Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.[Br:19][CH2:20][C:21](Br)=[O:22]>CCOCC>[Br:19][CH2:20][C:21]([N:1]1[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11]1)=[O:22]
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=C(Br)CBr
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)C1CCN(C(=O)CBr)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 50.1 %

Procedure:
A solution of ethyl isonipecotate (5.1 ml, 33 mMoles) in triethylamine (4.7 ml, 33 mMoles) was added dropwise to a stirred ice-cooled solution of bromoacetyl bromide (2.9 ml, 33 mMoles) in ether (75 ml) and stirring was continued for 1 hour. The resulting suspension was washed sequentially with water (2×20 ml), dilute sodium bicarbonate solution (20 ml), dilute citric acid solution (20 ml), water (20 ml) and saturated brine (30 ml), and then the organic fraction was dried (MgSO4) and concentrated under reduced pressure to give ethyl 1-(bromoacetyl)-piperidin-4-carboxylate (4.6 g) as a yellow oil which was used without further purification; NMR (CDCl3): 1.2 (t,3H), 1.6-2.1 (m,4H), 2.5 (m,1H), 2.9 (m,1H), 3.2 (m,1H), 3.8 (s, 2H+m,1H), 4.15 (q,2H), 4.3 (m,1H); m/e 278/280 (M+H)+.
Reaction SMILES: C(OC(=O)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2[CH:23]=[CH:22][N:21]=[C:20](Cl)[N:19]=2)[CH:13]=1)[CH:8]([CH3:10])[CH3:9])(C)(C)C.Br.[NH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[C:31]([Cl:36])[CH:30]=1>>[Cl:36][C:31]1[CH:30]=[C:29]([CH2:28][NH:27][C:20]2[N:19]=[C:18]([C:14]3[CH:15]=[CH:16][CH:17]=[C:12]([CH2:11][NH:7][CH:8]([CH3:9])[CH3:10])[CH:13]=3)[CH:23]=[CH:22][N:21]=2)[CH:34]=[CH:33][C:32]=1[OH:35]
Reactant: NCc1ccc(O)c(Cl)c1
Reactant: CC(C)N(Cc1cccc(-c2ccnc(Cl)n2)c1)C(=O)OC(C)(C)C
Agent: Br
Product: CC(C)NCc1cccc(-c2ccnc(NCc3ccc(O)c(Cl)c3)n2)c1

Procedure:
[3-(2-Chloro-pyrimidin-4-yl)-benzyl]-isopropyl-carbamic acid tert-butyl ester (intermediate 70) was coupled with 4-Aminomethyl-2-chloro-phenol hydrobromide salt (Intermediate 121) following procedure F then deprotected by procedure G. LC-MS showed the product had the expected M+H+ of 383. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.31 ppm) δ 8.5 (s, 1H) 8.4 (d, 1H) 8.3 (d, 1H) 7.8 (d, 1H) 7.7 (m, 1H) 7.6 (d, 1H) 7.4 (s, 1H) 7.2 (d, 1H) 6.9 (d, 1H) 4.3 (s, 1H) 3.6 (m, 2H) 3.5 (m, 1H) 1.4 (d, 6H)
Reaction SMILES: O[C@@H:2]1[CH2:22][C:21]2[C@:16]([CH3:24])([CH:17]=[CH:18][C:19](=[O:23])[CH:20]=2)[C@@H:15]2[C@@H:3]1[C@H:4]1[C@:12]([CH3:25])([CH2:13][CH2:14]2)[C@@H:7]([CH:8]([CH:10]=O)[CH3:9])[CH2:6][CH2:5]1.[CH3:26][C:27]([CH3:32])([CH2:30][OH:31])[CH2:28][OH:29].O>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:26][C:27]1([CH3:32])[CH2:30][O:31][CH:10]([CH:8]([C@@H:7]2[C@:12]3([CH3:25])[C@H:4]([C@H:3]4[C@H:15]([CH2:14][CH2:13]3)[C@:16]3([CH3:24])[C:21](=[CH:20][C:19](=[O:23])[CH:18]=[CH:17]3)[CH:22]=[CH:2]4)[CH2:5][CH2:6]2)[CH3:9])[O:29][CH2:28]1
Reactant: CC(C=O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Yield: 30.7 %

Procedure:
In 200 ml of benzene were dissolved 5.00 g (14.6 moles) of 7α-hydroxypregna-1,4-dien-3-one-20-carbaldehyde and 4.56 g (43.8 mmoles) of 2,2-dimethyl-1,3-propanediol, followed by addition of 100 mg of p-toluenesulfonic acid. The mixture was refluxed for 5 hours, with the byproduct water being constantly removed from the reaction system by means of a Dean-Stark trap. The reaction mixture was cooled to room temperature and washed with aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted with ether-hexane (70:30, v/v) and the extract was combined with the organic layer. This mixture was washed with aqueous sodium chloride solution and dried over magnesium sulfate and the solvent was distilled off under reduced pressure. Finally the residue was purified by silica gel chromatography (eleuent: ethyl acetate-hexane=1:10, v/v) to recover 5.53 g of 20-(5,5-dimethyl-1,3 -dioxan-2-yl)pregna-1,4,6-trien-3-one (yield: 92%).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[C:13]1([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:23][CH2:22]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.IC>C1COCC1>[C:13]1([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][C:24]([CH3:1])([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:23][CH2:22]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)NC(C)C
Reactant: CCOC(=O)C1CCN(CCc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C1(C)CCN(CCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.6 %

Procedure:
To 2.64 mL (18.9 mmol) of diisopropylamine in 30 mL of dry THF at -78° was added 6.9 mL (17.3 mmol) of 2.5 M n-butyllithium in hexanes. The mixture was allowed to warm to room temperature and then was cooled once again to -78°. To the stirred solution was added 4.11 g (15.7 mmol) of 1-(2-phenylethyl)-4-carboethoxypiperidine in 25 mL of dry THF. The mixture was allowed to warm to -40° and 0.98 mL (15.7 mmol) of iodomethane was added to the reaction mixture. The mixture was stirred at -40° for 15 minutes and then allowed to stir at room temperature for 3 hours. The mixture was evaporated to dryness and the residue was dissolved in water. The aqueous solution was extracted with methylene chloride and the extracts were dried and evaporated to give 3.70 g of 1-(2-phenylethyl)-4-methyl-4-carboethoxypiperidine as a yellow oil. NMR (CDCl3) δ7.15-7.21 (m, 5H); 4.11-4.20 (q, 4H); 2.71-2.94 (m, 4H): 2.52-2.61 (m, 2H): 2.11-2.24 (m, 4H); 1.47-1.59 (m, 2H); 1.21-1.30 (t, 3H); 1.20 (s, 3H).
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH2:11])[N:3]=1.[CH2:12]([O:19][C@H:20]1[C@H:36]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C@@H:35]([CH2:45][O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[O:34][CH:21]1OC(=O)C1C=CC([N+]([O-])=O)=CC=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:12]([O:19][C@H:20]1[C@H:36]([O:37][CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C@@H:35]([CH2:45][O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[O:34][C@H:21]1[N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([F:1])=[N:3][C:4]=2[NH2:11])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1nc(F)nc2nc[nH]c12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(F)nc2c1ncn2[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 21.5 %

Procedure:
A mixture of 2-fluoroadenine (0.50 g), 2,3,5-tri-O-benzyl-1-α-D-arabinofuranosyl chloride (freshly prepared from 2.22 g of 2,3,5-Tri-O-benzyl-1-O-p-nitrobenzoyl-D-arabinofuranose) and N,N-diisopropylethylamine (0.56 mL) in anhydrous N,N-dimethylformamide (10 mL) was stirred at ambient temperature for 3 days under a nitrogen atmosphere. The mixture was then concentrated under high vacuum and the residue was partitioned between dichloromethane (200 mL) and water (25 mL). The organic phase was washed sequentially with saturated NaCl (50 mL), 1M H3PO4 (50 mL) and saturated NaCl (25 mL), and was then dried over MgSO4 and decolorizing carbon. The dried solution was filtered and concentrated under vacuum. The residue was purified by silica gel chromotography with 1% methanol in dichloromethane as eluant. The appropriate fractions were combined and recrystalized from ethanol/toluene to obtain 0.39 g of the title compound. This material was identical by IR and TLC with an authentic sample.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]([C:10]([OH:12])=[O:11])[C:7]([OH:9])=[O:8])=[CH:2]1.[CH2:13](O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].CS(O)(=O)=O.C(Cl)Cl>C1COCC1>[S:1]1[CH:5]=[CH:4][C:3]([CH:6]([C:7]([O:9][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13])=[O:8])[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:11])=[CH:2]1
Reactant: O=C(O)C(C(=O)O)c1ccsc1
Reactant: CCCCCCCCCCCCO
Agent: CS(=O)(=O)O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCCCCCCCCCOC(=O)C(C(=O)OCCCCCCCCCCCC)c1ccsc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 64.1 %

Procedure:
In a one-necked flask, 3-thienylmalonic acid (10.0 g, 53.7 mmol) and 1-dodecanol (4 eq., 40.0 g, 215 mmol) were dissolved in THF (80 mL) at room temperature. To this solution was added methanesulphonic acid (1.99 g, 20.7 mmol). The reaction mixture was stirred at room temperature for 3 days. The solvent was then evaporated at 40° C. The residue was re-dissolved in CH2Cl2 to form a solution, which was loaded onto a column (eluent: CH2Cl2) to give didodecyl 2-(thiophen-3-yl)malonate (yield: 18.0 g, 69%). 1H NMR (CDCl3): 0.9 (6H, t), 1.3 (36H, m), 1.7 (4H, m), 4.2 (4H, t), 4.8 (1H, s), 7.2 (1H, d), 7.3 (1H, d), 7.4 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[NH2:19])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH3:15])[CH:9]=1)=[O:6].[CH3:20][O:21][C:22](=[O:35])[CH2:23][CH2:24][C:25]1[CH:30]=[C:29]([CH3:31])[C:28]([CH:32]=O)=[C:27]([CH3:34])[CH:26]=1>>[CH3:20][O:21][C:22](=[O:35])[CH2:23][CH2:24][C:25]1[CH:30]=[C:29]([CH3:31])[C:28]([C:32]2[NH:1][C:2]3[CH:3]=[C:4]([C:5](=[O:6])[NH:7][C:8]4[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH3:15])[CH:9]=4)[CH:16]=[CH:17][C:18]=3[N:19]=2)=[C:27]([CH3:34])[CH:26]=1
Reactant: COC(=O)CCc1cc(C)c(C=O)c(C)c1
Reactant: Cc1ccc(NC(=O)c2ccc(N)c(N)c2)cc1C
Product: COC(=O)CCc1cc(C)c(-c2nc3ccc(C(=O)Nc4ccc(C)c(C)c4)cc3[nH]2)c(C)c1

Procedure:
The title compound was prepared from 3,4-diamino-N-(3,4-dimethylphenyl)-benzamide and 3-(4-formyl-3,5-dimethylphenyl)-propionic acid methyl ester (from Example 6-17) analogous to Example 6-1. 1H NMR (Methanol-d4, 400 MHz): δ 8.32 (d, 1H), 7.91 (d, 1H), 7.79 (dd, 1H), 7.48 (s, 1H), 7.45 (dd, 1H), 7.15 (d, 1H), 7.08 (s, 2H), 3.67 (s, 3H), 2.97 (t, 2H), 2.71 (t, 2H), 2.30 (s, 3H), 2.27 (s, 3H), 2.15 (s, 6H). MS (m/z) 456.1 (M+1); Retention time: 1.44 min (Method 10).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:23][CH2:24][CH2:25][O:26][CH3:27])[CH:5]=[C:6]2[C:10]=1[N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:7]2.C(O[C:31]1(O[Si](C)(C)C)[CH2:33][CH2:32]1)C.C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[CH:31]1([NH:1][C:2]2[CH:3]=[C:4]([O:23][CH2:24][CH2:25][O:26][CH3:27])[CH:5]=[C:6]3[C:10]=2[N:9]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[CH:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:7]3)[CH2:33][CH2:32]1
Reactant: CCOC(=O)C1Cc2cc(OCCOC)cc(N)c2N1C(=O)OC(C)(C)C
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C1Cc2cc(OCCOC)cc(NC3CC3)c2N1C(=O)OC(C)(C)C
Yield: 75 %

Procedure:
To a mixture of 1-tert-butyl 2-ethyl 7-amino-5-(2-methoxyethoxy)indoline-1,2-dicarboxylate (2.76 g), [(1-ethoxycyclopropyl)oxy](trimethyl)silane (7.29 mL), acetic acid (4.19 mL) and ethanol (70 mL) was added sodium cyanoborohydride (122 mg), and the mixture was refluxed for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate and water. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give the title compound (2.30 g, yield 75%) as a pale-yellow oil from a fraction eluted with ethyl acetate-hexane (4:1, volume ratio).
Reaction SMILES: [F:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:6][C:5]([NH2:15])=[C:4]([N+:16]([O-])=O)[CH:3]=1.[H][H]>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([NH2:15])=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1
Reactant: CN1CCN(c2cc(N)c([N+](=O)[O-])cc2F)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN1CCN(c2cc(N)c(N)cc2F)CC1
Yield: 100 %

Procedure:
21.2 g of 4-fluoro-5-(4-methylpiperazin-1-yl)-2-nitrophenylamine in solution in 800 mL of methanol are hydrogenated under 1 bar of hydrogen pressure in the presence of 2.1 g of palladium-on-charcoal at 25° C. for 16 hours. The reaction crude is filtered through celite and the filtrate is concentrated under vacuum in a rotary evaporator. 18.7 g of 4-fluoro-5-(4-methylpiperazin-1-yl)benzene-1,2-diamine in the form of a black oil are isolated. 1H NMR (400 MHz, DMSO-d6, δ in ppm), for this batch, all the signals are broad with: 2.19 (s, 3H); 2.40 (m, 4H); 2.79 (m, 4H); 4.22 (s, 2H); 4.31 (s, 2H); from 6.24 to 6.33 (m, 2H). EI mass spectrum: m/z=224: M+. (base peak)—m/z=209: (M—CH3)+—m/z=153: (M−C4H9N)+—m/z=70: C4H8N+—m/z=43: C2H5N+.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl[N:11]1[CH2:20][CH:19]=[CH:18][C:17]2[N:16]=[CH:15][C:14]([N+:21]([O-:23])=[O:22])=[CH:13][C:12]1=2.[NH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31]>ClCCl.NCCNC(=O)OC(C)(C)C>[N+:21]([C:14]1[CH:15]=[N:16][C:17]2[C:12]([C:13]=1[NH:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[N:11][CH:20]=[CH:19][CH:18]=2)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1cnc2c(c1)N(Cl)CC=C2
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCNc1c([N+](=O)[O-])cnc2cccnc12
Temperature: 25 °C
Yield: 86.5 %

Procedure:
A solution of diisopropylethylamine (13.47 g, 0.10 mole) in dichloromethane (25 mL) was added to a solution of 5-chloro-3-nitro[1,5]naphthyridine (18.2 g, 0.086 mol) in dichloromethane (250 mL). A solution of tert-butyl N-(2-aminoethyl)carbamate (16.7 g, 0.10 mol) in dichloromethane (75 mL) was slowly added to the reaction mixture. The reaction mixture was heated at reflux overnight. Additional tert-butyl N-(2-aminoethyl)carbamate (1 g) was added and the reaction mixture was heated at reflux for an additional 3 hours. The reaction mixture was allowed to cool to ambient temperature and then it was diluted with additional dichloromethane, washed with water and with brine, dried, and then concentrated under vacuum to provide a dark solid. This solid was purified by flash chromatography (silica gel eluting with dichloromethane) to provide 24.8 g of 1,1-dimethylethyl N-{2-[(3-nitro[1,5]naphthyridin-4-yl)amino]ethyl}carbamate as a canary yellow solid. A portion (0.3 g) was recrystallized from toluene (10 mL) and heptane (10 mL) to provide 0.2 g of canary yellow needles, m.p. 149-151° C. Analysis: Calculated for C15H19N5O4: %C, 54.05; %H, 5.75; %N, 21.01. Found: %C, 54.17; %H, 5.73; %N, 20.90.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:16]2[N:15]=[C:14]([NH2:17])[N:13]3[N:18]=[C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:12]3[C:11]=2[CH:10]=[CH:9]1)(=O)=O.Cl.[F:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[N:35]1[CH2:36][CH2:37][N:38]([CH2:6][CH2:7][N:8]2[C:16]3[N:15]=[C:14]([NH2:17])[N:13]4[N:18]=[C:19]([C:21]5[O:22][CH:23]=[CH:24][CH:25]=5)[N:20]=[C:12]4[C:11]=3[CH:10]=[CH:9]2)[CH2:39][CH2:40]1
Reactant: CS(=O)(=O)OCCn1ccc2c1nc(N)n1nc(-c3ccco3)nc21
Reactant: Fc1ccc(F)c(N2CCNCC2)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1nc2c(ccn2CCN2CCN(c3cc(F)ccc3F)CC2)c2nc(-c3ccco3)nn12
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of the title D compound, 2-{5-amino-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl}ethyl methanesulfonate (0.06 g, 0.165 mmol) in dry DMF (5 mL), the title E compound, 1-(2,5-difluorophenyl)piperazine hydrochloride (0.33 mmol) and 0.06 mL of DIEA are added and the solution is stirred at 100° C. for 5 h. The reaction mixture is cooled to RT, and the solvent is removed under reduced pressure. To the residue, acetonitrile is added and the solution is stirred at 60° C. for 0.5 h. The solution is then cooled to RT, and the resulting solids are collected by filtration to give 7-(2-(4-(2,5-difluorophenyl)piperazin-1-yl)ethyl)-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine: LC/MS (M+1=465.2). 1H NMR (DMSO-d6, 400 MHz) δ 2.64 (m, 4H), 2.76 (t, 2H, J=64 Hz), 3.01 (m, 4H), 4.28 (t, 2H, J=6.4 Hz), 6.60 (d, 1H, J=3.2 Hz), 6.72 (m, 1H), 6.75 (m, 1H), 6.80-6.85 (m, 1H), 7.12 (m, 1H), 7.18 (m, 2H), 7.51 (br s, 2H), 7.91 (s, 1H). Anal. calculated for (C23H22F2N8O): C, 59.48; H, 4.77; F, 8.18; N, 24.12; O, 3.44. Found C, 59.45; H, 4.70; N, 24.19.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:15]3[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=[C:9]([NH:16][C:17](=[O:25])OC3C=CC=CC=3)[CH:8]=2)[CH:2]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][C:36]=1[C:37]([F:40])([F:39])[F:38])[NH:33][CH2:32][CH2:31]2>CN(C=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:15]3[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=[C:9]([NH:16][C:17]([N:33]3[C:34]4[C:30](=[CH:29][C:28]([O:27][CH3:26])=[C:36]([C:37]([F:39])([F:40])[F:38])[CH:35]=4)[CH2:31][CH2:32]3)=[O:25])[CH:8]=2)[CH:2]=1
Reactant: O=C(Nc1cc2c(c(-c3cccnc3)c1)OCC2)Oc1ccccc1
Reactant: COc1cc2c(cc1C(F)(F)F)NCC2
Solvent: CN(C)C=O
Product: COc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1cc3c(c(-c4cccnc4)c1)OCC3)CC2
Temperature: 25 °C
Yield: 25.6 %

Procedure:
Phenyl N-[2,3-dihydro-7-(pyrid-3-yl)benzofuran-5-yl]carbamate (D65) (0.20 g, 0.00060mole) in dry DMF (10 ml) was treated under argon with 5-methoxy-6 trifluoromethyl indoline (D11) (0.13 g, 0.00060 mole) and heated under reflux for 18 hours. The reaction was allowed to cool to ambient temperature and the solvent was removed in vacuo. The residue was dissolved in dichloromethane, washed with deionised water and 10% sodium hydroxide solution, dried (Na2SO4) and evaporated in vacuo. The resulting brown oil was purified by flash column chromatography on silica gel, eluting with 2% methanol/dichloromethane, followed by recrystallisation from ethyl acetate 60-80° petroleum ether to afford the title compound (0.07 g, 26%) as a beige solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[CH:4][CH:3]=1.Br[CH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1>>[CH3:30][O:29][C:27](=[O:28])[C:26]1[CH:31]=[CH:32][C:23]([CH2:22][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:14][CH2:13][CH2:12][C@H:11]3[CH2:15][N:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)=[O:9])=[CH:4][CH:3]=2)=[CH:24][CH:25]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: O=C(c1ccc(O)cc1)N1CCC[C@H]1CN1CCCC1
Product: COC(=O)c1ccc(COc2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)cc1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure B using (4-Hydroxy-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and methyl 4-(bromomethyl)benzoate. MS (ES+) 423.3
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([OH:7])=O)[CH3:2].[CH3:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[N:16]=[C:17]=[S:18].C(N(CC)CC)C>C(Cl)Cl>[CH3:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([CH3:8])[C:10]=1[N:16]1[C:5](=[O:7])[CH2:4][N:3]([CH2:1][CH3:2])[C:17]1=[S:18]
Reactant: CCNCC(=O)O
Reactant: Cc1cccc(C)c1N=C=S
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN1CC(=O)N(c2c(C)cccc2C)C1=S
Yield: 18.4 %

Procedure:
The title compound was prepared by the procedure described in Example 19 using 9.2 g of N-ethyl glycine, 8.2 g of 2,6-dimethylphenyl-isothiocyanate, 10.1 g of triethylamine, and 150 mL of methylene chloride. Purification was achieved through crystallization from ethanol. Title compound (2.3 g) was obtained as a white solid (2.3 g). m.p. 128°-131° C. Anal. Calcd. for. C13H16N2O S: C, 62.87; H, 6.49; N, 11.28. Found: C, 62.83; H, 6.50; N, 11.25. Mass spectrum (EI, M.+) m/z 248.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Na+].CO[C:16]1[C:21]([CH3:22])=[CH:20][C:19]([N+:23]([O-:25])=[O:24])=[CH:18][C:17]=1[CH3:26].Cl>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:16]2[C:17]([CH3:26])=[CH:18][C:19]([N+:23]([O-:25])=[O:24])=[CH:20][C:21]=2[CH3:22])[C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1c(C)cc([N+](=O)[O-])cc1C
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])cc(C)c1C(C#N)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Yield: 86.9 %

Procedure:
A mixture of (3,4-dichlorophenyl)acetonitrile (0.149 mol) in DMF (100 ml) was stirred at 0° C. under N2 flow. Sodium hydride (0.223 mol) was added portionwise. The mixture was stirred at 0° C. under N2 flow for 1 hour. A mixture of, 2-methoxy-1,3-dimethyl-5-nitrobenzene (0.149 mol) in DMF (100 ml) was added dropwise at 0° C. under N2 flow. The mixture was stirred at RT for 6 hours, then cooled, hydrolized with H2O and with HCl 3N and extracted with EtOAc. The organic layer was separated, washed several times with H2O, dried, filtered and the solvent was evaporated. The residue was crystallized from DIPE. The precipitate was filtered off and dried, yielding 43.4 g (87%) of (±)-α-(3,4-dichlorophenyl)-2,6-dimethyl-4-nitrobenzeneacetonitrile (interm. 48).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9]([C:12]3[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][CH:13]=3)=[N:10][NH:11][C:7]=2[CH:6]=[CH:5][N:4]=1.[H-].[Na+].CC1C=CC(S(O[CH:35]2[CH2:40][CH2:39][CH:38]([O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])[CH2:37][CH2:36]2)(=O)=O)=CC=1>CN(C=O)C>[Si:42]([O:41][CH:38]1[CH2:37][CH2:36][CH:35]([N:11]2[C:7]3[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[C:8]=3[C:9]([C:12]3[CH:13]=[CH:14][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:16][CH:17]=3)=[N:10]2)[CH2:40][CH2:39]1)([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43]
Reactant: Cc1ccc(S(=O)(=O)OC2CCC(O[Si](C)(C)C(C)(C)C)CC2)cc1
Reactant: COc1nccc2[nH]nc(-c3ccc(S(N)(=O)=O)cc3)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)nn2C1CCC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.2 %

Procedure:
To a solution of 4-(4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)benzenesulfonamide (50.0 mg) obtained in Step A of Example 100 in DMF (2 mL) was added sodium hydride (60% dispersion in mineral oil, 7.89 mg), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added 4-((tert-butyl(dimethyl)silyl)oxy)cyclohexyl 4-methylbenzenesulfonate (76.0 mg), and the mixture was stirred overnight at room temperature. The reaction mixture was extracted with water and ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (52.8 mg).