Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH:7]([C:9]1[CH:10]=[CH:11][C:12]2[O:16][CH:15]=[C:14]([CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21])[C:13]=2[CH:23]=1)=C>CC(O)(C)C.O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[CH:7]([C:9]1[CH:10]=[CH:11][C:12]2[O:16][CH:15]=[C:14]([CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21])[C:13]=2[CH:23]=1)=[O:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1ccc2occ(CCNC(C)=O)c2c1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(C)(C)O
Solvent: O
Product: CC(=O)NCCc1coc2ccc(C=O)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.10 g of osmium tetroxide in 2-methyl-2-propanol and then 8.70 g of sodium periodate are added at ambient temperature to a solution of 10 mmol of the product obtained in Step C in a mixture of 50 ml of dioxane and 25 ml of water. After stirring overnight at ambient temperature, the suspension is filtered and the filtrate is concentrated under reduced pressure. The resulting residue is taken up in dichloromethane. The organic phase is washed with water, dried and evaporated. The residue is purified by chromatography on silica gel to yield the title product.
Reaction SMILES: B(O)(O)[C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.Br[C:19]1[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27].C([O-])([O-])=O.[Na+].[Na+]>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.C1(C)C=CC=CC=1>[Br:25][C:22]1[CH:23]=[CH:24][C:19]([C:2]2[C:15]3[C:10]([C:9]4[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=4[CH:3]=2)=[CH:11][CH:12]=[CH:13][CH:14]=3)=[C:20]([N+:26]([O-:28])=[O:27])[CH:21]=1
Reactant: OB(O)c1cc2ccccc2c2ccccc12
Reactant: O=[N+]([O-])c1cc(Br)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(Br)ccc1-c1cc2ccccc2c2ccccc12

Procedure:
A 500 mL round bottom flask was charged with toluene (250 mL), phenanthracene-9-boronic acid (18.2 g, 82 mmol), 2,5-dibromonitrobenzene (23.1 g, 82.3 mmol), Pd(PPh3)4 (2.8 g, 2.5 mmol), and 2M Na2CO3 aqueous solution (124 mL).
Reaction SMILES: [CH3:1][C:2]1[S:6][CH:5]=[C:4]([CH2:7][OH:8])[CH:3]=1.[CH:9]1([C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[C:19]([N:22]4[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:23]4=[O:29])[CH:20]=[CH:21][C:14]=3[N:13]=2)[CH2:11][CH2:10]1.[CH2:30](P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH:9]1([C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[C:19]([N:22]4[CH:27]=[CH:26][C:25]([O:8][CH2:7][C:4]5[CH:3]=[C:2]([CH3:1])[S:6][CH:5]=5)=[CH:24][C:23]4=[O:29])[CH:20]=[CH:21][C:14]=3[N:13]=2)[CH2:10][CH2:11]1.[CH:9]1([C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[C:19]([N:22]4[CH:27]=[CH:26][C:25]([O:28][CH2:7][C:4]5[CH:3]=[CH:2][S:6][C:5]=5[CH3:30])=[CH:24][C:23]4=[O:29])[CH:20]=[CH:21][C:14]=3[N:13]=2)[CH2:10][CH2:11]1
Reactant: CCCCP(CCCC)CCCC
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Reactant: Cc1cc(CO)cs1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1cc(COc2ccn(-c3ccc4nc(C5CC5)n(C)c4c3)c(=O)c2)cs1
Product: Cc1sccc1COc1ccn(-c2ccc3nc(C4CC4)n(C)c3c2)c(=O)c1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of (5-methyl-3-thienyl)methanol (72 mg), 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (100 mg), tributylphosphine (0.264 ml), 1,1′-(azodicarbonyl)dipiperidine (269 mg) and THF (10 ml) was stirred at 60° C. for 3 h. The reaction mixture was partitioned between EtOAc and water, and the organic layer was washed with brine, dried with MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH), followed by NH silica gel column chromatography (hexane/EtOAc) to give the title compound as a mixture with 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-((2-methyl-3-thienyl)methoxy)pyridin-2(1H)-one. This mixture was subjected to HPLC separation (C18, mobile phase: H2O/CH3CN (0.1% TFA included)). The solution was neutralized with saturated Na2CO3 solution and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO4, filtered through a plug of silica gel and concentrated in vacuo. The resulting solid was recrystallized from EtOH to give the title compound (15.8 mg) as an off-white solid.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.CS(C)=O.[NH2:17][C:18]1[C:22]([O:23][CH2:24][CH3:25])=[CH:21][S:20][CH:19]=1>O>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:17][C:18]1[C:22]([O:23][CH2:24][CH3:25])=[CH:21][S:20][CH:19]=1)=[O:4]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CCOc1cscc1N
Solvent: CS(C)=O
Solvent: O
Product: CCOc1cscc1NC(=O)c1ccccc1N

Procedure:
A mixture of 14.4 g. of isatoic anhydride, 22 ml. of dimethylsulfoxide and some ground glass is stirred and put in an oil bath at 120° C. A mixture of 12.6 g. of 3-amino-4-ethoxythiophene in 17 ml. of dimethylsulfoxide is added dropwise over 30 minutes at 120°-129° C. The mixture is heated at 125°-129° C. for one hour, cooled, poured into ice and water and extracted with dichloromethane. The extract is dried over magnesium sulfate, filtered and evaporated to an oil. This oil is dissolved in methanol, filtered, cooled and a few drops of water are added. The solid is removed by filtration and the filtrate is evaporated to an oil. This oil is dissolved in methanol, a few drops of water are added and the mixture is chilled overnight. The solid is collected by filtration giving o-amino-N-(4-ethoxy-3-thienyl)-benzamide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[N:11][C:10]3[CH:22]=[CH:23][CH:24]=[N:25][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][C:34]=1[C:43](Cl)=[O:44].C(=O)(O)[O-].[Na+]>ClCCl.C(OCC)(=O)C>[CH:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][C:34]=1[C:43]([NH:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[N:11][C:10]3[CH:22]=[CH:23][CH:24]=[N:25][C:9]2=3)[CH:5]=[CH:6][CH:7]=1)=[O:44]
Reactant: Nc1cccc(-n2c(=O)c(Cc3cccnc3)nc3cccnc32)c1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cccc(-n2c(=O)c(Cc3cccnc3)nc3cccnc32)c1)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 39.7 %

Procedure:
To a mixture of 4-(3-aminophenyl)-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (480 mg) and triethylamine (0.23 ml) in dichloromethane (7 ml) was added 2-naphthoyl chloride (291 mg). The mixture was stirred at room temperature for 20 minutes, then poured into a mixture of ethyl acetate and aqueous sodium bicarbonate. The organic phase was separated, washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was crystallized from ethanol to give 4-[3-(2-naphthoylamino)phenyl]-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (280 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:9][C:8]([C:10](=O)[CH2:11][C:12](=O)[C:13]([F:16])([F:15])[F:14])=[N:7][C:6]=2[CH:19]=1.Cl.[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][NH2:32])=[CH:27][CH:26]=1)(=[O:24])=[O:23]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:9][C:8]([C:10]3[N:31]([C:28]4[CH:27]=[CH:26][C:25]([S:22]([CH3:21])(=[O:24])=[O:23])=[CH:30][CH:29]=4)[N:32]=[C:12]([C:13]([F:16])([F:15])[F:14])[CH:11]=3)=[N:7][C:6]=2[CH:19]=1
Reactant: CS(=O)(=O)c1ccc(NN)cc1
Reactant: O=C(CC(=O)C(F)(F)F)c1nc2cc(F)ccc2[nH]1
Agent: Cl
Product: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2nc3cc(F)ccc3[nH]2)cc1
Yield: 25 %

Procedure:
The procedure of Example 9 was repeated using 1-(6-fluorobenzimidazol-2-yl)-4,4,4-trifluorobutane-1,3-dione and 4-methylsulfonylphenylhydrazine hydrochloride as the starting materials to obtain 6-fluoro-2-[1-(4-methylsulfonylphenyl)-3-trifluoromethyl-1H-pyrazol-5-yl]benzimidazole (yield, 25%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:20]=[CH:19][C:8]2[N:9]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]([CH2:12]O)=[N:11][C:7]=2[CH:6]=1)=[O:4].S(Cl)([Cl:23])=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:20]=[CH:19][C:8]2[N:9]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]([CH2:12][Cl:23])=[N:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)nc(CO)n2CCC(C)C
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)nc(CCl)n2CCC(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a cooled (0° C.) solution of 2-hydroxymethyl-1-(3-methyl-butyl)-1H-benzoimidazole-5-carboxylic acid methyl ester (1.00 g, 3.62 mmol) in DCM (10 mL) was added thionyl chloride (396 μL, 5.43 mmol). The solution was stirred at 0° C. for 15 min. and concentrated in vacuo to give 2-chloromethyl-1-(3-methyl-butyl)-1H-benzoimidazole-5-carboxylic acid methyl ester; HCl salt (1.20 g, 100%) as a white solid, which was used without further purification:
Reaction SMILES: [O:1]1[C:6]2=[CH:7][C:8]3[C:9](=[O:15])[C:10](=[O:14])[NH:11][C:12]=3[CH:13]=[C:5]2[O:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH:19]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O.O.C(OCC)(=O)C>[C:20]1([CH:19]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:11]2[C:12]3[CH:13]=[C:5]4[O:4][CH2:3][CH2:2][O:1][C:6]4=[CH:7][C:8]=3[C:9](=[O:15])[C:10]2=[O:14])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1Nc2cc3c(cc2C1=O)OCCO3
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2cc3c(cc21)OCCO3
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.4 %

Procedure:
To a cooled (0° C.) solution of 2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole-7,8-dione (Lackey and Sternbach, Synthesis 1993:993-997) (1.73 g, 8.42 mmol) in anhydrous N,N-dimethylformamide (28 mL) was added sodium hydride (60% in mineral oil, 0.37 g, 9.26 mmol). The mixture was stirred at ambient temperature for 1 h and bromodiphenylmethane (2.39 g, 9.69 mmol) was added. After stirring at ambient temperature for 16 h, further bromodiphenylmethane (0.42 g, 1.68 mmol) was added. The mixture was stirred at ambient temperature for 8 h and then diluted with water (200 mL) and ethyl acetate (200 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous magnesium sulfate, filtered, concentrated in vacuo. The residue was purified by column chromatography, eluted with a 35% to 50% gradient of ethyl acetate in hexanes to afford 6-(diphenylmethyl)-2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole-7,8-dione (0.7 g, 22%) as a red solid: 1H NMR (300 MHz, CDCl3) δ 7.41-7.28 (m, 10H), 7.16 (s, 1H), 6.94-6.91 (m, 1H), 5.96 (s, 1H), 4.27-4.14 (m, 4H); MS (ES+) m/z 371.9 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[NH:17]1[C:25]2[C:20](=[CH:21][C:22](B(O)O)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1>>[NH:17]1[C:25]2[C:20](=[CH:21][C:22]([C:2]3[N:3]=[C:4]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)[C:5]4[S:10][CH:9]=[CH:8][C:6]=4[N:7]=3)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: Clc1nc(N2CCOCC2)c2sccc2n1
Product: c1cc2cc(-c3nc(N4CCOCC4)c4sccc4n3)ccc2[nH]1

Procedure:
2-Chloro-4-moropholinothieno[3.2-d]pyrimidine 4 was reacted with 5-indole boronic acid in General Procedure A on a 23.5 mmol scale to give 25.7 mg. of 271 after RP-HPLC purification. MS (Q1) 337.1 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH:16]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:17](O)=[O:18])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1.O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:27]=[CH:26][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH:16]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:17][OH:18])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C(O)C(CN1CCC(c2noc3cc(F)ccc23)CC1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OCC(CN1CCC(c2noc3cc(F)ccc23)CC1)c1ccccc1
Yield: 90.3 %

Procedure:
To 3-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidino)-2-phenylpropanoic acid (1.8 g, 5 mmol) in 25 ml dry toluene, stirred at 0° C., a solution of LiAlH4 in THF (5 ml, 1M, 5 mmol) was added dropwise. 20 min. after addition was completed the mixture was allowed to warm to room temperature for 15 min. whereupon H2O was added dropwise to precipitate aluminum hydroxide. To the organic phase was added 50 ml ether, and the mixture was washed with water and concentrated in vacuo to get 1.6 g of 3-(4-(6-fluoro -1,2-benzisoxazol-3-yl)piperidino)-2-phenylpropanol as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:15])[N:5]([CH3:14])[CH:6]=[CH:7][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].C1C(=O)N([I:23])C(=O)C1>CN(C=O)C.C(Cl)Cl>[I:23][C:6]1[N:5]([CH3:14])[C:4](=[O:15])[C:3]([O:2][CH3:1])=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CCOC(=O)c1ccn(C)c(=O)c1OC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1cc(I)n(C)c(=O)c1OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 50.3 %

Procedure:
To a solution of Intermediate 1 (101 mg, 0.478 mmol) in DMF (0.5 mL) was added NIS (108 mg, 0.478 mmol) at rt. The reaction was stirred at rt for 3 days. An additional equivalent of NIS (67 mg, 0.30 mmol) was added and the reaction mixture heated at 60° C. overnight. The reaction was allowed to cool, diluted with DCM (40 mL) and the organic portion washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was dissolved in a small amount of DCM and charged to a 12 g silica gel cartridge which was eluted with a 25 min gradient from 0-100% EtOAc/hexane to give Intermediate 19A (81 mg, 50% yield) as a yellow solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]2)=[O:9])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.CN1C(=O)CCC1.[CH3:33][S:34]([CH2:37][CH2:38][CH2:39][O:40][C:41]1[CH:42]=[CH:43][CH:44]=[C:45]2[C:49]=1[NH:48][N:47]=[C:46]2[C:50]1[CH:55]=[CH:54][N:53]=[C:52](S(C)=O)[N:51]=1)(=[O:36])=[O:35]>O>[OH:16][CH:13]1[CH2:14][CH2:15][N:10]([C:8]([CH:5]2[CH2:4][CH2:3][CH:2]([NH:1][C:52]3[N:51]=[C:50]([C:46]4[C:45]5[C:49](=[C:41]([O:40][CH2:39][CH2:38][CH2:37][S:34]([CH3:33])(=[O:35])=[O:36])[CH:42]=[CH:43][CH:44]=5)[NH:48][N:47]=4)[CH:55]=[CH:54][N:53]=3)[CH2:7][CH2:6]2)=[O:9])[CH2:11][CH2:12]1
Reactant: CS(=O)c1nccc(-c2n[nH]c3c(OCCCS(C)(=O)=O)cccc23)n1
Reactant: NC1CCC(C(=O)N2CCC(O)CC2)CC1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)CCCOc1cccc2c(-c3ccnc(NC4CCC(C(=O)N5CCC(O)CC5)CC4)n3)n[nH]c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (4-amino-cyclohexyl)-(4-hydroxy-piperidin-1-yl)-methanone (400 mg, 1.5 mmol), DIPEA (0.31 mL, 1.78 mmol) and NMP (1 mL) was stirred at RT for 1 h. Then, 7-(3-methanesulfonyl-propoxy)-3-(2-methanesulfinyl-pyrimidin-4-yl)-1H-indazole (200 mg, 0.5 mmol) was added to the mixture and stirred at 130° C. for 2.5 hours. The reaction mixture was then poured into water, and the precipitate was purified on a silica column using flash chromatography, eluting with hexane:EtOAc:MeOH 5:4.5:0.5 to yield (4-hydroxy-piperidin-1-yl)-(4-{4-[7-(3-methanesulfonyl-propoxy)-1H-indazol-3-yl]-pyrimidin-2-ylamino}-cyclohexyl)-methanone (Compound 308).
Reaction SMILES: [CH:1]([CH:3]1[C:15]2[C:6](=[C:7]3[C:12](=[C:13]([CH3:16])[CH:14]=2)[NH:11][C:10](=[O:17])[CH:9]=[CH:8]3)[O:5][CH2:4]1)=[O:2].[BH4-].[Na+].O>CO>[OH:2][CH2:1][CH:3]1[C:15]2[C:6](=[C:7]3[C:12](=[C:13]([CH3:16])[CH:14]=2)[NH:11][C:10](=[O:17])[CH:9]=[CH:8]3)[O:5][CH2:4]1
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OCC2C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OCC2CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.5 %

Procedure:
To 3-formyl-5-methyl-2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one (1.0 g) in methanol (80 ml), sodium borohydride (1.0 g) was added and stirred at room temperature for 30 minutes. After completion of the reaction, water was added and extracted with chloroform-methanol (4:1). The extract was dried and the solvent was evaporated. The residue was recrystallized from methanol-ether to obtain 0.59 g of 3-hydroxymethyl-5-methyl-2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one was obtained as colorless needles (58.5%).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.[C:13](OC)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=1.O>O1CCCC1.CCCCCC>[O:20]=[C:13]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COP(C)(=O)OC
Reactant: COC(=O)c1cccnc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: COP(=O)(CC(=O)c1cccnc1)OC
Reaction time: 1.33 h
Yield: 68.8 %

Procedure:
In argon atmosphere, 15.19 g of dimethyl methylphosphonate was dissolved in 170 ml of dry tetrahydrofuran, followed by dropwise addition of 1.55M n-butyl lithium solution in hexane at -78° C., which was then stirred at the same temperature for 80 minutes. Methyl nicotinate (16.79 g) dissolved in 50 ml of dry tetrahydrofuran was added dropwise and stirred at -78° C. for 20 hours, followed by addition of water. The organic solvent was distilled off under reduced pressure, which was extracted with methylene chloride. Alternatively, 2N hydrogen chloride was added to aqueous phase for neutralization, which was then extracted with ethyl acetate. The organic phase was washed in saturated aqueous sodium chloride, and dried over magnesium sulfate, to distill off the solvent under reduced pressure. The obtained residue was subjected to chromatography on a silica gel column, and from a fraction eluted with methanol-methylene chloride (5:95 v/v), 19.30 g of dimethyl 2-oxo-2-(3-pyridyl)ethylphosphonate was obtained.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][C@H:20]([OH:24])[C@@H:19]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12].[Br:31][C:32]1[CH:33]=[C:34]([CH2:41]Br)[C:35]2[O:39][CH:38]=[CH:37][C:36]=2[CH:40]=1>COCCOC.O>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][C@H:20]([O:24][CH2:41][C:34]2[C:35]3[O:39][CH:38]=[CH:37][C:36]=3[CH:40]=[C:32]([Br:31])[CH:33]=2)[C@@H:19]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](O)[C@@H]1c1ccccc1
Reactant: BrCc1cc(Br)cc2ccoc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H](OCc2cc(Br)cc3ccoc23)[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.5 %

Procedure:
Potassium bis(trimethylsilyl)amide (300 mg) was added to a stirred solution of [2S,3S]-N-tert-butoxycarbonyl-2-phenylpiperidine-3-ol (160 mg) in dry 1,2-dimethoxyethane (3.0 ml) under a dry nitrogen atmosphere. After 30 minutes 5-bromo-7-bromomethylbenzofuran (290 mg) was added, and the reaction stirred for 18 hours at room temperature. The resulting mixture was then diluted with water (50 ml), and extracted into ethyl acetate (2×50 ml). The organic layers were separated and washed with brine (20 ml), dried over MgSO4, filtered and the solvent removed under reduced pressure. Purification by MPLC (20% ethyl acetate/n-hexane), afforded [2S,3S]-1-tert-butoxycarbonyl-2-phenyl-3-[(5-bromobenzofuran-7-yl)methyloxy]piperidine as a yellow gum (136 mg). 1H NMR (360 MHz,CDCl3)δ1.43 (9H, s), 1.65 (2H, m), 1.92 (2H, m), 2.70 (1H, t d, J=7.2, 3.0 Hz), 3.74 (2H,m), 4.90 (2H, d, J=5.0 Hz), 5.74 (1H, br s), 6.71 (1H, d, J=1.0 Hz), 7.30-7.42 (4H, m), 7.58 (3H, m), 7.75 (1H, d, J=1.0 Hz); MS m/z CI+ 487 (M+H+).
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH:8]([O:10][CH3:11])[CH2:7][CH2:6][C:5]1=O)(=O)[CH3:2].[C:13]([CH2:15][C:16]([NH2:18])=[O:17])#[N:14].N1CCCCC1>C(O)C>[C:13]([C:15]1[C:16](=[O:17])[NH:18][C:1]([CH3:2])=[C:4]2[C:5]=1[CH2:6][CH2:7][CH:8]([O:10][CH3:11])[CH2:9]2)#[N:14]
Reactant: COC1CCC(=O)C(C(C)=O)C1
Reactant: N#CCC(N)=O
Solvent: CCO
Solvent: C1CCNCC1
Product: COC1CCc2c(c(C)[nH]c(=O)c2C#N)C1
Yield: 35 %

Procedure:
2-Acetyl-4-methoxycyclohexanone (1.02 g) and cyanoacetamide (0.462 g) were added to 5 ml of ethanol. After adding a small amount of piperidine, the mixture was heated under reflux for 2 hours. Deposited crystals were filtered out and recrystallized from methanol. There was obtained 0.42 g of 4-cyano-2,3,5,6,7,8-hexahydro-7-methoxy-1-methyl-3-oxoisoquinoline.
Reaction SMILES: [CH3:1][CH:2]1[C:7]([CH3:19])([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[N:15]=[N:16][NH:17][CH:18]=3)[CH:9]=2)[CH2:6][CH2:5][NH:4][CH2:3]1.C(=O)([O-])O.[Na+].I[CH2:26][CH2:27][NH:28][S:29]([CH2:32][CH3:33])(=[O:31])=[O:30]>CN(C)C=O>[NH3:4].[CH2:32]([S:29]([NH:28][CH2:27][CH2:26][N:4]1[CH2:5][CH2:6][C:7]([CH3:19])([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[N:15]=[N:16][NH:17][CH:18]=3)[CH:9]=2)[CH:2]([CH3:1])[CH2:3]1)(=[O:31])=[O:30])[CH3:33]
Reactant: CC1CNCCC1(C)c1cccc(-c2c[nH]nn2)c1
Reactant: CCS(=O)(=O)NCCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)NCCN1CCC(C)(c2cccc(-c3c[nH]nn3)c2)C(C)C1
Product: N
Temperature: 25 °C
Yield: 75.3 %

Procedure:
To a solution of 3,4-dimethyl-4-(3-(1H-1,2,3-triazol-4-yl)phenyl)piperidine (Preparation 44, 50 mg, 0.19 mmol) in N,N-dimethylformamide (2 mL) was added sodium hydrogencarbonate (25 mg, 0.29 mmol) and N-(2-iodoethyl)-1-ethanesulfonamide (Preparation 24, 60 mg, 0.23 mmol). The resultant mixture was heated at 60° C. overnight and then cooled to room temperature. The residue given was partitioned between saturated aqueous sodium hydrogencarbonate solution (25 mL) and ether (15 mL). The phases were separated and the aqueous layer was further extracted with ether (2×15 mL). The combined extracts were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with a gradient of CH2Cl2:MeOH:0.88 ammonia (100:8:1) to give the title compound as a colourless oil (28 mg, 38%).
Reaction SMILES: [CH3:1][C:2]1([CH2:6][OH:7])[CH2:5][O:4][CH2:3]1.[C:8]1(C)[C:9]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=1.N1C=CC=C[CH:20]=1>>[CH3:1][C:2]1([CH2:6][O:7][S:14]([C:9]2[CH:8]=[CH:13][C:12]([CH3:20])=[CH:11][CH:10]=2)(=[O:15])=[O:16])[CH2:5][O:4][CH2:3]1
Reactant: c1ccncc1
Reactant: CC1(CO)COC1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Product: Cc1ccc(S(=O)(=O)OCC2(C)COC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(3-Methyloxetan-3-yl)methanol (20 g, 190 mmol) was added to a solution of toluene sulfonylchloride (54.3 g, 285 mmol) in dry pyridine (100 ml) and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was poured into crushed ice and stirred vigorously for 30 min. The precipitates were filtered and dried to give toluene-4-sulfonic acid 3-methyl-oxetan-3-ylmethyl ester (37 g) as a white powder.