Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=[O:19])[C@@H:5]([NH2:18])[C@@H:6]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=1)[OH:7])C.[BH4-].[K+].Cl.[OH-].[Na+].N[C@H](CO)[C@@H:27]([C:29]1[CH:34]=[CH:33][C:32](S(C)(=O)=O)=[CH:31][CH:30]=1)O.Cl.C(OC(C1C=CC=CC=1)=N)C>CO.OCC(CO)O.O>[CH3:17][S:14]([C:11]1[CH:10]=[CH:9][C:8]([C@H:6]2[O:7][C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:18][C@@H:5]2[CH2:4][OH:19])=[CH:13][CH:12]=1)(=[O:15])=[O:16]
Reactant: CS(=O)(=O)c1ccc([C@@H](O)[C@H](N)CO)cc1
Reactant: CCOC(=O)[C@@H](N)[C@H](O)c1ccc(S(C)(=O)=O)cc1
Agent: CCOC(=N)c1ccccc1
Agent: Cl
Agent: [BH4-]
Solvent: CO
Solvent: OCC(O)CO
Solvent: O
Product: CS(=O)(=O)c1ccc([C@H]2OC(c3ccccc3)=N[C@@H]2CO)cc1
Temperature: 25 °C

Procedure:
(2S,3R)-Ethyl-2-amino-3-[4-(methylsulfonyl)phenyl]-3-hydroxy-propanoate (Compound VIc) (10 g, 0.0348 moles) in methanol (about 100 mL) is reacted in a reaction vessel with potassium borohydride (about 2.8 g, 0.0522 moles) over about 6 hours while maintaining the temperature below about 60° C. The reaction is cooled to ambient room temperature and about 1N HCl and water (about 15 mL) are added. Thereafter, the mixture is neutralized with sodium hydroxide (about 25%) to generate (1R,2R)-2-amino-1-[4-(methylsulfonyl)phenyl]-1,3-propanediol (Compound V wherein R1 is methylsulfonyl) in situ. Next, the methanol is evaporated, followed by the addition of 1,2-dichloroethane (about 250 mL). Next, benzenecarboximidic acid ethyl ester (Compound IV wherein R2 is phenyl and R4 is ethyl) (about 7.8 g, 0.0522 moles) is added with is heated to about 85° C. for about 6 hours. The reaction is then cooled, to below about 25° C. After cooling, glycerin is added (about 50 mL). Next, the 1,2-dichloroethane is distilled by heating to about 85° C., followed by continued heating to about 105° C. to about 110° C. for about 10 hours, then followed by cooling to below about 25° C. Thereafter, water is added (about 100 mL). The resulting solids are filtered, washed with about 1 to 1 water/isopropanol, then dried to yield (4R,5R)-4,5-Dihydro-5-[4-(methylsulfonyl)phenyl]-2-phenyl-4-oxazolemethanol (Compound II wherein R1 is methylsulfonyl and R2 is phenyl).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[NH:7])[NH2:6])[CH3:3].[Cl:8][CH2:9][C:10](=O)[CH2:11][C:12](OC)=[O:13].[Na]>CO>[CH2:2]([O:4][C:5]1[N:6]=[C:10]([CH2:9][Cl:8])[CH:11]=[C:12]([OH:13])[N:7]=1)[CH3:3]
Reactant: CCOC(=N)N
Reactant: COC(=O)CC(=O)CCl
Agent: Cl
Agent: [Na]
Solvent: CO
Product: CCOc1nc(O)cc(CCl)n1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A mixture of 24.9 g (0.2 mol) of O-ethylisourea hydrochloride and 21.5 g (0.14 mol) of methyl 4-chloroacetoacetate in 100 ml of methanol is treated at 0°-5° C. during 10 minutes with a solution of 7.55 g (0.33 mol) of sodium in 100 ml of methanol. The mixture is stirred at 0° C. for 2 hours and at room temperature for 18 hours and the solvent is then removed by evaporation under reduced pressure. The residue is dissolved in 300 ml of water and the solution is adjusted to a pH-value of 6. The resulting crystallline product is filtered off, washed with diethyl ether and dried at 40° C. In this manner there is obtained 2-ethoxy-4-chloromethyl-6-hydroxy-pyrimidine, m.p. 157°-159° C. By back-extracting the aqueous filtrate three times with 150 ml of chloroform each time there is obtained an additional amount of this product, m.p. 159°-161° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)=[C:12]([F:21])[CH:11]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3].[Li]CCCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:37])(=O)=O)=CC=1.O>C1COCC1>[F:37][C:18]1[S:17][C:16]([C:13]2[CH:14]=[CH:15][C:10]([C:7]3[CH:6]=[CH:5][C:4]([CH2:1][CH2:2][CH3:3])=[CH:9][CH:8]=3)=[CH:11][C:12]=2[F:21])=[CH:20][CH:19]=1
Reactant: CCCc1ccc(-c2ccc(-c3cccs3)c(F)c2)cc1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCc1ccc(-c2ccc(-c3ccc(F)s3)c(F)c2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4.0 g (13.5 mmol) of 2-(4′-propyl-3-fluorobiphenyl-4-yl)thiophene (“PGT-3-H”) are initially introduced at −20° C. in THF, and 9.3 ml (14.8 mmol) of n-BuLi (15% solution in hexane) are added dropwise. The mixture is warmed to 0° C. and stirred at this temperature for 30 min. The batch is cooled to −78° C., and a solution of 5.11 g (16.2 mmol) of N-fluorobenzenesulfonimide (NFSI) in THF is metered in. After 30 min at −78° C., the batch is warmed to room temperature. Water is added, and the mixture is extracted a number of times with MTBE. The combined organic phases are washed with water and sat. sodium chloride solution and dried using sodium sulfate. The solution is evaporated to dryness, and the residue is purified by chromatography (SiO2, n-pentane). The further purification is carried out by recrystallisation from ethanol and n-heptane, giving 2-fluoro-5-(3-fluoro-4′-propylbiphenyl-4-yl)thiophene (“PGT-3-F”) as a colourless solid having an m.p. of 64° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:15])=[CH:4][N:3]=1.[CH2:16]([N:18]1[CH2:24][CH2:23][C:22]2[CH:25]=[C:26]([NH2:29])[CH:27]=[CH:28][C:21]=2[CH2:20][CH2:19]1)[CH3:17].Cl.O1CCOCC1>C(O)(C)C>[Cl:15][C:5]1[C:6]([NH:8][CH2:9][CH2:10][C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:29][C:26]2[CH:27]=[CH:28][C:21]3[CH2:20][CH2:19][N:18]([CH2:16][CH3:17])[CH2:24][CH2:23][C:22]=3[CH:25]=2)=[N:3][CH:4]=1
Reactant: CNC(=O)CCNc1nc(Cl)ncc1Cl
Reactant: CCN1CCc2ccc(N)cc2CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: CCN1CCc2ccc(Nc3ncc(Cl)c(NCCC(=O)NC)n3)cc2CC1
Yield: 23.9 %

Procedure:
A solution of 3-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-propionamide (35 mg, 0.14 mmol) in isopropanol (3 mL) was treated 3-Ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (27 mg, 0.14 mmol) and 4N HCl/dioxane (0.035 mL, 0.14 mmol). The reaction was irradiated at 130° C. for a total of 20 minutes. A white precipitate formed in the reaction mixture, which was collected via vacuum filtration and triturated with acetonitrile (5 mL) to afford 3-[5-Chloro-2-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-propionamide (13.5 mg) as the HCl salt. LC/MS (ESI)=403.02 (M+H), MP=206.1° C. 1H NMR (400 MHz, DMSO, d6) δ 10.51 (m, 1H), 10.05 (m, 1H), 8.12 (s, 1H), 7.88 (m, 1H), 7.59 (s, 1H), 7.42 (m, 1H), 7.17 (d, 1H, J=8.34 Hz), 3.62 (m, 7H), 3.29 (m, 2H), 3.17 (m, 2H), 2.93 (m, 2H), 2.59 (s, 3H), 2.45 (m, 2H), 1.27 (m, 3H).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:11][C:12]1[N:22]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31]([CH:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=O)=[CH:26][CH:25]=2)[C:15]2=[N:16][C:17]([CH3:21])=[CH:18][C:19]([CH3:20])=[C:14]2[N:13]=1.[OH-].[Na+]>C1COCC1>[CH3:11][C:12]1[N:22]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH:30][CH2:31][CH:33]3[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH2:38]3)=[CH:26][CH:25]=2)[C:15]2=[N:16][C:17]([CH3:21])=[CH:18][C:19]([CH3:20])=[C:14]2[N:13]=1
Reactant: Cc1cc(C)c2nc(C)n(Cc3ccc(NC(=O)C4CCN(C)CC4)cc3)c2n1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1cc(C)c2nc(C)n(Cc3ccc(NCC4CCN(C)CC4)cc3)c2n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 3.6 %

Procedure:
Under argon atmosphere, a solution of aluminum trichloride (0.136 g, 1.02 mmol) in THF (2.5 mL) was dropped into a solution of lithium aluminum hydride (77.4 mg, 2.04 mmol) in THF (3.0 mL) at 0° C. Then, a solution of 1-methylpiperidine-4-carboxylic acid [4-(2,5,7-trimethyl-3H-imidazo[4,5-b]pyridin-3-ylmethyl)phenyl amide] (1.53 g, 3.31 mmol) obtained in Step 1 in THF (3.0 mL) was dropped into the mixture. The mixture was stirred at 0° C. for 15 minutes, then at room temperature for 1.5 hours. The reaction mixture was added with a 2 mol/L aqueous sodium hydroxide solution and extracted with ethyl acetate three times. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, then concentrated under reduced pressure. The obtained crystals were recrystallized from ethanol-diisopropyl ether to obtain Compound 159 (44.3 mg, 0.12 mmol, 23%).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[NH:26]([C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=1)N>>[O:13]=[C:12]1[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=[C:7]1[C:5]1[N:26]([C:28]2[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=2)[N:2]=[CH:3][CH:4]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Reactant: NNc1ccc(C(=O)O)cc1
Product: O=C(O)c1ccc(-n2nccc2-c2nn(-c3cccc(OC(F)(F)F)c3)ccc2=O)cc1

Procedure:
Reaction of 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and 4-hydrazino-benzoic acid according to example 43 gave the desired product. MS: M=442.9 (M)+
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:15]2[CH:20]=[C:19](O)[CH:18]=[C:17]([O:22][CH2:23][CH3:24])[CH:16]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[N:2].C(C1C=CC(NC(C2C=C(OS(C(F)(F)F)(=O)=O)C=C(OCC)C=2)C(OC)=O)=CC=1)#N.[S:56]1[CH:60]=[CH:59][CH:58]=[C:57]1B(O)O>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][CH:10]([C:15]2[CH:20]=[C:19]([C:57]3[S:56][CH:60]=[CH:59][CH:58]=3)[CH:18]=[C:17]([O:22][CH2:23][CH3:24])[CH:16]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:8]=1)#[N:2]
Reactant: OB(O)c1cccs1
Reactant: CCOc1cc(O)cc(C(Nc2ccc(C#N)cc2)C(=O)OC)c1
Agent: CCOc1cc(OS(=O)(=O)C(F)(F)F)cc(C(Nc2ccc(C#N)cc2)C(=O)OC)c1
Product: CCOc1cc(-c2cccs2)cc(C(Nc2ccc(C#N)cc2)C(=O)OC)c1

Procedure:
Analogously to Example 145, from methyl (RS)-(4-cyano-phenylamino)-(3-ethoxy-5-hydroxy-phenyl)-acetate via methyl (RS)-(4-cyano-phenylamino)-(3-ethoxy-5-trifluoromethanesulphonyloxy-phenyl)-acetate by reaction with thiophene-2-boronic acid there was obtained the compound methyl (RS)-(4-cyano-phenylamino)-(3-ethoxy-5-thiophen-2-yl-phenyl)-acetate, which was converted into methyl (RS)-(4-carbamimidoyl-phenylamino)-(3-ethoxy-5-thiophen-2-yl-phenyl)-acetate hydrochloride.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[S:4][C:3]=1[C:11]([NH:13][C:14]1[CH:19]=[C:18]([NH:20][C:21](=[O:33])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([C:31]#[N:32])([CH3:30])[CH3:29])[CH:23]=2)[CH:17]=[CH:16][C:15]=1[CH3:34])=[O:12].Cl[CH2:36]Cl.[Cl-].C[Zn+].O>C1COCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:31]([C:28]([C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[C:21]([NH:20][C:18]1[CH:17]=[CH:16][C:15]([CH3:34])=[C:14]([NH:13][C:11]([C:3]2[S:4][C:5]3=[N:6][CH:7]=[CH:8][N:9]=[C:10]3[C:2]=2[CH3:36])=[O:12])[CH:19]=1)=[O:33])([CH3:30])[CH3:29])#[N:32]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1sc2nccnc2c1Br
Reactant: ClCCl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: C[Zn+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1sc2nccnc2c1C
Temperature: 60 °C
Reaction time: 2 h
Yield: 455.3 %

Procedure:
To a solution of 7-bromo-N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide 42 (20 mg, 0.037 mmol) and 1,1′-bis(diphenylphosphino) ferrocene palladium (ii) chloride, complex with dichloromethane (1.513 mg, 1.871 μmol) in THF (1 mL) was added methylzinc chloride (0.037 mL, 0.075 mmol). The reaction was stirred at 60° C. for 2 h. Water was added and the resulting precipitate was collected. Purification by chromatography (20% EtOAc in CH2Cl2) gave the title compound N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)-7-methylthieno[2,3-b]pyrazine-6-carboxamide 43a (4 mg, 22%) NMR (400 MHz, CDCl3) 2.38 (s, 3H), 2.89 (s, 3H), 7.29 (m, 1H), 7.55 (m, 1H), 7.70-7.83 (m, 4H), 7.91 (s, 1H), 7.99 (m, 1H), 8.26 (d, J=1.9 Hz, 1H), 8.64 (d, J=2.3 Hz, 1H), 8.76 (d, J=2.3 Hz, 1H). (m/z)=470 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:21])[C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:10]=2)=[N:6][CH:7]=1.[CH:22](O)=O>>[Br:1][C:2]1[CH:3]=[C:4]2[N:21]=[CH:22][N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]4[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=4)[CH:10]=3)[C:5]2=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1Nc1cccc(-c2cccnc2)c1
Reactant: O=CO
Product: Brc1cnc2c(c1)ncn2-c1cccc(-c2cccnc2)c1
Temperature: 80 °C

Procedure:
A mixture of crude 5-bromo-N2-[3-(pyridin-3-yl)phenyl]pyridine-2,3-diamine and 98% formic acid was heated at 80° C. for 3 hours. The reaction was cooled, evaporated to dryness, the residue suspended in water and made basic by the cautious addition of solid sodium hydrogen carbonate. This was then extracted with ethyl acetate, the organics dried over anhydrous sodium sulphate, filtered and pre-adsorbed on to silica. Purification by silica gel chromatography eluting with dichloromethane/methanol/0.88 NH3 (95:4.5:0.5) furnished 6-bromo-3-[3-(pyridin-3-yl)phenyl]-3H-imidazo[4,5-b]pyridine as a tan solid (3.1 g, 89% over 2 steps), m.p. 212-213° C. (Found C, 57.24; H, 2.98; N, 15.57. C17H11BrN4. 0.25H2O requires C, 57.40; H, 3.26; N, 15.75); δH (400 MHz, d6-DMSO) 7.55 (1H, dd, J 5 and 5), 7.76 (1H, t, J 8), 7.86 (1H, d, J 8), 8.04 (1H, d, J 8), 8.22 (1H, d, J 8), 8.27 (1H, s), 8.56 (2H, d, J 6), 8.64 (1H, d, J 5), 9.04 (1H, s), 9.11 (1H, s); m/z (ES+) 351 and 353 (M++H).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1([CH3:24])[O:13][C:12]2[CH:14]=[CH:15][C:16]([C@H:18]3[O:22][C:21](=[O:23])[NH:20][CH2:19]3)=[CH:17][C:11]=2[CH2:10][O:9]1.Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][C:37]1[C:42]([Cl:43])=[CH:41][CH:40]=[CH:39][C:38]=1[Cl:44]>CN(C=O)C>[Cl:43][C:42]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:44])[C:37]=1[CH2:36][O:35][CH2:34][CH2:33][O:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][N:20]1[CH2:19][C@@H:18]([C:16]2[CH:15]=[CH:14][C:12]3[O:13][C:8]([CH3:24])([CH3:7])[O:9][CH2:10][C:11]=3[CH:17]=2)[O:22][C:21]1=[O:23]
Reactant: CC1(C)OCc2cc([C@@H]3CNC(=O)O3)ccc2O1
Reactant: Clc1cccc(Cl)c1COCCOCCCCCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4c(Cl)cccc4Cl)C(=O)O3)ccc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
Potassium tert-butoxide (4.38 g, 39 mmol) was added to a solution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (9.3 g, 39 mmol) in anhydrous DMF (100 mL) under N2 and the reaction stirred for 1 h at ambient temperature. A solution of 2-[2-(6-bromo-hexyloxy)-ethoxymethyl]-1,3-dichloro-benzene (15 g, 39 mmol) in anhydrous DMF (25 mL) was added and the reaction allowed to stir at ambient temperature for 20 h. The reaction mixture was poured into ice/water (350 mL) and extracted with ethyl acetate (300 mL). The organic layer was separated then washed successively with water/saturated brine (250 mL/25 mL), water/brine (25 mL/10 mL) and finally brine (150 mL), before drying over sodium sulfate. The solution was concentrated to dryness under vacuum to afford the title compound as an oil (21.6 g)—LC RT=6.8 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:13]([CH2:20][CH3:21])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:22]([CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1)#[CH:23].C(N(CC)CC)C>CN(C=O)C.[Cu]I.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>[CH2:20]([N:13]([CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[C:4]1[CH:3]=[C:2]([C:23]#[C:22][CH:24]2[CH2:25][CH2:26][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:28][CH2:29]2)[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]=1[CH3:12])[CH3:21]
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CCN(c1cc(Br)cc(C(=O)OC)c1C)C1CCOCC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(c1cc(C#CC2CCN(C(=O)OC(C)(C)C)CC2)cc(C(=O)OC)c1C)C1CCOCC1
Temperature: 80 °C
Yield: 98.1 %

Procedure:
To a solution of methyl 5-bromo-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzoate (1.80 g, 5.05 mmol) and tert-butyl 4-ethynylpiperidine-1-carboxylate (1.80 g, 8.59 mmol) in DMF (40 ml) was added triethylamine (2.82 ml, 20.2 mmol) and Copper(I) iodide (0.096 g, 0.505 mmol). The reaction mixture was degassed by bubbling nitrogen for 15 min. Then tetrakis(triphenylphosphine)palladium(0) (0.292 g, 0.253 mmol) was introduced and degassed for additional 10 min by bubbling nitrogen. The reaction mixture was heated at 80° C. for 6 h. The reaction was quenched with sat. NaHCO3, extracted with TBME (3×40 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography (0% to 40% AcOEt/Heptane) to give the titled compound (2.40 g, 98% yield). 1H-NMR (500 MHz) 3 ppm; 7.65 (s, 1H), 7.28 (s, 1H), 3.97 (brd, J=11.3 Hz, 2H), 3.90 (s, 3H), 3.76 (m, 2H), 3.34 (dt, J=2.0, 11.7 Hz, 2H), 3.24 (ddd, J=3.4, 8.8, 12.2 Hz, 2H), 3.08 (brs, 2H), 2.98 (brs, 1H), 2.80 (dddd, J=3.9, 3.9, 3.9, 3.9 Hz, 1H), 2.52 (s, 3H), 1.87 (m, 2H), 1.60-1.74 (m, 6H), 1.48 (s, 9H), 0.89 (t, J=6.8 Hz, 3H)); MS (ESI) [M+H]+485.4.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][C:9]1[C:14]2[NH:15][C:16](=[O:18])[O:17][C:13]=2[CH:12]=[C:11]([NH:19]C(=O)OC(C)(C)C)[CH:10]=1>C(Cl)Cl>[NH2:19][C:11]1[CH:10]=[C:9]([CH3:8])[C:14]2[NH:15][C:16](=[O:18])[O:17][C:13]=2[CH:12]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)cc2oc(=O)[nH]c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(N)cc2oc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
400 μL (5.30 mmol) TFA were added to 230 mg (0.900 mmol) tert-butyl (4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-yl)-carbamate in 5.0 ml DCM and the mixture was stirred for 1.5 h at RT. The reaction mixture was evaporated down and the residue was divided between semisaturated sodium hydrogen carbonate solution and EtOAc. The organic phase was dried on sodium sulphate, filtered and evaporated down.
Reaction SMILES: N(C[C@@H](C1C=CC(OCC2C=CC=CC=2)=C2C=1C=CC(=O)N2)O)=[N+]=[N-].[CH2:26]([O:33][C:34]1[CH:35]=[CH:36][C:37]([C@@H:45]([O:82][Si](C(C)(C)C)(C)C)[CH2:46][NH:47][C:48]([CH3:81])([CH3:80])[CH2:49][C:50]2[CH:51]=[C:52]([CH:77]=[CH:78][CH:79]=2)[C:53]([NH:55][CH2:56][C:57]2[C:58]([NH:70][CH:71]3[CH2:76][CH2:75][O:74][CH2:73][CH2:72]3)=[C:59]3[CH:67]=[N:66][N:65]([CH2:68][CH3:69])[C:60]3=[N:61][C:62]=2[CH2:63][CH3:64])=[O:54])=[C:38]2[C:43]=1[NH:42][C:41](=[O:44])[CH:40]=[CH:39]2)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([O:33][C:34]1[CH:35]=[CH:36][C:37]([C@@H:45]([OH:82])[CH2:46][NH:47][C:48]([CH3:80])([CH3:81])[CH2:49][C:50]2[CH:51]=[C:52]([CH:77]=[CH:78][CH:79]=2)[C:53]([NH:55][CH2:56][C:57]2[C:58]([NH:70][CH:71]3[CH2:72][CH2:73][O:74][CH2:75][CH2:76]3)=[C:59]3[CH:67]=[N:66][N:65]([CH2:68][CH3:69])[C:60]3=[N:61][C:62]=2[CH2:63][CH3:64])=[O:54])=[C:38]2[C:43]=1[NH:42][C:41](=[O:44])[CH:40]=[CH:39]2)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(CC(C)(C)NC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(OCc3ccccc3)c3[nH]c(=O)ccc23)c1
Agent: [N-]=[N+]=NC[C@H](O)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(CC(C)(C)NC[C@H](O)c2ccc(OCc3ccccc3)c3[nH]c(=O)ccc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 3, using Intermediate 52 as a substrate. ES/MS calcd. for C45H54N7O5+ 772.4. found m/z=772.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[CH:14]=[CH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[SH:16].[CH2:17](OS([O-])(=O)=O)CCCCCCCCCCC.[Na+].C(OC=O)=O>O>[S:16]1[C:3]2[CH:4]=[CH:5][C:6]3[C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=4[CH:13]=[CH:14][C:15]=3[C:2]=2[N:1]=[CH:17]1
Reactant: Nc1c(S)ccc2c1ccc1ccccc12
Reactant: CCCCCCCCCCCCOS(=O)(=O)[O-]
Agent: O=COC=O
Agent: [Na+]
Solvent: O
Product: c1ccc2c(c1)ccc1c2ccc2scnc21
Yield: 69 %

Procedure:
5 mmol of 1-amino phenanthren-2-thiol was added to 20 mL of water, and 20 mg of sodium dodecylsulfate was added while agitating to obtain a uniform mixture. 7.5 mmol of formic anhydride was added for 5 minutes. A precipitation product was obtained in 5-10 minutes. The precipitation product was filtrated and rinsed with 1 ml of water twice followed by drying under vacuum. A non-precipitated reaction mixture was extracted with 25 ml of ethyl acetate twice. The separated organic layer was dried with anhydrous sodium sulfate, and a solvent was removed using a rotatary evaporator under a reduced pressure to obtain phenanthrothiazole at a yield of 69%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][CH:43]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([CH:27]5[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]5)=[CH:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[C:8]([CH3:40])=[N:7]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][CH:43]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([CH:27]5[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]5)=[CH:25][CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)[C:8]([CH3:40])=[N:7]1
Reactant: Cc1nn(Cc2cccc(F)c2)c(C)c1-c1c[nH]c2ncc(-c3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nn(Cc2cccc(F)c2)c(C)c1-c1c[nH]c2ncc(-c3ccc(C4CCNCC4)cc3)cc12
Yield: 12.9 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(4-(3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidine-1-carboxylate (113 mg, 0.194 mmol) was deprotected in TFA/DCM (5/5 ml). This afforded 12 mg (12.9% yield) of the titled compound. 1H NMR (CD3OD, 300 MHz): δ 8.55 (s, 1H), 8.09-8.08 (d, 1H), 7.65-7.62 (m, 2H), 7.51 (s, 1H), 7.41-7.34 (m, 3H), 7.06-7.00 (m, 2H), 6.90-6.87 (s, 1H), 5.38 (s, 2H), 3.54-3.47 (m, 2H), 3.20-3.13 (m, 2H), 3.01-2.93 (m, 1H), 2.22 (s, 3H), 2.20 (s, 3H), 2.14-1.88 (m, 4H). MS: m/z=480.2 (M+1), HPLC: 98.73% in method B.
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].[Cl:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1>[OH-].[Na+].ClCCl>[Cl:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([N:4]([CH3:5])[O:3][CH3:2])=[O:12])=[CH:9][CH:8]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CNOC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 95 %

Procedure:
To a solution 11.38 gm (116.7 mMol) N-methoxy-N-methyl amine hydrochloride in 700 mL 1N sodium hydroxide was added a solution of 18.56 gm (106.04 mMol) 4-chlorobenzoyl chloride in 200 mL dichloromethane and the mixture was stirred at ambient temperature. After 18 hours the phases were separated and the remaining aqueous was extracted well with dichloromethane. All organic phases are combined, dried over sodium sulfate and concentrated under reduced pressure to give 27.9 gm (95%) of the title compound as a clear oil.
Reaction SMILES: C([O:3][C:4]1[CH:11]=[C:9]([OH:10])[CH:8]=[C:6]([OH:7])[CH:5]=1)C.C(=O)([O-])[O-].[Na+].[Na+]>Cl>[C:4]1([CH:11]=[C:9]([OH:10])[CH:8]=[C:6]([OH:7])[CH:5]=1)[OH:3]
Reactant: CCOc1cc(O)cc(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Oc1cc(O)cc(O)c1
Yield: 86 %

Procedure:
2 g of phloroglucinol monoethyl ether are stirred in 100 ml of concentrated hydrochloric acid (35%) at room temperature for 2 days. The mixture is then partially neutralised (pH 2-3) with aqueous sodium carbonate solution, the precipitated sodium chloride is filtered off and the filtrate is extracted with 150 ml of ether in a Kutscher-Steudel extractor for 18 hours. The ether extract is dried over sodium sulphate and concentrated, there being obtained 1.4 g to 1.55 g (86% to 95%) of phloroglucinol which has a melting point of 209°-210° C. after recrystallisation from water.