Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:22][C:5]2=[N:6][C:7]([CH3:21])=[CH:8][C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=1.O(C([N:37]1[CH:41]=[C:40](B(O)O)[CH:39]=[N:38]1)=O)C(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>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:20][C:16]1[CH:15]=[C:14]([S:11]([NH:10][C:9]2[CH:8]=[C:7]([CH3:21])[N:6]=[C:5]3[S:22][C:2]([C:40]4[CH:41]=[N:37][NH:38][CH:39]=4)=[C:3]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=4)[C:4]=23)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)n1cc(B(O)O)cn1
Reactant: Cc1cccc(-c2c(Br)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
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+]
Product: Cc1cccc(-c2c(-c3cn[nH]c3)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 120 °C

Procedure:
A suspension of N-[2-bromo-6-methyl-3-(3-methylphenyl)thieno[2,3-b]pyridin-4-yl]-3-chlorobenzenesulfonamide (Description 60) (214 mg, 0.421 mmol), 1-tert-butoxylcarbonyl-1H-pyrazole-4-boronic acid, pinacol ester (124 mg, 0.421 mmol), tetrakis(triphenylphosphine)palladium(0) (48.7 mg, 0.042 mmol) and aqueous sodium carbonate (2M) (0.421 mL, 0.843 mmol) was degassed under a nitrogen atmosphere for ca. 10 min before being subjected to microwave heating at 120° C. for 30 min. The reaction mixture was then partitioned between ethyl acetate and water (ca. 30 mL each). The aqueous layer was separated and re-extracted with ethyl acetate (ca. 25 mL) and the combined organic layer passed through a phase separator and the solvent removed in vacuo. Purification by chromatography on silica, eluting with a gradient of 0-80% ethyl acetate in cyclohexane, afforded the title compound (75 mg). LCMS (A) m/z: 495 [M+1]+, Rt 1.31 min (acidic).
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[K+].[CH3:6][C:7]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:8]=1[CH2:9][O:10][C:11]1[CH:12]=[C:13]([C:17](=[O:25])[CH2:18][CH2:19][C:20](OCC)=O)[CH:14]=[CH:15][CH:16]=1.Cl.[CH2:32]([OH:34])C>O>[CH3:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:7]([CH3:6])[C:8]=1[CH2:9][O:10][C:11]1[CH:12]=[C:13]([C:17](=[O:25])[CH2:18][CH2:19][CH2:20][C:32]([NH:2][OH:3])=[O:34])[CH:14]=[CH:15][CH:16]=1
Reactant: NO
Reactant: CCO
Reactant: CCOC(=O)CCC(=O)c1cccc(OCc2c(C)cccc2C)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1cccc(C)c1COc1cccc(C(=O)CCCC(=O)NO)c1

Procedure:
To a hydroxylamine hydrochloride solution in dry ethanol, add a solution of potassium hydroxide in dry ethanol at 35° C. Cool the mix and add Ethyl 4-(3-(2,6-dimethylbenzyloxy)phenyl)-4-oxobutyrate (Step C), and powdered potassium hydroxide. After few hours, reaction mixture can be diluted with water and neutralize with hydrochloric acid, filter and recrystallize to give title compound.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH:26]=[CH2:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:30](Br)[C:31]#[CH:32].C1(C)C=CC=CC=1>CN(C=O)C>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:32][C:31]#[CH:30])[C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH:26]=[CH2:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C#CCBr
Reactant: C=Cc1ccccc1-c1[nH]c2cc(C(=O)OC)ccc2c1C1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: C#CCn1c(-c2ccccc2C=C)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Yield: 84 %

Procedure:
Methyl 3-cyclohexyl-2-(2-vinylphenyl)-1H-indole-6-carboxylate was dissolved in DMF (0.277 M) and sodium hydride (1.2 eq.) was added. After the evolution of gas had ceased, a solution of propargylbromide in toluene (80% solution, 1.6 eq.) was added. After 3 h all volatiles were evaporated in vacuo. The residual material was purified by flash chromatography (PE:EtOAc, 20:1). After evaporation of the solvents, the product was obtained as a colourless foam (84%). MS (ES+): 398.4 (M+H+).
Reaction SMILES: S(O)(=O)(=O)C.S(O)(=O)(=O)C.O[C@@H:12]1[CH2:37][CH2:36][C@@:35]2([CH3:38])[C@H:14]([C@@H:15](O)[CH2:16][C@@H:17]3[C@@H:34]2[CH2:33][CH2:32][C@@:31]2([CH3:39])[C@H:18]3[CH2:19][CH2:20][C@@H:21]2[C@H:22]([CH3:30])[CH2:23][CH2:24][C:25](=O)[CH:26]([CH3:28])[CH3:27])[CH2:13]1.[Cl-:41].[Li+].[OH2:43]>CN(C)C=O>[Cl:41][CH:12]1[CH2:37][CH2:36][C@@:35]2([CH3:38])[C:14](=[CH:15][CH2:16][C@@H:17]3[C@@H:34]2[CH2:33][CH2:32][C@@:31]2([CH3:39])[C@H:18]3[CH2:19][CH2:20][C@@H:21]2[C@H:22]([CH3:30])[CH2:23][CH2:24][C:25](=[O:43])[CH:26]([CH3:27])[CH3:28])[CH2:13]1
Reactant: CC(C)C(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C[C@H](O)[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O
Reactant: [Cl-]
Agent: CS(=O)(=O)O
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(C)C(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4CC(Cl)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
To the solution of 3α,6α-dihydroxy-5β-cholestan-24-one dimesylate prepared (a) above in dimethylformamide (10 ml) was added lithium chloride (100 mg) and the mixture was refluxed for 30 minutes. After cooling, water was added to the reaction mixture and the mixture was extracted with diethyl ether. The ether layer was washed with water, dried over magnesium sulfate and evaporated to give an oily product, 3-chlorocholest-5-en-24-one.
Reaction SMILES: C([O:8][C:9](=[O:52])[C@H:10]([CH3:51])[N:11]([C:20](=[O:50])[C@H:21]([CH2:43][CH2:44][CH2:45][NH:46][C:47](=[NH:49])[NH2:48])[N:22]([N+:40]([O-])=O)[S:23]([C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][C:30]([O:38][CH3:39])=[C:31]([O:36][CH3:37])[CH:32]=2)[CH:27]=1)(=[O:25])=[O:24])[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)C1C=CC=CC=1.[H][H]>C(O)(=O)C.[Pd]>[N:22]#[N:40].[CH3:37][O:36][C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][C:30]=1[O:38][CH3:39])[CH:27]=[C:26]([S:23]([NH:22][C@H:21]([C:20]([N:11]([CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C@H:10]([C:9]([OH:52])=[O:8])[CH3:51])=[O:50])[CH2:43][CH2:44][CH2:45][NH:46][C:47](=[NH:48])[NH2:49])(=[O:25])=[O:24])[CH:35]=[CH:34]2
Reactant: COc1cc2ccc(S(=O)(=O)N([C@@H](CCCNC(=N)N)C(=O)N(CCc3ccccc3)[C@@H](C)C(=O)OCc3ccccc3)[N+](=O)[O-])cc2cc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1cc2ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)N(CCc3ccccc3)[C@@H](C)C(=O)O)cc2cc1OC
Product: N#N
Yield: 67 %

Procedure:
To a solution of 3.00 g of NG -nitro-N2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-phenethylalanine benzyl ester in 50 ml of acetic acid was added 0.5 of palladium-black and then the mixture was shaken in a hydrogen atmosphere for 100 hours at room temperature. At the end of this period, the ethanol solution was filtered to remove the catalyst and evaporated to dryness. The residue was washed several times with dry diethyl ether and chromatographed on 80 ml of Daiaion ®SK 102 ion exchange resin (200-300 mesh, H+ form, manufactured by Mitsubishi Chemical Industries Limited) packed in water, washed with water, and eluted with 3% ammonium hydroxide solution. The fraction eluted from 3% ammonium hydroxide was evaporated to dryness to give 1.64 g (67%) of N2 -(6,7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-phenethylalanine as an amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH2:22][N:23](C1CCCCO1)[OH:24].[C@@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH2:22][NH:23][OH:24]
Reactant: CSc1ccc(/C=C2/C(C)=C(CCN(O)C3CCCCO3)c3cc(F)ccc32)cc1
Agent: CC1(C)C2CC[C@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CO
Product: CSc1ccc(/C=C2/C(C)=C(CCNO)c3cc(F)ccc32)cc1

Procedure:
A mixture of the indene intermediate from Step 3 (1 g, 2.35 mmol) and (1R)-(-)-10-camphorsulfonic acid (546 mg, 2.35 mmol) in methanol (30 mL) was refluxed for 3 hours. The methanol was evaporated, the residue dissolved in ethyl acetate and the solution washed successively with water, twice with saturated aqueous sodium bicarbonate, and with water. After drying over Na2SO4, the residue obtained on evaporation of the solvent was triturated with ether and filtered to obtain the title compound as a yellow solid, mp: dec 126° C. which was identical to the product obtained in Method A, Step 4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Cl:13])[C:5]2[O:9][CH:8]([CH2:10]Br)[CH2:7][C:6]=2[CH:12]=1.[CH2:14]([NH2:18])[CH2:15][CH2:16][CH3:17]>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([Cl:13])[C:5]2[O:9][CH:8]([CH2:10][NH:18][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:7][C:6]=2[CH:12]=1
Reactant: Clc1cc(Cl)c2c(c1)CC(CBr)O2
Reactant: CCCCN
Product: CCCCNCC1Cc2cc(Cl)cc(Cl)c2O1
Product: Cl

Procedure:
33 g (0.118 mole) of 5,7-dichloro-2,3-dihydrobenzofuran-2-ylmethyl bromide and 200 ml of n-butylamine were stirred for 12 hours at 60° C. The mixture was evaporated down under reduced pressure, 100 ml of a 20% strength aqueous sodium hydroxide solution were added to the residue, and the mixture was then extracted by shaking with 300 ml of methylene chloride. The organic phase was washed with three times 70 ml of water, dried and evaporated down, the residue was dissolved in 300 ml of dry diethyl ether, the solution was gassed with dry hydrogen chloride at from 0° to +3° C., and the colorless crystalline precipitate was filtered off under suction, washed with dry diethyl ether and dried. 27 g of N-(5,7-dichloro-2,3-dihydrobenzofuran-2-ylmethyl)-N-butylamine hydrochloride of melting point 202°-205° C. were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Br:16])=[N:7][N:8]([CH:13]([CH3:15])[CH3:14])[C:9]2=[O:12])=[CH:4][CH:3]=1.[C:17]([O-])([O-])=O.[K+].[K+].CI>C1COCC1>[CH3:17][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Br:16])=[N:7][N:8]([CH:13]([CH3:14])[CH3:15])[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: CC(C)n1nc(Br)c2ccc(O)cc2c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc2c(Br)nn(C(C)C)c(=O)c2c1
Yield: 76.9 %

Procedure:
To a stirred solution of 7-hydroxy-2-Isopropyl-4-bromo-2H-phthalazin-1-one (0.4 g, 1.4 mmol) in THF (5 ml) were added successively, K2CO3 (0.59 g, 4.3 mmol) and methyl iodide (0.22 g, 1.55 mmol) and the mixture was heated to reflux for 24 hours. After this time, LC-MS indicated complete consumption of starting material, and the reaction mixture was concentrated under vacuum. The residue was re-dissolved in EtOAc (50 ml) and washed with water (2×30 ml), the organic layer was dried (MgSO4), filtered and concentrated under vacuum to give the title compound (0.32 g, 76% yield) as an orange powder.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:10]1[CH:23]=[CH:22][CH:21]=[CH:20][C:11]=1[C:12]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)=[O:13])#[N:9].Cl[C:25]1[N:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:8]([C:10]1[CH:23]=[CH:22][CH:21]=[CH:20][C:11]=1[C:12]([N:14]1[CH2:15][CH2:16][N:17]([C:25]2[N:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][N:26]=2)[CH2:18][CH2:19]1)=[O:13])#[N:9]
Reactant: N#Cc1ccccc1C(=O)N1CCNCC1
Reactant: COc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccnc(N2CCN(C(=O)c3ccccc3C#N)CC2)n1
Temperature: 100 °C
Yield: 52 %

Procedure:
A mixture of 1.0 g (3.04 mmol) of 1-(2-cyanobenzoyl)piperazine trifluoroacetate, 0.5 g (3.35 mmol) of 2-chloro-4-methoxypyrimidine and 1.0 g (6.68 mmol) of potassium carbonate in 20 mL of DMF is heated to 100° C. for 1 hour. The solvent is eliminated at reduced pressure and water is added. The resulting solid is filtered, washed with water and purified by chromatography over silica gel, using as eluent ethyl acetate, yielding 0.51 g (1.58 mmol) of 2-[4-(2-cyanobenzoyl)-1-piperazinyl]-4-methoxypyrimidine.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([N:14]4[C:18]([CH3:19])=[N:17][N:16]([CH:20]([CH3:22])[CH3:21])[C:15]4=[O:23])[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.IC1C=CC2C3N=C(N4C(C)=NN(C(C)C)C4=O)SC=3CCOC=2C=1.[CH3:51][C:52]([OH:69])([CH3:68])[CH2:53][N:54]1[CH:58]=[C:57](B2OC(C)(C)C(C)(C)O2)[CH:56]=[N:55]1>>[OH:69][C:52]([CH3:68])([CH3:51])[CH2:53][N:54]1[CH:58]=[C:57]([C:2]2[CH:25]=[CH:24][C:5]3[C:6]4[N:7]=[C:8]([N:14]5[C:18]([CH3:19])=[N:17][N:16]([CH:20]([CH3:22])[CH3:21])[C:15]5=[O:23])[S:9][C:10]=4[CH2:11][CH2:12][O:13][C:4]=3[CH:3]=2)[CH:56]=[N:55]1
Reactant: Cc1nn(C(C)C)c(=O)n1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cc1nn(C(C)C)c(=O)n1-c1nc2c(s1)CCOc1cc(I)ccc1-2
Product: Cc1nn(C(C)C)c(=O)n1-c1nc2c(s1)CCOc1cc(-c3cnn(CC(C)(C)O)c3)ccc1-2

Procedure:
Following the procedure for 473, a mixture of 4-(8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-2-isopropyl-5-methyl-2,4-dihydro-[1,2,4]triazol-3-one and 4-(8-iodo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-2-isopropyl-5-methyl-2,4-dihydro-[1,2,4]triazol-3-one and 2-methyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propan-2-ol were reacted to give 474 isolated as a white solid (34 mg, 59%). LCMS: RT=4.79 min, [M+H]+=481. 1H NMR δ (ppm) (DMSO-d6): 8.15 (1 H, d, J=8.26 Hz), 8.08 (1 H, s), 7.87 (1 H, d, J=0.74 Hz), 7.33 (1 H, dd, J=8.26, 1.84 Hz), 7.22 (1 H, d, J=1.82 Hz), 4.68 (1 H, s), 4.38-4.28 (3 H, m), 3.99 (2 H, s), 3.28 (2 H, m), 2.67 (3 H, s), 1.29 (6 H, t, J=6.68 Hz), 1.05 (6 H, s)
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:10][CH2:11][CH2:12][CH3:13])[C:5]([CH3:9])=[C:6]([CH3:8])[CH:7]=1.[F:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>N1C=CC=CC=1.O1CCCC1.C(OCC)(=O)C>[CH2:10]([N:4]1[C:5]([CH3:9])=[C:6]([CH3:8])[CH:7]=[C:2]([NH:1][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][C:16]([F:15])=[CH:17][CH:18]=2)[C:3]1=[O:14])[CH2:11][CH2:12][CH3:13]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCCCn1c(C)c(C)cc(N)c1=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCn1c(C)c(C)cc(NC(=O)c2ccc(F)cc2)c1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 54.2 %

Procedure:
3-Amino-1-butyl-5,6-dimethyl-2-pyridone (5-004-02) (117 mg) was dissolved in pyridine, (1 mL), and the reaction mixture was stirred under ice-cooling and nitrogen atmosphere, and to the reaction mixture was added dropwise a solution of 4-fluorobenzoyl chloride (0.08 mL) in tetrahydrofuran (1 mL) over 10 min, followed by stirring at the same condition. After 3 h, the reaction mixture was diluted with ethyl acetate and poured into ice-water, extracted once with ethyl acetate, washed with aqueous hydrochloric acid solution, water, an aqueous solution of sodium bicarbonate, and water, dried over magnesium sulfate, and evaporated under reduced pressure. The obtained crystal residue (202 mg) was recrystallized from methylene chloride/n-hexane to give 1-butyl-3-(4-fluorobenzoyl)amino-5,6-dimethyl-2-pyridone (5-004) (103 mg, 54.2%, m.p. 129 to 130° C.) as a colorless needle.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[CH:31]=4)=[O:28])=[CH:22][CH:21]=3)[CH:16]=[CH:15][N:14]=2)[NH:10][CH:9]=1)=[O:7].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.O.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:36][C:32]1[CH:31]=[C:30]([NH:29][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([O:19][C:17]3[CH:16]=[CH:15][N:14]=[C:13]([C:11]4[NH:10][CH:9]=[C:8]([C:6]([NH:5][CH2:4][CH2:3][CH:2]=[O:1])=[O:7])[CH:12]=4)[CH:18]=3)=[CH:21][CH:22]=2)=[O:28])[CH:35]=[CH:34][CH:33]=1
Reactant: Cc1cccc(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCCO)c[nH]4)c3)cc2)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCC=O)c[nH]4)c3)cc2)c1
Temperature: 25 °C
Reaction time: 1.33 h

Procedure:
To a stirred solution of N-(3-hydroxypropyl)-5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide (1.0 g, 2.06 mmol) in 20 ml of anhydrous DMF was added Dess-Martin periodinane (1.22 g, 2.88 mmol). The mixture was stirred at room temperature under nitrogen for 80 minutes and poured into 100 ml of water with vigorous stirring. Saturated NaHCO3 solution was added until pH=9. The precipitates were filtered, washed with water and dried in vacuo to give the crude 5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-(3-oxopropyl)-1H-pyrrole-3-carboxamide as light brown solid, which was used in the next step without further purification. Yield: 1.0 g, 100%.
Reaction SMILES: [C:1]1([CH:7](O)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)[Br:17].O>C(OCC)C>[Br:17][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: BrP(Br)Br
Reactant: OC(Cc1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: O
Product: BrC(Cc1ccccc1)c1ccccc1
Temperature: -10 °C
Yield: 84 %

Procedure:
To a solution of 12.0 (60.5 mmol) of 1,2-diphenylethanol in 50 mL of dry diethyl ether, 11.0 g (3.80 mL, 40.0 mmol) of PBr3 was added with vigorous stirring at −10° C. The resulting mixture was stirred for 12 hr at room temperature and then added to 350 mL of cold water. The organic layer was separated, and the aqueous layer was extracted with 2×100 mL of water. The combined organic extracts were washed with aqueous NaHCO3, dried over Na2SO4, and evaporated to dryness. This procedure gave 13.2 g (84%) of the title product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[S:9][C:8]=1[C:16]([O:18][CH3:19])=[O:17])[CH3:2].OO.NC(N)=[O:25].C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>CC#N>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[C:15]2[C:10](=[N+:11]([O-:25])[CH:12]=[CH:13][CH:14]=2)[S:9][C:8]=1[C:16]([O:18][CH3:19])=[O:17])[CH3:2]
Reactant: NC(N)=O
Reactant: CCOC(=O)COc1c(C(=O)OC)sc2ncccc12
Agent: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: CCOC(=O)COc1c(C(=O)OC)sc2c1ccc[n+]2[O-]
Temperature: 70 °C
Reaction time: 8 h
Yield: 46.7 %

Procedure:
To a mixture of methyl 3-(2-ethoxy-2-oxoethoxy)thieno[2,3-b]pyridine-2-carboxylate (500 mg), urea hydrogen peroxide (239 mg) and CH3CN (8 mL) was added TFAA (0.353 mL) at room temperature. The mixture was stirred at room temperature for 4 h and at 70° C. overnight. To the mixture were added urea hydrogen peroxide (80 mg) and TFAA (0.118 mL). The mixture was stirred at 70° C. for 2 h. After cooling, to the mixture was added saturated aqueous NaHCO3. The resulting precipitate was collected by filtration to give the title compound (246 mg). The filtrate was concentrated. The residue was extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo to give the title compound (85.1 mg). Total yield: 331 mg.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@@H:7]([OH:14])[CH2:6][C@@H:5]1[CH3:15])(=[O:3])[CH3:2].[F:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[F:24])N>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]([O:14][C:21]2[CH:19]=[CH:18][C:17]([F:16])=[C:23]([F:24])[CH:22]=2)[CH2:6][C@@H:5]1[CH3:15])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccccc2[C@@H](O)C[C@@H]1C
Reactant: Nc1ccc(F)c(F)c1
Product: CC(=O)N1c2ccccc2[C@H](Oc2ccc(F)c(F)c2)C[C@@H]1C
Yield: 63.6 %

Procedure:
A compound was produced in the same manner as in Example 12, using 60 mg of trans-1-acetyl-4-hydroxy-2-methyl-1,2,3,4-tetrahydroquinoline and 112 mg of 3,4-difluoroaniline, and thus 59 mg (64%) of the title compound was obtained as a colorless oily substance.
Reaction SMILES: [CH:1]12[CH2:6][CH:5]1[CH2:4][N:3]([C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[CH:16]=3)[C:10]([C:24](O)=[O:25])=[CH:9][N:8]=1)[CH2:2]2.[N:27]1([CH2:33][CH2:34][NH2:35])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C1COCC1.O>[CH:1]12[CH2:6][CH:5]1[CH2:4][N:3]([C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[CH:16]=3)[C:10]([C:24]([NH:35][CH2:34][CH2:33][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:25])=[CH:9][N:8]=1)[CH2:2]2
Reactant: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)O)cc1Cl
Reactant: NCCN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)NCCN2CCOCC2)cc1Cl
Reaction time: 4 h
Yield: 36.4 %

Procedure:
In THF (10 mL) were dissolved 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-chloro-4-methoxybenzyl)amino)-pyrimidine-5-carboxylic acid (150 mg, 0.40 mmol) and 2-morpholinylethylamine (59 mg, 0.45 mmol). HATU (190 mg, 0.50 mmol) and triethylamine (101 mg, 1 mmol) were then added. The reaction was conducted at ambient temperature for 4 h. Then the reaction mixture was diluted with water and extracted with DCM. The organic phase was dried, concentrated, and purified by silica gel column chromatography (DCM/methanol=20/1) to give 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-chloro-4-methoxybenzyl)amino)-N-(2-morpholinylethyl)pyrimidine-5-formamide as a white solid (71 mg, 36.5% yield).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]2[C:20]3[NH:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].C([N+]([CH2:29][CH3:30])(CC)CC)C>CC(C)=O>[C:30]1([C:9]2[CH:10]=[CH:11][C:12]3[C:13]4[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=4)[NH:19][C:20]=3[C:8]=2[C:4]2[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=2)[CH:29]=[CH:6][CH:7]=[CH:2][CH:3]=1
Reactant: Ic1cccc(-c2cccc3c2[nH]c2ccccc23)c1
Reactant: CC[N+](CC)(CC)CC
Agent: [OH-]
Solvent: CC(C)=O
Product: c1ccc(-c2ccc3c([nH]c4ccccc43)c2-c2ccccc2)cc1
Temperature: 70 °C

Procedure:
91 g (242 mmol) of 3-iodophenylcarbazole 11 and 91 g (246 mmol) of phenylcarbazoleboronic ester 12 are suspended in acetone, and a 350 ml of 20% tetraethylammonium hydroxide solution (493 mmol) are added, the mixture is carefully degassed using argon. 4.6 g (4 mmol) of tetrakis-triphenylphosphinepalladium are subsequently added. The reaction is heated to 70° C. The progress of the reaction is followed by means of thin-layer chromatography. When the reaction is complete, the batch is cooled to room temperature, and the precipitated product is filtered off with suction. The crude product is recrystallised from acetonitrile, giving a beige solid.
Reaction SMILES: [CH3:1][C:2]1[C:9]([C:10]2[S:11][C:12]([C:21]([NH2:23])=O)=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)=[C:5]2[S:6][CH:7]=[CH:8][N:4]2[N:3]=1.COC1C=CC(P2(=S)SP(C3C=CC(OC)=CC=3)(=S)[S:33]2)=CC=1.CCOC(C)=O.Cl>COCCOC>[CH3:1][C:2]1[C:9]([C:10]2[S:11][C:12]([C:21](=[S:33])[NH2:23])=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)=[C:5]2[S:6][CH:7]=[CH:8][N:4]2[N:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1nn2ccsc2c1-c1nc(-c2ccccc2)c(C(N)=O)s1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Cc1nn2ccsc2c1-c1nc(-c2ccccc2)c(C(N)=S)s1
Temperature: 80 °C
Reaction time: 1 h
Yield: 48.2 %

Procedure:
To a suspension of 2-(6-methylpyrazolo[5,1-b][1,3]thiazol-7-yl)-4-phenyl-1,3-thiazole-5-carboxamide (340 mg, 1.0 mmol) obtained above in DME (10 mL) was added 2,4-Bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane (485 mg, 1.2 mmol), and the mixture was stirred at 80° C. for 1 h. The reaction mixture was allowed to cool to rt, and then were added EtOAc (15 mL) and 1N hydrochloric acid (15 mL) and then the resulting suspension was filtered. The residue was washed with water (5 mL) and EtOAc (5 mL) to give the title compound (172 mg, 48%) as a yellow solid.