Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)(O)[O-].[K+].O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCC(=O)OCc1ccccc1
Temperature: -5 °C
Reaction time: 38 h

Procedure:
N-(t-Butoxycarbonyl)glycine (8.75 g, 0.05 mole) and benzyl bromide (9.4 g, 0.055 mole) were slurried in 20 ml of dimethylformamide and treated with 6.0 g (0.06 mole) of potassium bicarbonate under argon. After stirring for 38 hours, water was added to give a mass of chunky white solid which was filtered and washed with water. The solid was taken up in ethyl acetate, dried (sodium sulfate), evaporated to a solid, and recrystallized from 600 ml of hot hexane. Cooling to -5° C. for two hours and filtering gave 11.6 g of crystalline flakes, melting point 72°-73° C., in two crops.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][C:11]2[CH:12]=[C:13]3[C:22]4([CH2:26][O:25][C:24]([NH:27]C(=O)OC(C)(C)C)=[N:23]4)[C:19]4([CH2:21][CH2:20]4)[CH2:18][O:17][C:14]3=[CH:15][CH:16]=2)=[O:9])=[N:6][CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:27][C:24]1[O:25][CH2:26][C:22]2([C:13]3[C:14](=[CH:15][CH:16]=[C:11]([NH:10][C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=4)=[O:9])[CH:12]=3)[O:17][CH2:18][C:19]32[CH2:20][CH2:21]3)[N:23]=1
Reactant: CC(C)(C)OC(=O)NC1=NC2(CO1)c1cc(NC(=O)c3ccc(F)cn3)ccc1OCC21CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1=NC2(CO1)c1cc(NC(=O)c3ccc(F)cn3)ccc1OCC21CC1
Reaction time: 2 h
Yield: 41.1 %

Procedure:
To a mixture of tert-butyl (6′-{[(5-fluoropyridin-2-yl)carbonyl]amino}dispiro[cyclopropane-1,3′-chromene-4′,4″-[1,3]oxazol]-2″-yl)carbamate (135 mg, 0.288 mmol) and CH2Cl2 (5.4 mL) was added trifluoroacetic acid (1.30 mL, 17.0 mmol) at ambient temperature. After stirring for 2 hours at the same temperature, the mixture was concentrated at reduced pressure. The residue was partitioned between CHCl3 and saturated aqueous NaHCO3. The organic layer was washed with water, dried over Na2SO4 and filtered. The filtrate was concentrated at reduced pressure, and the residue was purified with column chromatography on silica gel (CHCl3-EtOH, a linear gradient of EtOH from 0 to 20%) to afford N-(2″-aminodispiro[cyclopropane-1,3′-chromene-4′,4″-[1,3]oxazol]-6′-yl)-5-fluoropyridine-2-carboxamide (43.6 mg).
Reaction SMILES: C([O:8][C:9]1[C:10]2[N:11]([C:16]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:17]([CH3:19])[N:18]=2)[CH:12]=[C:13]([CH3:15])[CH:14]=1)C1C=CC=CC=1>ClCCl.C(O)C.[Pd]>[OH:8][C:9]1[C:10]2[N:11]([C:16]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:17]([CH3:19])[N:18]=2)[CH:12]=[C:13]([CH3:15])[CH:14]=1
Reactant: CCOC(=O)c1c(C)nc2c(OCc3ccccc3)cc(C)cn12
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1c(C)nc2c(O)cc(C)cn12
Reaction time: 8 h

Procedure:
74 g (228 mmol) of ethyl 8-(benzyloxy)-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylate Example 16A were initially charged in 1254 ml of dichloromethane and 251 ml of ethanol, and 20.1 g 10% palladium on activated carbon (moistened with water 50%) were added under argon. The reaction mixture was hydrogenated overnight at RT and atmospheric pressure. The reaction mixture was filtered off through kieselguhr and concentrated. The crude product was purified by silica gel chromatography (dichloromethane:methanol=95:5). This gave 50.4 g (94% of theory) of the target compound.
Reaction SMILES: I.[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:4]=1[CH:5]=[N:6][NH:7][C:8](=[NH:11])SC.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)C>O>[CH2:17]([NH:24][C:8]([NH:7][N:6]=[CH:5][C:4]1[C:12]([Cl:16])=[CH:13][CH:14]=[CH:15][C:3]=1[Cl:2])=[NH:11])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CSC(=N)NN=Cc1c(Cl)cccc1Cl
Reactant: NCc1ccccc1
Agent: I
Solvent: CCO
Solvent: O
Product: N=C(NCc1ccccc1)NN=Cc1c(Cl)cccc1Cl

Procedure:
A solution of 93.6 g of methyl 3-(2,6-dichlorobenzylidene)thiocarbazimidate hydroiodide (U.S. Pat. No. 3,657,337) and 51.2 of benzylamine in 400 ml. of absolute ethanol is heated at reflux for 6 hours and then diluted while hot with 400 ml. of water, causing the separation of an oil. On standing, the oil crystallizes and the nearly colorless crystals are recovered by filtration. Recrystallization from aqueous ethanol gives the desired product as pale yellow crystals, m.p. 134°-137° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][N:3]=1.CCN(CC)CC.[CH:16]1([C:19](Cl)=[O:20])[CH2:18][CH2:17]1>C(Cl)Cl>[OH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:19]([CH:16]2[CH2:18][CH2:17]2)=[O:20])[CH:7]=1
Reactant: Nc1cc(O)ccn1
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(O)ccn1)C1CC1
Yield: 32.1 %

Procedure:
Dissolve 2-amino-pyridin-4-ol (5 g, 45.4 mmol) in DCM (30 mL), add Et3N (13.8 g, 136 mmol) and then cyclopropanecarbonyl chloride (14.2 g, 136 mmol) dropwise while keeping the temperature below 10° C. After addition, stir the reaction at room temperature for 16 hrs. Remove the solvent under reduced pressure, dissolve the residue in THF (40 mL), adjust pH=12 with 1N NaOH solution. Stir the mixture for 3 hrs. Concentrate to give the crude product. Purification by chromatography (silica gel, EtOAc:MeOH=9:1) affords the title compound (2.6 g, 32%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:16]2[C:11](=[CH:12][C:13]([Br:17])=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([S:36]([N:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])=[CH:32][CH:31]=1>CN(C)C=O>[C:1]([O:5][C:6]([C:8]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:16]2[C:11](=[CH:12][C:13]([Br:17])=[CH:14][CH:15]=2)[N:10]([CH2:29][C:30]2[CH:31]=[CH:32][C:33]([S:36](=[O:38])(=[O:37])[N:39]([CH3:40])[CH3:41])=[CH:34][CH:35]=2)[C:9]1=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)S(=O)(=O)c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)C1(C(=O)OC(C)(C)C)C(=O)Nc2cc(Br)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)c1ccc(CN2C(=O)C(C(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)c3ccc(Br)cc32)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 114.2 %

Procedure:
6-Bromo-2-oxo-1,2-dihydro-indole-3,3-dicarboxylic acid di-tert-butyl ester (5.10 g, 12.4 mmol) was dissolved in 40 ml of anhydrous N,N-dimethylformamide (DMF) under an atmosphere of dry N2. The solution was cooled to 0° C. after which time 60% sodium hydride in oil (500 mg, 12.4 mmol) was added and the solution was then stirred for 15 minutes at this temperature. The reaction mixture was the warmed to ambient temperature and stirred for 15 minutes after which time 4-bromomethyl-N,N-dimethyl-benzenesulfonamide (3.44 g, 12.4 mmol) was added. The mixture was stirred overnight after which time it was concentrated under vacuum and partitioned between DCM and water. The DCM layer was washed 3 more times with water, once with brine, dried over MgSO4, filtered and concentrated under vacuum to give 8.63 g of the titled compound as a yellow solid
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C([O:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])C>CO>[F:12][C:11]([F:14])([F:13])[C:10]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)=[O:9]
Reactant: CCOC(=O)C(F)(F)F
Reactant: C1CNCCN1
Solvent: CO
Product: O=C(N1CCNCC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.8 %

Procedure:
To a solution of piperazine (1.444 g, 16.8 mmol) in MeOH (10 mL) was added trifluroacetic acid ethyl ester (2.0 mL, 16.8 mmol) and the mixture stirred at room temperature overnight. The reaction was concentrated and purified by column chromatography on silica gel (CH2Cl2MeOH, 9:1) to afford the desired mono-protected piperazine adduct (1.77 g, 58%) as a pale yellow oil. 1H NMR (CDCl3) δ 1.70 (br s, 1H), 2.90-2.94 (m, 4H), 3.56-3.59 (m, 2H), 3.64-3.67 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:32])[C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:35][CH2:36][CH2:37][C:38]#[N:39]>>[C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:32])[C:16]2[CH:21]=[C:20]([O:22][CH2:35][CH2:36][CH2:37][C:38]#[N:39])[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(O)cc(Oc3ccc(C#N)cc3)c2)CC1
Reactant: N#CCCCBr
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cc(OCCCC#N)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 95.3 %

Procedure:
Using 0.75 g (1.66 mmol) of {4-[3-(4-cyanophenoxy)-5-hydroxybenzoylamino]cyclohexyl}carbamic acid tert-butyl ester and 4-bromo-butyronitrile (0.245 g, 1.66 mmol) and following the procedure of Example 42(b) afforded 0.82 g of the required product. 1H NMR (DMSO-d6): δ 1.20 (3H, m), 1.4 (9H, s), 1.8 (4H, m), 2.05 (3H, m), 2.65 (2H, m), 3.2 (1H, m), 3.7 (1H, m), 4.1 (2H, m), 6.76 (1H, d), 6.92 (1H, s), 7.14 (2H, d), 7.2 (1H, s), 7.34 (1H, s), 7.86 (2H, d), 8.28 (1H, d)
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]=O)=[CH:9][C:4]=2[O:3][CH2:2]1.[N:13]1([C:18]2[N:23]=[C:22]([CH:24]3[CH2:28][CH2:27][CH2:26][N:25]3[CH2:29][CH2:30][NH2:31])[CH:21]=[C:20]([CH3:32])[N:19]=2)[CH:17]=[CH:16][N:15]=[CH:14]1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][NH:31][CH2:30][CH2:29][N:25]3[CH2:26][CH2:27][CH2:28][CH:24]3[C:22]3[CH:21]=[C:20]([CH3:32])[N:19]=[C:18]([N:13]4[CH:17]=[CH:16][N:15]=[CH:14]4)[N:23]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cc1cc(C2CCCN2CCN)nc(-n2ccnc2)n1
Reactant: O=CCc1ccc2c(c1)OCO2
Product: Cc1cc(C2CCCN2CCNCCc2ccc3c(c2)OCO3)nc(-n2ccnc2)n1

Procedure:
(2-Benzo[1,3]dioxol-5-yl-ethyl)-{2-[2-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-pyrrolidin-1-yl]-ethyl}-amine was prepared following the procedures described in the preparation of Example 127 using benzo[1,3]dioxol-5-yl-acetaldehyde and 2-[2-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-pyrrolidin-1-yl]-ethylamine. [M+H]+ 421.55; 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 7.86 (s, 1H), 7.17 (s, 1H), 7.10 (s, 1H), 6.90 (d, 1H), 6.65 (d, 1H), 6.60 (dd, 1H), 5.88 (s, 2H), 3.50 (t, 1H), 3.21 (m, 1H), 2.82-2.64 (m, 5H), 2.50 (s, 3H), 2.40-2.20 (m, 4H), 1.95-1.66 (m, 4H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])O[CH2:12][CH2:11]2.S(Cl)(Cl)=O.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH2:39])[CH:28]=[CH:29][C:30]=1[O:31][CH2:32][CH2:33][N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:39]2[CH2:12][CH2:11][C:10]3[C:15](=[CH:16][CH:17]=[C:8]([O:7][CH2:6][C@@H:2]4[CH2:3][CH2:4][CH2:5][O:1]4)[CH:9]=3)[C:14]2=[O:18])[CH:28]=[CH:29][C:30]=1[O:31][CH2:32][CH2:33][N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: O=C1OCCc2cc(OC[C@@H]3CCCO3)ccc21
Reactant: COc1cc(N)ccc1OCCN1CCCC1
Solvent: O=S(Cl)Cl
Product: COc1cc(N2CCc3cc(OC[C@@H]4CCCO4)ccc3C2=O)ccc1OCCN1CCCC1

Procedure:
6-[(S)-1-(Tetrahydrofuran-2-yl)methoxy]isochroman-1-one was firstly converted with thionyl chloride by method B into the corresponding dichloride, and then reacted with 3-methoxy-4-(2-pyrrolidin-1-ylethoxy)phenylamine by method A. The product with the molecular weight of 466.58 (C27H34N2O5) was obtained in this way; MS (ESI): 467 (M+H+).
Reaction SMILES: [S:1]1[C:5]([C:6]2[N:10]3[N:11]=[C:12](Cl)[C:13]([CH3:16])=[C:14]([CH3:15])[C:9]3=[N:8][CH:7]=2)=[CH:4][C:3]2[CH:18]=[CH:19][CH:20]=[CH:21][C:2]1=2.CC1C=CC(S(O)(=O)=O)=CC=1.[NH2:33][C@H:34]1[CH2:39][CH2:38][C@H:37]([OH:40])[CH2:36][CH2:35]1>CS(C)=O>[S:1]1[C:5]([C:6]2[N:10]3[N:11]=[C:12]([NH:33][C@H:34]4[CH2:39][CH2:38][C@H:37]([OH:40])[CH2:36][CH2:35]4)[C:13]([CH3:16])=[C:14]([CH3:15])[C:9]3=[N:8][CH:7]=2)=[CH:4][C:3]2[CH:18]=[CH:19][CH:20]=[CH:21][C:2]1=2
Reactant: Cc1c(Cl)nn2c(-c3cc4ccccc4s3)cnc2c1C
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CS(C)=O
Product: Cc1c(N[C@H]2CC[C@H](O)CC2)nn2c(-c3cc4ccccc4s3)cnc2c1C
Temperature: 100 °C

Procedure:
To a solution of 3-(benzo[b]thiophen-2-yl)-6-chloro-7,8-dimethylimidazo[1,2-b]pyridazine (40 mg, 0.128 mmol, 1.0 equiv) in DMSO (1.00 mL) was added p-TSA (24 mg, 0.128 mmol, 1.0 equiv) and trans-4-aminocyclohexanol (73 mg, 0.638 mmol, 5.0 equiv) and heated to 100° C. for 24 h. Purification by column chromatography using 5% methanol in dichloromethane elution gave 31 mg, 62%.
Reaction SMILES: [CH2:1]([N:3]([CH2:34][CH3:35])[C:4]([NH:6][C:7]1[C:8]([C:18]2[NH:22][C:21]3[CH:23]=[C:24]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[C:25]([F:27])=[CH:26][C:20]=3[N:19]=2)=[N:9][N:10](C2CCCCO2)[CH:11]=1)=[O:5])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:34]([N:3]([CH2:1][CH3:2])[C:4]([NH:6][C:7]1[C:8]([C:18]2[NH:22][C:21]3[CH:23]=[C:24]([N:28]4[CH2:29][CH2:30][O:31][CH2:32][CH2:33]4)[C:25]([F:27])=[CH:26][C:20]=3[N:19]=2)=[N:9][NH:10][CH:11]=1)=[O:5])[CH3:35]
Reactant: CCN(CC)C(=O)Nc1cn(C2CCCCO2)nc1-c1nc2cc(F)c(N3CCOCC3)cc2[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(CC)C(=O)Nc1c[nH]nc1-c1nc2cc(F)c(N3CCOCC3)cc2[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 62.4 %

Procedure:
A solution of 95 mg of 1,1-diethyl-3-[3-(5-fluoro-6-morpholin-4-yl-1H-benzimidazol-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]urea in 3 mL of dichloromethane, to which 750 μL of trifluoroacetic acid are added, is stirred at ambient temperature for 48 hours. The reaction medium is concentrated to dryness and then purified by preparative LC/MS: injection of the product in 2.5 mL of DMSO, elution with a gradient of 5% to 95% of acetonitrile in water, containing respectively 0.07% of TFA, in 12 minutes. 49 mg of 1,1-diethyl-3-[3-(5-fluoro-6-morpholin-4-yl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]urea are isolated in the form of a trifluoroacetate salt. 1H NMR (300 MHz, DMSO-d6, δ in ppm): 1.23 (t, J=7.0 Hz, 6H); 3.00 (m, 4H); 3.41 (m partially masked, 4H); 3.78 (m, 4H); 7.11 (broad d, J=8.0 Hz, 1H); 7.33 (broad d, J=12.0 Hz, 1H); 7.99 (s, 1H); 9.78 (s, 1H); 13.0 (broad m, 2H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH2:6][C:7]([F:10])([F:9])[F:8])=[O:4].[C:11]([C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([C:24](Cl)=[O:25])=[CH:16][CH:15]=1)(=[O:13])[CH3:12].C(N(CC)CC)C>ClCCCl>[C:11]([C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([C:24]([NH:1][CH2:2][C:3](=[O:4])[NH:5][CH2:6][C:7]([F:10])([F:9])[F:8])=[O:25])=[CH:16][CH:15]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)c1ccc(C(=O)Cl)c2ccccc12
Reactant: NCC(=O)NCC(F)(F)F
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(C(=O)NCC(=O)NCC(F)(F)F)c2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75 %

Procedure:
A solution of 2-amino-N-(2,2,2-trifluoroethyl)acetamide (21.90 g, 0.14 mol) in 1,2-dichloroethane (80 mL) was added dropwise over 15 min to a solution of the product of Example 7, Step A (32.50 g, 0.14 mol) in 1,2-dichloroethane (160 mL) at a temperature of 25 to 30° C. The resulting mixture was further stirred for 10 min at 25° C. A solution of triethylamine (14.20 g, 0.14 mol) in 1,2-dichloroethane (80 mL) was then added dropwise over 44 min at 25° C., and the mixture was stirred further for 20 min at 25° C. The solvent was removed under reduced pressure, and the residue was dissolved in hot acetonitrile (50 mL). The mixture was then cooled to 25° C., and water (40 mL) was added dropwise. The mixture was further cooled to 0° C. and filtered. The isolated solid was washed with water (100 mL) and dried overnight in a vacuum oven (approximately 16-33 kPa at 50° C.) to provide the title product as an off-white solid (37 g, 75% yield) melting at 169-169° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([CH3:17])([CH3:16])[C:12]([O:14][CH3:15])=[O:13].[C:18]1(=[O:28])[NH:22][C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.[K].O>CN(C)C=O>[C:18]1(=[O:28])[N:22]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([CH3:17])([CH3:16])[C:12]([O:14][CH3:15])=[O:13])[C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12
Reactant: COC(=O)C(C)(C)CCCCCCCCCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C)(C)CCCCCCCCCN1C(=O)c2ccccc2C1=O
Temperature: 80 °C
Yield: 103 %

Procedure:
12.3 g of methyl 11-bromo-2,2-dimethylundecanoate in solution in 70 cm3 of N,N-dimethylformamide are added to 8.2 g of potassium phthalimide in 70 cm3 of N,N-dimethylformamide and the mixture is heated for 3 hours at a temperature in the region of 80° C. The solution is cooled to a temperature in the region of 20° C. and then poured into 1400 cm3 of distilled water. Acidification is carried out to a pH in the region of 2 using 4N hydrochloric acid and extraction is then carried out with a total of 1000 cm3 of ethyl acetate. The organic phase is washed with a total of 450 cm3 of distilled water, dried over magnesium sulphate, and then concentrated under reduced pressure (13.5 Pa) at a temperature in the region of 60° C. 15.4 g of methyl 11-phthalimido-2,2-dimethylundecanoate are thus obtained in the form of a pale yellow viscous oil [Rf =0.38; silica thin layer chromatography; eluent: cyclohexane/ethyl acetate 8/2 (by volume)].
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([CH:14]2[CH2:16][CH2:15]2)[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([CH3:44])[CH:39]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([CH:14]2[CH2:16][CH2:15]2)[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([CH3:44])[CH:39]=2)[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Reactant: CC(C)(C)OC(=O)Nc1cc(C2CC2)c(C(F)(F)F)cc1N
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(C4CC4)cc3NC(=O)OC(C)(C)C)c2)ccn1

Procedure:
The title compound was prepared (2-amino-5-cyclopropyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J39) (289 mg, 0.914 mmol) and 3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K12) (284 mg, 0.914 mmol) according to the general procedure M. Obtained as a yellow foam (368 mg, 73%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.C1(S)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[N:16]1[C:17]2[C:12](=[CH:11][N:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=3)[CH:18]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: COc1ccc(-c2cc3ncccc3cn2)cc1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Oc1ccc(-c2cc3ncccc3cn2)cc1
Temperature: 190 °C
Reaction time: 1 h
Yield: 72.4 %

Procedure:
To a solution of 2-bromo-3-pyridinecarboxaldehyde (1.86 g, 10 mmol) and 4′-methoxy phenylacetylene (1.58 g, 12 mmol) in triethylamine (40 mL) were added dichlorobis(triphenylphosphine)palladium (II) (140 mg, 2 mol %) and copper (I) iodide (20 mg, 1 mol %). The reaction mixture was heated at 50° C. under nitrogen for 3 h, then cooled to room temperature. The ammonium salt was removed by filtration. The filtrate was concentrated under reduced pressure leaving 2-(4-methoxy phenylethynyl)pyridine-3-carboxaldehyde (2.35 g, 99%) as a yellow solid. 2-(4-methoxy phenylethynyl)pyridine-3-carboxaldehyde (2.28 g, 9.60 mmol) and tert-butylamine (3.83 g, 60 mmol) were stirred under nitrogen for 24 h at room temperature. The resulting mixture was extracted with ether and dried over anhydrous Na2SO4. Removal of solvent gave the expected imine (2.72 g, 97%), which was used in next step without further purification. To a solution of the above imine (2.7 g, 9.23 mmol) in anhydrous DMF (50 mL) was added copper (I) iodide (0.190 g, 0.1 mmol). The reaction mixture was heated at 100° C. for 4 h, then cooled to room temperature and diluted with ether (200 mL). The organic layer was washed with a saturated aqueous ammonium chloride solution (3×100 mL). The organic layer was dried over anhydrous Na2SO4. Removal of solvent gave the crude compound as a dark-colored solid. Purification by column chromatography (silica gel 230-400 mesh; 30% ethyl acetate in hexanes as eluent) afforded 7-(4-methoxy phenyl)[1,6]naphthridine (0.730 g, 33%) as a brown solid. To a solution of 7-(4-methoxy phenyl)[1,6]naphthridine (0.485 g, 2.05 mmol) in anhydrous N-methyl-2-pyrrolidinone (5 mL) was added thiophenol (0.25 g, 2.26 mmol) and potassium carbonate (0.028 g, 0.205 mmol). The reaction mixture was stirred at 190° C. for 1 h under nitrogen. The reaction mixture was cooled to room temperature. The compound was purified by column chromatography to give 4-(1,6-naphthyridin-7-yl)phenol (0.33 g, 71%) as a pale yellow solid. Selected data: MS (ES) m/z: 223.95, 222.95; MP 219-221° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[Cl:10][CH2:11][C:12](O)=O>Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:12]([CH2:11][Cl:10])[NH:9][C:4]=2[CH:3]=1
Reactant: Nc1ccc(Cl)cc1N
Reactant: O=C(O)CCl
Agent: Cl
Product: ClCc1nc2ccc(Cl)cc2[nH]1
Temperature: 25 °C
Yield: 69.4 %

Procedure:
The solution of 4-chloro-1,2-phenylenediamine (1.43 g) and chloroacetic acid (1.43 g) in 4M HCl (10 ml) was heated to reflux for 1 h. After cooling to rt overnight the mixture was filtered and the filtrate was cooled in an ice bath. With stirring the solution was adjusted to pH 8 with 25% ammonia solution. A gummy precipitate is formed which is cooled for 1 h. The aqueous layer is removed by decantation and the residue crystallised from acetone/water to yield 5-chloro-2-chloromethylbenzimidazole (1.4 g) as brownish solid.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8]([NH2:10])=[O:9].C(N(CC)CC)C.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>ClCCl>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:1][C@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]2[C:8]([NH2:10])=[O:9])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: NC(=O)[C@@H]1CCCC[C@@H]1N
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)[C@@H]1CCCC[C@@H]1NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.1 %

Procedure:
To a solution of cis-2-aminocyclohexanecarboxylic acid amide (2.0 g, 14.0 mmol), and triethylamine (3.9 mL, 28 mmol) in dichloromethane (100 mL) was added 4-chlorobenzenesulfonyl chloride (2.95 g, 14.0 mmol). The resulting solution was stirred at room temperature for 18 h. The reaction was then diluted with dichloromethane (200 mL) and washed with H2O, 1.0 M HCl, brine, and dried over Na2SO4. Further purification by flash chromatography (silica gel, 1% to 10% MeOH/CHCl3) afforded cis-2-(4-chlorobenzenesulfonylamino)-cyclohexanecarboxylic acid amide (2.0 g) as a white solid in 45% yield over three steps: 1H NMR (DMSO-d6) δ 7.82 (m, 2 H), 7.63 (m, 2 H), 7.56 (d, 1 H, J=7.0 Hz), 7.22 (s br, 1 H), 6.80 (s br, 1 H), 3.43 (m, 1 H), 2.37 (m,1 H), 1.72 (m, 2 H), 1.45 (m, 3 H), 1.15 (m, 3 H); MS m/e 317.05 (M+H)+.