Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH:7]1[CH:11]=[C:10](/[CH:12]=[CH:13]/[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:9]=[N:8]1.Br[CH2:20]/[CH:21]=[CH:22]/[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(#N)C>[CH2:20]([N:7]1[CH:11]=[C:10](/[CH:12]=[CH:13]/[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:9]=[N:8]1)[CH:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)/C=C/c1cn[nH]c1
Reactant: BrC/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)/C=C/c1cnn(CC=Cc2ccccc2)c1
Temperature: 40 °C
Yield: 75.8 %

Procedure:
Cesium carbonate (0.490 g, 1.5 mmol) was added to a solution of (E)-ethyl 3-(1H-pyrazol-4-yl)acrylate (0.167 g, 1 mmol) in ACN (8 mL) at room temperature. The suspension was stirred and 1-((E)-3-bromoprop-1-enyl)benzene (0.256 g, 1.30 mmol) was added. The mixture was heated at 40° C. overnight. After cooling down to room temperature, the precipitated solids were filtered off. The filtrate was concentrated and purified by silica gel column chromatography using a 0-60% gradient of EtOAc in hexanes to provide the title compound as a colorless oil (0.214 g, 76%). ES+(M+H)+283
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][C:6]([N+:13]([O-])=O)=[CH:5][N:4]=1)#[N:2]>CCOC(C)=O.CC(O)=O.[Fe]>[NH2:13][C:6]1[CH:7]=[C:8]([C:9]([F:12])([F:10])[F:11])[C:3]([C:1]#[N:2])=[N:4][CH:5]=1
Reactant: N#Cc1ncc([N+](=O)[O-])cc1C(F)(F)F
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: N#Cc1ncc(N)cc1C(F)(F)F
Temperature: 65 °C
Reaction time: 2 h
Yield: 66.8 %

Procedure:
2-cyano-5-nitro-3-trifluoromethylpyridine (7 mg, 0.032 mmol) is dissolved in 1:1 EtOAc/AcOH (1 mL) and heated to 65° C. Iron powder (9 mg, 0.161 μmol, 5 eq, 325 mesh) is added and the mixture stirred for 2 hours. The mixture is filtered through celite, and the filtrate is concentrated under vacuo. The crude residue is purified by flash chromatography on silica gel (hexane/EtOAc) to afford 4 mg (67%) of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:12]=[CH2:13])=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2.[H][H]>CN(C=O)C.[Pd]>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:12][CH3:13])=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2
Reactant: C=Cc1ccc(N)c2c1CNC2=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: CCc1ccc(N)c2c1CNC2=O
Yield: 102.8 %

Procedure:
7-Amino-4-vinylisoindolinone (50.0 mg, 0.287 mmol) was dissolved in DMF (2.5 mL), and the solution was added with 10% Pd—C (10 mg) followed by stirring at room temperature for 1.8 hours under normal pressure and hydrogen atmosphere. The reaction mixture was filtered using Celite and the solvent of the filtrate was evaporated under reduced pressure to obtain 7-amino-4-ethylisoindolinone (52.0 mg, quantitative).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:9][CH:10]([CH2:13][SH:14])[CH2:11][OH:12]>>[OH:12][CH2:11][CH:10]1[CH2:13][S:14][CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[S:9]1
Reactant: O=Cc1ccccc1
Reactant: OCC(S)CS
Product: OCC1CSC(c2ccccc2)S1

Procedure:
According to the procedure of Example 1, 35 g. (0.33 mole) of benzaldehyde and 40 g. (0.33 mole) of 2,3-dimercaptopropanol were reacted to yield 63.6 g. of crude product. After recrystallization 42.4 (56%) of the desired product were obtained as shown by nmr spectroscopy.
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@:15]3([CH3:16])[CH:14]=[CH:13][C:12](=[O:20])[CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][C:3]2=[O:21].[CH3:22][Al](C)C.O>O1CCOCC1.C1(C)C=CC=CC=1.[Cu]Br>[CH3:22][C@@H:14]1[C@@:15]2([CH3:16])[C:10]([CH2:9][CH2:8][C@@H:7]3[C@@H:17]2[CH2:18][CH2:19][C@@:2]2([CH3:1])[C@H:6]3[CH2:5][CH2:4][C:3]2=[O:21])=[CH:11][C:12](=[O:20])[CH2:13]1
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: C[Al](C)C
Agent: [Cu]Br
Solvent: C1COCCO1
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@H]1CC(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2.84 g (10 mmol) of androsta-1,4-diene-3,17-dione is dissolved in 20 ml of anhydrous dioxane under nitrogen atmosphere. 143.3 mg (1 mmol) of copper(I) bromide is added and the solution is heated to 25° C. Then 9.4 ml (11 mmol) of a 10% solution of trimethyl aluminum in toluene is added to the reaction so that the temperature does not rise above 35° C. Then it is stirred for 1.5 hours more at 35° C. For hydrolysis, 0.54 ml of water mixed with 5 ml of dioxane is carefully added to the reaction and the solution is stirred for 15 minutes more. The inorganic solid is suctioned off and washed again with 30 ml of dioxane. After concentration by evaporation of the solution, 3.1 g of 1α-methylandrost-4-ene-3,17-dione is obtained, that is dissolved in 8 ml of methanol and cooled to -5° C. internal. temperature. 0.18 g of sodium borohydride is added to 0.5 ml of water cooled to 5° C. and the sodium borohydride-water solution is added to the solution of 1α-methyl-androst-4-ene-3,17-dione so that the temperature does not rise above -5° C. Then it is stirred for 40 minutes more at -5° C. After DC check to determine whether the reaction has occurred, 0.33 ml of acetic acid in 1 ml of water is carefully added until no more gas generation is detectable. The solution is taken up in 50 ml of ethyl acetate and washed twice with 20 ml of water each. The organic phase is dried with sodium sulfate. After concentration by evaporation of the solution and recrystallization from acetone, 2.29 g of 17β-hydroxy-1α-methyl-androst-4-en-3-one (75% of theory) of a melting point of 195° C. is obtained.
Reaction SMILES: N1CCCCC1.[CH:7]1([O:12][C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=2[O:21][CH3:22])[CH:16]=O)[CH2:11][CH2:10][CH2:9][CH2:8]1.C([CH2:26][C:27]([NH:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32]([OH:34])=[O:33])=[O:28])(O)=O.Cl>C1(C)C=CC=CC=1>[CH:7]1([O:12][C:13]2[CH:14]=[C:15](/[CH:16]=[CH:26]/[C:27]([NH:29][C:30]3[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=3[C:32]([OH:34])=[O:33])=[O:28])[CH:18]=[CH:19][C:20]=2[O:21][CH3:22])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: COc1ccc(/C=C/C(=O)Nc2ccccc2C(=O)O)cc1OC1CCCC1
Yield: 63.3 %

Procedure:
Piperidine (0.63 mL, 5.8 mmol) was added to a suspension of 3-cyclopentyloxy-4-methoxybenzaldehyde (1.4 g, 6.4 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (1.3 g, 5.8 mmol) in toluene (5.0 mL) and treated according to Procedure 2, acidifying with 1 M HCl. The crude product was recrystallised from EtOH/water providing (E)-2-{[3-(3-cyclopentyloxy-4-methoxyphenyl)-1-oxo-2-propenyl]amino}benzoic acid (1.4 g, 67%) as a yellow crystalline solid; mp 211-217° C.; δH (400 MHz, DMSO-d6) 1.57 (m, 2H, CH2), 1.70-1.72 (m, 4H, CH2), 1.91 (m, 2H, CH2), 3.78 (s, 3H, OCH3), 4.90 (t, J=5.6 Hz, 1H, OCH), 6.75 (d, J=15.6 Hz, 1H, CH═CHCO), 6.98 (d, J5′,6′=8.4 Hz, 1H, H5′), 7.16 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.24 (d, J5′,6′=8.4 Hz, 1H, Fe), 7.31 (s, 1H, H2′), 7.55 (d, J=15.6 Hz, 1H, CH═CHCO), 7.60 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 8.00 (d, J3,4=8.0 Hz, 1H, H3), 8.60 (d, J5,6=8.0 Hz, 1H, H6), 11.25 (s, 1H, NH), 13.57 (br s, 1H, CO2H); δC (100 MHz, DMSO-d6) 23.6, 32.2, 55.6, 79.5, 112.0, 113.6, 116.7, 119.9, 120.4, 122.2, 122.7, 127.2, 131.1, 134.0, 141.0, 141.6, 147.1, 151.5, 164.2, 169.4; HRMS (ESI) calculated for C22H23NO5 [M+Na]+ 404.1468. found 404.1468; vmax 751, 1254, 1504, 1583, 1661, 2948, 3516 cm−1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[CH:9]2)([O-:3])=[O:2].[OH-].[K+].[I:15]I>CN(C=O)C.S(=O)(=O)(O)[O-].[Na+]>[I:15][C:9]1[C:8]2[C:12](=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][CH:7]=2)[NH:11][N:10]=1
Reactant: II
Reactant: O=[N+]([O-])c1cccc2cn[nH]c12
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc2c(I)n[nH]c12
Reaction time: 2 h
Yield: 88.3 %

Procedure:
7-Nitroindazole (1.60 g, 9.80 mmol) was dissolved in DMF (100 mL), and potassium hydroxide (2.20 g, 39.20 mmol) and iodine (4.98 g, 19.61 mmol) were added in drops thereto. After stirring for 2 h, the reaction mixture was diluted with 10% aqueous sodium bisulfate solution. The resulting solid was collected and dried to give the title compound (2.50 g, Yield 88%).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[CH2:4][CH2:5][CH2:6][OH:7].[CH2:9](Br)[CH2:10][CH:11]([CH3:13])[CH3:12].[Br-].[Na+]>COCCOC>[CH2:9]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][OH:8])[CH2:10][CH:11]([CH3:13])[CH3:12]
Reactant: OCCCCO
Reactant: CC(C)CCBr
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)CCOCCCCO

Procedure:
To 12.2 g (0.279 mol) of 55% sodium hydride dispersion in oil, suspended in 400 cc of absolute 1,2-dimethoxy ethane, there is added dropwise, under nitrogen, over the course of 20 minutes and while stirring, 360 g (0.40 mol) of 1,4-butandiol in 50 cc of absolute 1,2-dimethoxy ethane. The mixture is stirred at 60° C. for 3 hours, 40.2 g (0.266 mol) of isopentyl bromide are then added and the mixture is stirred at 60° for 22 hours. The resulting sodium bromide is suction filtered, washed with ether and the filtrate is evaporated. For the removal of the excess 1,4-butandiol the residue is taken up in ether, washed three times with water, dried over sodium sulphate and evaporated. After the fractional distillation of the product, pure 4-isopentyloxy butanol, having a B.P. of 80°-81°/0.6 mm Hg, is obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH3:11])[C:3]=1[O:12][CH3:13].C([Li])CCC.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:24](Cl)=[O:25].O>O1CCCC1>[CH3:13][O:12][C:3]1[C:4]([O:10][CH3:11])=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[C:24](=[O:25])[C:23]1[CH:22]=[C:21]([O:20][CH3:19])[C:29]([O:30][CH3:31])=[C:28]([O:32][CH3:33])[CH:27]=1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: COc1ccc(Br)c(OC)c1OC
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2ccc(OC)c(OC)c2OC)cc(OC)c1OC
Reaction time: 0.5 h
Yield: 19.5 %

Procedure:
To a solution of bromobenzene 9 (0.21 g) in dry tetrahydrofuran (5 mL) cooled to −78° C. was added n-butyl lithium (0.38 mL, 2.5 M, 1.1 eq.). The solution was stirred for 30 min. and 3,4,5-trimethoxybenzoyl chloride (0.2 g) in anhydrous tetrahydrofuran was added. The resulting solution was then stirred for an additional 28 hours. The reaction was stopped with water, extracted with ethyl acetate and the solvent removed (in vacuo) to give a yellow oil. Separation by flash column chromatography (hexane-ethyl acetate, 3:1) afforded a colorless solid (0.06 g, 20.5%). The solid was recrystallized twice from ethyl acetate-hexane: m.p. 124.6-125.9° C., lit22 m.p. 121° C.; EIMS m/z 362 (M+), 345, 317, 181, 169, 151; 1H NMR δ 7.11 (1H, d, J=9.0 Hz, H6), 7.08 (2H, s, H2,6), 6.72 (1H, d, J=9.0 Hz, H5′), 3.94 (3H, s, OCH3), 3.93 (3H, s, OCH3), 3.90 (3H, s, OCH3), 3.85 (6H, s, OCH3,3,5), 3.80 (3H, s, OCH3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[N:16]([CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].CN([CH:28]=[O:29])C>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[C:11]3[N:16]([C:17]=2[CH:28]=[O:29])[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2cc3ccccn3c2)cc1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2cc3ccccn3c2C=O)cc1
Temperature: 55 °C
Reaction time: 0.67 h

Procedure:
A slurry of 20 g of 2-(4-methoxy phenyl) indolizine in 35 ml of DMF was added to a solution of 10 ml of phosphorus oxychloride in 30 ml of DMF at 10-20° C. After the reaction solution was stirred at 40° for 40 min., it was added to 200 g of ice. 120 g of 25 percent sodium hydroxide solution was added and the resulting mixture was heated to 55° C., cooled, and filtered. The air-dried product weighed 23 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][C:6]1[N:7]=[C:8]([C:12]([OH:14])=O)[O:9][C:10]=1[CH3:11].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.O[NH:41][C:42](=[NH:54])[C:43]1[CH:48]=[CH:47][C:46]([O:49][C:50]([F:53])([F:52])[F:51])=[CH:45][CH:44]=1>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][C:6]1[N:7]=[C:8]([C:12]2[O:14][N:54]=[C:42]([C:43]3[CH:44]=[CH:45][C:46]([O:49][C:50]([F:51])([F:52])[F:53])=[CH:47][CH:48]=3)[N:41]=2)[O:9][C:10]=1[CH3:11]
Reactant: Cc1oc(C(=O)O)nc1Cc1cccc(Br)c1
Reactant: N=C(NO)c1ccc(OC(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nc1Cc1cccc(Br)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 4 %

Procedure:
A solution of 4-(3-bromobenzyl)-5-methyloxazole-2-carboxylic acid (300 mg, 1.0 mmol), EDC.HCl (191 mg, 1.0 mmol) and HOBT (135 mg, 1.0 mmol) in DMF (10 mL) was stirred at RT for 2 h, and then N-hydroxy-4-(trifluoromethoxy)benzimidamide (220 mg, 1.0 mmol) was added. The mixture was stirred at 70° C. overnight, cooled to RT, treated with H2O (50 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with H2O (10 mL) and brine (10 mL), dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography (EtOAc:Petroleum ether=1:5) to afford 5-(4-(3-bromobenzyl)-5-methyloxazol-2-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole as a yellow oil (19 mg, 7%). MS (ES+) C20H13BrF3N3O3 requires 479, 481, found: 480, 482 [M+2+H]+(1:1). 1H NMR (500 MHz, CDCl3) δ 8.24 (d, J=8.5 Hz, 2H), 7.41-7.34 (m, 4H), 7.22-7.19 (m, 2H), 3.94 (s, 2H), 2.44 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:15]=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH:5][C:4]=1[N+:16]([O-:18])=[O:17].[NH:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:20]([O:22][CH3:23])=[O:21].[K].O>CN(C)C=O>[C:27]([O:26][C:24]([N:19]([CH2:2][C:3]1[CH:15]=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH:5][C:4]=1[N+:16]([O-:18])=[O:17])[C:20]([O:22][CH3:23])=[O:21])=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: COC(=O)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)c([N+](=O)[O-])c1
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)N(Cc1ccc(C(=O)OC(C)(C)C)cc1[N+](=O)[O-])C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
To a solution of tert-butyl 4-bromomethyl-3-nitrobenzoate (2.27 g, 7.2 mmol) (Int. J. Peptide Res. 1990, 36, 31) in dimethylformamide (25 mL) was added a suspension of potassium tert-butyl methyl iminodicarboxylate (J.C.S. Perkin I 1977, 1088-90) (1.56 g, 7.3 mmol) in dimethylformamide (20 mL). The dark brown solution was stirred 1 h and poured into water (400 mL), extracted with ethyl acetate (3×100 mL) and the combined organic layers were washed with water (5×75 mL), dried (sodium sulfate) and concentrated to give a pale orange oil which was purified by flash chromatography on silica gel (20% ethyl acetate/hexane) to give the title compound (2.15 g, 73%): 1H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 8.2 (d, 1H), 7.45 (d, 1H), 5.3 (s, 2H), 3.8 (s, 3H), 1.6 (s, 9H), 1.45 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12]Br)=[CH:6][CH:5]=1.Cl.[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)=[C:20]2[CH3:32]>>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][N:22]2[C:23]3[C:19](=[CH:18][C:17]([Cl:16])=[CH:25][CH:24]=3)[C:20]([CH3:32])=[C:21]2[C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(OCCBr)cc1
Reactant: Cc1c(-c2cccnc2)[nH]c2ccc(Cl)cc12
Agent: Cl
Product: COC(=O)c1ccc(OCCn2c(-c3cccnc3)c(C)c3cc(Cl)ccc32)cc1

Procedure:
4-(2-Bromo-ethoxy)-benzoic acid methyl ester (Example 61a) and 5-chloro-3-methyl-2-pyridin-3-yl-indol-1-yl (Example 2) are processed according to the method described in Example 59 to give 4-[2-(5-chloro-3-methyl-2-pyridin-3-yl-indol-1-yl)-ethoxy]-benzoic acid methyl ester. MS (ESI) m/z 421.01.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:35]=[CH:36][CH:37]=1)[O:7][C@H:8]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=2)[CH2:13][CH2:12]1)(=[O:3])[CH3:2].[CH3:38]I>>[C:1]([C:4]1[CH:5]=[C:6]([CH:35]=[CH:36][CH:37]=1)[O:7][C@H:8]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:18]=[C:19]([N:23]([CH3:38])[C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=2)[CH2:13][CH2:12]1)(=[O:3])[CH3:2]
Reactant: CI
Reactant: CC(=O)c1cccc(O[C@@H](CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccccc2)c1
Product: CC(=O)c1cccc(O[C@@H](CCN2CCC(c3cccc(N(C)C(=O)C(C)C)c3)CC2)c2ccccc2)c1

Procedure:
Prepared by Procedure T and Scheme AD using N-(3-{1-[(3S)-3-(3-acetylphenoxy)-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and methyl iodide: ESMS m/e: 513.2 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:20][C:21]2[CH:22]=[C:23]([CH:28]=[CH:29][C:30]=2[CH3:31])[C:24]([NH:26][CH3:27])=[O:25])=[N:5][C:6](S(C)(=O)=O)=[N:7][C:8]=1[N:9]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:10])#[N:2].[CH3:32][NH2:33]>O1CCOCC1>[C:1]([C:3]1[C:4]([NH:20][C:21]2[CH:22]=[C:23]([CH:28]=[CH:29][C:30]=2[CH3:31])[C:24]([NH:26][CH3:27])=[O:25])=[N:5][C:6]([NH:33][CH3:32])=[N:7][C:8]=1[N:9]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:10])#[N:2]
Reactant: CN
Reactant: CNC(=O)c1ccc(C)c(Nc2nc(S(C)(=O)=O)nc(N(C)CC(C)(C)C)c2C#N)c1
Solvent: C1COCCO1
Product: CNC(=O)c1ccc(C)c(Nc2nc(NC)nc(N(C)CC(C)(C)C)c2C#N)c1
Temperature: 80 °C

Procedure:
3-{5-Cyano-6-[(2,2-dimethyl-propyl)-methyl-amino]-2-methanesulfonyl-pyrimidin-4-ylamino}-4,N-dimethyl-benzamide (44 mg, 0.1 mmol) and methylamine (1 mL, 1M in THF) were mixed in p-dioxane (1 mL) in a sealed tube. The mixture was heated to 80° C. for overnight. The solvent was removed in vacuo, and the product (23 mg) was purified by the silica gel column chromatography. MS (m/z): 396 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][NH:7][C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.S(O)(O)(=O)=O.Cl[C:26]1[NH:27][CH2:28][CH2:29][N:30]=1>CC(O)C>[NH:30]1[CH2:29][CH2:28][N:27]=[C:26]1[NH:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][NH:7][C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: ClC1=NCCN1
Reactant: COc1ccc(C(=O)NCc2ccc(N)cc2)cc1
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: COc1ccc(C(=O)NCc2ccc(NC3=NCCN3)cc2)cc1
Temperature: 0 °C
Yield: 61.4 %

Procedure:
A mixture of N-(4-Aminobenzyl)-4-methoxybenzamide (15 g, 58.4 mmol), 2-chloroimidazoline sulfate (15.2 g, 74 mmol) and 2-propanol (380 mL) was heated at reflux for 2.5 h under N2. The mixture was cooled to 0° C. and filtered, and the filtrate was concentrated to dryness. To the resulting residue 10% aqueous sodium hydroxide was added to reach pH 13-14. The resulting suspension was filtered, and the solid N-[4-(4,5-dihydro-1H-imidazol-2-ylamino)-benzyl]-4-methoxybenzamide was crystallized from dichloromethane. Weight 11.9 g (61.4% yield). mp 160.3-160.6° C.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([O:12][C:13]1([CH2:16][O:17][C:18]2[CH:27]=[C:26]3[C:21]([C:22]([O:28][C:29]4[CH:34]=[CH:33][C:32]([NH:35][C:36]([C:38]5[C:39](=[O:51])[N:40]([C:45]6[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=6)[N:41]([CH3:44])[C:42]=5[CH3:43])=[O:37])=[CH:31][C:30]=4[F:52])=[CH:23][CH:24]=[N:25]3)=[CH:20][CH:19]=2)[CH2:15][CH2:14]1)=[O:11])=O)(C)(C)C.[ClH:53]>C(OCC)(=O)C>[ClH:53].[NH2:8][CH2:9][C:10]([O:12][C:13]1([CH2:16][O:17][C:18]2[CH:27]=[C:26]3[C:21]([C:22]([O:28][C:29]4[CH:34]=[CH:33][C:32]([NH:35][C:36]([C:38]5[C:39](=[O:51])[N:40]([C:45]6[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=6)[N:41]([CH3:44])[C:42]=5[CH3:43])=[O:37])=[CH:31][C:30]=4[F:52])=[CH:23][CH:24]=[N:25]3)=[CH:20][CH:19]=2)[CH2:14][CH2:15]1)=[O:11]
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OCC5(OC(=O)CNC(=O)OC(C)(C)C)CC5)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OCC5(OC(=O)CN)CC5)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15 %

Procedure:
The compound 1-((4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)-2-fluorophenoxy)quinolin-7-yloxy)methyl)cyclopropyl 2-(tert-butoxycarbonylamino)acetate (80 mg, 0.112 mmol) was dissolved in ethyl acetate (8 mL). 2 mL of HCl in ethyl acetate (0.93 mol/L) was added dropwise and the reaction was stirred at rt for 30 minute. The solid was collected by filtration and washed with ethyl acetate (10 mL×2) to afford the title compound as a white solid (11 mg, 15%).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[CH3:11][O:12][C:13](=[O:46])[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:24]([CH:25]([C:32](=[O:41])[NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([NH2:40])[CH:35]=3)[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[C:23]3[CH:42]=[CH:43][CH:44]=[CH:45][C:22]=3[N:21]=2)=[CH:16][CH:15]=1>ClCCl>[CH3:11][O:12][C:13](=[O:46])[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:24]([CH:25]([CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]3)[C:32](=[O:41])[NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([NH:40][CH:1]=[O:3])[CH:35]=3)[C:23]3[CH:42]=[CH:43][CH:44]=[CH:45][C:22]=3[N:21]=2)=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(-c2nc3ccccc3n2C(C(=O)Nc2cccc(N)c2)C2CCCCC2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: O=CO
Product: COC(=O)c1ccc(-c2nc3ccccc3n2C(C(=O)Nc2cccc(NC=O)c2)C2CCCCC2)cc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 62 %

Procedure:
A mixture of acetic anhydride (162 mg, 1.58 mmol, 2.2 equiv.) and formic acid (73 mg, 1.58 mmol, 2.2 equiv.) was heated to 60° C. for 15 minutes. The reaction was cooled to room temperature and a solution of 4-{1-[(3-amino-phenylcarbamoyl)-cyclohexyl-methyl]-1H-benzoimidazol-2-yl}-benzoic acid methyl ester (35 mg, 0.72 mmol, 1.0 equiv.) in dichloromethane (2 mL) was added and the reaction mixture stirred at room temperature for 16 hours. The reaction mixture was washed with 1 N HCl (2 mL) and the organic layer dried over magnesium sulphate. The reaction mixture was concentrated in vacuo to afford 4-{1-[cyclohexyl-(3-formylamino-phenylcarbamoyl)-methyl]-1H-benzoimidazol-2-yl}-benzoic acid methyl ester, 23 mg (62% yield) as a yellow solid, MS (ES+): 511 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[CH:5]2.[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[CH:18]=[CH2:19].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[O:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[N:7]1[C:8]2[C:4](=[CH:3][C:2](/[CH:19]=[CH:18]/[C:17]([O:21][CH2:22][CH3:23])=[O:20])=[CH:10][CH:9]=2)[CH:5]=[N:6]1
Reactant: Brc1ccc2c(cnn2C2CCCCO2)c1
Reactant: C=CC(=O)OCC
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: CCOC(=O)/C=C/c1ccc2c(cnn2C2CCCCO2)c1
Temperature: 90 °C
Yield: 86 %

Procedure:
To a solution of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.85 g, 3.02 mmol) in ACN (20 mL), ethyl acrylate (0.605 g, 6.05 mmol), tri-o-tolylphosphine (0.368 g, 1.209 mmol), and TEA (1.204 ml, 9.07 mmol) were added. The reaction mixture was purged with nitrogen and then Pd2(dba)3 CHCl3 adduct (0.313 g, 0.302 mmol) was added. The reaction was heated at 90° C. overnight. The solvent was removed under vacuum. The residue was dissolved in ethyl acetate (15 mL), washed with water (10 mL), brine (10 mL), and dried over sodium sulfate. The organic layer was concentrated under vacuum and the crude product was purified by flash chromatography on silica gel using hexane/ethyl acetate to give of (E)-ethyl 3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)acrylate as a yellow liquid (0.78 g, 76%). 1HNMR: 400 MHz, DMSO-d6: δ 1.25-1.26 (m, 3H), 1.58-1.62 (m, 2H), 1.76-1.77 (m, 1H), 1.97-2.07 (m, 2H), 2.39-2.42 (m, 1H), 3.73-3.79 (m, 1H), 3.88-3.91 (m, 1H), 4.21 (q, J=7.20 Hz, 2H), 5.87-5.88 (m, 1H), 6.64 (d, J=15.60 Hz, 1H), 7.76-7.77 (m, 2H), 7.81-7.87 (m, 1H), 8.12 (s, 1H), 8.18 (s, 1H). LCMS: RT 1.01 min; LCMS (ES-API), m/z 217 (M-THP).