Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([NH:27][CH2:28][CH2:29][OH:30])[CH2:23][CH2:22]2)[N:3]=1.Br[CH2:32][CH2:33][OH:34].C(=O)(O)[O-].[Na+]>O1CCOCC1>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([N:27]([CH2:32][CH2:33][OH:34])[CH2:28][CH2:29][OH:30])[CH2:23][CH2:22]2)[N:3]=1
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(N[C@H]2CC[C@H](NCCO)CC2)nc1N
Reactant: OCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(N[C@H]2CC[C@H](N(CCO)CCO)CC2)nc1N
Temperature: 113 °C

Procedure:
To a stirred solution of trans-[4-amino-2-[4-(2-hydroxy-ethylamino)-cyclohexylamino]-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (106 mg, 0.25 mmol, Example 120) in 1,4-dioxane (3 mL), 2-bromoethanol (80 uL, 1.12 mmol, Aldrich) and sodium bicarbonate (50 mg, 0.60 mmol) were added and the mixture was heated at 113° C. for 24 hours. The reaction was quenched with water and the mixture was extracted with ethyl acetate (3×10 mL) and the extracts were dried with sodium sulfate. The solvent was removed and the residue was chromatographed (8% 9N ammonia in methanol/dichloromethane) to give a pale yellow solid. 97 mg, 84%. MS (ES) MH+=466.
Reaction SMILES: [I-].CS[C:4]1[S:5][CH2:6][C@@H:7]2[CH2:16][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9][N+:8]=12.[NH2:17][C:18]1[C:26]2[C:21](=[N:22][CH:23]=[CH:24][CH:25]=2)[S:20][CH:19]=1>>[S:20]1[C:21]2=[N:22][CH:23]=[CH:24][CH:25]=[C:26]2[C:18]([N:17]=[C:4]2[N:8]3[CH2:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[CH2:16][C@H:7]3[CH2:6][S:5]2)=[CH:19]1
Reactant: Nc1csc2ncccc12
Reactant: CSC1=[N+]2Cc3ccccc3C[C@H]2CS1
Agent: [I-]
Product: c1ccc2c(c1)C[C@H]1CSC(=Nc3csc4ncccc34)N1C2
Yield: 73.9 %

Procedure:
By following the procedure of Example 2, but using (S)-3-methylthio-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinolinium iodide (6.7 g) and 3-aminothieno[2,3-b]pyridine (2.8 g) as the starting materials, (S)-3-[(thieno[2,3-b]pyrid-3-yl)imino]-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline (4.6 g) is obtained in the form of beige crystals, m.p.=145°-146° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([OH:15])=O.S(Cl)([Cl:18])=O>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([Cl:18])=[O:15]
Reactant: Cc1onc(-c2ccccc2)c1C(=O)O
Reactant: O=S(Cl)Cl
Product: Cc1onc(-c2ccccc2)c1C(=O)Cl
Yield: 93 %

Procedure:
A mixture of 5-methyl-3-phenyl-isoxazole-4-carboxylic acid (1.0 g, 4.9 mmol, commercially available) and thionyl chloride (5 ml) was heated under reflux for 3 h. Removal of excess volatiles by evaporation afforded 5-methyl-3-phenyl-isoxazole-4-carbonyl chloride (1.01 g, 93%) as a yellow oil, which was used without further purification in the next reaction.
Reaction SMILES: O.NN.[CH3:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:14]([CH3:15])[C:13]3[CH:16]=[CH:17][C:18]([O:32][CH3:33])=[C:19]([CH2:20][N:21]4C(=O)C5C(=CC=CC=5)C4=O)[C:12]=3[O:11][C:10]=2[C:34]=1[CH2:35][C:36]#[N:37].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[NH2:21][CH2:20][C:19]1[C:12]2[O:11][C:10]3[C:34]([CH2:35][C:36]#[N:37])=[C:6]([O:5][CH3:4])[CH:7]=[CH:8][C:9]=3[N:14]([CH3:15])[C:13]=2[CH:16]=[CH:17][C:18]=1[O:32][CH3:33]
Reactant: COc1ccc2c(c1CC#N)Oc1c(ccc(OC)c1CN1C(=O)c3ccccc3C1=O)N2C
Agent: NN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1ccc2c(c1CN)Oc1c(ccc(OC)c1CC#N)N2C
Yield: 90 %

Procedure:
2.0 ml of ethanolic hydrazine hydrate solution (1M) were added at room temperature to a suspension of 280 mg of [3,7-dimethoxy-6-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-ylmethyl)-10-methyl-10H-dibenz[b,e][1,4]-oxazin-4-yl]-acetonitrile. The reaction mixture was heated to 85° for 4 hours, the cooled and poured into methylene chloride and 10% sodium carbonate solution. The aqueous phase was extracted with ethylene chloride and the combined organic fractions were dried over magnesium chloride and concentrated. The residue was dried in a high vacuum and, after recrystallization from tert.-butyl methyl ether/methanol, 180 mg (90.1%) of 6-aminomethyl-3,7-dimethoxy-10-methyl-10H-dibenzo[b,e][1,4]oxazine-4-acetonitrile were obtained as a beige solid of m.p. 167°-169° (dec.).
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:8])[CH2:6][NH2:7])([CH3:3])[CH3:2].[Cl:9][C:10]1[CH:25]=[CH:24][C:13]([C:14](=O)[CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2=O)=[CH:12][CH:11]=1.O.Cl>C(O)(=O)C>[ClH:9].[CH:1]([NH:4][CH:5]([CH3:8])[CH2:6][N:7]1[C:17]2[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=2[CH:15]=[C:14]1[C:13]1[CH:12]=[CH:11][C:10]([Cl:9])=[CH:25][CH:24]=1)([CH3:3])[CH3:2]
Reactant: CC(C)NC(C)CN
Reactant: O=C(CC1CCCCC1=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CC(C)NC(C)Cn1c(-c2ccc(Cl)cc2)cc2c1CCCC2

Procedure:
5.8 g (0.05 mole) of 2-isopropylaminopropylamine are added dropwise to a stirred solution of 12.5 g (0.05 mole) of 2-(p-chloro-phenacyl)cyclohexanone [Example 20(a)] in glacial acetic acid dropwise under nitrogen. After refluxing for 5 hours, the reaction mixture is cooled and poured into 500 ml. of water. The pH is adjusted to 1 with dilute hydrochloric acid, at which point a tan solid separates. This solid is recrystallized from methanol and then twice from an isopropanol-ether mixture to give 1-(2-isopropylaminopropyl)-2-(p-chlorophenyl)-4,5,6,7-tetrahydroindole hydrochloride as tan crystals, m.p. 192°-194° C.
Reaction SMILES: [OH-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12])#[N:4].[C:14]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:19]=1[OH:28])([CH3:17])([CH3:16])[CH3:15].Cl>CS(C)=O>[C:24]([C:20]1[CH:21]=[C:22]([C:9]2[CH:8]=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[C:5]([C:3]#[N:4])[CH:10]=2)[CH:23]=[C:18]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:19]=1[OH:28])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: N#Cc1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)c1cc(-c2ccc([N+](=O)[O-])c(C#N)c2)cc(C(C)(C)C)c1O
Temperature: 80 °C
Yield: 24.5 %

Procedure:
A mixture of 30 mg (0.75 mmol) of powdered sodium hydroxide, 87 mg (0.59 mmol) of 2-cyano-1-nitrobenzene, 155 mg (0.75 mmol) of 2,6-di-t-butylphenol, and 1.0 mL of dimethylsulfoxide was heated at 80° C. for two hours and poured into 10 mL of 1N HCl, and the resulting aqueous mixture was extracted with three 10 mL portions of diethyl ether. The ether layers were combined, dried over magnesium sulfate, and concentrated. Purification of the residue by preparative thin layer chromatography and crystallization afforded 51 mg (24% yield) of 2,6-di-t-butyl-4-(3'-cyano-4'-nitrophenyl)phenol.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[C:21]([C:24]([N:26]4[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]4)=[O:25])=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])[CH:5]=[CH:4][C:3]=1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[C:45]([F:48])([F:47])[F:46].C(OCC)(=O)C.[ClH:55]>C(OCC)C>[ClH:55].[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[C:21]([C:24]([N:26]4[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]4)=[O:25])=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])[CH:5]=[CH:4][C:3]=1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[C:45]([F:47])([F:46])[F:48]
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)N2Cc3ccc(C(=O)N4CCNCC4)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The 4-[[10,11-dihydro-10-[[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl]-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]carbonyl]-1-piperazine-carboxylic acid, tert-butyl ester of Example 6 (0.85 g, 1.29 mmol) was added in one portion to stirred ethyl acetate (10 mL) saturated with hydrogen chloride gas at 0° C. A precipitate formed after several minutes. The reaction mixture was stirred for 90 minutes under anhydrous conditions. The reaction was then warmed to room temperature and diluted with diethyl ether. The precipitated product was collected by filtration and dried under high vacuum to provide the desired title compound hydrochloride salt (0.65 g) as an off-white foam.
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.Br[C:24]1[CH:25]=[C:26]([CH:32]=[CH:33][CH:34]=1)[O:27][CH2:28][C:29]([NH2:31])=[O:30].C(=O)([O-])[O-].[Na+].[Na+]>C(O)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>[OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@@H:3]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:24]2[CH:25]=[C:26]([O:27][CH2:28][C:29]([NH2:31])=[O:30])[CH:32]=[CH:33][CH:34]=2)=[CH:7][CH:6]=1)[CH3:14]
Reactant: NC(=O)COc1cccc(Br)c1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
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: CCO
Product: C[C@H](Oc1ccc(-c2cccc(OCC(N)=O)c2)cc1)[C@H](O)CCc1cccnc1
Temperature: 90 °C
Yield: 68.2 %

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.150 g, Example 33), 2-(3-bromophenoxy)acetamide (0.230 g), 2M aqueous sodium carbonate (0.50 ml) and tetrakis(triphenylphosphine)palladium(0) (0.025 g) in ethanol (3 ml). The reaction mixture was heated at 90° C. for 4 hours. After cooling, the solution was concentrated under reduced pressure, taken up in ethanol and concentrated again (twice). The residue was triturated with acetone and then filtered through silica gel. The filtrate was concentrated under reduced pressure, dissolved in dichloromethane, filtered and purified by normal-phase HPLC eluting with a gradient of 0-25% ethanol in dichloromethane to give a colourless solid, which was recrystallised from boiling ethyl acetate:isohexane (1:1) to give the title compound as a solid (0.138 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH:17]1([CH2:20][C@H:21]([NH:27]C(C2C=CC(C3CCOCC3)=C(OCC3CC3)N=2)=O)[C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[CH2:19][CH2:18]1>>[CH:17]1([CH2:20][C@H:21]([NH:27][C:14]([C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:13]=2)=[O:16])[C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[CH2:19][CH2:18]1
Reactant: O=C(N[C@@H](CC1CC1)c1nccs1)c1ccc(C2CCOCC2)c(OCC2CC2)n1
Reactant: O=C(O)c1cccc(-c2cccc(Cl)c2)n1
Product: O=C(N[C@@H](CC1CC1)c1nccs1)c1cccc(-c2cccc(Cl)c2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and (S)-2-cyclopropyl-1-thiazol-2-yl-ethylamine (Example 59 b) as starting materials, MS (LC/MS): 384.1 [M+H]+.
Reaction SMILES: COC([N:5]([C:23]1[C:32]([C:33]([O:35][CH3:36])=[O:34])=[C:31]2[C:26]([CH:27]3[CH2:37][CH:28]3[CH2:29][O:30]2)=[CH:25][CH:24]=1)[S:6]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[NH:16][C:17](=[O:22])[CH2:18][CH2:19][CH2:20]Cl)(=[O:8])=[O:7])=O.[CH3:38][NH:39][CH3:40]>C(#N)C>[CH3:38][N:39]([CH3:40])[CH2:20][CH2:19][CH2:18][C:17]([NH:16][C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[S:6]([NH:5][C:23]1[C:32]([C:33]([O:35][CH3:36])=[O:34])=[C:31]2[C:26]([CH:27]3[CH2:37][CH:28]3[CH2:29][O:30]2)=[CH:25][CH:24]=1)(=[O:8])=[O:7])=[O:22]
Reactant: COC(=O)c1c(N(C(=O)OC)S(=O)(=O)c2ccc(F)cc2NC(=O)CCCCl)ccc2c1OCC1CC21
Reactant: CNC
Solvent: CC#N
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2NC(=O)CCCN(C)C)ccc2c1OCC1CC21
Temperature: 40 °C

Procedure:
A mixture of methyl (1aRS,7bSR)-5-{N-[methoxycarbonyl]-N-[2-(4-chlorobutyryl-amino)-4-fluorobenzenesulfonyl]amino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (Intermediate 109, 0.15 g) and dimethylamine (30% aqueous solution, 5 mL) in acetonitrile (10 mL) was stirred and heated at 40° C. for 10 hours. After cooling, the mixture was concentrated under vacuum and the residue was extracted with a mixture of ethyl acetate and THF (50%), dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by thick layer chromatography on silica, eluting with a mixture of methanol and DCM (10%) to give methyl (1aRS,7bSR)-5-[2-(4-dimethylaminobutyrylamino)-4-fluorobenzenesulfonyl-amino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (0.14 g) as a yellow oil.
Reaction SMILES: [N:1]([CH:4]1[CH2:23][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19]CCC)=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N+:2]=[N-:3].[C:24]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)#[CH:25]>>[CH3:33][O:32][C:29]1[CH:30]=[CH:31][C:26]([C:24]2[N:3]=[N:2][N:1]([CH:4]3[CH2:23][N:8]4[C:9]5[C:14]([C:15]([CH2:16][C:17]([OH:19])=[O:18])=[C:7]4[CH2:6][CH2:5]3)=[CH:13][CH:12]=[CH:11][CH:10]=5)[CH:25]=2)=[CH:27][CH:28]=1
Reactant: C#Cc1ccc(OC)cc1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)CC(N=[N+]=[N-])CC2
Product: COc1ccc(-c2cn(C3CCc4c(CC(=O)O)c5ccccc5n4C3)nn2)cc1

Procedure:
The title compound was prepared using analogous procedures described in EXAMPLE 1 from propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)acetate and 1-ethynyl-4-methoxybenzene. 1H NMR (400 MHz, DMSO-d6): δ 12.14 (s, 1H), 8.67 (s, 1H), 7.78 (d, 2H), 7.48 (d, 1H), 7.42 (d, 1H), 7.13-6.99 (m, 4H), 5.40-5.30 (m, 1H), 4.74 (dd, 1H), 4.40 (dd, 1H), 3.80 (s, 3H), 3.61 (s, 2H), 3.12-3.01 (m, 2H). MS (+ESI) m/z: 403.1.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]([CH3:22])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH2:4][CH2:3]1.[Br:23][CH2:24][CH2:25][CH2:26][CH2:27]Br>>[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][O:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]([CH3:22])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH2:4][CH2:3]1
Reactant: CN([C@H]1CC[C@H](O)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: BrCCCCBr
Product: CN([C@H]1CC[C@H](OCCCCBr)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to example 11.11, trans-N-(4-Hydroxy-cyclohexyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide and 1,4-Dibrombutane were converted to yield trans-N-[4-(4-Bromo-butoxy)-cyclohexyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide as light yellow semisolid, MS: 320 [M−C4H8BrO].
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:4](=[O:11])[C:5]2[N:10]=[N:9][NH:8][C:6]=2[N:7]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH:25]=O.C(OC(=O)C)(=O)C>O1CCOCC1>[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH:25]=[CH:1][C:2]1[N:3]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:4](=[O:11])[C:5]2[N:10]=[N:9][NH:8][C:6]=2[N:7]=1
Reactant: O=Cc1ccccn1
Reactant: Cc1ccccc1-n1c(C)nc2[nH]nnc2c1=O
Solvent: CC(=O)OC(C)=O
Solvent: C1COCCO1
Product: Cc1ccccc1-n1c(C=Cc2ccccn2)nc2[nH]nnc2c1=O
Temperature: 70 °C
Reaction time: 8 h
Yield: 3.4 %

Procedure:
To a mixture of fused zinc chloride (0.551 g, 4.04 mmol) and dioxane (20 mL) was added 5-methyl-6-o-tolyl-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one (0.488 g, 2.02 mmol), 2-pyridinecarboxaldehyde (0.58 mL, 6.06 mmol), and acetic anhydride (0.57 mL, 6.06 mmol). The mixture was heated to 70° C. for 6 hours, cooled, and quenched with saturated sodium bicarbonate. This mixture was stirred overnight at ambient temperature. The dioxane was removed at reduced pressure and the resulting black liquid was extracted with methylene chloride. The organic phase was dried over magnesium sulfate, treated with activated carbon, filtered, and concentrated. The residue (1.5 g) was flash chromatographed on silica gel (50 g). Elution with 50% and 60% ethyl acetate/hexane gave 5-(2-pyridin-2-yl-vinyl)-6-o-tolyl-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one (0.023 g, 3.5%).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9](O)(=[O:13])[C:10]([CH3:12])=O>>[CH3:12][C:10]1[C:9](=[O:13])[NH:7][C:2]2[C:1]([N:8]=1)=[CH:6][CH:5]=[CH:4][CH:3]=2
Reactant: CC(=O)C(=O)O
Reactant: Nc1ccccc1N
Product: Cc1nc2ccccc2[nH]c1=O

Procedure:
Reaction between 1,2-phenylene-diamine and pyruvic acid gave after recrystallisation (EtOH) the title compound as a beige solid;
Reaction SMILES: C(OC(=O)[N:7]([CH2:13][CH2:14][CH2:15][CH3:16])[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)(C)(C)C.C(N(CC)CC)C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>C(Cl)Cl>[CH2:13]([NH:7][N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCN(C(=O)OC(C)(C)C)n1cccc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCNn1cccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 113.3 %

Procedure:
A mixture of butyl-pyrrol-1-yl-carbamic acid tert-butyl ester (1.435 g), triethylamine (2.06 mL) and TMSOTf (1.79 mL) in DCM was stirred at rt for 15 min. The mixture was then diluted with DCM, washed with water, saturated sodium chloride solution and then dried over sodium sulfate, filtered, concentrated to give the desired product as oil (943 mg). 1H NMR (CDCl3, δ in ppm): 6.74 (m, 2H), 6.04 (m, 2H), 4.9 (very broad, 1H), 3.11 (t, 2H, J=7.1 Hz), 1.44-1.22 (m, 4H), 0.92 (t, 2H, J=7.3 Hz).
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[C:24]([NH:27][C:28]1[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=1)[NH2:31])(=[O:26])[CH3:25]>CN(C=O)C>[C:24]([NH:27][C:28]1[CH:29]=[C:30]([NH:31]/[C:4](=[C:11]2\[C:12](=[O:23])[NH:13][C:14]3[C:19]\2=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)/[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:32]=[CH:33][CH:34]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)Nc1cccc(N)c1
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)Nc1cccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)c1

Procedure:
Prepared analogously to Example 82 from 3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 3-acetylamino-aniline in DMF.
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17]O)=[CH:13][CH:12]=1.O=S(Cl)[Cl:21]>C(Cl)Cl>[Cl:21][CH2:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][C:2]2[S:1][C:9]3[C:4]([N:3]=2)=[N:5][CH:6]=[CH:7][CH:8]=3)=[CH:12][CH:13]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(Oc2nc3ncccc3s2)cc1
Solvent: ClCCl
Product: ClCc1ccc(Oc2nc3ncccc3s2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of [4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)phenyl]methanol (1.0 equiv.) in CH2Cl2 (0.3 M), SOCl2 (1.2 equiv.) was slowly added over 1 h at rt. In some embodiments, an excess of thionyl chloride was used, which was distilled off prior to the subsequent reaction step. After stirring at rt for another 30 min, the precipitated solid was collected by filtration and washed with CH2Cl2 to afford the title compound (100%), which was used without further purification. MS (ESI): mass calcd. for C13H9ClN2OS, 276.0; m/z found, 277.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 8.55 (dd, J=4.9, 1.7, 1H), 8.47 (dd, J=8.0, 1.7, 1H), 7.62 (dt, J=8.7, 2.1, 2H), 7.52 (dt, J=8.7, 2.1, 2H), 7.39 (dd, J=8.0, 4.9, 1H), 6.42 (br s, 1H), 4.84 (s, 2H).
Reaction SMILES: Br[C:2]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([NH:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[CH:18]1([NH2:21])[CH2:20][CH2:19]1>C1COCC1.CCOC(C)=O>[C:7]([NH:6][C:4](=[O:5])[C:3]1[CH:11]=[CH:12][CH:13]=[C:14]([N+:15]([O-:17])=[O:16])[C:2]=1[NH:21][CH:18]1[CH2:20][CH2:19]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)NC(=O)c1cccc([N+](=O)[O-])c1Br
Reactant: NC1CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)c1cccc([N+](=O)[O-])c1NC1CC1
Temperature: 60 °C

Procedure:
A mixture of 2-bromo-N-tert-butyl-3-nitrobenzamide (460 mg, 1.52 mmol) and cyclopropanamine (350 μL, 4.55 mmol) in THF (10 mL) was heated at 60° C. for 18 h. The reaction mixture was diluted with EtOAc, washed with water, brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using EtOAC:DCM (1:1) as eluent to give N-tert-butyl-2-(cyclopropylamino)-3-nitrobenzamide: 1H NMR (400 MHz, CDCl3) δ 8.26 (1H, br), 8.09 (1H, dd, J=8.0, 4.0 Hz), 7.57 (1H, d, J=8.0 Hz), 6.72 (1H, t, J=8.0 Hz), 5.81 (1H, br), 2.98-2.92 (1H, m), 1.49 (9H, s), 0.82-0.76 (2H, m), 0.58-0.52 (2H, m); LC-MS (ESI) m/z 278.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:11][O:12][C:13](=[O:25])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([CH:22]=[O:23])[C:16]=1[F:24].CO.[OH-].[K+]>O>[CH3:11][O:12][C:13](=[O:25])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([CH:22]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[NH:8][CH:9]=2)[OH:23])[C:16]=1[F:24]
Reactant: COC(=O)Nc1ccc(F)c(C=O)c1F
Reactant: Brc1cnc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)Nc1ccc(F)c(C(O)c2c[nH]c3ncc(Br)cc23)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
Into a reaction flask under nitrogen, 5-bromo-1H-pyrrolo[2,3-b]pyridine (4, 1.00 g, 5.08 mmol) is combined with (2,4-difluoro-3-formyl-phenyl)-carbamic acid methyl ester (3, 1.09 g, 5.08 mmol), 10 mL of methanol and potassium hydroxide (0.41 g, 7.31 mmol). The reaction is stirred at room temperature overnight, then diluted with 30 mL of water and extracted with 1×50 mL, then 2×30 mL of ethyl acetate. The organic layers are combined, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with a gradient of ethyl acetate:hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (5, 1.91 g, 91%).
Reaction SMILES: [N+]([C:4]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-])=O.[SH:15][CH2:16][C:17]([O:19][CH3:20])=[O:18].C(N(CC)CC)C>CS(C)=O>[CH3:20][O:19][C:17]([C:16]1[S:15][C:4]2[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:5]=2[CH:6]=1)=[O:18]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: COC(=O)CS
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc2ccc([N+](=O)[O-])cc2s1
Temperature: 0 °C

Procedure:
24.8 g (126.7 mmol) of 2,4-dinitrobenzaldehyde, 13.4 g (126.7 mmol) of methyl mercaptoacetate and 35.3 ml (253.3 mmol) of triethylamine in 74.5 ml of DMSO are heated at 80° C. for 1 h. The reaction solution is poured into 250 ml of ice-water. The resulting precipitate is filtered off with suction, washed with water and dried at 50° C. under reduced pressure overnight. This gives 16.1 g (53.6% of theory) of the title compound.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH2:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH3:29])=[CH:23][CH:22]=2)([CH3:20])[CH3:19])[CH:11]=[CH:12][C:13]=1[F:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C>[O:1]([C:8]1[CH:9]=[C:10]([CH2:15][CH2:16][CH2:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH3:29])=[CH:23][CH:22]=2)([CH3:19])[CH3:20])[CH:11]=[CH:12][C:13]=1[F:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOc1ccc(C(C)(C)CC=Cc2ccc(F)c(Oc3ccccc3)c2)cc1
Reactant: [H][H]
Solvent: CCOC(C)=O
Product: CCOc1ccc(C(C)(C)CCCc2ccc(F)c(Oc3ccccc3)c2)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 2.0 g of 1-(3-phenoxy-4-fluorophenyl)-4-(4-ethoxyphenyl)-4-methyl-1-pentene, 0.2 g of 5% pd-C and 40 ml of ethyl acetate was put in a 200 ml autoclave and pressed up to 10 kg/cm2G with hydrogen gas, and stirred at 80° C. for three hours. After cooling, the reaction mixture was filtered and the solvent was evaporated, and the residue was purified by column chromatography on silica gel to 1.7 g of 1-(3-phenoxy-4-fluorophenyl)-4-(4-ethoxyphenyl)-4-methylpentane.