Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.[CH2:20]([OH:23])[C:21]#[CH:22].Cl>O1CCCC1.[Cl-].[Na+].O.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:22]#[C:21][CH2:20][OH:23])=[CH:4][CH:3]=1
Reactant: C#CCO
Reactant: Fc1ccc(I)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: OCC#Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-fluoro-1-iodobenzene (11.0 g, 50.0 mmol) in anhydrous tetrahydrofuran (90 mL) was degassed and copper(I) iodide (0.29 g, 1.5 mmol), tetrakis(triphenylphosphine)palladium (1.75 g, 1.5 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (9.25 g, 60.0 mmol) were added. The reaction solution was degassed again and propargyl alcohol (3.5 mL, 60.0 mmol) was added dropwise under inert atmosphere at ambient temperature. The obtained yellow suspension was stirred at ambient temperature overnight, then treated with brine (10 mL) and acidified with 2 M hydrochloric acid to pH˜2. The phases were separated and the aqueous phase was extracted with ether (4×50 mL). The combined organic phases were washed with water (3×30 mL) and brine (2×30 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo yielding brown solid. The residue was purified by column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 90:10) and the obtained light yellow solid was crystallized from hexane yielding 3-(4-fluorophenyl)prop-2-yn-1-ol as light yellow needles.
Reaction SMILES: C[O-].[Na+].O=[C:5]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:6][CH2:7][CH:8]=O.[CH:17]1[CH2:21][CH:20]=[CH:19][CH:18]=1.C(Cl)Cl>CO>[CH2:10]([C:5]1[CH:6]=[CH:7][CH:8]=[C:17]2[C:18]=1[CH:19]=[CH:20][CH2:21]2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C1=CCC=C1
Reactant: CCCCCCCC(=O)CCC=O
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCCCCCCc1cccc2c1C=CC2
Temperature: 0 °C
Reaction time: 3 h
Yield: 33.5 %

Procedure:
20.4 ml of a 30 percent strength solution of sodium methanolate (111 mmol) in methanol were initially introduced into the reaction vessel at 0° C., and a mixture of 9.0 g (44.5 mmol) of 4-oxoundecylaldehyde and 4.0 ml (49 mmol) of cyclopentadiene was added in the course of 30 minutes. After the mixture had been stirred at 0° C. for 2 hours and at room temperature for a further 3 hours, it was hydrolyzed, methylene chloride was added and the mixture was filtered over Corolite. The organic phase was separated off, dried over MgSO4 and evaporated. Column chromatography with hexane as the mobile phase gave 3.2 g (34%) of the indene 17. For the NMR data, see Table 1.
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[N:10]=[N:11][C:12]([C:30]([NH2:32])=[O:31])=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[O:23])=[CH:18][CH:17]=3)[N:14]=2)[CH2:4]1.CCN(C(C)C)[CH:36]([CH3:38])[CH3:37].CC(C)=O.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.O1CCOCC1.O>[CH:36]([NH:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[N:10]=[N:11][C:12]([C:30]([NH2:32])=[O:31])=[C:13]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([C:22]([N:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)=[O:23])=[CH:20][CH:21]=3)[N:14]=2)[CH2:4]1)([CH3:38])[CH3:37].[ClH:1]
Reactant: NC(=O)c1nnc(N2CCC[C@@H](N)C2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)N[C@@H]1CCCN(c2nnc(C(N)=O)c(Nc3ccc(C(=O)N4CCOCC4)cc3)n2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (R)-3-(3-aminopiperidin-1-yl)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide HCl salt (100 mg, 0.21 mmol) in 1,2-dichloroethane (10 mL) and dioxane (10 mL) was added DIEA (0.18 mL, 1.05 mmol) and then acetone (0.31 mL, 4.2 mmol). The mixture was stirred for 3 h at RT. To the mixture was added HOAc (0.12 mL, 2.1 mmol) and then NaBH(OAc)3 (223 mg, 1.05 mmol). The mixture was stirred at RT overnight and then water (2 mL) was added. The mixture was concentrated in vacuo and subjected to reverse phase preparative HPLC to afford the title compound as HCl salt (50) (17 mg). MS found for C23H32N8O3 as (M+H)+ 469.2, (M−H)− 467.3. UV: λ=268 nm.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[C@@H:22]12[NH:29][C@@H:26]([CH2:27][CH2:28]1)[CH2:25][O:24][CH2:23]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:29]3[C@H:22]4[CH2:28][CH2:27][C@@H:26]3[CH2:25][O:24][CH2:23]4)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: C1C[C@H]2COC[C@@H]1N2
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1[C@@H]2CC[C@H]1COC2

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with (1R,5S)-3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (904316-92-3) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=380.6 [MH+].
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH:15]=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([Mg]Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[NH4+].[Cl-]>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH:15]([OH:16])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: O=CCC1CCN(Cc2ccccc2)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(Cc1ccccc1)CC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
To a solution of 4 g (18.24 mmol) of 1-Benzyl-4-(2-oxoethyl)piperidine in 40 mL of THF at 0° C. was added 20 mL (36.5 mmol) of benzyl magnesium chloride (2M in THF, Aldrich). THe reaction mixture was warmed to rt and stirred for 30 min. The reaction mixture was poured into 100 mL of sat'd NH4Cl solution and extracted with EtOAc. The combined organic fractions were washed with sat'd Nacl solution, and dried over MgSO4 and filtered. The filtrate was concentrated and purified by chromatography (silica, hexanes:ehtyl acetate, 4:1) to give 5.32 g of the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:18][CH3:19])[C:6]=2[N:7]=1.[CH2:20]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[CH:21]=[CH2:22]>>[CH2:20]([N:23]1[CH2:28][CH2:27][N:26]([C:2]2[N:3]=[CH:4][C:5]3[C:11](=[O:12])[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:18][CH3:19])[C:6]=3[N:7]=2)[CH2:25][CH2:24]1)[CH:21]=[CH2:22]
Reactant: CCOC(=O)c1cn(CC)c2nc(Cl)ncc2c1=O
Reactant: C=CCN1CCNCC1
Product: C=CCN1CCN(c2ncc3c(=O)c(C(=O)OCC)cn(CC)c3n2)CC1
Yield: 79 %

Procedure:
2-(4'-Allyl-piperazino)-5-oxo-6-carbethoxy-8-ethyl-5,8 -dihydro-pyrido(2,3-d)pyrimidine is prepared, in a yield of 79%, by condensing 2-chloro-5-oxo-6-carbethoxy-8-ethyl-5,8 -dihydro-pyrido(2,3-d)pyrimidine with 1-allyl-piperazine, as indicated in the preceding Examples. It is a solid which melts in two stages; melting point 131° C., solidification, followed by melting point 143° C. [after recrystallisation from a mixture of benzene (1 volume) and isopropyl ether (1 volume)]. Analysis for C19H25N5O3 (molecular weight 371.43); Calculated % C 61.44, H 6.78, N 18.86; Found % C 61.10, H 6.75, N 18.75.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([I:16])=[CH:14][N:13]=[C:12]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[CH3:23][C:24](OC(C)=O)=[O:25]>C1COCC1.O.C1COCC1>[CH:1]1([C:4]2[N:8]([C:24](=[O:25])[CH3:23])[N:7]=[C:6]([NH:9][C:10]3[C:15]([I:16])=[CH:14][N:13]=[C:12]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: Ic1cnc(-c2ccccc2)nc1Nc1cc(C2CC2)[nH]n1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)n1nc(Nc2nc(-c3ccccc3)ncc2I)cc1C1CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.4 %

Procedure:
To the solution of N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-iodo-2-phenylpyrimidin-4-amine (3 g, 7.44 mmol) in THF/H2O (50 mL/25 mL), a solution of Ac2O (1.5 g, 14.88 mmol, 2.0 equiv.) in THF (5 mL) was added dropwise. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was filtered to afford compound 1-(5-cyclopropyl-3-(5-iodo-2-phenylpyrimidin-4-ylamino)-1H-pyrazol-1-yl)ethanone (2.2 g, 66%). LC-MS (m/z): 446.0 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][C:7]([OH:9])=O)[N:3]=[CH:2]1.[CH:10]1([O:14][C:15]2[CH:16]=[C:17]([N:23]3[CH2:28][CH2:27][NH:26][C@@H:25]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:24]3)[CH:18]=[CH:19][C:20]=2[O:21][CH3:22])[CH2:13][CH2:12][CH2:11]1>>[CH:10]1([O:14][C:15]2[CH:16]=[C:17]([N:23]3[CH2:28][CH2:27][N:26]([C:7](=[O:9])[CH2:6][C:4]4[N:3]=[CH:2][NH:1][CH:5]=4)[C@@H:25]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:24]3)[CH:18]=[CH:19][C:20]=2[O:21][CH3:22])[CH2:11][CH2:12][CH2:13]1
Reactant: COc1ccc(N2CCN[C@@H](CC(C)C)C2)cc1OC1CCC1
Reactant: O=C(O)Cc1c[nH]cn1
Product: COc1ccc(N2CCN(C(=O)Cc3c[nH]cn3)[C@@H](CC(C)C)C2)cc1OC1CCC1

Procedure:
Prepared by the method outlined for Example 189 using 2-(1H-imidazol-4-yl)acetic acid and (S)-1-(3-cyclobutlyoxy-4-methoxy-phenyl)-3-isobutyl-piperazine (Example 34, Compound 122) as starting materials. Product as a light brown solid (17%). LC/MS (Method B) 2.57 min, [M+1]+ 427.0. Potency class A.
Reaction SMILES: FC(F)(F)C1C=C(C(C2C=CC(OC)=CC=2)CC(OCC)=O)C=CC=1.[F:26][C:27]([F:49])([F:48])[C:28]1[CH:29]=[C:30]([CH:34]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[CH2:35][CH2:36][C:37]([OH:39])=O)[CH:31]=[CH:32][CH:33]=1.C(#N)CCC.C(O)(=O)CCC.CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C(O)CC>[F:49][C:27]([F:48])([F:26])[C:28]1[CH:29]=[C:30]([CH:34]2[C:40]3[C:41](=[CH:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=3)[C:37](=[O:39])[CH2:36][CH2:35]2)[CH:31]=[CH:32][CH:33]=1
Reactant: COc1ccc(C(CCC(=O)O)c2cccc(C(F)(F)F)c2)cc1
Agent: CCOC(=O)CC(c1ccc(OC)cc1)c1cccc(C(F)(F)F)c1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCCC(=O)O
Solvent: CCCO
Solvent: CCCC#N
Product: COc1ccc2c(c1)C(=O)CCC2c1cccc(C(F)(F)F)c1
Yield: 81 %

Procedure:
Ethyl 3-(3-trifluoromethylphenyl)-3-(4-methoxyphenyl)propionate was converted to 4-(3-trifluoromethylphenyl)-4-(4-methoxyphenyl) butanoic acid by standard methods, viz. reduction of the propionate ester to the propanol (93%) tosylation (81%), conversion to the butyronitrile (67%) and hydrolysis to the butanoic acid (85%), which was obtained as a pale yellow oil. This oil (10 g) was stirred overnight at room temperature in a solution of methanesulphonic acid (100 g) and phosphorus pentoxide (21 g). The mixture was poured onto ice, extracted with ether, the extracts washed with dilute sodium hydroxide, dried (MgSO4) and filtered through a short column of alumina. Removal of the ether gave 4-(3-trifluoromethylphenyl)-7-methoxy-1-tetralone as a pale yellow oil (7.65 g, 81%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][CH2:12][C:13]2[C:14]([NH2:21])=[N:15][C:16]([S:19][CH3:20])=[N:17][CH:18]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[N:22]#[C:23]Br>CN(C)C=O>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([N:11]2[CH2:12][C:13]3[C:14](=[N:15][C:16]([S:19][CH3:20])=[N:17][CH:18]=3)[N:21]=[C:23]2[NH2:22])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(NCc2cnc(SC)nc2N)cc(OC)c1
Reactant: N#CBr
Solvent: CN(C)C=O
Product: COc1cc(OC)cc(N2Cc3cnc(SC)nc3N=C2N)c1
Temperature: 25 °C
Yield: 27.1 %

Procedure:
Into a solution of 25.0 g (81.6 mmol) of 5-[(3,5-dimethoxy-phenylamino)-methyl]-2-methylsulfanyl-pyrimidin-4-ylamine in 125 mL of dry dimethylformamide cooled to 5° C., was added a solution of 10.1 g (95.5 mmol) of cyanogen bromide in 25 mL of dry dimethylformamide portionwise. After the addition of the cyanogen bromide solution the ice bath was removed, and the reaction was allowed to warm to room temperature over 30 minutes. The reaction was warmed to 80° C. for 4 hours, then added to 500 mL of 1N NaOH. The aqueous suspension was extracted with dichloromethane (7×150 mL). The dichloromethane layers were combined and concentrated in vacuo. The residue was dissolved in dichloromethane, extracted three times with a saturated solution of sodium chloride, dried over magnesium sulfate, and concentrated in vacuo. The residue was dissolved in tetrahydrofuran, added silica gel, and concentrated in vacuo. The residue was chromatographed down silica gel, eluting first with ethyl acetate, then switching to ethyl acetate/ethanol (9:1 v/v), giving product which was slightly impure. This product was rechromatographed down silica gel, eluting with first chloroform, then switching to chloroform/methanol (9:0.5 v/v), to give 7.34 g (24%) of the title compound: mp 198-204° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)[CH2:6][CH3:7])[CH3:2].C(N(CC)CC)C.[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>C1COCC1>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][C:25]([Cl:24])=[CH:26][CH:27]=2)=[CH:13][CH:14]=1)[CH2:6][CH3:7])[CH3:2]
Reactant: CCOC(=O)C(CC)Cc1ccc(N)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C(CC)Cc1ccc(NC(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C

Procedure:
A solution of ethyl-2-(p-aminobenzyl)-butyrate (3.3 g) and triethylamine (1.5 g) in anhydrous THF (70 ml) is slowly (10 minutes) addioned with a solution of p-chlorobenzoylchloride (2.6 g) in 30 ml of anhydrous THF. It is stirred for an hour at room temperature, then filtered and the solution as obtained is vacuum evaporated. The obtained solid residue is crystallized from methanol providing 4 g amide with m.p. 119°-120° C. Analysis:
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:28]=[CH:27][C:13]3/[C:14](=[CH:23]/[C:24](O)=[O:25])/[C:15]4[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=4[CH2:17][CH2:18][C:12]=3[CH:11]=2)[C:7]2[CH:29]=[CH:30][CH:31]=[CH:32][C:6]=2[N:5]=1)[CH2:2][CH3:3].[CH3:33][S:34]([NH2:37])(=[O:36])=[O:35].C1CCN2C(=NCCC2)CC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.O>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:28]=[CH:27][C:13]3/[C:14](=[CH:23]/[C:24]([NH:37][S:34]([CH3:33])(=[O:36])=[O:35])=[O:25])/[C:15]4[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=4[CH2:17][CH2:18][C:12]=3[CH:11]=2)[C:7]2[CH:29]=[CH:30][CH:31]=[CH:32][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CS(N)(=O)=O
Reactant: CCCc1nc2ccccc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\C(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCCc1nc2ccccc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\C(=O)NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.5 %

Procedure:
(E)-[2-(2-Propylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetic acid (60 mg, 0.14 mmol) obtained in Example 2 was dissolved in DMF (0.6 mL), N,N′-carbonyldiimidazole (92 mg, 0.57 mmol) was added, and the mixture was stirred at room temperature for 1 hr. Methanesulfonamide (68 mg, 0.71 mmol) and DBU (106 μL, 0.71 mmol) were added to the reaction mixture, and the mixture was stirred at 80° C. for 2 hr. Water and 5% aqueous citric acid solution were added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was filtered to give the title compound (compound 12) (29 mg, 41%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[C:26]([CH3:27])=[CH:25][C:24]([N+:28]([O-])=O)=[CH:23][N:22]=4)[CH2:17][CH2:16]3)[N:12]=[C:11]([N:31]3[CH2:35][CH2:34][CH2:33][CH:32]3[CH3:36])[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([N:31]3[CH2:35][CH2:34][CH2:33][CH:32]3[CH3:36])[N:12]=[C:13]([N:15]3[CH2:16][CH2:17][N:18]([C:21]4[N:22]=[CH:23][C:24]([NH2:28])=[CH:25][C:26]=4[CH3:27])[CH2:19][CH2:20]3)[CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1cc([N+](=O)[O-])cnc1N1CCN(c2cc(-c3ccc(F)c(Cl)c3)nc(N3CCCC3C)n2)CC1
Solvent: CCOC(C)=O
Product: Cc1cc(N)cnc1N1CCN(c2cc(-c3ccc(F)c(Cl)c3)nc(N3CCCC3C)n2)CC1
Temperature: 25 °C

Procedure:
Heat a mixture of 4-(3-chloro-4-fluoro-phenyl)-6-[4-(3-methyl-5-nitro-pyridin-2-yl)-piperazin-1-yl]-2-(2-methyl-pyrrolidin-1-yl)-pyrimidine (300 mg, 0.59 mmol) and SnCl2-2H2O (529 mg, 2.95 mmol) in EtOAc at 80° C. for 16 h. Cool to room temperature and partition between EtOAc and 1N NaOH. Wash with water, dry the solution (Na2SO4), and concentrate under reduced pressure. Purify the residue by flash column eluting with EtOAc to afford the title compound as a light-yellow solid. 1H NMR (400 MHz, CDCl3): δ 1.30 (t, 3H, J=6.4 Hz, CH3); 1.69 (m, 1H, CH2CH2); 1.91 (m, 1H, CH2CH2); 2.06 (m, 2H, CH2CH2); 2.28 (s, 3H, Ar—CH3); 3.10 (m, 4H); 3.47 (br, 2H, NH2); 3.68 (m, 4H); 3.77 (m, 4H); 4.34 (m, 1H); 6.25 (s, 1H, Ar—H); 6.88 (d, J=2.0 Hz, 1H); 7.18 (m, 1H); 7.70 (d, 1H, J=3.2 Hz); 7.89 (m, 1H); 8.07 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)[CH3:2].Br[C:17]1[CH:22]=[CH:21][C:20]([CH:23]([CH3:29])[C:24]([NH:26][CH2:27][CH3:28])=[O:25])=[CH:19][CH:18]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>O1CCOCC1>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:11][CH2:12][N:13]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH3:29])[C:24]([NH:26][CH2:27][CH3:28])=[O:25])=[CH:19][CH:18]=3)[CH2:14][CH2:15]2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C2CCNCC2)cc1
Reactant: CCNC(=O)C(C)c1ccc(Br)cc1
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: C1COCCO1
Product: CCNC(=O)C(C)c1ccc(N2CCC(c3ccc(OCC)cc3)CC2)cc1
Temperature: 45 °C
Reaction time: 12 h

Procedure:
41 mg (0.20 mmol) 4-(4-Ethoxy-phenyl)-piperidine (XV.1) are added to a mixture of 51 mg (0.20 mmol) 2-(4-bromo-phenyl)-N-ethyl-propionamide (IV.3), 77 mg (0.80 mmol) sodium tert-butyrat, 24 mg (0.08 mmol) 2-(di-tert-butylphosphino)biphenyl and 18 mg (0.02 mmol) tris-(dibenzylidenaceton)-dipalladium(0) in 1 mL 1,4-dioxane. The mixture is stirred for 12 h at 45° C. After that time, the solvent is removed in vacuo and the residue is purified by HPLC (column: Waters XBridge 50; eluent A: water+0.1% NH4OH, eluent B: MeOH) to yield the desired product.
Reaction SMILES: [CH2:1]([C@H:5]1[C@@H:10]([NH2:11])[CH2:9][CH2:8][C@@H:7]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])[CH2:6]1)[CH2:2][CH2:3][CH3:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:41]([NH:48][C@@H:49]([C:51](O)=[O:52])[CH3:50])([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42].C(N(CC)C(C)C)(C)C>CN(C=O)C.C(Cl)Cl>[CH2:1]([C@@H:5]1[CH2:6][C@H:7]([N:12]([CH:14]([CH3:15])[CH3:16])[CH3:13])[CH2:8][CH2:9][C@@H:10]1[NH:11][C:51](=[O:52])[C@H:49]([NH:48][C:41](=[O:42])[O:43][C:44]([CH3:46])([CH3:45])[CH3:47])[CH3:50])[CH2:2][CH2:3][CH3:4]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCCC[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCC[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1NC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of (1R,3R,4S)-3-butyl-N1-isopropyl-N1-methylcyclohexane-1,4-diamine (81 mg, 0.35 mmol; see Example 3a, Step 4) in 1:1 DMF/methylene chloride (5 mL) was charged successively with HATU (162 mg, 0.43 mmol), N-Boc D-Alanine (67 mg, 0.35 mmol), and N,N-diisopropylethylamine (0.31 mL, 1.77 mmol). The reaction was stirred for 16 h at RT, concentrated in vacuo, and diluted with EtOAc. The organic phase was washed successively with sat. NaHCO3, water, 1N HCl, water, and brine before being dried (sodium sulfate), filtered, and concentrated in vacuo to afford tert-butyl (R)-1-((1S,2R,4R)-2-butyl-4-(isopropyl(methyl)amino)cyclohexylamino)-1-oxopropan-2-ylcarbamate. MS found: (M+H)+=398.4.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[CH3:11][O:12][C:13]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:14]=1[NH2:15]>C1COCC1>[CH3:11][O:12][C:13]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:14]=1[NH:15][CH:1]=[O:3]
Reactant: O=CO
Reactant: COc1ccc([N+](=O)[O-])cc1N
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: COc1ccc([N+](=O)[O-])cc1NC=O
Temperature: 55 °C
Reaction time: 2 h
Yield: 102 %

Procedure:
A mixture of formic acid (0.45 ml, 0.012 mole) and acetic anhydride (1.06 ml, 0.011 mole) was stirred at 55° C. under Ar for 2 h, and cooled to room temperature. Dry THF (10 ml) was added. To this solution was added 2-methoxy-5-nitroaniline (0.69 g, 0.004 mole). After stirring for 1 h, the suspension was evaporated in vacuo to leave the title compound as a brown solid (0.80 g, 99%).
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:12][C:13]#[N:14])[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[CH:5]=[CH:4]1.Br[CH2:16][CH2:17][CH2:18][CH2:19]Br.CCOCC>CS(C)=O.CCCCCC.C(OCC)(=O)C>[N:3]1([C:12]2([C:13]#[N:14])[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[CH:5]=[CH:4]1
Reactant: N#CCn1ccc2cccnc21
Reactant: BrCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: N#CC1(n2ccc3cccnc32)CCCC1
Yield: 86.9 %

Procedure:
To a suspension of sodium hydride (60%) (8.6 g, 215.79 mmol) in dimethyl sulfoxide (90 mL) was added dropwise a mixture of pyrrolo[2,3-b]pyridin-1-yl-acetonitrile (392) (15.4 g, 98.09 mmol) and 1,4-dibromo-butane (31.7 g, 147.13 mmol) dissolved in dimethyl sulfoxide: ether (180 mL, 1:1) at 0° C. and the reaction mixture was stirred for 30 min at same temperature, then stirred at room temperature for 24 h. (TLC, 40% ethyl acetate in hexane, Rf=0.6). After completion of the reaction, the reaction mixture was quenched with 1N HCl (100 mL). Water (100 mL) was added and the mixture was extracted with ethyl acetate (3×100 mL). The separated organic part was washed with water (3×100 mL) and brine (2×100 mL) and dried and concentrated to get a crude product which was purified by Combi-Flash column (eluted at 10-20% ethyl acetate in hexane) to afford 1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentanecarbonitrile (393) (18 g, 87%) as a light yellow crystalline solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](O)=[O:29])=[C:24]([F:31])[CH:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:35])=O>C(Cl)Cl.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([Cl:35])=[O:29])=[C:24]([F:31])[CH:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(C(=O)O)c(F)c3)c2CC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(C(=O)Cl)c(F)c3)c2CC1
Reaction time: 2 h
Yield: 94.6 %

Procedure:
To a solution of 3-tert-butoxycarbonyl-6-(4-carboxy-3-fluoro-benzylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.95 g, 4.21 mmol) in DCM (20 mL) at 0° C. under nitrogen, add three drops of DMF and oxalyl chloride (1.06 g, 8.41 mmol). Stir for 2 h and concentrate in vacuo to afford the desired intermediate as a yellow oil (1.93 g, 95%).