Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.[H][H]>[OH-].[OH-].[Pd+2].C(O)C>[Si:19]([O:18][CH:16]1[CH2:17][NH:14][CH2:15]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OC1CNC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43.1 %

Procedure:
Add 20% palladium hydroxide on activated carbon (0.946 g) and ethanol (20 mL) to a Parr pressure vessel. Purge the reaction vessel with nitrogen, pressurize the reaction mixture with hydrogen (400 kPa), seal the vessel and agitate the mixture at RT for 15 min. Vent the hydrogen from the reaction vessel and purge the reaction vessel with nitrogen. Add 1-benzhydryl-3-(tert-butyl-dimethylsilanyloxy)-azetidine (3.89 g, 0.0110 mol) and ethanol (80 mL) to the pressure vessel. Purge the reaction vessel with nitrogen, pressurize the reaction mixture with hydrogen (400 kPa), seal the vessel and agitate the reaction at RT for 6 h. Turn off the agitation, vent the excess hydrogen from the vessel and purge the vessel with nitrogen. Sample the reaction mixture for analysis. Once the reaction is shown to be complete, filter the reaction mixture to remove the catalyst, concentrate and purify (silica gel chromatography, eluting with 5:95 to 10:90 2 M ammonia in methanol:DCM) to give the title compound (889 mg, 43%).
Reaction SMILES: [CH2:1]([C:8]1[NH:13][C:12](=[O:14])[C:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]4[CH:28]=[C:29](I)[S:30][C:23]=34)=[C:17]([F:32])[CH:16]=2)=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][N:34]1[CH2:39][CH2:38][N:37]([CH2:40][C:41]#[CH:42])[CH2:36][CH2:35]1.C(N(CC)CC)C>C1COCC1.[Cu]I.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>[CH2:1]([C:8]1[NH:13][C:12](=[O:14])[C:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]4[CH:28]=[C:29]([C:42]#[C:41][CH2:40][N:37]5[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]5)[S:30][C:23]=34)=[C:17]([F:32])[CH:16]=2)=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CCN1CCN(C)CC1
Reactant: O=c1[nH]c(Cc2ccccc2)ncc1-c1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1CCN(CC#Cc2cc3nccc(Oc4ccc(-c5cnc(Cc6ccccc6)[nH]c5=O)cc4F)c3s2)CC1
Temperature: 50 °C
Reaction time: 3 h
Yield: 83.3 %

Procedure:
A mixture of 2-benzyl-5-(3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)phenyl)pyrimidin-4(3H)-one (8.0 mg, 0.014 mmol), 1-methyl-4-(prop-2-ynyl)piperazine (Example 17, Step A; 5.0 mg, 0.036 mmol), copper(I) iodide (0.1 mg, 0.0007 mmol), and triethylamine (0.020 ml, 0.14 mmol) in THF (0.5 mL) was sparged with N2 for 5 minutes, and then Pd(PPh3)4 (1.0 mg, 0.0007 mmol) was added. The sealed reaction was stirred at 50° C. for 3 hours. The reaction mixture was purified directly by silica gel chromatography, eluting with 10:1 dichloromethane/methanol. The desired product (6.6 mg, 81%) was obtained as a pale yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 8.58 (d, J=5.5 Hz, 1H), 8.29 (s, 1H), 7.93 (dd, J=1.9, 12.5 Hz, 1H), 7.81 (s, 1H), 7.74 (m, 1H), 7.54 (t, J=8.6 Hz, 1H), 7.39-7.32 (m, 4H), 7.29-7.24 (m, 1H), 6.76 (d, J=5.1 Hz, 1H), 3.94 (s, 2H), 3.68 (s, 2H), 2.55-2.46 (m, 8H), 1.23 (s, 3H). LRMS (ESI pos) m/e 566 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=1.[CH2:10]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[CH3:11]>CN(C=O)C.O>[CH2:10]([N:12]1[CH2:17][CH2:16][N:15]([C:2]2[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=2)[CH2:14][CH2:13]1)[CH3:11]
Reactant: CCN1CCNCC1
Reactant: O=Cc1ccc(Cl)nc1
Solvent: O
Solvent: CN(C)C=O
Product: CCN1CCN(c2ccc(C=O)cn2)CC1
Yield: 89 %

Procedure:
6-chloropyridine-3-carbaldehyde (5.0 g, 35.32 mmol) and 1-ethylpiperazine (20.16 g, 176.60 mmol, 22.42 mL) were heated overnight in a mixture of DMF/water (1:1, 40 mL) at 100° C. The reaction mixture was extracted with ethyl acetate (2×100 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to dryness to provide 6-(4-ethylpiperazin-1-yl)pyridine-3-carbaldehyde, which was used in the next reaction without any further purification (6.91 g, 89% yield); 1H NMR (400 MHz, DMSO-d6): δ 0.99 (t, 3H), 2.31 (q, 2H), 2.39 (m, 4H), 3.66 (m, 4H), 6.91 (d, J=9.2 Hz, 1H), 7.82 (d, J=9.2 Hz, 1H), 8.55 (s, 1H), 9.7 (s, 1H); LRMS (ES+) m/z 219.8.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[BH4-].[Na+]>C(O)C>[N:10]1([CH2:5][C:4]2[CH:3]=[C:2]([OH:1])[CH:9]=[CH:8][CH:7]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: O=Cc1cccc(O)c1
Reactant: C1COCCN1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Oc1cccc(CN2CCOCC2)c1
Reaction time: 1 h
Yield: 26.5 %

Procedure:
To a solution of 15 g. (0.123 mole) of 3-hydroxybenzaldehyde in 150 ml of ethanol is added 26.5 g (0.304 mole) of morpholine. Then 4.7 g (0.124 mole) of sodium borohydride is added portionwise over 1 hour. The solution is stirred for 1 hour and allowed to sit overnight. The solvent is then evaporated via a rotary evaporator and the residue triturated with 200 ml cold water. After acidification with concentrated HCl, the solution is extracted with ethyl acetate. The aqueous layer is basified with ammonium hydroxide and extracted again with 100 ml ethyl acetate. The organic layer is dried over MgSO4, filtered and evaporated. The residue is recrystallized twice from acetonitrile to give 6.3 g of product m.p. 113°-15° C.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:32]([O:37][CH2:38][CH3:39])(=[O:36])[C@H:33]([CH3:35])[OH:34].[C:40]1([C:46]2[CH:51]=[CH:50][C:49](O)=[CH:48][CH:47]=2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>O1CCCC1>[C:40]1([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:45]=[CH:44][C:43]([O:34][C@H:33]([CH3:35])[C:32]([O:37][CH2:38][CH3:39])=[O:36])=[CH:42][CH:41]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)[C@H](C)O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](C)Oc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Diethylazodicarboxylate (8.66 ml) in dry tetrahydrofuran (25 ml) was added dropwise over 30 minutes to a stirred solution of triphenylphosphine (13.11 g), (S)-(−)-ethyl lactate (5.67 ml) and 4-phenylphenol (8.51 g) in dry tetrahydrofuran (100 ml). The resulting solution was stirred at room temperature for 18 hours then concentrated under reduced pressure. A mixture of isohexane: ether (9:1) (200 ml) was added to the residue and stirred at room temperature for 30 minutes. The solution was filtered and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with isohexane : dichloromethane (2:3) to give the sub-title compound as an oil (11.79 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:11][CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])=[N:4][CH:5]=[N:6][C:7]=1[CH:8](Cl)[CH3:9].[CH3:20][OH:21].C[O-].[Na+]>CO>[Cl:1][C:2]1[C:3]([NH:11][CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])=[N:4][CH:5]=[N:6][C:7]=1[CH:8]([O:21][CH3:20])[CH3:9]
Reactant: CC(Cl)c1ncnc(NC(C)c2ccccc2)c1Cl
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Product: COC(C)c1ncnc(NC(C)c2ccccc2)c1Cl
Temperature: 60 °C
Reaction time: 13 h

Procedure:
In 20 ml of methanol was dissolved 1.11 g of 5-chloro-6-(1-chloroethyl)-4-(1-phenylethylamino)pyrimidine, and to the mixture was added 1.3 g of a 28% sodium methoxide methanol solution. The mixture was stirred at 60° C. for 13 hours.
Reaction SMILES: [CH2:1]1[CH2:14][O:13][C:8]23[O:9][CH2:10][CH2:11][O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16][CH:17]=[C:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.[OH:28][C@H]1CC[C@@]2(C)[C@]3(O[C@H]3C[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CCC2=O)C1>>[CH2:11]1[CH2:10][O:9][C:8]23[O:13][CH2:14][CH2:1][O:2][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16][C@@H:17]5[O:28][C@@:18]65[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]6)[C@@H:6]2[CH2:7]3)[CH3:5])[O:12]1
Reactant: C[C@]12CCCCC1=CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Reactant: C[C@]12CC[C@H]3[C@@H](C[C@@H]4O[C@@]45C[C@@H](O)CC[C@]35C)[C@@H]1CCC2=O
Product: C[C@]12CC[C@H]3[C@@H](C[C@@H]4O[C@@]45CCCC[C@]35C)[C@@H]1CC13OCCOC12OCCO3
Yield: 45 %

Procedure:
17,17-Bis(ethylendioxy)-5α,6α-epoxyandrostane was prepared in 45% yield from 3,3:17,17-bis(ethylendioxy)-5-androstene by the procedure described above for the preparation of 3β-hydroxy-5α,6α-epoxyandrostan-17-one (Prepn. 4). The crude product was purified by flash chromatography (SiO2, n-hexane/EtOAc 80/20). 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 3.92-3.75 (m, 8H), 2.68 (m, 1H), 2.56 (d, 1H), 1.99-1.06 (m, 18H), 1.09 (s, 3H), 0.78 (s, 3H).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].[H-].[Na+].[C:8]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][C:22]2[C:27]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=3)=[C:26](Cl)[N:25]=[CH:24][N:23]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9].Cl>>[C:8]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][C:22]2[C:27]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=3)=[C:26]([O:4][CH2:3][CH2:2][CH2:1][OH:5])[N:25]=[CH:24][N:23]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: COc1cccc(Oc2c(Cl)ncnc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Reactant: OCCCO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCCO)c1

Procedure:
To 1,3-propanediol (7 ml) is added sodium hydride (60% dispersion-type, 312 mg), and thereto is added 4-tert-butyl-N-{6-chloro-5-(3-methoxyphenoxy)pyrimidin-4-yl}benzenesulfonamide (707 mg). The reaction mixture is reacted at 90° C. for two hours, and then reacted at 130° C. for one hour. The reaction solution is acidified with 10% hydrochloric acid, and extracted with ethyl acetate, and the ethyl acetate layer is washed, dried, and concentrated to dryness under reduced pressure. The residue is purified by silica gel column chromatography (solvent; chloroform/ethyl acetate=10:1), and crystallized from ethyl acetate/diisopropyl ether to give 4-tert-butyl-N-{6-(3-hydroxypropyloxy)-5-(3-methoxyphenoxy)pyrimidin-4-yl}benzenesulfonamide (315 mg) as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][C:8]=2[C:9]#[N:10])=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20].[H-].[Na+].Cl[C:26]1[CH:27]=[C:28]2[N:35]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][CH2:33][N:29]2[C:30](=[O:32])[N:31]=1>>[C:39]([O:38][C:36]([N:35]1[C:28]2[N:29]([C:30](=[O:32])[N:31]=[C:26]([O:16][CH2:15][C:12]3[CH:13]=[CH:14][C:7]([O:6][C:5]4[CH:17]=[CH:18][C:2]([Cl:1])=[C:3]([C:19]([F:20])([F:21])[F:22])[CH:4]=4)=[C:8]([C:9]#[N:10])[CH:11]=3)[CH:27]=2)[CH2:33][CH2:34]1)=[O:37])([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(Cl)nc2=O
Reactant: N#Cc1cc(CO)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)c(C#N)c1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 2-(4-chloro-3-(trifluoromethyl)phenoxy)-5-(hydroxymethyl)benzonitrile NaH and tert-butyl 7-chloro-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][N:7]=2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:53][CH2:54][C@H:55]1[CH2:60][CH2:59][CH2:58][CH2:57][C@H:56]1[OH:61]>CN(C=O)C>[CH:1]1([CH2:4][O:5][C:6]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[CH:13][C:9]([C:10]([NH:53][CH2:54][C@@H:55]3[CH2:60][CH2:59][CH2:58][CH2:57][C@@H:56]3[OH:61])=[O:12])=[CH:8][N:7]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cnc(OCC2CC2)c(-c2ccc(F)cc2)c1
Reactant: NC[C@H]1CCCC[C@H]1O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC[C@@H]1CCCC[C@@H]1O)c1cnc(OCC2CC2)c(-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.4 %

Procedure:
6-Cyclopropylmethoxy-5-(4-fluoro-phenyl)-nicotinic acid (0.50 g, 2 mmol) was dissolved in DMF (20 mL). To the solution was added TBTU (0.62 g, 2 mmol), N,N-diisopropylethyl amine (1.5 mL, 9 mmol) and cis-2-aminomethyl-1-cyclohexanol (317 mg, 2 mmol). The reaction mixture was stirred for 18 h at room temperature. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica (n-heptane/ethyl acetate gradient) to yield 585 mg of the title compound as a colorless solid, MS (ISP) 399.2 (M+H)+.
Reaction SMILES: Cl.[CH3:2][C:3]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][CH2:19][CH3:20])[C:13]([CH3:21])=[C:12]2[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)([CH3:7])[C:4](O)=[O:5].[CH:28]1([NH2:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH:28]1([NH:34][C:4](=[O:5])[C:3]([CH3:7])([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH2:18][CH2:19][CH3:20])[C:13]([CH3:21])=[C:12]3[C:22]2[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=2)[CH3:2])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CCCn1c(C)c(-c2ccncc2)c2cc(OC(C)(C)C(=O)O)ccc21
Reactant: NC1CCCCC1
Agent: Cl
Product: CCCn1c(C)c(-c2ccncc2)c2cc(OC(C)(C)C(=O)NC3CCCCC3)ccc21

Procedure:
In accordance with a procedure analogous to that of Example 128, the above compound was prepared from 2-methyl-2-[2-methyl-1-propyl-3-(4-pyridyl)-1H-indole-5-yloxy]propanoic acid hydrochloride and cyclohexylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:19][C:20]2[C:21]3[N:28]([CH2:29][CH2:30][O:31][CH2:32][CH2:33]O)[CH:27]=[CH:26][C:22]=3[N:23]=[CH:24][N:25]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1.C(N(CC)CC)C.[CH3:42][S:43](Cl)(=O)=O.C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][C:20]2[C:21]3[N:28]([CH2:29][CH2:30][O:31][CH2:32][CH2:33][S:43][CH3:42])[CH:27]=[CH:26][C:22]=3[N:23]=[CH:24][N:25]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1
Reactant: OCCOCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSCCOCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Reaction time: 1 h

Procedure:
The compound (150 mg) of Example 147 was dissolved in tetrahydrofuran (10 mL) and triethylamine (1.50 mL) and methanesulfonyl chloride (0.70 mL) were added under ice-cooling, and the mixture was stirred for 1 hr. Saturated aqueous sodium hydrogen carbonate was added to this reaction solution under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated, and the residue was dissolved in a mixed solvent of N,N-dimethylformamide (5.0 mL) and tetrahydrofuran (4.0 mL). Sodium methanethiolate (180 mg) was added, and the mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated. The residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:methanol=100:0→ethyl acetate:methanol=90:10) to give the title compound (123 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH:8]=[CH:9][N:10](C(OCC3C=CC=CC=3)=O)[C:6]=2[CH:5]=[CH:4][N:3]=1.[C:21](Cl)(=[O:23])[CH3:22]>>[NH:10]1[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:21](=[O:23])[CH3:22])[C:7]=2[CH:8]=[CH:9]1
Reactant: Nc1nccc2c1ccn2C(=O)OCc1ccccc1
Reactant: CC(=O)Cl
Product: CC(=O)Nc1nccc2[nH]ccc12

Procedure:
N-(1H-pyrrolo[3,2-c]pyridin-4-yl)acetamide (Intermediate 25) was prepared from benzyl 4-amino-1H-pyrrolo[3,2-c]pyridine-1-carboxylate in an analogous manner using acetyl chloride.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].O.[N+:7]([C:10]1[CH:19]=[C:18]2[C:13]([NH:14][C:15](=[O:21])[C:16](=[O:20])[NH:17]2)=[CH:12][C:11]=1[S:22](Cl)(=[O:24])=[O:23])([O-:9])=[O:8]>>[CH3:1][O:2][CH2:3][CH2:4][NH:5][S:22]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:10]=1[N+:7]([O-:9])=[O:8])[NH:17][C:16](=[O:20])[C:15](=[O:21])[NH:14]2)(=[O:23])=[O:24]
Reactant: O=c1[nH]c2cc([N+](=O)[O-])c(S(=O)(=O)Cl)cc2[nH]c1=O
Reactant: COCCN
Solvent: O
Product: COCCNS(=O)(=O)c1cc2[nH]c(=O)c(=O)[nH]c2cc1[N+](=O)[O-]
Reaction time: 16 h
Yield: 59 %

Procedure:
To a solution of 3.76 g (0.05 mole) of 2-methoxyethylamine in 15 ml of water 6.11 g (0.02 mole) of 1,2,3,4-tetrahydro-7-nitro-2,3-dioxo-6-quinoxalinesulfonyl chloride are added at room temperature, under stirring. The mixture is stirred at room temperature for 6 hours and then allowed to stand for 16 hours. The separated crystals are filtered off, washed successively with water and acetone, filtered again, dried and dissolved in a slight amount of hot dimethyl sulfoxide. The product is precipitated from this solution with water. Thus 4.05 g (59%) of 1,2,3,4-tetrahydro-N-(2-methoxy-ethyl)-7-nitro-2,3-dioxo-6-quinoxaline sulfonamide are obtained, m.p.: 320-321° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1([F:45])[CH2:11][CH:10]1[C:12]([NH:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19]([C:30]3[NH:34][C:33]4[CH:35]=[CH:36][C:37]([N:39]5[CH2:44][CH2:43][O:42][CH2:41][CH2:40]5)=[CH:38][C:32]=4[N:31]=3)=[N:20][N:21]2C2CCCCO2)=[CH:17][CH:16]=1)=[O:13]>C(Cl)Cl>[F:45][C:9]1([F:8])[CH2:11][CH:10]1[C:12]([NH:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19]([C:30]3[NH:31][C:32]4[CH:38]=[C:37]([N:39]5[CH2:44][CH2:43][O:42][CH2:41][CH2:40]5)[CH:36]=[CH:35][C:33]=4[N:34]=3)=[N:20][NH:21]2)=[CH:17][CH:16]=1)=[O:13]
Reactant: O=C(Nc1ccc2c(-c3nc4cc(N5CCOCC5)ccc4[nH]3)nn(C3CCCCO3)c2c1)C1CC1(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc2c(-c3nc4ccc(N5CCOCC5)cc4[nH]3)n[nH]c2c1)C1CC1(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.3 %

Procedure:
TFA (546 mg, 4.78 mmol) was added to solution of 2,2-difluoro-N-(3-(5-morpholino-1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)cyclopropan-ecarboxamide (25 mg, 0.048 mmol) in CH2Cl2 (5 mL). The reaction mixture was stirred overnight at room temperature, and then the solvent was removed in vacuo. Purification by flash chromatography (5% CH3OH/CH2Cl2) afforded the title compound (11 mg) as a solid. 1H NMR: (400 MHz, CD3OD): δ 8.28 (d, 1H, J=1.2 Hz), 8.19 (d, 1H, J=8.8 Hz), 7.61 (d, 1H, J=9.2 Hz), 7.33 (dd, 1H, J=1.6 and 8.8 Hz), 7.25 (dd, 1H, J=2.0 and 8.8 Hz), 7.13 (s, 1H), 3.86 (m, 4H), 3.21 (m, 4H), 2.78-2.70 (m, 1H), 2.14 (m, 1H), 1.90-1.84 (m, 1H); ESI-MS [M+H]+: 439.1.
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14]C(=O)OCC2C=CC=CC=2)[CH2:10][CH2:9]1.[CH2:25]([S:27](Cl)(=[O:29])=[O:28])[CH3:26].Cl>ClCCl>[CH2:25]([S:27]([N:8]1[CH2:9][CH2:10][CH:11]([NH2:14])[CH2:12][CH2:13]1)(=[O:29])=[O:28])[CH3:26]
Reactant: O=C(NC1CCNCC1)OCc1ccccc1
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N1CCC(N)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (10 mL) was added to a dichloromethane (90 mL) solution of Benzyl piperidin-4-ylcarbamate (5.09 g) at 0° C. followed by the dropwise addition of ethane sulfonylchloride (which may be referred to as sso10; 3.2 mL; TCI) and the resulting mixture was stirred overnight slowly raising to room temperature. 1 N Hydrochloric acid (90 mL; WAKO) was added to the reaction mixture solution, the resulting mixture was stirred for approx. 10 minutes, then the reaction mixture was extracted with chloroform, the organic layer was dried, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (Yamazen; chloroform/methanol). Palladium hydroxide (20% by weight, Wet-type, 5 g; NECHEM) was added to a methanol (90 mL) solution of this product under a nitrogen atmosphere. The atmosphere in a reaction vessel was replaced with hydrogen at room temperature, the resulting mixture was stirred overnight, the atmosphere in the reaction vessel was returned to a nitrogen atmosphere, the residue was removed by filtration, the solvent was evaporated under reduced pressure, and the residue was dried to give the title compound (3.32 g).
Reaction SMILES: [CH:1]1[N:6]=[C:5](Cl)[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.[CH2:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH2:29][NH2:30])=[CH:21]1.C(N(CC)CC)C>C(O)C>[CH2:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH2:29][NH:30][C:5]2[C:4]3[N:8]=[CH:9][N:10]([C:3]=3[N:2]=[CH:1][N:6]=2)[C@@H:11]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]2[OH:19])=[CH:21]1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: NCC1=CCc2ccccc21
Solvent: CCO
Solvent: CCN(CC)CC
Product: OC[C@H]1O[C@@H](n2cnc3c(NCC4=CCc5ccccc54)ncnc32)[C@H](O)[C@@H]1O
Yield: 22.3 %

Procedure:
A reaction mixture of 1.4 g of 6-chloropurine riboside, 1.6 g of [1H-inden-3-yl]methylamine as prepared in Example E hereinafter and 1.5 g of triethylamine in 150 ml ethanol is refluxed for 24 hours. Volatiles are evaporated under reduced pressure and residue is purified on Prep-500A using one prepacked silica gel column and 10% methanoldichloromethane as an eluant at a rate of 150 ml/min. Evaporation of solvent from pure fractions affords 0.43 g (22%) of N6 -[1H-inden-3-yl]methyl adenosine having a melting point of 200°-202° C. Anals. calcd. for C20H21N5O4.0.3 CH3OH; Found: C=60.20; H=5.53; N=17.29; C=60.49; H=5.44; N=17.25.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][CH:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]([F:34])([F:33])[F:32])[C:19]4[CH:35]=[CH:36][CH:37]=[CH:38][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)(=O)=O.[C:39]([N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40]>C(N(CC)CC)C>[F:34][C:31]([F:32])([F:33])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH:20]1[C:19]2[CH:35]=[CH:36][CH:37]=[CH:38][C:18]=2[C:17]2[N:16]=[C:15]([NH:14][C:11]3[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][N:49]4[CH2:48][CH2:47][N:46]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:51][CH2:50]4)=[CH:13][CH:12]=3)[N:24]=[CH:23][C:22]=2[CH2:21]1
Reactant: CS(=O)(=O)OCCc1ccc(Nc2ncc3c(n2)-c2ccccc2C(c2ccccc2C(F)(F)F)C3)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(CCc2ccc(Nc3ncc4c(n3)-c3ccccc3C(c3ccccc3C(F)(F)F)C4)cc2)CC1

Procedure:
This was synthesized by using 4-(6-(2-(trifluoromethyl)phenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate, N-boc-piperazine and triethylamine as described in general procedure 2 to afford the desired product. M.p.=234-235° C. 1H NMR 400 MHz (DMSO-d6) δ 8.44 (d, J=7.6 Hz, 1 H), 8.18 (s, 1 H), 7.72 (d, J=7.6 Hz, 1 H), 7.66 (d, J=8.0 Hz, 1 H), 7.46-7.34 (m, 3 H), 7.27-7.21 (m, 3 H), 7.15-7.13 (m, 2 H), 6.90 (d, J=7.6 Hz, 1 H), 4.81 (t, J=7.2 Hz, 1 H), 3.49-3.47 (m, 4 H), 3.23-3.18 (m, 1 H), 3.07-3.01 (m, 1 H), 2.83-2.79 (m, 2 H), 2.65-2.61 (m, 2 H), 1.48 (s, 9 H). LCMS 630 (M+H).