Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])[C:3]=1[C:13]([NH:16][CH2:17][CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2([C:31]([O:33][CH3:34])=[O:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH2:20][CH2:19]1)=[N:14][OH:15].CC(C)([O-])C.[K+]>CN1CCCC1=O.O>[CH2:9]([O:8][C:4]1[C:3]2[C:13]([NH:16][CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([CH2:24][C:25]4([C:31]([O:33][CH3:34])=[O:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH2:20][CH2:19]3)=[N:14][O:15][C:2]=2[CH:7]=[CH:6][CH:5]=1)[CH:10]([CH3:12])[CH3:11]
Reactant: COC(=O)C1(CN2CCC(CNC(=NO)c3c(F)cccc3OCC(C)C)CC2)CCOCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)C1(CN2CCC(CNc3noc4cccc(OCC(C)C)c34)CC2)CCOCC1
Temperature: 100 °C
Yield: 36.3 %

Procedure:
To a solution of methyl 4-{[4-({[(2-fluoro-6-isobutoxyphenyl)(hydroxyimino)methyl]amino}methyl)-piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-carboxylate (0.84 g, 1.8 mmol, EXAMPLE 16, Step 8) in N-methylpyrrolidone (9.0 mL) was added potassium tert-butoxide (0.22 g, 2.0 mmol) at room temperature. The mixture was heated at 100° C. for 5 h and cooled to room temperature. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL×2) and washed with water (50 mL). The combined extracts were dried over magnesium sulfate and concentrated in vacuo to give an oil. The residual oil was purified by silica gel column chromatography (hexane/ethyl acetate 1:1 to 1:2) to give 0.30 g (36%) of the title compound as a colorless viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11][C:12]1[NH:13][C:14]2[C:19]([N:20]=1)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=2.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11][C:12]1[N:13]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)[C:14]2[C:19]([N:20]=1)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=2
Reactant: COc1ccc(OC)c(Sc2nc3c(N)ncnc3[nH]2)c1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Product: COc1ccc(OC)c(Sc2nc3c(N)ncnc3n2Cc2ccc([N+](=O)[O-])cc2)c1
Yield: 10 %

Procedure:
The title compound was prepared from 8-(2,5-dimethoxy-phenylsulfanyl)-9H-purin-6-ylamine and 1-bromomethyl-4-nitro-benzene by a procedure similar to examples 1 and 2. The compound was purified by preparative HPLC. 8-(2,5-Dimethoxy-phenylsulfanyl)-9-(4-nitro-benzyl)-9H-purin-6-ylamine: Yield 10%, 1H NMR (DMSO-d6) δ 8.20 (s, 1H), 8.04 (d, J=6.8 Hz, 2H), 7.57 (bs, 2H), 7.30 (d, 6.8 Hz, 2H), 6.88 (d, J=8.4 Hz, 1H), 6.70 (dd, J=9.2, 3.2 Hz, 1H), 6.25 (d, J=2.8 Hz, 1H), 5.52 (s, 2H), 3.71 (s, 3H), 3.52 (s, 3H); LC-MS [M+H]+ 439.1.
Reaction SMILES: [N+](C1C=CC(O[C:11]([C:13]2[C:14]3[CH:23]=[C:22]([CH2:24][CH3:25])[O:21][C:15]=3[C:16]([O:19][CH3:20])=[N:17][CH:18]=2)=[O:12])=CC=1)([O-])=O.[NH2:26][C:27]1[C:32]([Cl:33])=[CH:31][N:30]=[CH:29][C:28]=1[Cl:34]>>[Cl:34][C:28]1[CH:29]=[N:30][CH:31]=[C:32]([Cl:33])[C:27]=1[NH:26][C:11]([C:13]1[C:14]2[CH:23]=[C:22]([CH2:24][CH3:25])[O:21][C:15]=2[C:16]([O:19][CH3:20])=[N:17][CH:18]=1)=[O:12]
Reactant: Nc1c(Cl)cncc1Cl
Reactant: CCc1cc2c(C(=O)Oc3ccc([N+](=O)[O-])cc3)cnc(OC)c2o1
Product: CCc1cc2c(C(=O)Nc3c(Cl)cncc3Cl)cnc(OC)c2o1
Yield: 74.8 %

Procedure:
Starting from 2-ethyl-7-methoxyfuro[2,3-c]pyridine-4-carboxylic acid 4-nitrophenyl ester (0.20 g) and 4-amino-3,5-dichloropyridine (0.11 g). Purification by trituration with ether gave the title compound (0.16 g) as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:9]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:10])(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:7][CH:8]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:9]([N:11]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1)=[O:10]
Reactant: CC(C)(C)OC(=O)NC(C(=O)N1CCOCC1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(C(=O)N1CCOCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (2-morpholin-4-yl-2-oxo-1-phenylethyl)carbamic acid tert-butyl ester (3.0 mmol) in CH2Cl2 (6.0 mL) is added TFA (2.0 mL) at 0° C. After stirring at room temperature for 24 h, the reaction mixture is basified to pH 8 with sat. aq NaHCO3. The mixture is extracted with CH2Cl2, and then the combined organic extracts are dried over Na2SO4 and concentrated in vacuo to give the title compound; 1H NMR (CDCl3) δ 2.02 (s, 2H), 3.09-3.14 (m, 1H), 3.20-3.25 (m, 1H), 3.34-3.40 (m, 1H), 3.46-3.60 (m, 3H), 3.65-3.71 (m, 1H), 3.74-3.80 (m, 1H), 7.27-7.34 (m, 5H).
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[NH:8][CH:7](SC)[NH:6][C:5]1=[O:13])([CH3:3])[CH3:2].C(O)(=O)C.[CH:18]1([NH2:21])[CH2:20][CH2:19]1>O>[CH:1]([N:4]1[C:9](=[O:10])[NH:8][CH:7]([NH:21][CH:18]2[CH2:20][CH2:19]2)[NH:6][C:5]1=[O:13])([CH3:3])[CH3:2]
Reactant: CSC1NC(=O)N(C(C)C)C(=O)N1
Reactant: NC1CC1
Solvent: CC(=O)O
Solvent: O
Product: CC(C)N1C(=O)NC(NC2CC2)NC1=O
Temperature: 150 °C
Reaction time: 3 h

Procedure:
1-Isopropyl-4-methylthiotetrahydro-1,3,5-triazine-2,6-dione (6.0 g.) (obtained as described in U.K. patent specification No. 1,435,585) and cyclopropylamine acetate (17.85 g.) were heated together and stirred at 150° C. for 3 hours. The mixture was then cooled and water (150 ml.) was added. The white solid which formed was collected, washed with water and dried to give 1-isopropyl-4-cyclopropylaminotetrahydro-1,3,5-triazine-2,6-dione, m.p. 237°-239° C.
Reaction SMILES: C(N(CC)CC)C.I[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH2:18])(=[O:17])=[O:16].[CH:19]#[C:20][CH2:21][CH3:22]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[C:19]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH2:18])(=[O:17])=[O:16])#[C:20][CH2:21][CH3:22]
Reactant: NS(=O)(=O)c1ccccc1I
Reactant: C#CCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC#Cc1ccccc1S(N)(=O)=O
Reaction time: 18 h

Procedure:
0.1 g of bis(triphenylphosphine)palladium(II) chloride, 0.05 g of copper iodide and 18.5 ml of triethylamine are added to a solution of 5 g of 2-iodobenzenesulfonamide in 70 ml of N,N-dimethylformamide. At room temperature, argon and 1-butyne are slowly introduced. After 18 hours the thin-layer chromatogram no longer shows any 2-iodobenzenesulfonamide. The dimethylformamide is evaporated off at 0.1 torr and 40°, and the residue is chromatographed on 300 g of silica gel (Merck ST 60, 40-63 μm). Methylene chloride is used as eluant. In that manner, after concentration of the product-containing fractions at 15 torr and 40°, white pulverulent 2-(but-1-yn-1-yl)-benzenesulfonamide is obtained: 1H-NMR (300 MHz, CDCl3): 8.0 (d, d, 1H); 7.35 (d, d, 1H); 7.29 (d, t, 1H); 7.23 (d, t, 1H); 5.13 (s, 2H); 2.32 (q, 2H); 1.18 (t, 3H).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([N:22]5[CH2:27][CH2:26][N:25]([CH2:28][C:29](O)=[O:30])[CH2:24][CH2:23]5)=[N:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:32]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH3:33][N:34](C)C=O.C(N(CC)C(C)C)(C)C.CN.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>O1CCCC1>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([N:22]5[CH2:23][CH2:24][N:25]([CH2:28][C:29]([NH:34][CH3:33])=[O:30])[CH2:26][CH2:27]5)=[N:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:32]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(N3CCN(CC(=O)O)CC3)nc1OCC2
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)CN1CCN(c2ccc3c(n2)OCCn2cc(-c4ncnn4C(C)C)nc2-3)CC1
Temperature: 25 °C

Procedure:
2-(4-(2-(1-Isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepin-9-yl)piperazin-1-yl)acetic acid (0.050 g, 0.00011 mol) was dissolved in N,N-Dimethylformamide (1.79 mL, 0.0231 mol) and treated sequentially with N,N-Diisopropylethylamine (0.119 mL, 0.000686 mol) 2.00 M of Methylamine in Tetrahydrofuran (0.228 mL) then N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (0.0521 g, 0.000137 mol). Stir at r.t. 2 h. Add sat. sodium bicarbonate, extract with ethyl acetate. Dry organics over sodium sulfate and concentrate to give 334, analyzed by rHPLC. MS: (ESI+)=452.2
Reaction SMILES: C([O:5][C:6](=[O:48])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([NH:16][CH:17]2[C:23](=[O:24])[N:22]([C:25]([CH:35]([CH3:37])[CH3:36])([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:26](=[O:28])[NH2:27])[C:21]3[CH:38]=[CH:39][CH:40]=[CH:41][C:20]=3[C:19]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[N:18]2)=[O:15])[CH:8]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:35]([C:25]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:26](=[O:28])[NH2:27])[N:22]1[C:21]2[CH:38]=[CH:39][CH:40]=[CH:41][C:20]=2[C:19]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)=[N:18][CH:17]([NH:16][C:14](=[O:15])[NH:13][C:9]2[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=2)[C:6]([OH:48])=[O:5])[C:23]1=[O:24])([CH3:37])[CH3:36]
Reactant: CC(C)C(C(N)=O)(c1ccccc1)N1C(=O)C(NC(=O)Nc2cccc(C(=O)OC(C)(C)C)c2)N=C(c2ccccc2)c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(C(N)=O)(c1ccccc1)N1C(=O)C(NC(=O)Nc2cccc(C(=O)O)c2)N=C(c2ccccc2)c2ccccc21
Reaction time: 2 h
Yield: 60.4 %

Procedure:
A solution of 3-{3-[1-(Isopropyl-phenyl-carbamoylmethyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]-ureido}-benzoic acid tert-butyl ester (145 mg, 0.225 mmol), prepared as in Example 5A, in anhydrous DCM (2 mL) at 0-5--C. under nitrogen is treated with triflouroacetic acid (2 mL). After stirring for 2 hrs., the reaction mixture is concentrated in vacuo and triturated with anhydrous ether. The resulting slurry is filtered and the product dried overnight under high vacuum at ambient temperature to provide the title compound as a crystalline solid (80 mg, 0.136 mmol). 1H NMR (300 MHz, d6-DMSO) δ=0.96 (d, J=6.8 Hz, 6H); 4.12 (d, J=16.6 Hz, 1H); 4.23 (d, J=16.6 Hz, 1H); 4.71-6.76 (m, 1H); 5.18-5.27 (m, 1H); 7.24-7.70 (m, 19H); 8.02 (b, 1H); 9.22 (b, 1H). MS (FAB): [M+H]+ =590.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.C([O-])(=O)C.[NH4+].[N+:16]([CH2:19][CH3:20])([O-:18])=[O:17]>>[CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:19]([N+:16]([O-:18])=[O:17])[CH3:20])=[CH:5][CH:4]=1
Reactant: CSc1ccc(C=O)cc1
Reactant: CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CSc1ccc(C=C(C)[N+](=O)[O-])cc1

Procedure:
A stirred solution of 4-methylsulfanyl-benzaldehyde (5.0 g, 28.8 mmol) and ammonium acetate (0.666 g, 8.6 mmol) in nitroethane (17 ml, 236 mmol) is heated at reflux for 5 hours. The solvent is removed and the residue is dissolved in CHCl3 (100 ml) and washed with water (100 ml) followed by brine (100 ml). After drying (MgSO4) the solvent is removed to give the title compound as a yellow solid which is used crude in the next step.
Reaction SMILES: C(O)(=O)C.[NH:5]1[CH2:8][CH:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6]1.[CH:16]([C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1)=O.C([BH3-])#N.[Na+].[C-]#N>CO>[C:22]([C:21]1[CH:24]=[CH:25][C:18]([CH2:16][N:5]2[CH2:6][CH:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8]2)=[CH:19][CH:20]=1)#[N:23]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CC(C)(C)OC(=O)C1CNC1
Agent: [BH3-]C#N
Agent: [C-]#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)C1CN(Cc2ccc(C#N)cc2)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a solution of tert-butyl azetidine-3-carboxylate acetic acid salt (92.0 g, 0.423 mol) in methanol (1.0 L) at room temperature was added 4-formylbenzonitrile (50.8 g, 0.381 mol). The reaction mixture was cooled to 0° C., and sodium cyanoborohydride (28.8 g, 0.458 mol) was added portion-wise (caution: potential cyanide generation). The reaction mixture was allowed to warm to room temperature and stirring continued overnight. After the reaction mixture was concentrated under reduced pressure the residue was diluted with 10% aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was collected, washed with brine and dried over anhydrous sodium sulfate. Concentration under reduced pressure followed by purification by silica gel chromatography using 20% ethyl acetate in petroleum ether afforded tert-butyl 1-(4-cyanobenzyl)azetidine-3-carboxylate (89%) (After chromatography, Int.1-D contained a small amount of 4-hydroxymethylbenzonitrile but was taken forward to the next step without further purification). LC/MS M+1=273.18. 1H NMR (400 MHz, CDCl3) δ ppm 1.46 (s, 9H), 3.22-3.31 (m, 3H), 3.48-3.56 (m, 2H), 3.66 (s, 2H), 7.39 (d, J=8.28 Hz, 2H), and 7.60 (d, J=8.28 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=2[CH:17]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[C:31]([S:32]([CH:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])=[CH:30][CH:29]=[CH:28][C:27]=2[F:38])[C:22]([Cl:39])=[CH:21][N:20]=1>>[Cl:39][C:22]1[C:23]([NH:25][C:26]2[C:31]([S:32]([CH:35]([CH3:36])[CH3:37])(=[O:34])=[O:33])=[CH:30][CH:29]=[CH:28][C:27]=2[F:38])=[N:24][C:19]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=3[CH:17]=2)=[N:20][CH:21]=1
Reactant: CC(C)S(=O)(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CCN1C(=O)CCC(C)(C)c2ccc(N)cc21
Product: CCN1C(=O)CCC(C)(C)c2ccc(Nc3ncc(Cl)c(Nc4c(F)cccc4S(=O)(=O)C(C)C)n3)cc21

Procedure:
Title compound was prepared from 8-Amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and (2,5-Dichloro-pyrimidin-4-yl)-[2-fluoro-6-(propane-2-sulfonyl)-phenyl]-amine in an analogous manner to Example 1221d. Product was obtained as a white foam. (12 mg, 8%). LCMS 562.18 (M+H), HPLC purity 99%, 1H-NMR (CDCl3, 400 MHz) δ 8.27 (s, 1H), 8.17 (s, 1H), 7.81 (d, J=7.1 Hz), 7.49-7.42 (m, 3H), 7.20 (d, J=6.5 Hz, 1H), 7.13 (d, J=8.3 Hz, 1H), 6.99 (s, 1H), 3.75-3.65 (bs, 2H), 3.13-3.03 (m, 1H), 2.29-2.24 (m, 2H), 1.67-1.61 (m, 2H), 1.33 (s, 6H), 1.25 (d, J=6.7 Hz, 6H), 1.20 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[NH:6][C:7]([NH2:16])=[C:8]2[C:12]([N:13]=1)=[N:11][C:10]([O:14][CH3:15])=[N:9]2)[CH3:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1>CN(C=O)C.ClCCl>[NH2:16][C:7]1[N:6]=[C:5]([O:4][CH:2]([CH3:1])[CH3:3])[N:13]=[C:12]2[C:8]=1[N:9]=[C:10]([O:14][CH3:15])[N:11]2[CH2:24][CH2:25][CH2:26][CH2:27][CH:28]1[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])[CH2:32][CH2:33]1
Reactant: COc1nc2nc(OC(C)C)[nH]c(N)c-2n1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCCBr)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1nc2c(N)nc(OC(C)C)nc2n1CCCCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 41.7 %

Procedure:
To a solution of 2-[(1-methylethyl)oxy]-8-(methyloxy)-1H-purin-6-amine (37 mg, 0.166 mmol) in DMF (0.5 ml) was added potassium carbonate (55 mg, 0.398 mmol) followed by a solution of 1,1-dimethylethyl 4-(4-bromobutyl)-1-piperidinecarboxylate (58 mg, 0.181 mmol) in DMF (0.2 ml) and the mixture was stirred at room temperature for 72 hours. The mixture was diluted with dichloromethane (5 ml) and washed with water (5 ml). The layers were separated using a hydrophobic frit, the aqueous layer was extracted again with dichloromethane (5 ml) and the combined organic extracts were evaporated. The residue was dissolved in methanol (0.6 ml) and purified by MDAP (Method A). The appropriate fractions were combined and evaporated under a stream of nitrogen in a blowdown apparatus to give the title compound as a colourless gum (32 mg).
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH:11]=[C:10]2[CH2:12][CH:13]=[CH:14][CH:15]=[C:9]2[O:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2)=[O:4].[OH:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C(OCC)(=O)C>[CH2:12]1[C:10]2=[CH:11][N:5]([C:3](=[O:4])[CH2:2][O:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:29][CH:30]=3)[C:6]3[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=3[O:8][C:9]2=[CH:15][CH:14]=[CH:13]1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: O=C(CBr)N1C=C2CC=CC=C2Oc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1ccc(OCC(=O)N2C=C3CC=CC=C3Oc3ccccc32)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 32.4 %

Procedure:
Title compound 455 (0.890 g, 2.81 mmol) and the methyl 4-hydroxybenzoate (0.512 g, 3.37 mmol) were dissolved in acetonitile (10.0 mL) and the cesium carbonate (1.83 g, 5.62 mmol) was added. The reaction mixture was stirred at 100° C. in a sealed tube for 4 hours. The mixture was cooled down to room temperature and diluted with ethyl acetate. The organic layer was washed with water (2 times) and brine, dried over sodium sulfate, filtered and evaporated. The crude was purified by flash chromatography (30-40% ethyl acetate in hexanes) to afford title compound 456 (355 mg, 32%) as white foam. MS (m/z): 390.3 (M+H).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([OH:19])[CH:12]=2)=[CH:5][N:4]=1.Br[CH2:21][CH2:22][CH2:23][NH:24][S:25](=[O:37])([C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:36])[CH3:35])=[CH:29][CH:28]=1)=[O:26].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH2:21][CH2:22][CH2:23][NH:24][S:25](=[O:26])([C:27]3[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:36])[CH3:35])=[CH:29][CH:28]=3)=[O:37])[CH:12]=2)=[CH:5][N:4]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)NCCCBr)cc1
Reactant: COc1ccc(Cc2cnc(N)nc2N)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Cc2cnc(N)nc2N)cc1OCCCNS(=O)(=O)c1ccc(NC(C)=O)cc1
Reaction time: 18 h

Procedure:
A mixture of 2.82 g (0.01 mole) of 2,4-diamino-5-(3'-hydroxy-4'-methoxybenzyl)pyrimidine hydrochloride, 3.36 g (0.01 mole) of N1 -(3-bromopropyl)-N4 -acetylsulfanilamide, 2.76 g of anhydrous K2CO3, and 20 ml of dimethylformamide is heated with stirring at 100° for 18 hr. The mixture is concentrated in vacuo to a dark oil, which is shaken with a mixture of water and chloroform. The oily material which remaines insoluble in the water and chloroform is chromatographed on silica gel. Elution with chloroform-methanol, (85:15) gives fractions containing 0.55 g (11%) of 2,4-diamino-5-{3'-[3"-(N4 -acetylsulfanilamido)propoxy-4'-methoxybenzyl}pyrimidine, m.p. 96°-98°. Spectral data are consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]1[C:7]([SH:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].C([O-])([O-])=O.[K+].[K+].Cl[CH2:18][C:19](=[O:25])[CH2:20][C:21]([O:23][CH3:24])=[O:22]>CN(C=O)C>[OH:10][C:3]1[C:2]([CH3:1])=[C:7]([S:8][CH2:18][C:19](=[O:25])[CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:6]=[C:5]([CH3:9])[CH:4]=1
Reactant: COC(=O)CC(=O)CCl
Reactant: Cc1cc(O)c(C)c(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CC(=O)CSc1cc(C)cc(O)c1C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a mixture of 2,5-dimethyl-3-sulfanylphenol (126 mg) and DMF (dry) (8.0 mL) were added K2CO3 (124 mg) and methyl 4-chloro-3-oxobutanoate (0.096 mL) at 0° C. The mixture was stirred at 0° C. for 3 h. The mixture was quenched with water at 0° C. and extracted with EtOAc. The organic layer was washed successively with water and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (179 mg).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([OH:20])=[O:19])=[CH:16][C:3]1=2.C([O-])([O-])=O.[K+].[K+].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30].O>CN(C)C=O>[CH3:32][O:31][C:29](=[O:30])[CH2:28][O:19][C:18](=[O:20])[CH2:17][C:15]1[CH:14]=[CH:13][C:4]2[O:5][CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:2](=[O:1])[C:3]=2[CH:16]=1
Reactant: O=C(O)Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COC(=O)Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Temperature: 50 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
A mixture of 15 g (0.052 m) of 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid in 100 ml of dimethylformamide and 3.87 g (0.028 m) of K2CO3 was warmed to an internal temperature of 50° C. in an atmosphere of nitrogen for 1.5 hours. To this mixture, 9.41 g (0.062 m) of methyl bromoacetate was added dropwise and the mixture was held at 50° C. overnight. The reaction mixture was poured into water and extracted with ether. The ether extract was washed with 5% NaHCO3 and water, dried over Na2SO4, filtered and evaporated to give 16.5 g (94%) of an oil of methyl(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)acetoxyacetate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)[C:5]([O:33][CH3:34])=[CH:4][C:3]=1[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=1.[S:42]1[N:46]=[CH:45][C:44]([NH2:47])=[N:43]1.C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:47][C:44]4[CH:45]=[N:46][S:42][N:43]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)[C:5]([O:33][CH3:34])=[CH:4][C:3]=1[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=1
Reactant: Nc1cnsn1
Reactant: COc1cc(-c2cccc(F)c2)c(Cl)cc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(-c2cccc(F)c2)c(Cl)cc1-c1nccc2cc(S(=O)(=O)Nc3cnsn3)ccc12
Reaction time: 0.17 h
Yield: 56.8 %

Procedure:
A vial was charged with perfluorophenyl 1-(2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)isoquinoline-6-sulfonate (INTERMEDIATE TTTT; 45 mg, 0.074 mmol), 1,2,5-thiadiazol-3-amine (8.21 mg, 0.081 mmol), and THF (0.5 mL) to give a clear solution. The vial was cooled in an ice-water bath for 5 min, then lithium bis(trimethylsilyl)amide (1M in THF) (162 μl, 0.162 mmol) was added drop wise. After 10 min, the mixture was diluted with a small amount of methanol to give a solution which was purified directly by chromatography on silica gel (12-g Redi-Sep Gold column, 0-5% MeOH/DCM) to give 1-(2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-N-(1,2,5-thiadiazol-3-yl)isoquinoline-6-sulfonamide (22.2 mg, 0.042 mmol, 57.1% yield) as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=12.50 (br. s., 1H), 8.81-8.69 (m, 2H), 8.50 (s, 1H), 8.18 (d, J=5.4 Hz, 1H), 8.00 (dd, J=1.9, 8.9 Hz, 1H), 7.88 (d, J=8.9 Hz, 1H), 7.65-7.52 (m, 2H), 7.48-7.39 (m, 2H), 7.35-7.29 (m, 1H), 7.27 (s, 1H), 3.70 (s, 3H). m/z (ESI) 527.2 (M+H)+.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][N:31]([C:37](=[O:38])[CH2:36][O:35][CH3:34])[CH2:32][CH2:33]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: COCC(=O)Cl
Reactant: COc1ccc(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)c1
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4ccc(OC)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f18) and commercially methoxyacetyl chloride the title compound is obtained as colorless solid.