Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH2:10][NH:11][C:12]2[C:17]([NH2:18])=[N:16][CH:15]=[C:14]([Br:19])[N:13]=2)=[CH:2]1.[N:20]([O-])=O.[Na+].OS(O)(=O)=O.[OH-].[Na+]>CC(O)=O.O.O>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH2:10][N:11]2[C:12]3=[N:13][C:14]([Br:19])=[CH:15][N:16]=[C:17]3[N:18]=[N:20]2)=[CH:2]1
Reactant: Nc1ncc(Br)nc1NCc1c[nH]c2ncccc12
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Brc1cnc2nnn(Cc3c[nH]c4ncccc34)c2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.9 %

Procedure:
To the ice-cooled mixture of N2-((1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-6-bromopyrazine-2,3-diamine (48 mg, 0.15 mmol) in HOAc/H2O (1.5 mL/1.5 mL) was added NaNO2 (31 mg, 0.45 mmol) in water (0.2 mL). The reaction was stirred for 1.5 h in an ice bath, then aqueous H2SO4 (49%, 0.1 mL) was added. The resulting mixture was allowed to warm to room temperature and stir overnight, then was adjusted to pH>8 with 3 N aqueous NaOH solution, and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered and concentrated to give the title compound (46 mg) MS (m/z): 332 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:16]([F:19])([F:18])[F:17])[CH2:14][CH2:13][O:12][CH2:11][C:10]([NH2:15])=[N:9]1.[N+:20]([O-])([O-:22])=[O:21].[K+].CC(OC)(C)C>S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:20]([O-:22])=[O:21])=[CH:4][C:3]=1[C:8]1([C:16]([F:19])([F:17])[F:18])[CH2:14][CH2:13][O:12][CH2:11][C:10]([NH2:15])=[N:9]1
Reactant: O=[N+]([O-])[O-]
Reactant: NC1=NC(c2ccccc2F)(C(F)(F)F)CCOC1
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: COC(C)(C)C
Product: NC1=NC(c2cc([N+](=O)[O-])ccc2F)(C(F)(F)F)CCOC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
To a solution of 5-(2-fluoro-phenyl)-5-trifluoromethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-ylamine (1.12 g, 4.05 mmol) in 12 mL concentrated sulfuric acid (95%) was added potassium nitrate (533 mg, 5.27 mmol) in two portions. The reaction mixture was stirred at rt for 30 minutes, it was then poured onto ice water and TBME was added. The layers were separated, washed with water and TBME. The combined aqueous layers were basified with solid Na2CO3 and extracted with EtOAc. The EtOAc layers were dried over MgSO4.H2O and evaporated to give 1.29 g of the title compound was a white solid.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17](/[CH:22]=[CH:23]/[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:30]([O:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][C:45](Cl)=[O:46])=[CH:40][CH:39]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Si:30]([O:37][C:38]1[CH:39]=[CH:40][C:41]([CH2:44][C:45]([NH:21][C:18]2[C:17](/[CH:22]=[CH:23]/[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:16][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])=[CH:14][CH:13]=3)=[CH:20][N:19]=2)=[O:46])=[CH:42][CH:43]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(/C=C/c3ccccc3)n2)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Nc2ncc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)nc2/C=C/c2ccccc2)cc1
Temperature: 50 °C
Reaction time: 15 h
Yield: 69.7 %

Procedure:
Under an argon atmosphere, to a mixture of (E)-5-[4-(tert-butyldimethylsilyloxy)phenyl]-3-styrylpyrazin-2-amine (7b) (500 mg, 1.24 mmol) and 4-(dimethylamino)pyridine (15.3 mg, 125 μmol) dissolved in anhydrous pyridine (20 mL) was added 2-[4-(tert-butyldimethylsilyloxy) phenyl]acetyl chloride (10) prepared above at 0° C. and the mixture was heated with stirring at 50° C. for 15 hours. After cooling to room temperature, to this was added water and the product was extracted with ethyl acetate (100 mL×3). The combined organic extract was washed successively with water (200 mL) and brine (200 mL), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (silica gel 50 g, n-hexane/ethyl acetate=3/1) to give Compound 11b (563 mg, 864 μmol, 69.7%) as a yellow solid. Rf=0.29 (n-hexane/ethyl acetate=3/1); 1H NMR (400 MHz, DMSO-d6) δ 0.17 (s, 6H), 0.24 (s, 6H), 0.96 (s, 9H), 0.97 (s, 9H), 3.66 (s, 2H), 6.81-6.91 (m, 3H, includes AA′BB′), 6.99-7.04 (AA′BB′, 2H), 7.28-7.40 (m, 7H, includes AA′BB′), 7.82 (d, 1H, J=16 Hz), 8.11-8.19 (AA′BB′, 2H), 8.91 (s, 1H), 10.66 (s, 1H); 13C NMR (75.5 MHz, DMSO-d6) δ −4.5 (2C), −4.6 (2C), 17.8, 17.9, 25.5 (6C), 42.0, 119.7 (2C), 120.3 (2C), 122.5, 127.1 (2C), 128.2 (2C), 128.5, 128.7 (2C), 128.9, 129.0, 130.3 (2C), 133.8, 136.0, 137.8, 142.8, 143.9, 148.0, 154.0, 156.7, 170.6; IR (KBr, cm−1) 471, 521, 638, 691, 746, 781, 806, 839, 914, 968, 1007, 1080, 1103, 1169, 1263, 1325, 1371, 1391, 1414, 1439, 1472, 1510, 1566, 1605, 1659, 2857, 2886, 2930, 2055, 3028, 3057, 3217; HRMS (ESI+) m/z 674.3203 ([M+Na]+, C38H49N3NaO3Si2+ requires 674.3205).
Reaction SMILES: [N:1]([C@H:4]([CH:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]1=2)[C:5]([OH:7])=[O:6])=[N+]=[N-].[ClH:23].[H][H]>O1CCCC1.O.[Pd]>[ClH:23].[NH2:1][C@H:4]([CH:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]1=2)[C:5]([OH:7])=[O:6]
Reactant: [N-]=[N+]=N[C@@H](C(=O)O)C1c2ccccc2CCc2ccccc21
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: N[C@@H](C(=O)O)C1c2ccccc2CCc2ccccc21

Procedure:
To a solution of (R)-α-azido-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-acetic acid (3.5 g, 1.9 mmol) in tetrahydrofuran (75 mL), water (10 mL), and concentrated hydrochloric acid (1 mL) is added palladium on carbon (0.5 g, 20%). The mixture is shaken under 52 pounds per square inch (psi) of hydrogen at 25° C. for 6 hours. Solid is filtered. The filtrate is concentrated in vacuo to give a light green solid, which is recrystallized in 3N hydrochloric acid (with activated charcoal) to give the title compound as a white solid, 2.84 g; mp 313°-314° C. (dec), [α]D =-47.6° (c=1.0, methanol).
Reaction SMILES: Cl[CH:2]1[C:6](=[O:7])[C:5]([C:8]2[C:13]([CH2:14][CH3:15])=[CH:12][C:11]([CH3:16])=[CH:10][C:9]=2[CH2:17][CH3:18])=[C:4]([O:19][CH3:20])[CH2:3]1.N12CCCN=C1CCCCC2.[O:32]1[CH:36]=[CH:35][CH:34]=[CH:33]1>>[CH2:14]([C:13]1[CH:12]=[C:11]([CH3:16])[CH:10]=[C:9]([CH2:17][CH3:18])[C:8]=1[C:5]1[C:6](=[O:7])[CH:2]2[CH:3]([C:4]=1[O:19][CH3:20])[CH:36]1[O:32][CH:33]2[CH:34]=[CH:35]1)[CH3:15]
Reactant: c1ccoc1
Reactant: CCc1cc(C)cc(CC)c1C1=C(OC)CC(Cl)C1=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCc1cc(C)cc(CC)c1C1=C(OC)C2C3C=CC(O3)C2C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 5-chloro-2-(2,6-diethyl-4-methylphenyl)-3-methoxycyclopent-2-enone (0.530 g, 1.81 mmol) in furan (40 ml) at room temperature is added by syringe pump over two hours a solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (0.540 ml, 3.62 mmol) in furan (10 ml). The reaction is stirred at room temperature for a further 30 minutes and then evaporated to dryness under reduced pressure. The residue is diluted with water (50 ml), 2 M aqueous hydrochloric acid (25 ml) is added and the mixture is extracted with ethyl acetate (3×50 ml). The combined organic extracts are washed with brine (20 ml), dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated to dryness under reduced pressure. The residue is purified by column chromatography on silica gel to give (1RS,2RS,6SR,7SR)-4-(2,6-diethyl-4-methylphenyl)-5-methoxy-10-oxa-tricyclo[5.2.1.02,6]deca-4,8-dien-3-one.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1.O.[NH2:25][NH2:26]>C(O)C>[NH:25]([C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1)[NH2:26]
Reactant: CCCOc1ccccc1-c1nc2nc(SC)ncc2c(=O)[nH]1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCCOc1ccccc1-c1nc2nc(NN)ncc2c(=O)[nH]1

Procedure:
A stirred mixture of 7-methylthio-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (1.31 g) and hydrazine hydrate (3 ml) in ethanol (30 ml) was heated under reflux for 3 hours to yield a yellow precipitate. The reaction mixture was cooled overnight and the yellow precipitate was collected and washed with ethanol and water to yield the title compound, 0.80 g, m.p. 219-220° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C@H:10]([C@@H:14]([NH:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH3:15])[C:11]([OH:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24](OC=O)(=[O:26])C>N1C=CC=CC=1>[C:1]1([CH2:7][CH2:8][CH2:9][C@H:10]([C@@H:14]([N:16]([CH:24]=[O:26])[O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH3:15])[C:11]([OH:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](NOC1CCCCO1)[C@@H](CCCc1ccccc1)C(=O)O
Reactant: CC(=O)OC=O
Solvent: c1ccncc1
Product: C[C@@H]([C@@H](CCCc1ccccc1)C(=O)O)N(C=O)OC1CCCCO1
Temperature: 25 °C
Reaction time: 6 h
Yield: 81 %

Procedure:
To a solution of (2R,3S)-2-(3-phenyl-1-propyl)-3-(2-tetrahydropyranyloxyamino)butanoic acid (21.4 g, 66.7 mmol) in pyridine (100 mL) at 0° C. is added formic acetic anhydride (30 mL). The resulting solution is allowed to warm to 25° C., stirred for 6 h, and then concentrated to dryness under reduced pressure. The resulting gum is dissolved in EtOAc (300 mL) and washed sequentially with 1 N hydrochloric acid (200 mL) and saturated aqueous sodium chloride solution. The organic layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure providing (2R,3S)-2-(3-phenyl-1-propyl)-3-(formyl-2-tetrahydropyranyloxyamino)butanoic acid as an oil (18.9 g, 81% yield). ESI-MS m/z 372 (M+Na)+348 (M−1)31 .
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:26]=[C:25]([CH2:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH2:35][C:36]([NH2:38])=[O:37])[C:24]([C:39]([F:42])([F:41])[F:40])=[CH:23][N:22]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:26]=[C:25]([CH2:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH2:35][C:36]([NH2:38])=[O:37])[C:24]([C:39]([F:40])([F:42])[F:41])=[CH:23][N:22]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(N3CCC(N)CC3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl(1-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)carbamate (I79) (138 mg, 0.231 mmol) was dissolved in dry dichloromethane (10 mL) under an atmosphere of nitrogen. Trifluoroacetic acid (1.0 mL, 13 mmol) was added to the solution and the reaction was stirred at room temperature overnight. The volatiles were removed in vacuo, EtOAc (50 mL) and sat. aq. NaHCO3 (50 mL) were added to the residue and the layers were separated.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:15])[NH:10]2.C(N(CC)CC)C.[CH2:23]=[C:24]1[O:28][C:26](=[O:27])[CH2:25]1>C(Cl)(Cl)Cl>[C:26]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:15])[NH:10]2)(=[O:27])[CH2:25][C:24]([CH3:23])=[O:28]
Reactant: C=C1CC(=O)O1
Reactant: O=C1CCc2c(cccc2OCCO)N1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)CC(=O)OCCOc1cccc2c1CCC(=O)N2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2 Grams of 5-(2-hydroxyethoxy)-3,4-dihydrocarbostyril and 2 ml of triethylamine were added to 50 ml of chloroform, then 1 g of diketene was added dropwise thereto, and the whole reaction mixture was stirred at room temperature for 2 days. The insoluble matter formed in the reaction mixture was removed by filtration, and the filtrate was concentrated, then the residue obtained was purified by silica gel column chromatography (eluant: chloroform), the eluate obtained was concentrated and the residue was recrystallized from chloroform-ether to yield 1.5 g of 5-(2-acetoacetoxyethoxy)-3,4-dihydrocarbostyril in the form of colorless needle-like crystals. Melting point: 134.5°-135.5° C.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([NH:16][C:17]([NH:19][NH:20][C:21]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=2)=[O:22])=[O:18])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[H][H]>C(O)C.[Pd]>[NH2:29][C:26]1[CH:27]=[CH:28][C:23]([C:21]([NH:20][NH:19][C:17]([NH:16][C:7]2[CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:8]=2)=[O:18])=[O:22])=[CH:24][CH:25]=1
Reactant: CC(C)(C)c1cc(NC(=O)NNC(=O)c2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)c1cc(NC(=O)NNC(=O)c2ccc(N)cc2)cc(C(C)(C)C)c1O
Yield: 75 %

Procedure:
In a 250 ml Parr flask, 0.72 g (1.68 mmoles) of N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-[(4-nitrophenyl)carbonylamino]-urea is dissolved in 30 ml of absolute ethanol in the presence of 10% Pd/C. The mixture is agitated under 20 PSI of hydrogen, at 30° C., for. two hours. After filtration on celite, the filtrate is concentrated under vacuum. The evaporation residue is suspended in diethyl ether (20 ml), agitated and filtered to produce a pale yellow powder with a yield of 75%. Melting point: 245-246° C.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:8][CH:7]2[CH2:9][CH:4]1[CH:5]=[CH:6]2.[CH2:10]([O:12][CH:13](OCC)[CH:14]=[CH2:15])[CH3:11].[Cl-].[NH4+]>O1CCCC1.[Cu]Br>[CH2:10]([O:12][CH:13]=[CH:14][CH2:15][CH2:2][CH:3]1[CH2:8][CH:7]2[CH2:9][CH:4]1[CH:5]=[CH:6]2)[CH3:11]
Reactant: BrCC1CC2C=CC1C2
Reactant: C=CC(OCC)OCC
Agent: [Cu]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC=CCCC1CC2C=CC1C2
Reaction time: 20 h

Procedure:
A Grignard reagent was customarily prepared from 200 g of 5-bromomethyl-2-norbornene in 500 ml of dry tetrahydrofuran. The Grignard reagent was added dropwise over one hour to a mixture of 130 g of 3,3-diethoxy-1-propene, 1.0 g of copper (I) bromide and 300 ml of dry tetrahydrofuran at 20° C. Stirring was continued for 20 hours whereupon the reaction solution was added to a saturated aqueous solution of ammonium chloride to stop reaction. After hexane extraction, the organic layer was successively washed with water, saturated sodium bicarbonate water and saturated sodium chloride water, dried over anhydrous sodium sulfate, and concentrated in vacuum, yielding 5-(4-ethoxy-3-buten-1-yl)-2-norbornene.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[CH:10][CH:9]=2)=[O:5])C.[OH-].[K+].O>CO.O>[N+:15]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:14]2)([O-:17])=[O:16]
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Yield: 108.4 %

Procedure:
5-Nitro-1H-indole-2-carboxylic acid ethyl ester 15 (194 mg, 0.83 mmol) and KOH (342 mg, 5.25 mmol) were stirred in MeOH/water (8 mL/4 mL) at room temperature for 21.5 h. More water was added to dilute the solution. The mixture was concentrated to remove the organic solvent. The remaining solution was washed with DCM (100 mL). The aqueous solution was adjusted with 1 N HCl to pH 2.9, extracted with EtOAc (2×15 mL). The combined EtOAc extraction was washed with brine, dried over sodium sulfate, concentrated to afford the product as solid (185.5 mg, 97% yield). 1H-NMR (DMSO-d6): 8.718 (d, J=2.0-2.5 Hz, 1 H, Ar—H), 8.116 (dd, J=2.0-2.5 Hz and 9.0-9.5 Hz, 1 H, Ar—H), 7.583 (d, J=9.0-9.5 Hz, 1 H, Ar—H), 7.378 (d, J=1.5 Hz, 1 H, Ar—H). LC-MS: 207.1 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].N1CCOCC1.[CH3:17][C:18]1([CH3:28])[O:22][C:21](=[CH:23][C:24](Cl)=[O:25])[C:20](=[O:27])[O:19]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH:6][C:24](=[O:25])[CH:23]=[C:21]1[C:20](=[O:27])[O:19][C:18]([CH3:17])([CH3:28])[O:22]1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Solvent: C1COCCN1
Solvent: ClCCl
Product: CC1(C)OC(=O)C(=CC(=O)NCc2ccc(Cl)c(Cl)c2)O1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirred suspension of 3,4-dichlorobenzylamine (17.6 mg, 0.1 mmol) and resin bound morpholine (100 mg, 2.5–4.0 mmol/1 g) in CH2Cl2 (2 mL) was added (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride (20 mg, 0.11 mmol) and the mixture stirred for 1 h. The mixture filtered and the filtrate concentrated to give the product as a white solid (33 mg, 100% yield). 1H NMR (500 MHz, CDCl3) δ: 7.39 (2H, m), 7.15 (1H, m), 6.60 (1H, s), 5.89 (1H, s), 4.50 (2H, d, J=6.0 Hz), 1.74 (6H, s). MS calcd for C14H14Cl2NO4 [M+H]+: 330.03. found: 330.1.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[C:9]1([N:15]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:21]3[C:16]2=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C=O)C>[Br:8][C:24]1[CH:25]=[CH:26][C:27]2[N:15]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:16]3[C:21]([C:22]=2[CH:23]=1)=[CH:20][CH:19]=[CH:18][CH:17]=3
Reactant: c1ccc(-n2c3ccccc3c3ccccc32)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Brc1ccc2c(c1)c1ccccc1n2-c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.2 %

Procedure:
NBS (19.31 g, 109 mmol) in DMF was added to 9-phenyl-9H-carbazole (24 g, 99 mmol) in 200 mL at 0° C. dropwise. The reaction was monitored by HPLC. The reaction was quenched by adding 500 mL of water after 2 h. After stirring at room temperature for 24 h, the clear solution was decanted and solid residue was dissolved in dichloromethane and washed with water and LiCl solution. The solution was dried with MgSO4 and the solvent was evaporated. The residue was used for the next step without further purification. The product contains starting material, monobromo, and dibromo. 31 g of product was obtained.
Reaction SMILES: CN(CCN(C)C)C.[Li]CCCC.[C:14]([O:18][C:19](=[O:28])[NH:20][C:21]1[CH:22]=[N:23][C:24]([Cl:27])=[CH:25][CH:26]=1)([CH3:17])([CH3:16])[CH3:15].[I:29]I>CCOCC>[C:14]([O:18][C:19](=[O:28])[NH:20][C:21]1[CH:22]=[N:23][C:24]([Cl:27])=[CH:25][C:26]=1[I:29])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)nc1
Reactant: II
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Nc1cnc(Cl)cc1I
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 98.7 %

Procedure:
To a solution of TMEDA (1.45 g, 12.5 mmol) in dry Et2O (30 mL) was added dropwise n-BuLi (5.0 mL, 12.5 mmol) at −78° C. The mixture was stirred for 0.5 h at −78° C. A solution of (6-chloro-pyridin-3-yl)-carbamic acid tert-butyl ester (1.14 g, 5.0 mmol) in dry Et2O (10 mL) was added dropwise to the reaction mixture at −78° C. and the resultant mixture was continued to stir for 1 h at −78° C. A solution of I2 (1.52 g, 6.0 mmol) in dry Et2O (10 mL) was added dropwised at −78° C. The mixture was continued to stir for 1 h at this temperature. The reaction was quenched with saturated aqueous NH4Cl. The organic layer was separated and the aqueous phase was extracted with ethyl acetate (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under reduced pressure to give a residue, which was purified by column (petroleum ether/ethyl acetate=10/1) to obtain (6-chloro-4-iodo-pyridin-3-yl)-carbamic acid tert-butyl ester (1.75 g, 30%). 1H NMR (400 MHz, CDCl3) δ 8.95 (br s, 1H), 7.73 (s, 1H), 6.64 (br s, 1H), 1.54 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH3:12])[C:6]=1[CH2:7][CH2:8][C:9]([OH:11])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C(N(CC)C(C)C)(C)C>ClCCl>[CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH3:12])[C:6]=1[CH2:7][CH2:8][C:9]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[O:11]
Reactant: C1COCCN1
Reactant: Cc1c[nH]c(C)c1CCC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c[nH]c(C)c1CCC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
To a suspension of 3-(2,4-dimethyl-1H-pyrrol-3-yl)-propionic acid (10 g, 60.8 mmol) in 60 ml of dichloromethane was added 1,1′-carbonyldiimidazole (11.6 g, 71.8 mmol) followed morpholine (5.5 ml, 60.8 mmol) and N,N-diisopropylethylamine (Hunig's base, 10 ml, 60.8 mmol). The dark red reaction mixture was stirred at room temperature overnight and poured into ice water. The organic layer was washed with brine until the wash had a pH of about 6, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified on a silica gel column eluting with dichloromethane-methanol (98:2) to give 13.84 g (96%) of 3-(2,4-dimethyl-1H-pyrrol-3-yl)-1-morpholin-4-yl-propan-1-one.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:16]2[O:15][C:10]3([CH2:14][CH2:13][CH2:12][CH2:11]3)[CH2:9][C:8]=2[C:7]([C:17]2[C:18]([CH3:30])([CH3:29])[C:19](=[O:28])[N:20]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:21]=2)=[CH:6][CH:5]=1.[F:31][CH:32]([F:44])[O:33][C:34]1[CH:35]=[CH:36][C:37]([CH3:43])=[C:38]([CH:42]=1)[C:39](O)=[O:40]>>[F:31][CH:32]([F:44])[O:33][C:34]1[CH:35]=[CH:36][C:37]([CH3:43])=[C:38]([C:39]([N:25]2[CH2:26][CH2:27][CH:22]([N:20]3[C:19](=[O:28])[C:18]([CH3:30])([CH3:29])[C:17]([C:7]4[C:8]5[CH2:9][C:10]6([O:15][C:16]=5[C:4]([O:3][CH3:2])=[CH:5][CH:6]=4)[CH2:11][CH2:12][CH2:13][CH2:14]6)=[N:21]3)[CH2:23][CH2:24]2)=[O:40])[CH:42]=1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)c2c1OC1(CCCC1)C2
Reactant: Cc1ccc(OC(F)F)cc1C(=O)O
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cc(OC(F)F)ccc4C)CC3)C(=O)C2(C)C)c2c1OC1(CCCC1)C2

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(7-methoxy-3H-spiro[1-benzofuran-2,1′-cyclopentan]-4-yl)-4,4-dimethyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one (compound B6) and 5-(difluoromethoxy)-2-methylbenzoic acid (compound F4) as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) and by crystallization from DCM and diethyl ether to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1I.[C:23]1([CH3:32])[CH:28]=[CH:27][CH:26]=[C:25](B(O)O)[CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[C:16]([C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([CH3:32])[CH:24]=2)=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: Cc1cccc(B(O)O)c1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cccc(-c2ccccc2C(=O)NCCc2c[nH]c3ccc(Cl)cc23)c1
Yield: 29.2 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methylbiphenyl-2-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176 mmol), m-tolylboronic acid (0.025 g; 0.176 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 10% ethyl acetate in dichloromethane) furnished 0.020 g (30%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-methylbiphenyl-2-carboxamide as a white solid.