Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH2:30][O:31][CH3:32])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>>[CH:33]1([C:36]([N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]3[C:14]4[N:15]=[CH:16][N:17]=[C:18]([C:19]5[C:27]6[O:26][CH2:25][O:24][C:23]=6[CH:22]=[CH:21][C:20]=5[O:28][CH2:29][CH2:30][O:31][CH3:32])[C:13]=4[NH:12][CH:11]=3)=[O:9])[CH2:5][CH2:6]2)=[O:37])[CH2:35][CH2:34]1
Reactant: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCNCC4)c[nH]c13)OCO2
Reactant: O=C(Cl)C1CC1
Product: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCN(C(=O)C5CC5)CC4)c[nH]c13)OCO2

Procedure:
Starting from 4-[5-(2-methoxy-ethoxy)-benzo[1,3]dioxol-4-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A187) and cyclopropanecarbonyl chloride the title compound was obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[C:16]([C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1)#[N:17]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:22]3[CH:23]=[C:18]([CH:19]=[CH:20][CH:21]=3)[C:16]#[N:17])[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1cccc(C#N)c1

Procedure:
The title compound, MS: m/e=319.8 (M+H+), was prepared in accordance with the general method of example 7 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 3-cyano-benzene boronic acid.
Reaction SMILES: C(CC(O)=O)#N.[F-:7].[Cs+].[CH2:9]([Sn:13](C1SC=CC=1)([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11][CH3:12].ClCCl>C1(C)C=CC=CC=1.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>[Sn:13]([F:7])([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: [F-]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#CCC(=O)O
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCC[Sn](F)(CCCC)CCCC
Temperature: 120 °C
Reaction time: 12 h

Procedure:
1 is halogenated chromophore 2 is metalated conjugated system step a) Reaction of 1 and 2 by palladium mediated Stille coupling results in formation of compound 3; step b) The carboxylaldehyde moiety is introduced to compound 3 by Vilsmaier-Haak reaction; And step c) transformed by reaction of 4 with cyano-acetic acid to the targeted 5. Step a) Under inert atmosphere, to a mixture of chromophore 1, 1 mol % catalysator Pd(PPh3)4, 1 equivalent of CsF in toluene, 1.2 equivalent of tributylstannyl-thiophene were added. The reaction mixture was stirred at 120° C. for 12 h. After cooling to room temperature, dichloromethane was added. The white salt (Bu3SnF) formed during the reaction was filtered off and the solvent removed under reduced pressure. Purification of the crude product was performed by column chromatography on silica gel with (2/8) dichloromethane/ethylacetate to give the pure thiophene derived squarylium dye 3. Analytical Data for 3
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.Cl[C:11](=[O:16])[C:12]([O:14][CH3:15])=[O:13]>>[CH3:15][O:14][C:12](=[O:13])[C:11]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][C:4]=1[CH3:9])=[O:16]
Reactant: Cc1cc(Cl)ccc1N
Reactant: COC(=O)C(=O)Cl
Product: COC(=O)C(=O)Nc1ccc(Cl)cc1C

Procedure:
In a manner similar to that employed in Referential Example 242, the title compound was prepared from 4-chloro-2-methylaniline and methyl chlorooxoacetate.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[Cl:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[N:34]=[C:33]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)[CH:32]=[CH:31]2>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:41]2[CH2:42][CH2:43][N:38]([C:33]3[CH:32]=[CH:31][C:30]4[C:35](=[CH:36][CH:37]=[C:28]([Cl:27])[CH:29]=4)[N:34]=3)[CH2:39][CH2:40]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: Clc1ccc2nc(N3CCNCC3)ccc2c1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3ccc4cc(Cl)ccc4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 6-chloro-2-piperazin-1-yl-quinoline.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH:12]=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23](=O)[CH3:24])[CH:18]=1)(=O)[CH3:15].[OH-].[K+]>C(O)C>[N:1]1[C:2]2[C:3](=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)[CH:12]=[CH:15][C:14]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:24]=[CH:12][C:3]3[C:2](=[C:11]4[C:6](=[CH:5][CH:4]=3)[CH:7]=[CH:8][CH:9]=[N:10]4)[N:1]=2)[CH:18]=1
Reactant: CC(=O)c1cccc(C(C)=O)c1
Reactant: Nc1c(C=O)ccc2cccnc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: c1cc(-c2ccc3ccc4cccnc4c3n2)cc(-c2ccc3ccc4cccnc4c3n2)c1
Yield: 83 %

Procedure:
101 g of 8-amino-7-quinoline carboaldehyde was reacted with 45 g of 1,3-diacetylbenzene and 100 g of 85% potassium hydroxide in 1800 ml of ethanol for 10 hours while refluxing and a reactant was treated by a normal method to obtain 100 g of 1,3-di(1,10-phenanthroline-2-yl)benzene. 40.8 g of this 1,3-di(1,10-phenanthroline-2-yl)benzene was reacted with 400 ml of phenyl lithium (0.94 M cyclohexane-ether solution) in 750 ml of toluene for 2.5 hours while cooling with ice and a reactant was treated by a normal method. The obtained product was reacted with 118 g of nitrobenzene at 110° C. for 3 hours and a reactant was treated by a normal method to obtain 22.8 g of E-20.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([C@@H:27]([NH2:29])[CH3:28])=[CH:23][CH:22]=1>>[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([C@@H:27]([NH:29][C:5]2[N:10]=[C:9]([N:11]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[N:13]=[CH:12]3)[CH:8]=[CH:7][N:6]=2)[CH3:28])=[CH:23][CH:22]=1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Reactant: Cc1ccc([C@H](C)N)cc1
Product: Cc1ccc([C@H](C)Nc2nccc(-n3cnc4ccccc43)n2)cc1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with (S)-1-(4-methylphenyl)ethylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (ESI): m/e 330.3 (M+1). 1H NMR (500 MHz, CDCl3): δ partial 8.53 (s, 1H); 8.39 (d, J=5.3 Hz, 1H), 7.84 (d, J=8.3 Hz, 1H); 6.78 (d, J=5.5 Hz, 1H); 5.75 (br s, 1H); 5.20 (br s, 1H); 2.36 (s, 3H); 1.63 (d, J=6.8 Hz, 3H).
Reaction SMILES: C1([C:7]2[CH:19]=[CH:18][C:17]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[CH:8]=2)C=CC=CC=1.Br[C:21]1[CH:22]=[CH:23][C:24]2[N:25]([S:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)(=[O:37])=[O:36])[C:26]3[C:31]([C:32]=2[CH:33]=1)=[CH:30][C:29](Br)=[CH:28][CH:27]=3.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu]I>[C:7]1([C:14]2[CH:13]=[CH:12][C:11]3[N:10]([C:21]4[CH:22]=[CH:23][C:24]5[N:25]([S:35]([C:38]6[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=6)(=[O:37])=[O:36])[C:26]6[C:31]([C:32]=5[CH:33]=4)=[CH:30][C:29]([N:10]4[C:9]5[CH:8]=[CH:7][C:19]([C:11]7[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=7)=[CH:18][C:17]=5[C:16]5[C:11]4=[CH:12][CH:13]=[CH:14][CH:15]=5)=[CH:28][CH:27]=6)[C:9]4[C:17]([C:16]=3[CH:15]=2)=[CH:18][CH:19]=[CH:7][CH:8]=4)[CH:19]=[CH:18][CH:17]=[CH:9][CH:8]=1
Reactant: c1ccc(-c2ccc3c(c2)[nH]c2ccccc23)cc1
Reactant: O=S(=O)(c1ccccc1)n1c2ccc(Br)cc2c2cc(Br)ccc21
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=S(=O)(c1ccccc1)n1c2ccc(-n3c4ccccc4c4cc(-c5ccccc5)ccc43)cc2c2cc(-n3c4ccccc4c4cc(-c5ccccc5)ccc43)ccc21

Procedure:
8.0 g (42.2 mmol) of copper(I) iodide and 11.7 ml (97.5 mmol) of trans-cyclohexanediamine are added to a vigorously stirred suspension of 56.9 g (234 mmol) of 2-phenylcarbazole, 54.4 g (117 mmol) of 3,6-dibromo-9-(phenylsulfonyl)-9H-carbazole and 416.4 g (1961 mmol) of potassium phosphate in 1170 ml of dioxane, and the mixture is subsequently heated under reflux for 16 h. After cooling, the precipitated solid is filtered off with suction, washed three times with 50 ml of toluene, three times with 50 ml of ethanol:water (1:1, v:v) and three times with 100 ml of ethanol. Yield: 80 g (101 mmol), 86%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[CH2:26]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][C@H:29]1[CH3:34])[CH3:27]>>[CH2:26]([N:28]1[CH2:33][CH2:32][N:31]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:25])[C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:20])[CH2:30][C@H:29]1[CH3:34])[CH3:27]
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Reactant: CCN1CCNC[C@H]1C
Product: CCN1CCN(C(=O)c2ccc(-n3ncc(-c4ccc(C#N)c(F)c4C)c3O)nc2)C[C@H]1C

Procedure:
The title compound was prepared in a manner similar to Example 303 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (R)-1-ethyl-2-methylpiperazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.22 (m, J=7.20, 7.20 Hz, 6H) 2.33 (d, J=2.27 Hz, 3 H) 2.91-4.72 (m, 9 H) 7.63 (br. s., 1 H) 7.71-7.79 (m, 1 H) 7.94-8.81 (m, 4 H) 9.52-10.21 (m, 1 H). ESI-MS m/z [M+H]+ 449.3.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:12][NH:11][CH2:10][CH2:9][NH:8]1.[CH2:13]([N:15]1[C:24]2[C:19](=[CH:20][C:21]([F:27])=[C:22](F)[C:23]=2[F:25])[C:18](=[O:28])[C:17]([C:29]([OH:31])=[O:30])=[CH:16]1)[CH3:14]>N1C=CC=CC=1>[CH2:13]([N:15]1[C:24]2[C:19](=[CH:20][C:21]([F:27])=[C:22]([N:11]3[CH2:10][CH2:9][NH:8][CH:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH2:12]3)[C:23]=2[F:25])[C:18](=[O:28])[C:17]([C:29]([OH:31])=[O:30])=[CH:16]1)[CH3:14]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Reactant: c1ccc(C2CNCCN2)nc1
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(c4ccccn4)C3)c(F)c21
Yield: 66.7 %

Procedure:
The 320 mg of 2-(2-pyridinyl)piperazine, 270 mg of 1-ethyl-1,4-dihydro-6,7,8-trifluoro-4-oxo-3-quinolinecarboxylic acid and 5 ml of pyridine were stirred at 70°-80° C. for 4 hours, then cooled and the pyridine removed in vacuo. The residue was taken up in methanol and then precipitated with ether. The solid was collected and dried, giving 275 mg of the desired product, mp 222°-224° C. (dec.).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[N:16]=[C:15]([C:17]#[N:18])[C:14]([CH2:19][N:20]([CH3:31])[C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24][CH2:23][CH2:22]2)=[C:13]([CH3:32])[N:12]=1)[CH3:2].CC(C[AlH]CC(C)C)C.Cl.[OH-].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O>[NH2:18][CH2:17][C:15]1[C:14]([CH2:19][N:20]([CH3:31])[C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24][CH2:23][CH2:22]2)=[C:13]([CH3:32])[N:12]=[C:11]([C:4]2[C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:9][CH3:10])[N:16]=1
Reactant: CCc1cccc(CC)c1-c1nc(C)c(CN(C)[C@H]2CCCc3ccccc32)c(C#N)n1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCc1cccc(CC)c1-c1nc(C)c(CN(C)[C@H]2CCCc3ccccc32)c(CN)n1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a flask containing 2-(2,6-diethylphenyl)-6-methyl-5-({methyl[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}methyl)pyrimidine-4-carbonitrile (50 mg, 0.118 mmol) in toluene (5.0 mL) is cooled to 0° C. using an ice bath. DIBAL (0.354 mL of a 1.5 M solution in toluene, 3.0 eq., 0.53 mmol) is then added and the reaction is allowed to proceed for 3 h warming to room temperature. HCl (1.0 M, 1.0 mL) is added and allowed to stir for 10 min, followed by basification with NaOH (5N. EtOAc (20 mL) is added and the organic layer is washed with NaHCO3 (10%, 100 mL), brine (100 mL) and dried over Na2SO4. SiO2 plate chromatography eluting with 20:1 CHCl3:MeOH affords the title compound as a white foam. [mass expected (428.61); mass found (428.38)].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][S:9][CH2:10][CH2:11][C:12]#[N:13])[N:3]=1.[F:14][C:15]([F:21])([F:20])[CH2:16][N:17]=[C:18]=[S:19]>C(#N)C>[F:14][C:15]([F:21])([F:20])[CH2:16][NH:17][C:18](=[S:19])[NH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][S:9][CH2:10][CH2:11][C:12]#[N:13])[N:3]=1
Reactant: N#CCCSCc1nccc(N)n1
Reactant: FC(F)(F)CN=C=S
Solvent: CC#N
Product: N#CCCSCc1nccc(NC(=S)NCC(F)(F)F)n1

Procedure:
To a solution of 3-(4-aminopyrimid-2-ylmethylthio)propionitrile (1.7 g.) in acetonitrile (40 ml.) was added 2,2,2-trifluoroethylisothiocyanate (2 ml.) and the solution heated under reflux for 17 hours. The acetonitrile was evaporated in vacuo and the residue dissolved in EtOAc, treated with decolourising carbon, filtered and evaporated to give 3-[4-(3-[2,2,2-trifluoroethyl]thioureido)pyrimid-2-ylmethylthio]propionitrile as an orange solid, m.p. 108°-110°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:15]O>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([O:7][CH3:15])=[O:6]
Reactant: Cc1cc(C(=O)O)ccn1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccnc(C)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 61 %

Procedure:
To an ice-cooled suspension of 1.32 g (9.62 mmol) of 2-methylisonicotinic acid in 20 mL of MeOH was added 1.47 mL (20.2 mmol) of thionyl chloride. The ice-bath was removed and the reaction was stirred at rt. After 22 h, the MeOH was evaporated and the residue was taken up in H2O. The aqueous mixture was neutralized with saturated NaHCO3, then extracted with Et2O. The organic extracts were washed with saturated NaCl, dried over MgSO4, then filtered through a bed of celite. Eva-poration of solvent in vacuo afforded the title compound as a yellow liquid (0.89 g, 61%): 1H NMR (CDCl3): d 8.66 (d, 1H); 7.72 (s, 1H); 7.64 (d, 1H); 3.98 (s, 3H); 2.64 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]=1[C:14]([OH:16])=O)[CH3:3].C(N1C=CN=C1)([N:19]1C=CN=C1)=O.[OH-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH3:1][CH:2]([O:4][C:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]=1[C:14]([NH2:19])=[O:16])[CH3:3]
Reactant: CC(C)Oc1c(C(=O)O)oc2ccccc12
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)Oc1c(C(N)=O)oc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
A suspension of 3-(1-methylethoxy)-2-benzofurancarboxylic acid (200 mg, 0.91 mmol) and 1,1'-carbonyldiimidazole (191 mg, 1.18 mmol) in 5 mL of tetrahydrofuran is heated at reflux for 1 hour. The reaction solution is cooled to room temperature and aqueous ammonium hydroxide (3 mL) is added and the reaction mixture is stirred at room temperature for 2 hours. The reaction is diluted with ethyl acetate and washed with 1N HCl, saturated aqueous NaHCO3, and brine. The organic phase is dried over magnesium sulfate, filtered, and concentrated in vacuo. Chromatography eluting with ethyl acetate:hexane (1:1) provides 3-(1-methylethoxy)-2-benzofurancarboxamide in 77% yield; mp=82°-83° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([O:26][C:27](=[O:29])[CH3:28])=[CH:6][C:7]2[CH2:8][CH2:9][C@@H:10]3[C@@H:19]([C:20]=2[CH:21]=1)[CH2:18][CH2:17][C@@:15]1([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]1[O:22][C:23](=[O:25])[CH3:24])[CH3:2].C(O)(=[O:32])C>[O-2].[O-2].[O-2].[Cr+6]>[CH2:1]([O:3][C:4]1[C:5]([O:26][C:27](=[O:29])[CH3:28])=[CH:6][C:7]2[C:8](=[O:32])[CH2:9][C@@H:10]3[C@@H:19]([C:20]=2[CH:21]=1)[CH2:18][CH2:17][C@@:15]1([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]1[O:22][C:23](=[O:25])[CH3:24])[CH3:2]
Reactant: CCOc1cc2c(cc1OC(C)=O)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC(C)=O)CC[C@@H]12
Reactant: CC(=O)O
Agent: [Cr+6]
Agent: [O-2]
Product: CCOc1cc2c(cc1OC(C)=O)C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC(C)=O)CC[C@@H]12
Temperature: 15 °C
Reaction time: 0.58 h
Yield: 55 %

Procedure:
A solution of chromium trioxide (1.6 g, 16 mmol) in 90% glacial acetic acid (7.5 mL) was added dropwise at 15° C. to a solution of 2-ethoxy-3,17β-diacetyl derivative (5), (1.5 g, 3.7 mmol) in glacial acetic acid (12 mL). The resulting mixture was stirred at 15° C. for 35 min. The mixiure was poured onto ice-water mixture (150 mL) and compound was extracted into ethyl acetate (3×180 mL). The combined organic layer was washed with water (100 mL), NaHCO3 solution (100 mL), water (100 mL), brine (100 mL), and dried over anhydrous sodium sulfate. The organic layer, upon evaporation under reduced pressure, provided a crude compound, which on purification on a silica gel column using hexane: ethyl acetate mixture aas eluant gave 1.20 g (55%) of estradiol (7): mp 195° C.; IR (KBr) 2980-2810, 1765, 1730, 1715, 1665, 1600, 1500, 918, 880 cm-1 ; 1H NMR (CDCl3) δ 0.89 (s, 3 H), 1.30-1.85 (m, 9 H), 1.90-2.45 (m, 11 H), 2.47-2.85 (m, 2 H), 4.15 (q, J=6.4 Hz, 2 H), 4.78 (t, J=8.5 Hz, 1 H), 6.95 (s, 1 H), 7.77 (s, 1 H). Anal. (C24H30O6) C, H.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[F:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([F:28])=[CH:22][C:21]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:21]3[CH:22]=[C:23]([F:28])[C:24]([O:26][CH3:27])=[CH:25][C:20]=3[F:19])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: COc1cc(F)c(B(O)O)cc1F
Product: CCCNC(=O)c1nnc2c(-c3cc(F)c(OC)cc3F)cccc2c1N
Yield: 66.6 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (116 mg, 0.375 mmol) and (2,5-difluoro-4-methoxyphenyl)boronic acid (140 mg, 0.75 mmol) were reacted to afford the title compound (93 mg, 67% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.15 (t, J=6.0 Hz, 1H), 8.46 (dd, J=8.0, 1.7 Hz, 1H), 7.76-7.86 (m, 2H), 7.44 (dd, J=11.8, 6.8 Hz, 1H), 7.22 (dd, J=11.3, 7.4 Hz, 1H), 3.93 (s, 3H), 3.29 (apparent q, J=7.0 Hz, 2H), 1.59 (apparent sextet, J=7.0 Hz, 2H), 0.91 (t, J=7.0 Hz, 3H). MS APCI, m/z=373 (M+H) HPLC 2.03 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O.O.NN>CO.CCOC(C)=O.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]([NH:10][C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(Nc1cccc([N+](=O)[O-])c1)N1CCCC1
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cccc(NC(=O)N2CCCC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 184.8 %

Procedure:
Pyrrolidine-1-carboxylic acid (3-nitro-phenyl)-amide (850 mg, 3.40 mmol) was dissolved in 1:1 MeOH-EtOAc (100 mL). Raney®-Nickel was added (3 full spatulas) followed by hydrazine monohydrate (1.70 g, 34.0 mmol) over a 5 minute period. The reaction mixture was stirred at rt for 16 hours then filtered through celite, washing the precipitate with EtOAc (10×10 mL). The filtrate was evaporated in vacuo and the residue dissolved in EtOAc (50 mL). The solution was washed with saturated brine solution (2×50 mL), dried (Na2SO4), filtered, and the solvent evaporated in vacuo. The crude product was then purified by column chromatography (Flashmaster, 40-63 mesh silica gel, EtOAc→10% MeOH-EtOAc) to provide the title compound as a pale yellow solid (1.29 g, 92%); LC-MS, Rt=0.99 min (MeOH-FA), m/z 206 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][C:5]=2[O:4][CH:3]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>>[CH3:25][S:26]([NH:1][C:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([O:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:11]([NH:13][S:14]([CH3:17])(=[O:15])=[O:16])=[CH:12][C:5]=2[O:4][CH:3]=1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: CS(=O)(=O)Nc1cc2occ(N)c(=O)c2cc1Oc1ccccc1
Product: CS(=O)(=O)Nc1cc2occ(NS(C)(=O)=O)c(=O)c2cc1Oc1ccccc1

Procedure:
3-Amino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one was reacted with methanesulfonyl chloride to obtain 3,7-bis(methylsulfonylamino)-6-phenoxy-4H-1-benzopyran-4-one.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]([OH:8])=[O:7])[CH2:3]1.Cl.Cl[C:11]1[N:16]=[CH:15][N:14]=[C:13]([N:17]2[C:21](=[O:22])[C:20]([N:23]3[CH:27]=[CH:26][N:25]=[N:24]3)=[CH:19][NH:18]2)[CH:12]=1.[OH-].[Na+]>O>[O:22]=[C:21]1[N:17]([C:13]2[N:14]=[CH:15][N:16]=[C:11]([N:2]3[CH2:5][CH:4]([C:6]([OH:8])=[O:7])[CH2:3]3)[CH:12]=2)[NH:18][CH:19]=[C:20]1[N:23]1[CH:27]=[CH:26][N:25]=[N:24]1
Reactant: O=C(O)C1CNC1
Reactant: O=c1c(-n2ccnn2)c[nH]n1-c1cc(Cl)ncn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C1CN(c2cc(-n3[nH]cc(-n4ccnn4)c3=O)ncn2)C1

Procedure:
55 mg (0.4 mmol) of azetidine-3-carboxylic acid hydrochloride are initially charged in 2 ml of water. 100 mg (0.3 mmol) of the compound from Example 12A are added, and the pH is adjusted to 7 using aqueous 1 N sodium hydroxide solution. The mixture is reacted in a single mode microwave (Emrys Optimizer) at 150° C. for 1 h. The reaction mixture is concentrated under reduced pressure and purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). Yield: 15 mg (13% of theory)
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([CH2:8][NH:9][CH2:10][C:11]2[S:15][C:14]([C:16]#[N:17])=[CH:13][CH:12]=2)=[N:5][C:4]2[CH2:18][CH2:19][O:20][CH2:21][C:3]1=2.[F:22][C:23]1[CH:40]=[CH:39][C:26]([C:27]([CH:29]2[CH2:34][CH2:33][N:32]([CH2:35][C:36](O)=[O:37])[CH2:31][CH2:30]2)=[O:28])=[CH:25][CH:24]=1.CC#N.O>C(O)=O>[C:16]([C:14]1[S:15][C:11]([CH2:10][N:9]([CH2:8][C:6]2[NH:7][C:2](=[O:1])[C:3]3[CH2:21][O:20][CH2:19][CH2:18][C:4]=3[N:5]=2)[C:36](=[O:37])[CH2:35][N:32]2[CH2:33][CH2:34][CH:29]([C:27](=[O:28])[C:26]3[CH:25]=[CH:24][C:23]([F:22])=[CH:40][CH:39]=3)[CH2:30][CH2:31]2)=[CH:12][CH:13]=1)#[N:17]
Reactant: N#Cc1ccc(CNCc2nc3c(c(=O)[nH]2)COCC3)s1
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Solvent: CC#N
Solvent: O
Solvent: O=CO
Product: N#Cc1ccc(CN(Cc2nc3c(c(=O)[nH]2)COCC3)C(=O)CN2CCC(C(=O)c3ccc(F)cc3)CC2)s1

Procedure:
Following general procedure of Example 5, the title compound was prepared (0.01 g) from 5-(((4-oxo-4,5,7,8-tetrahydro-3H-pyrano[4,3-d]pyrimidin-2-yl)methylamino)methyl)thiophene-2-carbonitrile and 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid. 1H NMR (400 MHz, MeOD) δ ppm 8.03-8.18 (m, 2H), 7.50-7.79 (m, 1H), 7.21-7.34 (m, 2H), 7.01-7.14 (m, 1H), 4.81-4.89 (m, 2H), 4.51-4.62 (m, 2H), 4.33-4.49 (m, 4H), 3.85-4.04 (m, 2H), 3.67-3.82 (m, 2H), 3.38-3.65 (m, 1H), 3.08-3.28 (m, 2H), 2.46-2.68 (m, 2H), 1.98-2.27 (m, 4H). HRMS calculated for C28H23F1N3O4S1 550.1924. found (ESI, [M+H]+) 550.1933. MS (ESI) m/z 550.6 (M+H)+. Retention time: 3.3 min (5-95% CH3CN/H2O over 7.75 min with 0.1% formic acid, Inertsil ODS3 100×3 mm C18 column with flow rate of 1.0 mL/min).