Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:13]=[C:14]([C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH:15]=[C:16]([Cl:18])[CH:17]=1.C(N(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[Br:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH2:9][C:19]([C:14]2[CH:15]=[C:16]([Cl:18])[CH:17]=[C:12]([Cl:11])[CH:13]=2)([OH:24])[C:20]([F:23])([F:22])[F:21])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(Br)nc1
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Solvent: CCCCN(CCCC)CCCC
Solvent: Cc1ccccc1
Product: O=C(CC(O)(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(Br)nc1
Temperature: 60 °C
Reaction time: 13 h
Yield: 38.4 %

Procedure:
1.00 g (4.99 mmol) of 1-(6-bromopyridin-3-yl)-ethanone, 1.21 g (4.99 mmol) of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 2.42 g of toluene and 0.28 g (1.50 mmol) of tributylamine were fed and the mixture was stirred for 13 hours at 60° C. After cooling the reaction solution to room temperature, the solid was filtered under reduced pressure to obtain 0.85 g of 1-(6-bromopyridin-3-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one as a white solid (yield 38.4%)
Reaction SMILES: [CH3:1][N:2]1[CH2:10][C:9]2[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]3[CH3:17])=[N:7][C:6]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:33])OC4C=CC=CC=4)=[CH:20][CH:19]=3)=[N:5][C:4]=2[CH2:3]1.CCN(CC)CC.[NH2:41][CH2:42][CH2:43][CH2:44][OH:45]>CN(C=O)C>[OH:45][CH2:44][CH2:43][CH2:42][NH:41][C:25]([NH:24][C:21]1[CH:20]=[CH:19][C:18]([C:6]2[N:7]=[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]3[CH3:17])[C:9]3[CH2:10][N:2]([CH3:1])[CH2:3][C:4]=3[N:5]=2)=[CH:23][CH:22]=1)=[O:33]
Reactant: NCCCO
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)nc2c1CN(C)C2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NCCCO)cc2)nc2c1CN(C)C2
Temperature: 50 °C
Yield: 24.2 %

Procedure:
To a stirring solution of (S)-phenyl 4-(6-methyl-4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenylcarbamate (intermediate 10) (50 mg, 0.12 mmol) in dry DMF, was added Et3N (51 μL, 0.36 mmol) and 3-aminopropan-1-ol (42 μL, 0.56 mmol). The reaction mixture was then heated at 50° C. for 2 hours. The solvent was then removed in vacuo and the crude residue was purified by prep. LCMS (high pH) affording the title compound as clear oil (12.5 mg, 0.029 mmol, 26%).
Reaction SMILES: C(OC(C)C)(=O)C.[Si:8]([O:15][C:16]1[C:17]([CH3:26])=[C:18]([CH:23]=[CH:24][CH:25]=1)[C:19]([O:21][CH3:22])=[O:20])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].C1(O)C=CC=CC=1.[Br:34]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>>[Br:34][CH2:26][C:17]1[C:16]([O:15][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:9])[CH3:10])=[CH:25][CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1cccc(O[Si](C)(C)C(C)(C)C)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CC(=O)OC(C)C
Solvent: Oc1ccccc1
Product: COC(=O)c1cccc(O[Si](C)(C)C(C)(C)C)c1CBr
Temperature: 70 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
The isopropyl acetate solution of methyl 3-((tert-butyldimethylsilyl)oxy)-2-methylbenzoate (157 g, 560 mmol, from step 2, with an amount of residue free phenol≦0.2%) was added to a 3 liter jacketed bottom drop reactor. Additional isopropyl acetate was added and the mixture was distilled under vacuum at 40 to 55° C., if necessary, to bring total volume to about 9× (1410 mL, KF≦0.05%). 1-Bromopyrrolidine-2,5-dione (NBS, 103.6 g, 580 mmol, 0.66×) and 2,2′-(diazene-1,2-diyl)bis(2-methylpropanenitrile) (AIBN, 1.9 g, 11 mmol, 0.012×) were added to the solution. The reaction mixture was heated to 70° C. over at least 2 hours and stirred at 70° C. for 2 hours. The color changed from orange to yellow. If conversion was less than 95%, additional 0.05 molar equiv. of NBS was added and the mixture was stirred at 70° C. for 1 hour. The process was repeated, in necessary, until conversion reached 95%. The mixture was cooled to 20° C. and held at 20° C. for at least 1 hour. The solid (succinimide) was filtered and washed with isopropyl acetate (75 mL, 0.5×). The filtrate was washed with solution of sodium sulfite (157 g, 1×) in water (1413 mL, 9×), followed by water (315 mL, 2×). The organic layer was distilled under vacuum at 30 to 40° C. to ˜2× volume. Additional isopropyl acetate (315 mL, 2×) was added and distilled back to 2× volume, if necessary, until KF was no more than 0.1%. Then the organic layer was distilled at 30 to 40° C. to give methyl 2-(bromomethyl)-3-((tert-butyldimethylsilyl)oxy)benzoate as an oil (expected 180 g, 90% yield); 1H NMR (DMSO-d6, 300 MHz) δ 7.47 (dd, J=7.8, 1.2 Hz, 1H), 7.37 (t, J=8.1 Hz, 1H), 7.15 (dd, J=8.1, 1.2 Hz, 1H), 4.96 (s, 2H), 3.86 (s, 3H), 1.03 (s, 9H), 0.30 (s, 6H) ppm.
Reaction SMILES: [N:1]([O-])=O.[Na+].[CH3:5][C:6]1[C:10]([CH2:11][N:12]2[CH:16]=[C:15]([C:17]([NH:19][NH2:20])=[O:18])[CH:14]=[N:13]2)=[C:9]([CH3:21])[O:8][N:7]=1>C(O)(=O)C>[CH3:5][C:6]1[C:10]([CH2:11][N:12]2[CH:16]=[C:15]([C:17]([N:19]=[N+:20]=[N-:1])=[O:18])[CH:14]=[N:13]2)=[C:9]([CH3:21])[O:8][N:7]=1
Reactant: Cc1noc(C)c1Cn1cc(C(=O)NN)cn1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1noc(C)c1Cn1cc(C(=O)N=[N+]=[N-])cn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 94.4 %

Procedure:
Sodium nitrite (450 mg, 6.5 mmol, in H2O) (10 mL) was added dropwise, over 10 minutes, to a suspension of 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazole-4-carbohydrazide (example 10-1b) (1 g, 4.3 mmol) in 10% aqueous acetic acid (50 mL) and cooled to 0° C. via an ice water bath. The reaction was stirred for an additional 15 minutes then extracted with ethyl acetate (3×, 75 mL). The combined organic extracts were washed with aqueous saturated sodium carbonate (100 mL) followed by H2O (100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The solid product was triturated with ethyl acetate/hexanes (1/9) and dried en vacuo to afford 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazole-4-carbonyl azide (1 g, 93%) as a white solid. 1H NMR (CDCl1, 400 MHz): δ2.20 (s, 3H), 2.44 (s, 3H), 5.07 (s, 2H), 7.81 (s, 1H), 7.93 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[O:25]C.B(Br)(Br)Br>>[Cl:17][C:13]1[CH:12]=[C:11]([S:8]([C:6]2[CH:5]=[CH:4][C:3]([C:18]3[C:19]([OH:25])=[CH:20][CH:21]=[C:22]([F:24])[CH:23]=3)=[C:2]([F:1])[CH:7]=2)(=[O:10])=[O:9])[CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccc(F)cc1-c1ccc(S(=O)(=O)c2cccc(Cl)c2)cc1F
Agent: BrB(Br)Br
Product: O=S(=O)(c1cccc(Cl)c1)c1ccc(-c2cc(F)ccc2O)c(F)c1

Procedure:
The subtitle compound was prepared by the method of example 2 step (iii) using the product of step (iii) and boron tribromide.
Reaction SMILES: S(=O)(=O)(O)O.COCCOC[O:12][C:13]1[CH:33]=[CH:32][C:16]([C:17]([NH:19][CH2:20][C@H:21]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:22]([O:24][CH3:25])=[O:23])=[O:18])=[CH:15][CH:14]=1>O1CCCC1.CO>[OH:12][C:13]1[CH:33]=[CH:32][C:16]([C:17]([NH:19][CH2:20][C@H:21]([N:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)[C:22]([O:24][CH3:25])=[O:23])=[O:18])=[CH:15][CH:14]=1
Reactant: COCCOCOc1ccc(C(=O)NC[C@@H](C(=O)OC)N2CCCCC2)cc1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)[C@H](CNC(=O)c1ccc(O)cc1)N1CCCCC1
Temperature: 35 °C
Reaction time: 18 h
Yield: 92.7 %

Procedure:
1.5 ml of 98% sulphuric acid are added to a solution of 9.6 g (24.3 mmol) of methyl (S)-3-[4-(2-methoxyethoxymethoxy)benzoylamino]-2-piperidin-1-yl-propanoate in 50 ml of tetrahydrofuran and 50 ml of methanol. The reaction medium is then stirred at 35° C. for 18 h. The solvents are concentrated under vacuum to 80% then the residue is taken up in ethyl acetate and hydrolysed. The pH is brought to 8 with a saturated aqueous solution of sodium hydrogen carbonate. The product is extracted with ethyl acetate. The organic phase is washed with water then with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated under vacuum. 6.9 g (93%) of methyl (S)-3-(4-hydroxybenzoylamino)-2-piperidin-1-ylpropanoate are obtained in the form of a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:27]=[CH:26][C:5]2[CH:6]([C:18]3[C:19](=[O:25])[NH:20][C:21](=[O:24])[NH:22][CH:23]=3)[C:7]3[CH:14]=[CH:13][C:12]([CH:15]([CH3:17])[CH3:16])=[CH:11][C:8]=3[CH:9]=[CH:10][C:4]=2[CH:3]=1.[CH2:28]([O:30][C:31]([C:33]1[O:34][C:35]([CH2:38]Br)=[CH:36][CH:37]=1)=[O:32])[CH3:29]>>[CH3:1][C:2]1[CH:27]=[CH:26][C:5]2[CH:6]([C:18]3[C:19](=[O:25])[NH:20][C:21](=[O:24])[N:22]([CH2:38][C:35]4[O:34][C:33]([C:31]([O:30][CH2:28][CH3:29])=[O:32])=[CH:37][CH:36]=4)[CH:23]=3)[C:7]3[CH:14]=[CH:13][C:12]([CH:15]([CH3:17])[CH3:16])=[CH:11][C:8]=3[CH:9]=[CH:10][C:4]=2[CH:3]=1
Reactant: Cc1ccc2c(c1)C=Cc1cc(C(C)C)ccc1C2c1c[nH]c(=O)[nH]c1=O
Reactant: CCOC(=O)c1ccc(CBr)o1
Product: CCOC(=O)c1ccc(Cn2cc(C3c4ccc(C)cc4C=Cc4cc(C(C)C)ccc43)c(=O)[nH]c2=O)o1

Procedure:
The subtitle compound was prepared from the product of step (vi) (1 g) and 5-bromomethyl-2-furancarboxylic acid ethyl ester (J. Chem. Soc. Perkin Trans. 1, 1981, 1125, Bull. Chem. Soc. Jpn. 1987, 60, 1807)(0.65 g) according to the method of example 1 step (iv). Purification was by chromatography eluting with 20% ethyl acetate in toluene. Yield 0.375 g.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[C:22]([CH3:27])=[CH:23][CH:24]=[CH:25][CH:26]=2)(=[O:20])=[O:19])[N:11]([CH3:28])[C:10]=1[C:29]([OH:31])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][N:33](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.CCN(CC)CC.Cl.CN>CN(C)C=O>[CH3:32][NH:33][C:29]([C:10]1[N:11]([CH3:28])[C:12]([CH2:16][NH:17][S:18]([C:21]2[C:22]([CH3:27])=[CH:23][CH:24]=[CH:25][CH:26]=2)(=[O:20])=[O:19])=[CH:13][C:14](=[O:15])[C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:31]
Reactant: Cc1ccccc1S(=O)(=O)NCc1cc(=O)c(OCc2ccccc2)c(C(=O)O)n1C
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1c(OCc2ccccc2)c(=O)cc(CNS(=O)(=O)c2ccccc2C)n1C
Reaction time: 0.5 h
Yield: 22.6 %

Procedure:
To a stirred solution of 3-benzyloxy-1-methyl-4-oxo-6-[(toluene-2-sulfonylamino)-methyl]-1,4-dihydro-pyridine-2-carboxylic acid (13-02) (600.0 mg, 1.36 mmol) in dimethylformamide (10 mL) were added HBTU (O-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate) (772.74 mg, 2.04 mmol) and triethylamine Et3N (0.942 mL, 6.78 mmol). The mixture was stirred for 30 min., then methylamine hydrochloride salt (274.88 mg, 4.07 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, it was quenched with ice cold water and then extracted with ethyl acetate. Then combined organic layer was washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. It was then purified using normal column chromatography to get 3-benzyloxy-1-methyl-4-oxo-6-[(toluene-2-sulfonylamino)-methyl]-1,4-dihydro-pyridine-2-carboxylic acid methylamide (15-02) (140.0 mg, 22.64%) as an off white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[C:56]([O:60][C:61]([N:63]1[CH2:68][CH2:67][N:66]([CH2:69][CH2:70][NH2:71])[CH2:65][CH2:64]1)=[O:62])([CH3:59])([CH3:58])[CH3:57]>CN(C=O)C.CO>[C:56]([O:60][C:61]([N:63]1[CH2:64][CH2:65][N:66]([CH2:69][CH2:70][NH:71][C:30]([C:26]2[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])(=[O:11])=[O:12])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])=[O:32])[CH2:67][CH2:68]1)=[O:62])([CH3:59])([CH3:58])[CH3:57]
Reactant: CC(C)(C)OC(=O)N1CCN(CCN)CC1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NCCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.7 %

Procedure:
To a solution of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (505 mg, 1 mmol) in DMF (10 mL) was added HOBt (202 mg, 1.3 eq.), EDAC.HCl (288 mg, 1.5 eq.) and TEA (302 mg, 3 eq.). After stirring at rt for 30 mins, to the mixture was added 4-(2-amino-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (298 mg, 1.3 eq.). After stirring at 40° C. for overnight, the reaction was diluted with methanol (2 mL), the precipitate was collected by vacuum filtration, washed with methanol, water and dried to give 700 mg of 4-[2-({5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carbonyl}-amino)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester as a yellow solid.
Reaction SMILES: [C:1]([C:4]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=2[C:23]([F:26])([F:25])[F:24])[C:12]2[C:11](=[O:27])[NH:10][CH:9]=[CH:8][C:7]=2[NH:6][C:5]=1[CH3:28])(=[O:3])[CH3:2].FC(F)(F)S(O[CH2:35][CH3:36])(=O)=O.CO>C1COCC1>[CH2:35]([O:27][C:11]1[N:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[CH:13]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[C:23]([F:26])([F:25])[F:24])[C:4]([C:1](=[O:3])[CH3:2])=[C:5]([CH3:28])[NH:6]2)[CH3:36]
Reactant: CCOS(=O)(=O)C(F)(F)F
Reactant: CC(=O)C1=C(C)Nc2cc[nH]c(=O)c2C1c1ccc([N+](=O)[O-])cc1C(F)(F)F
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1nccc2c1C(c1ccc([N+](=O)[O-])cc1C(F)(F)F)C(C(C)=O)=C(C)N2
Reaction time: 0.17 h

Procedure:
976 mg (2.48 mmol) of 3-acetyl-2-methyl-4-[4-nitro-2-(trifluoromethyl)phenyl]-4,6-dihydro-1,6-naphthyridin-5(1H)-one are suspended in THF (60 ml), and 3 ml (3 mmol) of N′″-(tert-butyl)-N,N′,N″-tris[tris(dimethylamino)phosphoranylidene]phosphorimide triamide (phosphazene base P4-t-Bu; 1 M in hexane) are added. Then 389 μl (2.97 mmol) of ethyl trifluoromethanesulfonate are added to the dark red solution. The decolorized solution is stirred for a further 10 min and then mixed with methanol and concentrated. The residue is purified by preparative HPLC to result in 240 mg (23% of theory) of the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][CH3:9])[CH2:4][CH2:3]1.C([Li])CCC.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18](Cl)[N:17]=1>O1CCCC1>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][CH2:9][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([Cl:15])[N:17]=2)[CH2:4][CH2:3]1
Reactant: CNC1CCN(C)CC1
Reactant: Clc1cccc(Cl)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN1CCC(NCc2cccc(Cl)n2)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
Dissolve 1-methyl-4-(methylamino)piperidine (10 mL, 68.8 mmol) in tetrahydrofuran (50 mL) and cool to −78° C. Slowly add n-butyllithium (1.6 N in hexane, 43 mL, 68.8 mmol) to the reaction mixture and stir at −78° C. for 30 min. Warm the reaction mixture to room temperature and stir for 30 min. Then cool the reaction mixture to −78° C. and add 2,6-dichloropyridine (11.2 g, 75.7 mmol) in tetrahydrofuran (50 mL). Stir the reaction mixture at −78° C. for 15 min, warm to room temperature, and then heat to 60° C. for 19 hr. Cool the reaction mixture to room temperature and partition between ethyl acetate and water. Separate the organic layer and extract the aqueous layer with dichloromethane (2×50 mL). Combine organic extracts, dry (MgSO4), filter, and concentrate in vacuo. Purify the residue by column chromatography on silica gel using a gradient of 2%-10% (2M NH3 in methanol) in CH2Cl2 to give of the title intermediate (11.91 g, 72%): mass spectrum (ion spray): m/z=240.1 (M+1); 1H NMR: δ (CDCl3, ppm) 7.34 (t, J=7.6, 16.0 Hz, 1H), 6.50 (d, J=8.0 Hz, 1H), 6.33 (d, J=8.8 Hz, 1H), 4.41 (m, 1H), 2.94 (m, 2H), 2.86 (s, 3H), 2.32 (s, 3H), 2.15 (m, 2H), 1.84 (m, 2H), 1.68 (m, 2H).
Reaction SMILES: [CH:1]([NH:3][C:4]1[NH:5][CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[C:8]=1[C:9]([NH2:11])=[O:10])=[O:2].[H][H]>[Pd].CO>[CH:1]([NH:3][C:4]1[NH:5][CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[C:8]=1[C:9]([NH2:11])=[O:10])=[O:2]
Reactant: NC(=O)c1c(-c2ccc([N+](=O)[O-])cc2)c[nH]c1NC=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1c(-c2ccc(N)cc2)c[nH]c1NC=O
Yield: 61.4 %

Procedure:
0.23 g (0.834 mmol) of 2-formylamino-4-(4-nitrophenyl)-1H-pyrrole-3-carboxamide is added at a temperature in the region of 25° C. to a suspension of 0.030 g (0.0285 mmol) of 10% palladium on carbon in 15 cm3 of methanol. After hydrogenation for 5 hours in an autoclave under 2 bar of hydrogen, at a temperature in the region of 25° C., the reaction mixture is filtered, the catalyst is rinsed with three times 5 cm3 of methanol and then the filtrate is concentrated to dryness under reduced pressure (2.7 kPa) to give 0.125 g of 2-formylamino-4-(4-aminophenyl)-1H-pyrrole-3-carboxamide, in the form of a green solid. 1H NMR (400 MHz, (CD3)2SO, —δ in ppm) 5.13 (broad s, 2H); 5.43 (broad m, 1H); 6.27 (d, J=2.5 Hz, 1H); 6.60 (d, J=9.0 Hz, 2H); 6.80 (broad m, 1H); 6.99 (d, J=9.0 Hz, 2H); 8.34 (d, J=1.5 Hz, 1H); 10.9 (broad s, 1H); 11.25 (broad s, 1H)
Reaction SMILES: [C-:1]#[N:2].[K+].Br[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10]>O.CO>[C:1]([CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])#[N:2]
Reactant: [C-]#N
Reactant: COC(=O)CCCCBr
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)CCCCC#N
Yield: 74.3 %

Procedure:
Potassium Cyanide (4 g, 61.44 mmol) is dissolved in 70 mL water and 200 mL methanol. To the solution 10 g (51.2 mmol) of methyl 5-bromopentanoate is added and the mixture is refluxed overnight. The reaction mixture is concentrated to dryness. To the residue, 100 mL of EtOAc is added to extract the product. The organic is washed with water three times, dried and concentrated to yield 5.37 g (74%) of methyl 5-cyanopentanoate as an oil.
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=O)=[C:9]([N:17]2[CH2:21][CH2:20][O:19][C:18]2=[O:22])[CH:8]=1.[CH:24]1([C:27]2[CH:28]=[C:29]([CH3:39])[C:30]([N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[N:31][CH:32]=2)[CH2:26][CH2:25]1>>[CH:24]1([C:27]2[CH:28]=[C:29]([CH3:39])[C:30]([N:33]3[CH2:34][CH2:35][N:36]([C:11]([C:10]4[CH:15]=[CH:16][C:7]([N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:23])=[CH:8][C:9]=4[N:17]4[CH2:21][CH2:20][O:19][C:18]4=[O:22])=[O:13])[CH2:37][CH2:38]3)=[N:31][CH:32]=2)[CH2:26][CH2:25]1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Reactant: COC(=O)c1ccc(N2CCCS2(=O)=O)cc1N1CCOC1=O
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCS3(=O)=O)cc2N2CCOC2=O)CC1
Yield: 9.5 %

Procedure:
Using methyl 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-(2-oxooxazolidin-3-yl)benzoate (170 mg) described in Preparation Example 32 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (110 mg) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Example 109, the title compound (25 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:7]=[C:6]([F:16])[C:3]=1[CH2:4][OH:5].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30](Cl)=[O:31])[C@H:26]([CH2:33][CH3:34])[CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:7]=[C:6]([F:16])[C:3]=1[CH2:4][O:5][C:30]([N:27]1[CH2:28][CH2:29][N:24]([C:22]([O:21][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:23])[CH2:25][C@H:26]1[CH2:33][CH3:34])=[O:31]
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)Cl
Reactant: COCCCOc1cc(F)c(CO)c(Cl)c1
Product: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1c(F)cc(OCCCOC)cc1Cl
Yield: 77 %

Procedure:
This compound was prepared from 2-chloro-6-fluoro-4-(3-methoxy-propoxy)-benzylalcohol and (R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid tert-butyl ester according to the procedure described in Example 179 to give the product as a colorless oil (576 mg; 77%); MS (ISP): 506.4 (M+NH4)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[CH:17])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.[N+:33]([CH2:36][CH3:37])([O-])=[O:34]>C(#N)C.CN(C)C1C=CN=CC=1>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[O:34][N:33]=[C:36]([CH3:37])[CH:17]=3)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: C#Cc1cccc2oc(C(=O)OCC)c(C)c12
Reactant: CC[N+](=O)[O-]
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CCOC(=O)c1oc2cccc(-c3cc(C)no3)c2c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 25 %

Procedure:
To a solution of 4-ethynyl-3-methyl-benzofuran-2-carboxylic acid ethyl ester (228 mg, 0.99 mmol, 1 eq.) in acetonitrile (5 mL) under argon, was added di-tert-butyl dicarbonate (327 mg, 1.5 mmol, 1.5 eq.), and 4-(dimethylamino)pyridine (12 mg, 0.1 mmol, 0.1 eq.). Nitroethane (79 uL, 1.1 mmol, and 1.1 eq.) in acetonitrile (5 mL) was added drop-wise to the reaction mixture, and the reaction was stirred at room temperature for 72 hours. After work-up and flash column chromatography, 3-methyl-4-(3-methyl-isoxazol-5-yl)-benzofuran-2-carboxylic acid ethyl ester was obtained in 25% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.4 (t, J=7.1 Hz, 3 H) 2.3 (s, 3 H) 2.4 (s, 3 H) 4.4 (q, J=7.1 Hz, 2 H) 6.8 (s, 1 H) 7.5 (dd, J=7.5, 0.9 Hz, 1 H) 7.6 (m, 1 H) 7.9 (dd, J=8.5, 0.9 Hz, 1 H).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]([C:13]2[NH:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([O:22][CH2:23][CH2:24][O:25][CH2:26][CH3:27])[C:15]=3[N:14]=2)=[O:12])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Br[CH2:29][C:30]([NH:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][N:34]=1)=[O:31].C([O-])(=O)C>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]([C:13]2[N:17]([CH2:29][C:30](=[O:31])[NH:32][C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][N:34]=3)[C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([O:22][CH2:23][CH2:24][O:25][CH2:26][CH3:27])[C:15]=3[N:14]=2)=[O:12])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: O=C(CBr)Nc1ccc(Cl)cn1
Reactant: CCOCCOc1cccc2[nH]c(C(=O)NC3CCN(C(C)C)CC3)nc12
Agent: CC(=O)[O-]
Product: CCOCCOc1cccc2c1nc(C(=O)NC1CCN(C(C)C)CC1)n2CC(=O)Nc1ccc(Cl)cn1

Procedure:
1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-4-(2-ethoxy-ethoxy)-1H-benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide was prepared by a procedure according to example 108 (v) starting from 540.0 mg (1.44 mmol) 4-(2-Ethoxy-ethoxy)-1H-benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide and 359.8 mg (1.44 mmol) 2-bromo-N-(5-chloro-pyridin-2-yl)-acetamide. The title compound was transformed into its acetate affording a colorless amorphous material.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][C:3]=1[NH2:16].[CH3:17][C:18]1([CH3:27])[CH2:23][CH2:22][C:21](B(O)O)=[CH:20][CH2:19]1>>[CH3:17][C:18]1([CH3:27])[CH2:23][CH2:22][C:21]([C:2]2[CH:7]=[C:6]([CH2:8][CH2:9][N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[CH:5]=[CH:4][C:3]=2[NH2:16])=[CH:20][CH2:19]1
Reactant: Nc1ccc(CCN2CCOCC2)cc1Br
Reactant: CC1(C)CC=C(B(O)O)CC1
Product: CC1(C)CC=C(c2cc(CCN3CCOCC3)ccc2N)CC1

Procedure:
The title compound was prepared by Suzuki coupling of 2-bromo-4-(2-morpholin-4-yl-ethyl)-phenylamine (as prepared in Example 33, step (b)) and 4,4-dimethyl-1-cyclohexen-1-ylboronic acid according to the procedure in Example 1, step (e). Mass spectrum (ESI, m/z): Calcd. for C20H30N2O, 315.2 (M+H). found 315.1.