Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=1[N+:25]([O-:27])=[O:26])[O:18][CH2:19][CH2:20]Br>C1(C)C=CC=CC=1>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:20][CH2:19][O:18][C:17]2[CH:22]=[CH:23][C:24]([N+:25]([O-:27])=[O:26])=[C:15]([OH:14])[CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(OCCBr)cc1O
Reactant: c1ccc(CC2CCNCC2)cc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(OCCN2CCC(Cc3ccccc3)CC2)cc1O
Yield: 93110 %

Procedure:
From a mixture of 4-benzylpiperidine (820 mg, 4.68 mmol), 2-(3-hydroxy-4-nitrophenoxy)ethyl bromide (556 g, 2.26 mmol) and KI (180 mg) in toluene (25 mL) was obtained 750 g (97%) of 4-benzyl-1-(2-(3-hydroxy-4-nitrophenoxy)ethyl)piperidine as a yellow powder, mp. 136-7° C. 1H NMR (CDCl3): 1.28-1.40 (m, 2H), 1.50-1.68 (m, 1H), 2.02-2.10 (m, 2H), 2.545 (d, 2H, J=7), 2.792 (t, 2H, J=6), 2.93-2.97 (m, 2H), 4.151 (t, 2H, J=6), 6.50-6.53 (m, 2H), 7.13-7.31 (m, 5H), 8.027 (d, 1H, J=10).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][C:11](O)=[CH:12][CH:13]=2)[N:5]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:3]=1[Cl:19].[Cl:20]P(Cl)C1C=CC=CC=1>>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][C:11]([Cl:20])=[CH:12][CH:13]=2)[N:5]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:3]=1[Cl:19]
Reactant: COC(=O)c1nc(-c2ccc(O)nc2)cc(N)c1Cl
Reactant: ClP(Cl)c1ccccc1
Product: COC(=O)c1nc(-c2ccc(Cl)nc2)cc(N)c1Cl
Temperature: 50 °C
Yield: 34.6 %

Procedure:
Methyl 4-amino-3-chloro-6-(6-hydroxy-3-pyridinyl)pyridine-2-carboxylate (0.30 g, 1.07 mmol) was suspended in neat dichlorophenylphosphine (2.5 mL, 1.84 mmol) and the mixture was heated to 50° C. for 1 hr. The volatiles were removed in vacuo and the residue purified by column chromatography (1:1, Hexanes/EtOAc) to give of methyl 4-amino-3-chloro-6-(6-chloro-3-pyridinyl)pyridine-2-carboxylate (0.11 g, 0.37 mmol).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[CH2:21]([N:23]([CH2:38][CH3:39])[CH2:24][CH2:25][NH:26][C:27]([C:29]1[C:33]([CH3:34])=[C:32]([CH:35]=O)[NH:31][C:30]=1[CH3:37])=[O:28])[CH3:22]>C(O)C.N1CCCCC1>[CH2:38]([N:23]([CH2:21][CH3:22])[CH2:24][CH2:25][NH:26][C:27]([C:29]1[C:33]([CH3:34])=[C:32]([CH:35]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:19])[F:20])[CH:4]=3)[NH:13][C:12]2=[O:18])[NH:31][C:30]=1[CH3:37])=[O:28])[CH3:39]
Reactant: O=C1Cc2c(cccc2-c2cccc(C(F)(F)F)c2)N1
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(C(F)(F)F)c4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 51.9 %

Procedure:
To a solution of 4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (69.3 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (69.0 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide 2,4-dimethyl-5-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (68 mg, 52%).
Reaction SMILES: F[C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].[CH:24]1([CH2:29][NH2:30])[CH2:28][CH2:27][CH2:26][CH2:25]1>CCO>[CH:24]1([CH2:29][NH:30][C:2]2[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH2:9][C:10]([F:12])([F:13])[F:11])[CH2:14][C:15]([F:17])([F:18])[F:16])=[O:7])=[CH:4][C:3]=2[N+:21]([O-:23])=[O:22])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: NCC1CCCC1
Reactant: O=C(c1ccc(F)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F
Solvent: CCO
Product: O=C(c1ccc(NCC2CCCC2)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F

Procedure:
Following the general procedure for Intermediate 2 using 4-fluoro-3-nitro-N,N-bis(2,2,2-trifluoroethyl)benzamide (122 mg, 0.350 mmol) and cyclopentylmethyl amine (42 mg, 0.420 mmol) in 3 mL of EtOH containing TEA (0.075 mL, 0.525 mmol). The product was purified by flash chromatography on silica gel using 3:1/hexanes:EtOAc as eluent. Yield: 141 mg (94%); 1H NMR (400 MHz, CHLOROFORM-D) δ 1.30 (m, 2H), 1.64 (m, 4H), 1.89 (m, 2H), 2.26 (m, 1H), 3.24 (dd, J=7.23, 5.04 Hz, 2H), 4.23 (q, J=8.42 Hz, 4H), 6.91 (d, J=8.97 Hz, 1H), 7.50 (dd, J=8.97, 2.20 Hz, 1H), 8.26 (d, J=2.20 Hz, 1H), 8.33 (s, 1H); MS (ESI) 427.82 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](O)=[C:14]([C:19]#[N:20])[CH:15]=[N:16]2)=[CH:11][C:10]=1[O:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:27])=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:27])=[C:14]([C:19]#[N:20])[CH:15]=[N:16]2)=[CH:11][C:10]=1[O:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(O)c(C#N)cnc2cc1OCc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)c(C#N)cnc2cc1OCc1ccccc1

Procedure:
To a stirred suspension of 1 g of 7-benzyloxy-4-hydroxy-6-methoxy-quinoline-3-carbonitrile in 10 ml of methylene chloride was added 5 ml of oxalyl chloride (2M in methylene chloride), and 2 drops of N,N-dimethylformamide. The mixture was refluxed for 20 min and to it was slowly added aqueous sodium bicarbonate until the bubbling ceased. Following separation of the layers, the organic layer was evaporated to a small volume, then passed through a plug of magnesol. Elution with 50 ml methylene chloride, followed by evaporation provided 0.6 g of 7-benzyloxy-4-chloro-6-methoxy-quinoline-3-carbonitrile as a pale yellow solid, mp 282-284° C.; mass spectrum (electrospray, m/e) M+H 325.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Li]CCCC.C(NC(C)C)(C)C.[CH3:21][S:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[N:37][OH:38])[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:25][CH:24]=1.[Br:39][C:40]([F:47])([F:46])[C:41](OCC)=O>C1COCC1.Cl>[Br:39][C:40]([F:47])([F:46])[C:41]1[O:38][N:37]=[C:29]([C:26]2[CH:25]=[CH:24][C:23]([S:22][CH3:21])=[CH:28][CH:27]=2)[C:30]=1[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CCOC(=O)C(F)(F)Br
Reactant: CSc1ccc(C(Cc2ccccc2)=NO)cc1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CSc1ccc(-c2noc(C(F)(F)Br)c2-c2ccccc2)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 11.9 %

Procedure:
Lithium diisopropylamide, prepared from n-BuLi (2. 5 mmol) and diisopropylamine (2.5 mmol), was added dropwise to a solution of 1-(4-methylsulfanylphenyl)-2-phenylethanone oxime (5) (257 mg, 1 mmol) in dry THF (25 mL) at −20° C. The reaction mixture was stirred at −20° C. for 1 h and then allowed to warm to room temperature for 1 h. The reaction mixture was cooled to −78° C. and ethyl bromodifluoroacetate (153 μL, 1.2 mmol) was added in one portion. After 5 h at −78° C., the reaction mixture was allowed to warm to room temperature, diluted with 1M HCl (10 mL) and extracted with CH2Cl2. The organic extracts were dried over anhydrous MgSO4, filtered and concentrated to dryness. The yellow residue was then treated with concentrated H2SO4 (25 mL) at 0° C. overnight. The reaction mixture was poured over ice-cold H2O and extracted with CH2Cl2. The organic extracts were dried over anhydrous MgSO4, filtered and concentrated. Purification by flash column chromatography with hexanes-EtOAc (4:1) yielded 6 (47 mg, 12%) as a colorless syrup: 1H NMR (CDCl3) δ 2.52 (3H, s, SMe), 7.23-7.50 (9H, m, Ar). HRMS (FAB) Calculated for C17H13BrF2NOS (MH+, 395.9865). Found: 395.9861.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].CI.CS(C)=O.Br.[Br:14][C:15]1[CH:16]=[N:17][C:18](O)=[N:19][CH:20]=1>O>[Br:14][C:15]1[CH:20]=[N:19][C:1](=[O:4])[N:17]([CH3:18])[CH:16]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ncc(Br)cn1
Agent: Br
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CI
Product: Cn1cc(Br)cnc1=O
Temperature: 15 °C
Reaction time: 16 h
Yield: 45.1 %

Procedure:
With cooling with ice, potassium carbonate (7.56 g, 54.7 mmol) and methyl iodide (1.27 ml, 20.3 mmol) were added to a dimethyl sulfoxide (100 mL) solution of 5-bromo-2-hydroxypyrimidine hydrobromide (4.0 g, 15.6 mmol), and stirred at 15° C. for 16 hours. Water was added to the reaction mixture, and extracted three times with ethyl acetate. The organic layer was washed with saturated brine, dried with anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was suspended in ethyl acetate, then filtered and dried to obtain the entitled compound (1.33 g, 45%).
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].C([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[N:18][C:19]([N:29]3[CH2:34][CH2:33][CH:32]([O:35][C:36]4[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=4[F:43])[CH2:31][CH2:30]3)=[C:20]([NH:25][CH:26]([CH3:28])[CH3:27])[N:21]=2)[CH2:16]1)C1C=CC=CC=1>C1COCC1.CO.[OH-].[OH-].[Pd+2]>[F:43][C:37]1[CH:38]=[C:39]([F:42])[CH:40]=[CH:41][C:36]=1[O:35][CH:32]1[CH2:31][CH2:30][N:29]([C:19]2[N:18]=[C:17]3[CH2:16][NH:15][CH2:24][CH2:23][C:22]3=[N:21][C:20]=2[NH:25][CH:26]([CH3:28])[CH3:27])[CH2:34][CH2:33]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CN(Cc1ccccc1)CC2
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CNCC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 6-benzyl-3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (73.0 mg, 0.120 mmol) and Pd(OH)2 on carbon (20 wt %, 7 mg, 9.97 μmol) in THF (601 μL) was stirred at rt under an atmosphere of hydrogen (balloon). After 3 h, the mixture was diluted with MeOH, filtered through a pad of Celite™, washing with MeOH, and concentrated to afford the title compound as its TFA salt (62.3 mg, 100%) as a yellow oil, which was used without further purification. ESI-MS m/z [M+H]+ 404.3.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+].Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Br)cnc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cc(Br)cnc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.8 %

Procedure:
To a solution of methyl 5-bromo-2-fluoronicotinate (90 mg, 0.38 mmol) in 2 mL of THF was added 1N NaOH (1.0 mL, 1.0 mmol) at room temperature. The reaction was stirred at room temperature for 2 h before it was neutralized by 1.0 mL of 1N HCl. The solution was then concentrated under reduced pressure and the residue was purified on preparative (RP) HPLC to provide 5-Bromo-2-fluoronicotinic acid (55 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[C:7](=[C:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:6]=2[CH:22]=1.[CH3:23][N:24](CCI)[C:25](C1C=CC=CC=1)(C1C=CC=CC=1)[C:26]1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C(C)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[C:7](=[C:16]3[CH2:17][CH2:18][N:19]([CH2:26][CH2:25][NH:24][CH3:23])[CH2:20][CH2:21]3)[C:6]=2[CH:22]=1
Reactant: Fc1ccc2c(c1)C(=C1CCNCC1)c1ccccc1CC2
Reactant: CN(CCI)C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CNCCN1CCC(=C2c3ccccc3CCc3ccc(F)cc32)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 4-(10,11-dihydro-3-fluoro-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine (5 g; 0.017 mol) and 2-[N-methyl-N-(triphenylmethyl)amino]ethyl iodide (7.3 g; 0.017 mol) in 30 ml of methyl isobutyl ketone (MiBk) is heated to the refluxing temperature. Potassium carbonate (4.7 g; 0.034 mol) is added in a single portion at this temperature, and the mixture is then heated to the refluxing temperature under an argon atmosphere for 10 h. The mixture is cooled, filtered and evaporated to dryness. The residual oil is then taken up with methylene chloride and the mixture is washed with water and with saline, dried over magnesium sulphate and then evaporated to dryness. 100 ml of 1N hydrochloric acid are added to the oil obtained, and the mixture is then stirred for 5 hours at room temperature. The tritylmethanol is separated off by filtration, the mother liquors are neutralized with 2N aqueous sodium hydroxide, the product is extracted using methylene chloride and the extract is dried over magnesium sulphate and evaporated. The oil obtained is used without further purification in the following stage.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[C:13]1[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][CH3:21])[CH2:17][CH:18]=1>CCOC(C)=O.CO>[CH3:1][C:2]1[C:3]([CH:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][CH3:21])[CH2:17][CH2:18]2)=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:7]=1)[NH2:8]
Reactant: CCCN1CC=C(c2cc(OC)c([N+](=O)[O-])cc2C)CC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCN1CCC(c2cc(OC)c(N)cc2C)CC1
Reaction time: 8 h
Yield: 91.3 %

Procedure:
4-[2-Methyl-5-(methyloxy)-4-nitrophenyl]-1-propyl-1,2,3,6-tetrahydropyridine (0.7 g, 2.41 mmol) was place in a 250 mL high pressure vessel and dissolved in 60 mL of 1 to 1 EtOAc/MeOH. 5 wt % Platinum(sulfided)/carbon (0.256 g, 0.12 mmol) was added followed quickly by a rubber septum. The flask was evacuated and filled with N2 six times to remove any oxygen. The vessel was then pressurized with H2 (60 psi). The solution stirred overnight. The next morning the vessel was evacuated and filled with N2 six times to remove any H2. The solution was filtered through celite and evaporated to give the title compound of step D (0.577 g, 2.2 mmol, 91%). 1H NMR (400 MHz, DMSO-d6) δ ppm 6.57 (s, 1H), 6.37 (s, 1H), 4.37 (bs, 2H), 3.69 (s, 3H), 2.88-2.98 (m, 2H), 2.43-2.52 (m, 1H), 2.19-2.29 (m, 2H), 2.06 (s, 3H), 1.91-2.01 (m, 2H), 1.53-1.64 (m, 4H), 1.38-1.48 (m, 2H), 0.84 (t, J=7.42 Hz, 3H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]([CH3:31])[N:21]=3)[N:18]=2)[N:13](COCC[Si](C)(C)C)[CH:12]=1)=[O:10].C(O)(C(F)(F)F)=O>ClCCl>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]([CH3:31])[N:21]=3)[N:18]=2)[NH:13][CH:12]=1)=[O:10]
Reactant: COc1ccc2c(c1)c(-c1cnc3c(n1)c(C(=O)N[C@@H]1CCCC[C@@H]1N)cn3COCC[Si](C)(C)C)nn2C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)c(-c1cnc3[nH]cc(C(=O)N[C@@H]4CCCC[C@@H]4N)c3n1)nn2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
To a pale yellow solution of N-((1R,2S)-2-aminocyclohexyl)-2-(5-methoxy-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (21 mg, 38.2 μmol) in dichloromethane (3.00 mL) was added TFA (1.48 g, 1.00 mL, 13.0 mmol, Eq: 340), the reaction mixture turned dark red and was stirred at 25° C. overnight then concentrated. The residue was re-dissolved in 5 mL of a solution of (dichloromethane/MeOH/ammonium hydroxide; 60:10:1) and stirred at 25° C. for 3 h, then evaporated to a light yellow solid, dissolved in dichloromethane (added few drops MeOH and heating) and purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 10% over 15 min (MeOH containing 10% ammonium hydroxide)/dichloromethane. The pure product dissolved in hot MeOH and allowed to stand overnight for solid formation. The solid was separated by decantation and dried under high vacuum to give N-((1R,2S)-2-aminocyclohexyl)-2-(5-methoxy-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (9 mg, 21.5 μmol, 56.2%) as a white solid. MS (M+H)+=420 (100% purity); 1H NMR (DMSO-d6) δ: 9.02 (s, 1H), 8.34-8.45 (m, 2H), 8.07 (d, J=2.3 Hz, 1H), 7.69 (d, J=9.4 Hz, 1H), 7.29 (dd, J=9.3, 2.5 Hz, 1H), 4.14 (s, 3H), 4.01-4.10 (m, 1H), 3.88 (s, 3H), 3.05 (d, J=3.8 Hz, 1H), 1.50-1.82 (m, 6H), 1.40 (br. s., 2H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].C([O-])(O)=[O:16].[Na+].C(Cl)(Cl)Cl.CO.CCOC(C)=O>CC#N>[OH:16][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13]
Reactant: O=C(O)c1ccc(CBr)c([N+](=O)[O-])c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: O=C(O)c1ccc(CO)c([N+](=O)[O-])c1
Yield: 80 %

Procedure:
In a round-bottom flask provided with reflux system, 4.5 g (17.3 mmols) of 4-bromomethyl-3-nitrobenzoic acid were placed, and an aqueous NaHCO3 saturated solution is added (135 mL). The reaction was stirred and allowed to stand at 90-95° C. The progress of the reaction was monitored by thin layer chromatography (TLC) (chloroform/MeOH/AcOEt, 100:50:0.1, v/v) or by HPLC of an acidified aliquot in a linear gradient 0-100% MeCN in 15 minutes in a Symmetry C18 column (150×4.6 mm×5 μm, 100 Å, Waters) retention time for the final product: 7.12 min; retention time for the initial product: 10.39 min. The reaction was completed in 30 minutes. The solution obtained was hot filtered and the reaction was quenched with HCl (12N) to a pH between 1-2 and was extracted with AcOEt (3×100 mL), the different organic fractions were combined, washed with a satured NaCl aqueous solution and dried over MgSO4 anh. The AcOEt was evaporated in vacuo. The product was obtained as a pale yellow solid in a 80% yield. The product has been characterized by HPLC (tr) 7.12 min (linear gradient 0-100% in 15 minutes), HPLC-MS (196 Da) and Rf=0.3 by TLC (Chloroform/MeOH/AcOEt, 100:50:0.1, v/v), NMR-1H 400 MHz in CD3OD: Signals: 2H: singlet 4.98 ppm, 1H: doublet, 7.96 ppm (J: 21 Hz), 1H: doublet of doublets, 8.26 ppm (4 Hz, 20 Hz), 1H: doublet, 8.56 ppm (4 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][C:3]=1[NH:13][C:14]([NH:16][C:17]([O:19][CH3:20])=[O:18])=[S:15].[C:21](Cl)(=[O:23])[CH3:22]>O1CCCC1>[C:21]([NH:1][C:2]1[CH:7]=[C:6]([S:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][C:3]=1[NH:13][C:14]([NH:16][C:17]([O:19][CH3:20])=[O:18])=[S:15])(=[O:23])[CH3:22]
Reactant: CCCCSc1ccc(NC(=S)NC(=O)OC)c(N)c1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Product: CCCCSc1ccc(NC(=S)NC(=O)OC)c(NC(C)=O)c1
Reaction time: 2 h

Procedure:
0.7 G. of 2-amino-4-n-butylthio-1-(3-methoxycarbonyl-2-thioureido)benzene is dissolved in 20 ml. tetrahydrofuran and treated with 1.5 ml. of acetyl chloride. The mixture is stripped after two hours and the residue recrystallized from methanol, yielding pure 2-acetamido-4-n-butylthio-1-(3-methoxycarbonyl-2-thioureido)benzene.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)([C:21]3[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=3)[OH:20])[CH:8]=2)[N:3]=1.[CH:34]1([C:40](O)=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.Cl.C(C(NCCCN(C)C)=N)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C1COCC1.O>[Cl:18][C:14]1[CH:13]=[C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:27]4[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=4)([OH:20])[C:21]4[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=4)[CH:8]=3)[N:3]=[C:2]([NH:1][C:40]([CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[O:41])[N:11]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)C1CCCCC1
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(N)nc(-c3cccc(Cl)c3)c2c1
Agent: CCC(=N)NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(NC(=O)C3CCCCC3)nc(-c3cccc(Cl)c3)c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 4.9 %

Procedure:
A mixture of 2-amino-4-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-6-quinazolinemethanol (0.00021 mol), obtained in Example B19, cyclohexanecarboxylic acid (1.2 equiv, 0.000252 mol), N′-(ethylcarbonimidoyl)-N,N-dimethyl-1,3-propanediamine, monohydrochloride (1.5 equiv, 0.000315 mol), 1-hydroxy-1H-benzotriazole (1.5 equiv, 0.000315 mol) and triethylamine (1.5 equiv, 0.000315 mol) in THF (2 ml) was stirred at room temperature for 18 hours, then taken up in water. The organic layer was separated and the solvent was evaporated. The residue was purified by HPLC. The product fractions were collected and the solvent was evaporated, yielding 0.006 g (4.8%) of N-[4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-2-quinazolinyl]-cyclohexanecarboxamide, MS (ESI) m/z: 586 588 590.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.CS(C)=O.[CH:18]([C:21]1[C:26]([CH2:27][OH:28])=[C:25]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[C:24]([CH2:36][N:37]2CCOCC2)=[C:23]([CH:43](C)C)[N:22]=1)([CH3:20])[CH3:19].C(N(CC)CC)C>C(Cl)Cl>[C:36]([C:24]1[C:25]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[C:26]([CH:27]=[O:28])[C:21]([CH:18]([CH3:20])[CH3:19])=[N:22][C:23]=1[CH3:43])#[N:37]
Reactant: CC(C)c1nc(C(C)C)c(CN2CCOCC2)c(-c2ccc(F)cc2)c1CO
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CS(C)=O
Product: Cc1nc(C(C)C)c(C=O)c(-c2ccc(F)cc2)c1C#N
Temperature: -70 °C
Reaction time: 0.17 h

Procedure:
4.4 g (21 mmol) of trifluoroacetic anhydride in 15 ml of methylene chloride are added dropwise at -78° C. to 1.1 g (14 mmol) of DMSO in 8 ml of methylene chloride p.A. and the mixture is stirred for 10 minutes at -70° C. 2.1 g (7 mmol) of compound 2 from Example 143 are then added in 50 ml of methylene chloride, the mixture is stirred for 1 h at -70° C., 5.8 ml (42 mmol) of triethylamine are now added and the mixture is stirred for 4 h at room temperature. It is washed with saturated sodium chloride solution, concentrated, chromatographed over 100 g of silica gel (230-400 mesh, φ4 cm, petroleum ether/ethyl acetate 10:1) and recrystallized from ethyl acetate/petroleum ether.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.Br[CH2:24][C:25]1([CH3:30])[O:29][CH2:28][CH2:27][O:26]1.[OH-].[Na+]>CN(C=O)C>[C:11]1([C:10]2[C:3]3[C:2]([NH:1][CH2:24][C:25]4([CH3:30])[O:29][CH2:28][CH2:27][O:26]4)=[N:7][CH:6]=[N:5][C:4]=3[O:8][C:9]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ncnc2oc(-c3ccccc3)c(-c3ccccc3)c12
Reactant: CC1(CBr)OCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC1(CNc2ncnc3oc(-c4ccccc4)c(-c4ccccc4)c23)OCCO1
Temperature: 120 °C
Yield: 13.7 %

Procedure:
A stirred mixture of 4-amino-5,6-diphenylfuro[2,3-d]pyrimidine (50 mg, 0.17 mmol), 2-bromomethyl-2-methyl-[1,3]dioxolane (prepared according to Visweswariah et al., Synthesis, 1982, 4, 309-310) (38 mg, 0.21 mmol) and sodium hydroxide granules (21 mg, 0.53 mmol) in DMF (1 mL) was heated in a microwave at 120° C. for 5 minutes. The resulting mixture was filtered and purified by preparative HPLC to give a beige solid (9 mg). 1H NMR (CDCl3): 8.39 (1H, s), 7.52-7.41 (7H, m), 7.23-7.18 (3H, m), 5.05 (1H, br s), 3.77-3.63 (4H, m), 3.50 (2H, m), 1.19 (3H, s). LC/MS: 388 (MH+).