Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:12]([O:13][CH3:14])=[N:11][N:10]=[C:9]1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16]1([C:19]2[C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]([CH3:38])[CH:20]=2)[CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[CH2:1]([N:8]1[C:12]([O:13][CH3:14])=[N:11][N:10]=[C:9]1[C:28]1[C:19]([CH:16]2[CH2:18][CH2:17]2)=[CH:20][C:21]([CH3:38])=[C:22]([CH:27]=1)[C:23]([O:25][CH3:26])=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1nnc(Br)n1Cc1ccccc1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C2CC2)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2nnc(OC)n2Cc2ccccc2)c(C2CC2)cc1C
Temperature: 90 °C
Yield: 89.3 %

Procedure:
A mixture of 4-benzyl-3-bromo-5-methoxy-4H-1,2,4-triazole (compound 91.3, 1.2 g, 4.48 mmol), methyl 4-cyclopropyl-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 91.1, 1.56 g, 4.93 mmol), PdCl2(dppf)CH2Cl2 (0.37 g, 0.45 mmol) and potassium carbonate (3.10 g, 22.5 mmol) in dioxane (50 mL) and water (20 mL) was degassed with argon. The mixture was heated at 90° C. for 18 hours under argon, then cooled to room temperature. The mixture was diluted with ethyl acetate (300 mL) and washed with water then brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexanes:EtOAc 10:1 to 4:1) to yield 1.51 g (89%) of the title compound as thick oil. m/z (ES+) 378 (M+H)+.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH3:12][S:13]([N:16]([CH2:31][CH2:32][Cl:33])[N:17]([S:27]([CH3:30])(=[O:29])=[O:28])C(OC1C=CC=CC=1)=O)(=[O:15])=[O:14]>>[CH2:5]([O:4][C:2]([N:17]([S:27]([CH3:30])(=[O:29])=[O:28])[N:16]([S:13]([CH3:12])(=[O:15])=[O:14])[CH2:31][CH2:32][Cl:33])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CS(=O)(=O)N(CCCl)N(C(=O)Oc1ccccc1)S(C)(=O)=O
Product: CS(=O)(=O)N(CCCl)N(C(=O)OCc1ccccc1)S(C)(=O)=O

Procedure:
2-Benzyloxycarbonyl-1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine (compound 11) was prepared by reacting benzyl chloroformate with compound 2 using a procedure similar to that described for compound 10d. The compound was isolated as a thick oil in a yield of approximately 41.3% by weight. 1H NMR (acetone-d): δ 7.2-7.6 (5H, m, aromatic H), 5.4 (2H, s, ArCH2), 3.5-4.0 (4H, m, CH2CH2Cl), 3.4 and 3.1 (6H, 2s, 2 CH3SO2).
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][CH:16]2[OH:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:28])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]I.[CH3:29][NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([F:43])([F:42])[C:38]([F:41])([F:40])[F:39].[Cl-].[Na+]>CN1CCCC1=O>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C@@H:16]2[OH:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:28])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:30]([CH3:29])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([F:42])([F:43])[C:38]([F:39])([F:40])[F:41]
Reactant: CNCCCCCCC(F)(F)C(F)(F)F
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCCI)[C@H]3[C@@H]1CCC2O
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CN(CCCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CC[C@H](O)[C@@]1(C)C[C@@H]2F)CCCCCCC(F)(F)C(F)(F)F
Yield: 69 %

Procedure:
A solution of 690 mg of 11β-fluor-7α-(6-iodohexyl)-estra-1,3,5(10)-triene-3,17-diol in 15 ml of 1-methyl-2-pyrrolidinone is stirred with 810 mg of methyl-(7,7,8,8,8-pentafluor-octyl)-amine for 3 hours at a bath temperature of 80° C. For working-up, the batch is added to saturated sodium chloride solution, extracted with ether, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with dichloromethane/methanol/ammonia (25%). 576 mg of 11β-fluoro-7α-{6-[methyl-(7,7,8,8,8-pentafluor-octyl)-amino]-hexyl}-estra-1,3,5(10)-triene-3,17β-diol is obtained as a foam, [α]D=+42° (c=0.5 in CHCl3).
Reaction SMILES: [P:1]([OH:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].C(NCC)C.[C:14]([P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])(=[O:16])[CH3:15]>>[CH2:3]([O:2][P:1]([C:14]([P:17](=[O:24])([O:18][CH2:19][CH3:20])[O:21][CH2:22][CH3:23])([OH:16])[CH3:15])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:4]
Reactant: CCOP(O)OCC
Reactant: CCOP(=O)(OCC)C(C)=O
Solvent: CCNCC
Product: CCOP(=O)(OCC)C(C)(O)P(=O)(OCC)OCC

Procedure:
Diethyl hydrogen phosphite (1.0 mole) and diethyl amine (1.0 mole) were combined in a round bottom flask. Diethyl acetylphosphonate (1.0 mole) was added dropwise, with stirring. The reaction mixture was maintained at a temperature of about 75° C. for an additional 2 hours after all of the diethyl acetyl phosphonate was added. The resulting mixture was distilled under reduced pressure to yield tetraethyl 1-hydroxyethylidene bisphosphonic acid as a pale yellowish liquid which crystallized at -15° C. into small needle-shaped crystals.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](OC(=O)C)(=[O:14])[CH3:13].O1CCCC1>O>[C:12]([NH:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccc(C(=O)O)c1N
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1c(C)cccc1C(=O)O
Temperature: 80 °C
Reaction time: 13 h
Yield: 38 %

Procedure:
A mixture of 1.51 g of 2-amino-3-methylbenzoic acid, 1.0 g of acetic anhydride and 20 ml of tetrahydrofuran was stirred at 80° C. for 13 hours. The reaction mixture was allowed to cool to room temperature, poured into water, and extracted with ethyl acetate two times. The organic layers were combined, washed successively with water and an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was washed with ethyl acetate to obtain 0.72 g of 2-acetylamino-3-methylbenzoic acid of the formula:
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH:5]([C:8]1[S:12][CH2:11][N:10]([CH3:13])[CH:9]=1)[O:6][CH3:7])=O.Cl.[NH2:19][OH:20].N1C=CC=CC=1.Cl>CO>[OH:20][N:19]=[CH:1][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH:5]([C:8]1[S:12][CH2:11][N:10]([CH3:13])[CH:9]=1)[O:6][CH3:7]
Reactant: NO
Reactant: COC(C1=CN(C)CS1)c1ccccc1C=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: COC(C1=CN(C)CS1)c1ccccc1C=NO
Yield: 75.7 %

Procedure:
To 1.39 g (6 mmol) of 5-(2-formyl-α-methoxybenzyl)-3-methylthiazole in 12 ml of methanol was added 0.83 g (12 mmol) of hydroxylamine hydrochloride and 1.07 ml (13.2 mmol) of pyridine and stirred under reflux for 2 hours. After completion of the reaction, 200 ml of 0.1N hydrochloric acid was added and extracted twice with 100 ml of dichloromethane. The dichloromethane layer was dried over anhydrous magnesium and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane) to give 5-(2-hydroxyiminomethyl-α-methoxybenzyl)-3-methylthiazole (1.20 g, 81.2%) as oil.
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].Cl.[C:10]1([NH:16][NH2:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CCO>[CH:2]([C:3]1[CH:4]=[C:5]([NH2:6])[N:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:17]=1)([CH3:8])[CH3:1]
Reactant: CC(C)C(=O)CC#N
Reactant: NNc1ccccc1
Agent: Cl
Solvent: CCO
Product: CC(C)c1cc(N)n(-c2ccccc2)n1
Temperature: 65 °C
Yield: 77.8 %

Procedure:
Using the procedure described in Example 308A Step 1, to a solution of 4-methyl-3-oxopentanenitrile (303 mg, 2.7 mmol) prepared as described in Example 122A Step 1, in anhydrous EtOH (6 ml) was added phenylhydrazine hydrochloride (473 mg, 3.3 mmol) and the reaction mixture was heated at 65° C. overnight. The residue was purified by silica gel chromatography (hexane/ethyl acetate 2-50%) to afford 3-isopropyl-1-phenyl-1H-pyrazol-5-amine (423 mg, 77%) as a solid. 1H NMR (300 MHz, CDCl3) δ 1.22 (d, J=6 Hz, 6H), 3.86 (brs, 2H), 5.35 (s, 1H), 7.21-7.49 (m, 5H); LC-MS (ESI) m/z 202 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1>[CH2:21]([NH:13][CH2:12][CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(CCN)cc1OC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(CCNCc2ccccc2)cc1OC
Reaction time: 0.04 h

Procedure:
N-benzyl-2-(3,4-dimethoxyphenyl)ethylamine was prepared using a system (FRX200, Syrris Limited) including a microflow reactor. For this purpose, 83 μl (0.5 mmol) of 2-(3,4-dimethoxyphenyl)ethylamine and 5 ml of tetrahydrofuran were added to the first storage unit of the system including the microflow reactor, and then 70 μl (0.5 mmol) of triethylamine was added thereto. Meanwhile, 60 μl (0.5 mmol) of benzyl bromide and 5 ml of tetrahydrofuran were added to the second storage unit of the system. The reactants included in the first and second storage units were transferred through the first and second flow channels to the mixing unit, and then transferred through the third flow channel into the microflow reactor including microchannels. The first and second flow channels could transfer 360 μl (180 μl for each flow channel) of the reactants to the microflow reactor. The microflow reactor was set at a capacity of 250 μl, a temperature of 100° C. and a pressure of 8 bar. The reactants in the first and second storage units were set such that they were passed through the first to third flow channels at a flow rate of 0.05 ml/min and introduced into the microflow reactor. Also, the residence time of the reactants in the microflow reactor was set at 2.5 minutes.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][CH3:23])=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[CH3:28][N:29]([CH3:34])[CH2:30][C:31](O)=[O:32].O=P(Cl)(Cl)Cl>CO>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]([CH3:23])[C:31](=[O:32])[CH2:30][N:29]([CH3:34])[CH3:28])=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: CN(C)CC(=O)O
Reactant: CNc1ccc(-n2cc(CNC(=O)c3ccc(Cl)s3)nn2)cc1
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)CC(=O)N(C)c1ccc(-n2cc(CNC(=O)c3ccc(Cl)s3)nn2)cc1

Procedure:
5-Chloro-N-((1-(4-(methylamino)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (34 mg, 0.1 mmol), prepared as shown in Example 17, was dissolved in 10 mL methanol and treated with MP-carbonate for 1 hr. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in 3 mL pyridine and N,N-dimethylglycine (16 mg, 0.1 mmol) was added. The mixture was then stirred in ice bath. POCl3 (28 μL, 0.3 mmol) was added. The reaction was stirred for 20 min and quenched with methanol. The mixture was concentrated and directly subjected to prep HPLC to isolate the title compound. MS found for C19H21ClN6O2S (M+H)+ 433.1, 435.1 (Cl pattern).
Reaction SMILES: Cl.[CH:2]1([N:7]2[C:11]3[N:12]=[C:13]([NH2:16])[N:14]=[CH:15][C:10]=3[C:9]3[CH:17]=[CH:18][N:19]=[CH:20][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3]1.Cl[C:22]1[N:42]=[CH:41][CH:40]=[CH:39][C:23]=1[C:24]([N:26]1[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]1)=[O:25]>>[CH:2]1([N:7]2[C:11]3[N:12]=[C:13]([NH:16][C:41]4[CH:40]=[CH:39][C:23]([C:24]([N:26]5[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]5)=[O:25])=[CH:22][N:42]=4)[N:14]=[CH:15][C:10]=3[C:9]3[CH:17]=[CH:18][N:19]=[CH:20][C:8]2=3)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccnc2Cl)CC1
Reactant: Nc1ncc2c3ccncc3n(C3CCCC3)c2n1
Agent: Cl
Product: O=C(c1ccc(Nc2ncc3c4ccncc4n(C4CCCC4)c3n2)nc1)N1CCNCC1

Procedure:
Compound 350 was prepared as a light yellow solid (HCl salt) from compound 4 and compound 351 using chemistry similar to that described in example 200. 1H NMR (500 MHz, DMSO-d6) δ ppm 11.06 (1 H, br. s.), 9.70 (1 H, s), 9.47 (1 H, s), 9.39 (2 H, br. s.), 8.67-8.75 (2 H, m), 8.51 (1 H, d, J=1.7 Hz), 8.37 (1 H, d, J=8.6 Hz), 8.02 (1 H, dd, J=8.7, 2.3 Hz), 5.43 (1 H, dq, J=8.9, 8.8 Hz), 3.77 (4 H, br. s.), 3.18 (4 H, br. s.), 2.42-2.48 (2 H, m), 2.02-2.20 (4 H, m), 1.70-1.83 (2 H, m). LCMS-ESI (POS), M/Z, M+1: Found 443.2.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[OH:6][C:7]1[CH:16]=[CH:15][C:14]2[NH:13][C:12](=O)[CH:11]=[CH:10][C:9]=2[C:8]=1[CH:18]=[O:19]>CN(C=O)C>[Cl:3][C:12]1[CH:11]=[CH:10][C:9]2[C:8]([CH:18]=[O:19])=[C:7]([OH:6])[CH:16]=[CH:15][C:14]=2[N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=Cc1c(O)ccc2[nH]c(=O)ccc12
Solvent: CN(C)C=O
Product: O=Cc1c(O)ccc2nc(Cl)ccc12
Temperature: 20 °C
Reaction time: 20 h
Yield: 80.3 %

Procedure:
POCl3 (973 μL, 10.4 mmol) was added dropwise to a DMF (5 mL) solution of 6-hydroxy-2-oxo-1,2-dihydroquinoline-5-carbaldehyde (658 mg, 3.48 mmol) at 0° C. The mixture was stirred for 20 hours at 20° C. then cooled to 0° C. Upon addition of ice water the product precipitated. It was filtered, washed with water and dried on air to afford 580 mg (88%) of the title compound. MS (ESI): 208 (M+H)+. 1H NMR (δ, DMSO (2.5 ppm)): 11.95 (s, 1H, OH), 10.70 (s, 1H, CHO), 9.38, 8.10, 7.67 and 7.55 (4d, 4×1H).
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=O)[C:5]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([CH3:15])[N:3]=1.P(Cl)(Cl)([Cl:18])=O.CN(C)C1C=CC=CC=1>>[Cl:18][C:6]1[C:5]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([CH3:15])[N:3]=[C:2]([CH3:1])[N:7]=1
Reactant: CCOC(=O)Cc1c(C)nc(C)[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CCOC(=O)Cc1c(C)nc(C)nc1Cl
Yield: 98 %

Procedure:
A mixture of ethyl (2,6-dimethyl-3H-pyrimidin-4-on-5yl)acetate (1.13 g, 5.4 mmol), phosphorous oxychloride (10 mL, and N,N-dimethylaniline (1.3 mL, 10.3 mmol) was heated under reflux for 3.5 h. The reaction mixture was concentrated, poured onto ice, and the resulting mixture was extracted with ether. The combined extracts were washed with water, dried (MgSO4), and concentrated to give 1.2 g (98%) of product as a yellow oil.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:18]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19]1.C(OCC)(=O)C.B(F)(F)F.CCOCC>CCOCC>[C:1]1([C:7]2[N:8]=[CH:9][N:10]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23][O:18]3)[C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1=COCCC1
Reactant: c1ccc(-c2nc[nH]c2-c2ccccc2)cc1
Agent: FB(F)F
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: c1ccc(-c2ncn(C3CCCCO3)c2-c2ccccc2)cc1

Procedure:
A mixture of 27 g (0.122 mole) 4,5-diphenylimidazole, 21 g (0.25 mole) dihydropyran, 250 ml ethyl acetate and 4.0 g BF3.Et2O was refluxed for five days. The nearly clear solution was diluted with ether and filtered to remove 0.6 g insoluble starting material. The ether filtrate was washed several times with 10% NaHCO3 then dried and evaporated. TLC showed starting material still present, so the crude product was chromatographed on 2 lb. SilicAR CC-7, eluting with toluene containing 20 to 40% ethyl acetate. The pure 4,5-diphenyl-1-(2-tetrahydropyranyl) imidazole thus obtained weighed 30.3 g (82%) and had mp 170°-171°.
Reaction SMILES: CS(O[CH2:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@H:16]2[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([CH2:23][O:24][CH3:25])[O:17]2)=[C:9]([NH:26][CH2:27][CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]=1)(=O)=O.C(N(CC)CC)C.[C:48]1([SH:54])[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>O1CCCC1>[C:35]1([CH:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27][NH:26][C:9]2[N:8]=[C:7]([CH2:6][S:54][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[C@H:16]2[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([CH2:23][O:24][CH3:25])[O:17]2)[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(COS(C)(=O)=O)nc32)[C@H](O)[C@@H]1O
Reactant: Sc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CSc4ccccc4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 36.7 %

Procedure:
{9-[(2R,3R,4S,5R)-3,4-Dihydroxy-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}methyl methanesulfonate (400 mg, 0.7 mmol) (Preparation 25), triethylamine (0.2 ml, 1.4 mmol) and thiophenol (100 mg, 0.9 mmol) were dissolved in tetrahydrofuran (3 ml) and the reaction mixture stirred for 24 hr at room temperature. The solvent was then removed under reduced pressure and the residue purified by column chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol (99:1) increasing in polarity to (95:5). This gave the title compound (150 mg) as a foam. MS: 584 (MH+).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O.ClC(OCC)=O.[CH2:24]([NH2:27])[CH2:25][NH2:26].Cl>C(Cl)(Cl)Cl>[ClH:8].[NH2:26][CH2:25][CH2:24][NH:27][C:11](=[O:13])[C:10]1[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=1[Cl:8]
Reactant: NCCN
Reactant: O=C(O)c1ccccc1Cl
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: NCCNC(=O)c1ccccc1Cl
Temperature: 0 °C
Yield: 108.9 %

Procedure:
22.1 ml (0.16 mol) of triethylamine are added dropwise at 10° to a suspension of 23.5 g (0.15 mol) of 2-chlorobenzoic acid in 200 ml of chloroform. 14.8 ml (0.155 mol) of ethyl chloroformate are then added dropwise at the same temperature. After completion of the addition (1 hour), the mixture is poured on to ice/water. The chloroform phase is separated, dried over magnesium sulfate and gently concentrated to about 60 ml. The thus-obtained solution is added dropwise at 10° to a solution of 40.1 ml (0.6 mol) of ethylenediamine in 400 ml of chloroform. After completion of the addition, the difficulty soluble neutral constituents are filtered off, the filtrate is concentrated and excess ethylenediamine is removed in a high vacuum. The residue obtained (31.5 g) is converted into the hydrochloride which is purified by recrystallization from ethanol/ether. There are obtained 19.2 g of N-(2-aminoethyl)-2-chlorobenzamide hydrochloride (see Example 6 of German Offenlegungsschrift 2.362.568), m.p. 155°-158°. An analytically pure sample melts at 159°-161°.
Reaction SMILES: [CH2:1]([OH:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[H-].[Na+].[C:9]([O:13][C:14]([N:16]1[CH2:22][CH2:21][C:20]2[C:23]([S:28][CH2:29][C:30]3[N:31]=[N:32][C:33](Cl)=[CH:34][CH:35]=3)=[C:24]([Cl:27])[CH:25]=[CH:26][C:19]=2[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>C1COCC1.O>[C:9]([O:13][C:14]([N:16]1[CH2:22][CH2:21][C:20]2[C:23]([S:28][CH2:29][C:30]3[N:31]=[N:32][C:33]([O:6][CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])=[CH:34][CH:35]=3)=[C:24]([Cl:27])[CH:25]=[CH:26][C:19]=2[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)CO
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(Cl)nn3)c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)COc1ccc(CSc2c(Cl)ccc3c2CCN(C(=O)OC(C)(C)C)CC3)nn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.9 %

Procedure:
To a stirred solution of neopentyl alcohol (105 mg, 1.19 mm ol) in THF (5 mL) at ambient temperature add sodium hydride (31 mg, 95%, 1.19 mmol) and continue stirring for 3 h at ambient temperature. Add a solution of 3-tert-butoxycarbonyl-7-chloro-6-(6-chloro-pyridazin-3-ylmethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (315 mg, 0.59 mmol) in THF (1 mL) and continue stirring overnight at ambient temperature and then at 60° C. for 1 h. Dilute with water, extract the reaction mixture three times with EtOAc, dry over anhydrous Na2SO4, and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (6:1) to give 3-tert-butoxycarbonyl-7-chloro-6-[6-(2,2-dimethyl-propoxy)-pyridazin-3-ylmethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a clear oil (81 mg, 28%). MS (APCI+) m/z: 492 (M+H)+, 392 (M+H−Boc)+. Use a method similar to the General Procedure 1-4 to give the title compound as a white powder. MS (APCI+) m/z: 392 (M+H)+, m/z: 322 M+H−C5H11)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[N:7]([CH2:9][CH2:10][CH2:11][C:12]#[C:13][C:14]1[CH:19]=[C:18]([C:20](=[O:32])[NH:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=2)[CH:17]=[CH:16][C:15]=1[NH2:33])[CH3:8])([CH3:4])([CH3:3])[CH3:2]>C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl.CN(C)C=O>[CH3:31][O:30][C:24]1[CH:23]=[C:22]([NH:21][C:20]([C:18]2[CH:19]=[C:14]3[C:15](=[CH:16][CH:17]=2)[NH:33][C:12]([CH2:11][CH2:10][CH2:9][N:7]([CH3:8])[C:6](=[O:34])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:13]3)=[O:32])[CH:27]=[CH:26][C:25]=1[O:28][CH3:29]
Reactant: COc1ccc(NC(=O)c2ccc(N)c(C#CCCCN(C)C(=O)OC(C)(C)C)c2)cc1OC
Agent: Cl[Pd]Cl
Solvent: N#Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)c2ccc3[nH]c(CCCN(C)C(=O)OC(C)(C)C)cc3c2)cc1OC
Temperature: 80 °C

Procedure:
A 500 mL round bottom flask was charged with {5-[2-amino-5-(3,4-dimethoxy-phenylcarbamoyl)-phenyl]-pent-4-ynyl}-methyl-carbamic acid tert-butyl ester (3.4 g, 7.27 mmol), dichlorobis(benzonitrile)palladium (II) (0.558 g, 1.45 mmol), and dimethylformamide (80 mL) and the resulting mixture heated to 80° C. for 24 h. The resulting mixture was then concentrated in-vacuo and the residue purified via flash silica gel chromatography (Analogix IF-280, SF25-40 g column, gradient 90:10-10:90 heptane:EtOAc) to yield tert-butyl 3-(5-(3,4-dimethoxyphenylcarbamoyl)-1H-indol-2-yl)propyl(methyl)carbamate. 1H NMR (300 MHz, CDCl3) δ 7.84 (s, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.57 (s, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.00 (d, J=8.6 Hz, 1H), 6.85 (d, J=8.6 Hz, 1H), 6.32 (s, 1H), 3.93 (s, 3H), 3.89 (s, 3H), 3.31-3.41 (m, 2H), 2.89 (s, 3H), 2.66-2.77 (m, 2H), 1.83-1.94 (m, 2H), and 1.53 (s, 9H). MS (ES+) 468 (M+1).
Reaction SMILES: [CH2:1]([S:4][C:5]1[N:10]=[C:9]([N:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:20])[C:14]=3[CH:13]=[N:12]2)[CH:8]=[CH:7][N:6]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:28][CH2:29][S:30][CH3:31].CN1C(=O)CCC1>O>[CH3:31][S:30][CH2:29][CH2:28][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:14]=1[CH:13]=[N:12][N:11]2[C:9]1[CH:8]=[CH:7][N:6]=[C:5]([S:4][CH2:1][CH2:2][CH3:3])[N:10]=1
Reactant: CSCCCl
Reactant: CCCSc1nccc(-n2ncc3c(O)cccc32)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCSc1nccc(-n2ncc3c(OCCSC)cccc32)n1
Temperature: 80 °C
Yield: 93.3 %

Procedure:
1-(2-Propylsulfanyl-pyrimidin-4-yl)-1H-indazol-4-ol (600 mg), potassium carbonate (1.104 g) and 1-chloro-2-methylsulfanyl-ethane 401.9 mg) were added to NMP (6 mL), and the mixture was heated to 80° C. for three hours. The mixture was cooled, diluted with water and filtered. The collected solid was washed with water and dried under reduced pressure to give 705 mg of 4-(2-Methylsulfanyl-ethoxy)-1-(2-propylsulfanyl-pyrimidin-4-yl)-1H-indazole.