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Clc1cnc2[nH]cc(I)c2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1cc(I)c2cc(Cl)cnc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 78.3 %

Procedure:
To a solution of 5-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine (2, 5.00 g, 18.0 mmol) in 80.0 mL of N,N-dimethylformamide, sodium hydride (1.1 g, 60% in mineral oil, 27.0 mmol) was added slowly. A solution of benzenesulfonyl chloride (11, 2.40 mL, 18.8 mmol) in 10.0 mL of N,N-dimethylformamide was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 15 hours, then poured into ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting solid was washed with 5% ethyl acetate in hexane, isolated by filtration, and dried to provide the desired compound (12, 5.9 g). 1H NMR was consistent with the compound structure. 1-Benzenesulfonyl-3-iodo-5-methyl-1H-pyrrolo[2,3-b]pyridine 13
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[C:6](=[N:7][C:8](SC)=[N:9][CH:10]=2)[N:5]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=1)[CH:2]=[CH2:3].[CH2:23]([O:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=2)[CH2:30][CH2:29]1)[CH3:24]>>[CH2:23]([O:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[CH:36][C:37]([NH:38][C:8]3[N:7]=[C:6]4[N:5]([C:16]5[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=5)[N:4]([CH2:1][C:2]#[CH:3])[C:12](=[O:13])[C:11]4=[CH:10][N:9]=3)=[CH:39][CH:40]=2)[CH2:30][CH2:29]1)[CH3:24]
Reactant: C=CCn1c(=O)c2cnc(SC)nc2n1-c1cccc(C)n1
Reactant: CCOCCN1CCN(c2ccc(N)cc2)CC1
Product: C#CCn1c(=O)c2cnc(Nc3ccc(N4CCN(CCOCC)CC4)cc3)nc2n1-c1cccc(C)n1

Procedure:
31.8 mg of the entitled compound was obtained as a yellow solid in the same manner as in Example 113-1 to 113-2, for which, however, 2-allyl-1-(6-methylpyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one was used in place of 2-allyl-1-[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one used in Example 113-1, and 4-[4-(2-ethoxyethyl)piperazin-1-yl]aniline was used in place of 4-(4-methylpiperazin-1-yl)aniline used in Example 113-2.