Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH2:12])=[S:11])[CH:6]=[CH:7][CH:8]=1.Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([C@H:23]2[CH2:28][CH2:27][C@H:26]([CH2:29][C:30]([O:32]CC)=[O:31])[CH2:25][CH2:24]2)=[CH:19][CH:18]=1)=O.O.[OH-].[Li+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[S:11][CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C@H:23]4[CH2:28][CH2:27][C@H:26]([CH2:29][C:30]([OH:32])=[O:31])[CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[N:12]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(NC(N)=S)c1
Reactant: CCOC(=O)C[C@H]1CC[C@H](c2ccc(C(=O)CBr)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cccc(Nc2nc(-c3ccc([C@H]4CC[C@H](CC(=O)O)CC4)cc3)cs2)c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
1-(3-Methoxyphenyl)-2-thiourea (0.01 g, 0.054 mmol) was added to a solution of the product from Example 48A (0.02 g, 0.054 mmol) in ethanol (0.5 mL) and heated at 80° C. for 1 h. The solvent was then removed in vacuo and the residue taken up in tetrahydrofuran (1 mL) and water (0.5 mL). Lithium hydroxide monohydrate (0.005 g, 0.1 mmol) was added to the reaction mixture and stirred at 50° C. for 3 h. The solvents were then removed and the residue purified by RP-HPLC to afford the title compound as a white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.09-1.18 (m, 2 H), 1.45-1.54 (m, 2 H), 1.62-1.69 (m, 1 H), 1.70-1.77 (m, 1 H), 1.80-1.88 (m, 4 H), 2.13 (d, J=7 Hz, 2 H), 3.78 (s, 3 H), 6.54 (dd, J=8.24, 1.83 Hz, 1 H), 7.10-7.16 (m, 1 H), 7.20-7.27 (m, 1 H), 7.29 (d, J=8.24 Hz, 2 H), 7.51-7.56 (m, 1 H), 7.79-7.83 (d, J=8.24 Hz, 2 H), 10.25 (s, 1 H), 1.2.05 (s, 1 H): MS (ESI) m/e 423.2 (M+H).
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[CH2:7]([CH:9]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=1)[CH3:8]>O1CCCC1.C(N(CC)CC)C.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.[Cu]I>[CH2:7]([CH:9]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])=[CH:16][CH:17]=1)[CH3:8]
Reactant: CCCCC(CC)COc1ccc(I)cc1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCC(CC)COc1ccc(C#C[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 64.5 h
Yield: 0.1 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.52 g, 0.45 mmol) was added to a degassed suspension of trimethylsilyl acetylene (3.00 mL, 2.09 g, 21.2 mmol), 4-(2-ethylhexyloxy)iodobenzene (2) (4.27 g, 12.9mmol) and copper (I) iodide (294 mg, 1.54 mmol) in tetrahydrofuran (20 mL) and triethylamine (30 mL). The mixture was stirred under argon at room temperature for 64.5 h. The solution was filtered through a short plug of silica with dichloromethane as eluent and the solvent removed. The residue was purified by column chromatography over silica with light petroleum as eluent to leave [4-(2-ethylhexyloxy)phenylethynyl]trimethylsilane (3) (2.93 mg, 75%) as a clear, colourless oil. (Found: C, 75.35; H, 9.85. Cl9H30OSi requires C, 75.43; H, 10.0%); ν-max(film)/cm−2156 (C≡C); δH(400 MHz, CDCl3) 0.25 (9 H, s, SiMe3), 0.92 (6 H, m, CH3), 1.30-1.51 (8 H, m, CHCH2CH2CH2CH3 and CHCH2CH3) 1.72 (1 H, OCH2CR), 3.84 (2 H, d, J5, OCH2CH) and 6.82 and 7.40 (4 H, AA′BB′, phenyl H); δc(100.6 MHz, CDCl3) 0.1, 11.1, 14.1, 23.0, 23.8, 29.0, 30.4, 39.3, 70.5, 92.2, 105.3, 114.3, 114.8, 133.4 and 159.6.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]([CH3:20])([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:10]=[N:11][OH:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][N:22]([C:27]1[CH:28]=[C:29]([CH:42]=[C:43]([C:45]#[CH:46])[CH:44]=1)[C:30]([NH:32][C@@H:33]([C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)[CH3:34])=[O:31])[S:23]([CH3:26])(=[O:25])=[O:24].C(N(CC)CC)C>CN(C=O)C>[CH3:21][N:22]([C:27]1[CH:28]=[C:29]([CH:42]=[C:43]([C:45]2[O:12][N:11]=[C:10]([C@@:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])([CH3:20])[CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:46]=2)[CH:44]=1)[C:30]([NH:32][C@@H:33]([C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)[CH3:34])=[O:31])[S:23]([CH3:26])(=[O:25])=[O:24]
Reactant: C#Cc1cc(C(=O)N[C@H](C)c2ccc(F)cc2)cc(N(C)S(C)(=O)=O)c1
Reactant: CC(C)(C)OC(=O)N[C@@](C)(C=NO)Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@@H](NC(=O)c1cc(-c2cc([C@@](C)(Cc3ccccc3)NC(=O)OC(C)(C)C)no2)cc(N(C)S(C)(=O)=O)c1)c1ccc(F)cc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-2-tert-butoxycarbonylamino-2-methyl-3-phenylpropanal oxime (Intermediate L, 30 mg, 0.11 mmol) in 0.5 mL DMF, cooled to 5° C., was added a solution of N-bromosuccinimide from Step B (29 mg, 0.165 mmol) in 0.5 mL DMF dropwise. After stirring at 5° C. for 1 h, a solution of 3-(N-methyl-N-(methylsulfonyl)amino)-5-ethynyl-N—((R)-1-(4-fluorophenyl)ethyl)benzamide (124 mg, 0.33 mmol) and triethylamine (0.023 mL, 0.165 mmol) in 0.2 mL DMF was added. The reaction was stirred at rt for 1 week and then heated to 50° C. overnight. Purification by reverse phase preparative HPLC (5-95% CH3CN in water containing 0.1% TFA) gave 3-(N-methyl-N-(methylsulfonyl)amino)-5-(3-((R)-2-tert-butoxycarbonylamino-1-phenylpropan-2-yl)isoxazol-5-yl)-N—((R)-1-(4-fluorophenyl)ethyl)benzamide. 1H NMR (CDCl3) δ 8.02 (s, 1H), 7.90 (m, 1H), 7.86 (m, 1H), 7.38 (m, 2H), 7.26 (m, 3H), 7.08 (m, 4H), 6.60 (s, 1H), 6.44 (d, J=7.6 Hz, 1H), 5.31 (m, 1H), 5.01 (bs, 1H), 3.53 (d, J=12.9 Hz, 1H), 3.39 (s, 3H), 3.34 (m, 1H), 2.89 (s, 3H), 1.63 (m, 6H), 1.44 (s, 9H).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]4[C:27](=[O:28])[O:26][C:25]([CH3:30])([CH3:29])[O:24][C:23]=4[CH:31]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH:34]1([CH2:39][CH2:40][C:41](Cl)=[O:42])[CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][N:18]([C:19]3[CH:20]=[CH:21][C:22]4[C:27](=[O:28])[O:26][C:25]([CH3:29])([CH3:30])[O:24][C:23]=4[CH:31]=3)[C:41](=[O:42])[CH2:40][CH2:39][CH:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)CCC1CCCC1
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)OC(C)(C)OC4=O)cc2)cc1
Product: CCCCc1ccc(C#Cc2ccc(CN(C(=O)CCC3CCCC3)c3ccc4c(c3)OC(C)(C)OC4=O)cc2)cc1

Procedure:
The titled compound was prepared following the procedure I using 7-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one and 3-cyclopentylpropanoyl chloride as a white powder (44%). 1H NMR (CDCl3, 300 MHz) δ 7.92 (d, J=8.3 Hz, 1H), 7.42 (m, 4H), 7.14 (m, 4H), 6.77 (m, 1H), 6.60 (br s, 1H), 4.89 (s, 2H), 2.61 (t, J=7.5 Hz, 2H), 2.16 (m, 2H), 1.71 (s, 6H). 1.68-1.28 (m, 13H), 1.03-0.88 (m, 5H). HPLC, Rt: 6.24 min (Purity: 99%).
Reaction SMILES: O([C:8]([O:10][CH2:11][CH2:12][S:13][C:14]1[N:19]2[CH:20]=[CH:21][N:22]=[C:18]2[CH:17]=[CH:16][CH:15]=1)=[O:9])C1C=CC=CC=1.[NH2:23][CH2:24][CH2:25][CH2:26][OH:27]>C(Cl)(Cl)Cl>[OH:27][CH2:26][CH2:25][CH2:24][NH:23][C:8]([O:10][CH2:11][CH2:12][S:13][C:14]1[N:19]2[CH:20]=[CH:21][N:22]=[C:18]2[CH:17]=[CH:16][CH:15]=1)=[O:9]
Reactant: O=C(OCCSc1cccc2nccn12)Oc1ccccc1
Reactant: NCCCO
Solvent: ClC(Cl)Cl
Product: O=C(NCCCO)OCCSc1cccc2nccn12
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 55.6 %

Procedure:
To 5-[2-(phenoxycarbonyloxy)ethylthio]imidazo[1,2-a]pyridine (1.10 g, 3.50 mmoles) was added 3-aminopropanol (0.27 ml, 3.52 mmoles) and the mixture was stirred at 120° C. for 1.5 hours. The reaction mixture was cooled by standing and chloroform was added thereto, which was washed with water and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. Then, the residue was purified by column chromatography (eluent: methanol/chloroform=1:20) to obtain 575 mg of the desired product (55.6%, colorless crystals).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10])(=O)[NH2:2].P(Cl)(Cl)(Cl)=O.Cl.[H][H]>C(O)C.[Pd]>[NH2:2][CH2:1][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10]
Reactant: NC(=O)c1cncc(C(=O)O)c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O=P(Cl)(Cl)Cl
Product: NCc1cncc(C(=O)O)c1
Temperature: 100 °C

Procedure:
A mixture of 5-carbamoyl-nicotinic acid (compound F3) (5.00 g) and phosphorus oxychloride (50 mL, 0.55 mol) is heated to 100° C. for 5 h. After usual workup the crude product is dissolved in ethanol acidified with hydrochloric acid and hydrogenated with the use of Pd/C (1.00 g, 5% Pd) at 4 bar hydrogen pressure for 16 h. After filtration of the catalyst, the mixture is evaporated, and the residue is treated with ethanol and extracted several times with chloroform.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].Cl[CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[CH:26]=1.O>CN(C)C=O>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([C:27]4[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=4)[CH:26]=3)=[CH:14][CH:15]=2)[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: FC(F)(F)c1ccc(-c2cncc(CCl)c2)cc1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1ccc(-c2cncc(COc3ccc(CCCCn4ccnn4)cc3)c2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46.8 %

Procedure:
A solution of 37 mg (0.17 mmol) 4-(4-[1,2,3]triazol-1-yl-butyl)phenol in 2.0 ml N,N-dimethylformamide was treated at 0° C. with 7 mg (0.17 mmol) of 60% sodium hydride and stirred at 0° C. for 30 min. Then 50 mg (0.17 mmol) 3-Chloromethyl-5-(4-trifluoromethyl-phenyl)-pyridine were added and stirred continued at r. t. over night. After addition of 4 ml water, the precipitate was isolated, washed thoroughly with water, n-heptane and diisopropylether. The residue was dried at 40° C. to give 36 mg (46%) of the title compound as light brown powder.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.[N:13]([C:16]1[C:24]([I:25])=[CH:23][C:19]([C:20](O)=[O:21])=[C:18]([O:26][CH3:27])[CH:17]=1)=[N+:14]=[N-:15]>>[CH3:12][N:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:20](=[O:21])[C:19]2[CH:23]=[C:24]([I:25])[C:16]([N:13]=[N+:14]=[N-:15])=[CH:17][C:18]=2[O:26][CH3:27])[CH2:7]1
Reactant: CN1CCc2c(N)cccc2C1
Reactant: COc1cc(N=[N+]=[N-])c(I)cc1C(=O)O
Product: COc1cc(N=[N+]=[N-])c(I)cc1C(=O)Nc1cccc2c1CCN(C)C2

Procedure:
The title compound was prepared in an analogous manner to Example 1 from 5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and 4-azido-5-iodo-2-methoxybenzoic acid.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:7][C@H:6]([N:8]2[CH:12]=[C:11]([NH:13][C:14](=[O:26])[CH2:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:18][CH:17]=3)[N:10]=[CH:9]2)[CH2:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[NH2:1][C@@H:4]1[CH2:5][C@H:6]([N:8]2[CH:12]=[C:11]([NH:13][C:14](=[O:26])[CH2:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:18][CH:17]=3)[N:10]=[CH:9]2)[CH2:7]1
Reactant: [N-]=[N+]=N[C@H]1C[C@@H](n2cnc(NC(=O)Cc3cccc4ccccc34)c2)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: N[C@H]1C[C@@H](n2cnc(NC(=O)Cc3cccc4ccccc34)c2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
N-[1-(cis-3-azido-cyclobutyl )-1H-imidazol-4-yl]-2-naphthalen-1-yl-acetamide (Preparation 4, Step 4; 330 mg, 0.95 mmol) was treated with triphenylphosphine (301 mg, 1.15 mmol) in tetrahydrofuran (10 mL) and water (1 mL) at 23° C. The solution was stirred at room temperature for 18 h. The solvent was removed in vacuo and the resulting residue was purified by silica gel chromatography (20:1:0.5 chloroform-methanol-ammonium hydroxide) to afford 289 mg (95% yield) of N-[1-(cis-3-amino-cyclobutyl)-1H-imidazol-4-yl]-2-naphthalen-1-yl-acetamide; 1H NMR (400 MHz, CD3OD) δ8.05 (d, J=7.5 Hz, 1H), 7.87 (d, J=7.9 Hz, 1H), 7.79 (d, J=9.0 Hz, 1H), 7.45 (m, 5H), 7.35 (s, 1H), 4.26 (m, 1H), 4.16 (s, 2H), 3.29 (m, 2H), 3.16 (m, 1H), 2.75 (m, 2H), 2.1 (m, 2H); MS (AP/Cl): 321.3 (M+H)+.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:4]=1[O:5][CH2:6][CH:7]([OH:10])[CH2:8][NH2:9].[H][H]>[Pd]>[ClH:1].[ClH:1].[ClH:1].[NH2:2][C:3]1[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:4]=1[O:5][CH2:6][CH:7]([OH:10])[CH2:8][NH2:9]
Reactant: NCC(O)COc1ccc([N+](=O)[O-])cc1N
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Product: NCC(O)COc1ccc(N)cc1N

Procedure:
0.02 mol (5.3 g) of the 1-(2'-amino-4'-nitrophenoxy)-3-aminopropan-2-ol monohydrochloride prepared according to Example 4 is introduced into 50 ml of 96° strength alcohol and 0.2 g of 10% strength palladium-on-charcoal. The mixture is heated at 85° C. for one hour under 35 bars of hydrogen. After cooling, it is filtered to remove the catalyst, the filtrate being collected in 20 ml of iced ethanol saturated with hydrogen chloride. The expected product precipitates in the form of the trihydrochloride. After recrystallisation of this trihydrochloride from an ethanol/water mixture, it melts with decomposition at 236°-238° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].[CH3:16][N:17]([CH3:28])[CH2:18][CH2:19][NH:20][C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][N:22]=1>>[Cl:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13](=[O:15])[CH3:14])=[C:2]2[NH:27][C:24]1[CH:23]=[N:22][C:21]([NH:20][CH2:19][CH2:18][N:17]([CH3:28])[CH3:16])=[CH:26][CH:25]=1
Reactant: CN(C)CCNc1ccc(N)cn1
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Cl
Product: CC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(NCCN(C)C)nc1
Yield: 45.5 %

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)ethanone (300 mg, 1.2 mmol) was reacted with N2-[2-(dimethylamino)ethyl]pyridine-2,5-diamine (320 mg, 1.5 mmol) to afford the desired product (210 mg, 37%) as an orange solid: 1H NMR (500 MHz, CDCl3) δ 11.41 (br s, 1H), 9.02 (s, 1H), 8.13-8.07 (m, 1H), 7.95 (d, J=2.5 Hz, 1H), 7.47 (dd, J=8.7, 1.1 Hz, 1H), 7.29-7.23 (m, 1H), 6.44 (d, J=8.8 Hz, 1H), 5.12 (t, J=5.1 Hz, 1H), 3.41 (q, J=5.7 Hz, 2H), 2.69 (s, 3H), 2.60 (t, J=6.0 Hz, 2H), 2.30 (s, 6H); ESI MS m/z 385 [M+H].+
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[Br:7][C:8]1[C:9]([O:31][CH3:32])=[C:10]([NH2:30])[CH:11]=[C:12]([C:14]2[C:26]3[C:25]([CH3:27])=[C:24]([CH3:28])[S:23][C:22]=3[C:21]([Br:29])=[C:20]3[C:15]=2[CH:16]=[CH:17][CH:18]=[CH:19]3)[CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:6][O:5][C:3](=[O:4])[CH2:2][NH:30][C:10]1[CH:11]=[C:12]([C:14]2[C:26]3[C:25]([CH3:27])=[C:24]([CH3:28])[S:23][C:22]=3[C:21]([Br:29])=[C:20]3[C:15]=2[CH:16]=[CH:17][CH:18]=[CH:19]3)[CH:13]=[C:8]([Br:7])[C:9]=1[O:31][CH3:32]
Reactant: COc1c(N)cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc1Br
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CNc1cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc(Br)c1OC
Reaction time: 48 h
Yield: 71.1 %

Procedure:
Methyl bromoacetate (0.285 mL, 3.01 mmol) was added to a stirred, room temperature suspension of 3-bromo-5-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-methoxy-phenylamine (0.260 g, 0.529 mmol) and potassium carbonate (0.411 g, 3.00 mmol) in DMF (1.7 mL). After two days, more methyl bromoacetate (0.135 mL, 1.5 mmol) and the reaction mixture was stirred for a day longer. The reaction mixture was added to water and the solid was filtered and washed with water. The solid was triturated with pet. ether and dried at 60° C. under vacumm to provide the title compound as a white solid (0.212 g, 71%): mp 194-198° C.: NMR (DMSO-d6); 8.17 (dd, J=8, 1 Hz, 1H), 7.63 (ddd, J=8, 6, 1 Hz, 1H), 7.53-7.45 (m, 2H), 6.77 (d, J=2 Hz, 1H), 6.54 (d, J=2 Hz, 1H), 6.10 (t, J=7 Hz, 1H), 3.97 (dd, J=7, 4 Hz, 2H), 3.83 (s, 3H), 3.52 (s, 3H),2.43 (s, 3H), 1.69 (s, 3H); MS (FAB+): 2 bromine isotope pattern 561, 563, 565; Anal. Calc. for C24H21Br2NO3S: C, 51.17; H, 3.76; N, 2.49. Found: C, 50.43; H, 3.63; N, 2.53.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]1[N:16]=[C:15]([C:17]3[C:18]([N:37]([CH3:42])[S:38]([CH3:41])(=[O:40])=[O:39])=[CH:19][C:20]4[O:24][C:23]([C:25]5[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=5)=[C:22]([C:32]([NH:34][CH3:35])=[O:33])[C:21]=4[CH:36]=3)[CH:14]=[CH:13][C:12]=1[CH2:43]O)[NH:6]2.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:11]4[N:16]=[C:15]([C:17]5[C:18]([N:37]([CH3:42])[S:38]([CH3:41])(=[O:39])=[O:40])=[CH:19][C:20]6[O:24][C:23]([C:25]7[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=7)=[C:22]([C:32]([NH:34][CH3:35])=[O:33])[C:21]=6[CH:36]=5)[CH:14]=[CH:13][C:12]=4[CH2:43][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(CO)c(-c4cc5c(F)cccc5[nH]4)n3)cc12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3C4)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
5-(6-(4-fluoro-1H-indol-2-yl)-5-(hydroxymethyl)pyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (280 mg, 0.45 mmol) was dissolved in THF (8 mL). To the resulting mixture was added diisopropyl azodicarboxylate (184 mg, 0.91 mmol) and PPh3 (238 mg, 0.91 mmol). The resulting mixture was stirred at RT overnight. Preparative TLC gave 5-(10-fluoro-5H-pyrido[2′,3′:3,4]pyrrolo[1,2-a]indol-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (230 mg, yield: 85%) MS (M+H)+: 599.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH2:9][C:10](Cl)=[O:11].[NH:14]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:15]1[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(N(CC)CC)C.Cl>O1CCCC1>[CH3:13][C:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH2:9][C:10]([N:14]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:15]1[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:11]
Reactant: CCOC(=O)C1CCCCN1
Reactant: Cc1cc(C)c(CC(=O)Cl)c(C)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C1CCCCN1C(=O)Cc1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
223 g (1.125 mol) of mesityleneacetyl chloride are added dropwise at 0° to 10° C. to 182 ml (1.157 mol) of ethyl pipecolinate and 162 ml (1.157 mol) of triethylamine in 1,200 ml of absolute tetrahydrofuran (THF), followed by stirring for 1 hour at room temperature. After the mixture has been stirred into 5 liters of ice water and 500 ml of 1N HCl, the product is filtered off with suction, washed with water and dried in vacuo at 50° C. over P2O5. 342.3 g (95.2% of theory) of ethyl N-(2,4,6-trimethylphenylacetyl)-piperidine-2-carboxylate are obtained.
Reaction SMILES: [OH-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]#[N:14])=[CH:4]1.[CH3:15]I.O>CO>[CH3:15][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]#[N:14])=[CH:4]1
Reactant: N#CCc1c[nH]c2ccccc12
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1cc(CC#N)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
20 cm3 of 50% aqueous sodium hydroxide solution are added to a mixture of 7.8 g (0.05 mol) of 3-indolylacetonitrile, 14.2 g (0.1 mol) of methyl iodide and 0.83 g of a solution of Triton B in methanol at a rate such that the temperature of the reaction mixture does not exceed 35° C. (approximately 1 h 30 min), and the reaction mixture is then stirred for 3 hours at room temperature; thereafter, 100 cm3, of water are added while cooling and the mixture is extracted with diethyl ether, the ether extract is thereafter washed with water to neutrality, dried over sodium sulphate and then filtered, the ether is evaporated off and the residue is crystallised in a sufficient quantity of pentane; the solid thereby obtained is drained and then dried.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:12]([C:13]([NH2:15])=[O:14])=[C:11]([NH2:16])[NH:10][N:9]=2)=[CH:3][CH:2]=1.[OH:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>CCO.N1CCCCC1>[C:1]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:12]([C:13]([NH2:15])=[O:14])=[C:11]([N:16]=[CH:28][C:27]3[CH:30]=[CH:31][C:24]([OH:23])=[CH:25][CH:26]=3)[NH:10][N:9]=2)=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: NC(=O)c1c(Nc2ccc(-c3ccccc3)cc2)n[nH]c1N
Solvent: C1CCNCC1
Solvent: CCO
Product: NC(=O)c1c(Nc2ccc(-c3ccccc3)cc2)n[nH]c1N=Cc1ccc(O)cc1

Procedure:
3-([1,1′-biphenyl]-4-ylamino)-5-amino-1H-pyrazole-4-carboxamide was then suspended in 8 mL EtOH and 4-hydroxybenzaldehyde (325 mg, 1 eq.) and piperidine (4 drops) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 3-([1,1′-biphenyl]-4-ylamino)-5-((4-hydroxybenzylidene)amino)-1H-pyrazole-4-carboxamide as a yellow powder. Powder was washed with EtOH to remove any excess 4-hydroxybenzaldehyde. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:25]([OH:27])=O.Cl.[N:33]1[CH:38]=[CH:37][C:36]([C:39]2([NH2:42])[CH2:41][CH2:40]2)=[N:35][CH:34]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[F:1][C:2]1[C:7]2[C:8]([C:18]([NH:19][CH3:20])=[O:21])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([C:25](=[O:27])[NH:42][C:39]2([C:36]3[CH:37]=[CH:38][N:33]=[CH:34][N:35]=3)[CH2:41][CH2:40]2)[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: NC1(c2ccncn2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)c(F)c12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ccncn5)CC4)ccc3C)c(F)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.050 g, 0.114 mmol, 1.0 eq), 1-(pyrimidin-4-yl)cyclopropanamine HCl (0.015 g, 0.113 mmol, 1.0 eq) in DMF at 0° C. was added TEA (0.060 g, 0.594 mmol, 5.0 eq) and BOP reagent (0.076 g, 0.172 mmol, 1.5 eq). The reaction mixture was stirred at RT overnight. The reaction mixture was diluted with water and extracted with EtOAc. the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative HPLC. Yield: 0.035 g (57.37%). 1H NMR (400 MHz, CD3OD): δ 9.00 (d, J=1.2 Hz, 1H), 8.60 (d, J=5.6 Hz, 1H), 7.98-7.90 (m and dd, 3H), 7.85 (d, J=2.0 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.51-7.49 (two overlapping d, 2H), 7.35-7.28 (m, 3H), 2.96 (s, 3H), 2.30 (s, 3H), 1.84-1.81 (m, 2H), 1.52-1.49 (m, 2H). 19F NMR (376.57 MHz, CD3OD): δ −76.94 (TFA), −112.22, −122.76 LCMS: (ES+) m/z=539.2 (M+H)+