Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[N:9]=2)=[CH:6][C:5]([C@H:34]([N:36]2[CH2:41][CH2:40][N:39]([S:42]([CH3:45])(=[O:44])=[O:43])[CH2:38][CH2:37]2)[CH3:35])=[CH:4][N:3]=1.[Cl:46][C:47]1[N:52]=[CH:51][C:50]([NH2:53])=[CH:49][C:48]=1[O:54][CH3:55].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[Cl:46][C:47]1[N:52]=[CH:51][C:50]([NH:53][C:2]2[C:7]([C:8]3[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)[CH2:25][C:26]4[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=4)[N:9]=3)=[CH:6][C:5]([C@H:34]([N:36]3[CH2:37][CH2:38][N:39]([S:42]([CH3:45])(=[O:44])=[O:43])[CH2:40][CH2:41]3)[CH3:35])=[CH:4][N:3]=2)=[CH:49][C:48]=1[O:54][CH3:55]
Reactant: COc1cc(N)cnc1Cl
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc([C@@H](C)N4CCN(S(C)(=O)=O)CC4)cnc3F)n2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc([C@@H](C)N4CCN(S(C)(=O)=O)CC4)cnc3Nc3cnc(Cl)c(OC)c3)n2)cc1
Reaction time: 1 h
Yield: 74.1 %

Procedure:
At 0° C., a solution of (R)-4-(2-fluoro-5-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (Example 146, Step 6) (155 mg, 0.244 mmol) and 6-chloro-5-methoxypyridin-3-amine (Small Molecules, Inc) (77 mg, 0.488 mmol) in 1 mL of THF was treated with sodium bis(trimethylsilyl)amide (0.853 mL of 1.0 M solution in THF, 0.853 mmol) and the dark red solution was stirred at that temperature for 1 h. It was quenched with 4 mL of saturated aqueous ammonium chloride solution and extracted with EtOAc (2×20 mL). The combined organic phases were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. The residue was loaded on a silica gel column and eluted with 50-100% EtOAc in DCM to give the title compound (140 mg, 74% yield) as an orange amorphous solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.11 (s, 1H), 8.70 (d, J=2.40 Hz, 1H), 8.37 (d, J=2.30 Hz, 1H), 8.18 (dd, J=8.8, 2.40 Hz, 2H), 7.28 (m, 4H), 6.90 (m, 4H), 4.85-4.81 (m, 4H), 3.87 (s, 3H), 3.74 (s, 3H), 3.70 (s, 3H), 3.60 (m, 1H), 3.04 (m, 4H), 2.78 (s, 3H), 2.59 (s, 3H), 2.47 (m, 4H), 1.34 (m, 3H). m/z (ESI, positive ion) 774.9 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:3][C@H:4]([CH2:8][C:9]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:10])[C:5]([OH:7])=O.[NH2:25][CH:26]([CH2:40][CH3:41])[CH:27]([C:29]1[O:33][N:32]=[C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:30]=1)[OH:28]>>[C:34]1([C:31]2[N:30]=[C:29]([C:27]([CH:26]([NH:25][C:5](=[O:7])[C@@H:4]([CH2:8][C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[O:10])[CH2:3][C:2]([CH3:1])([CH3:24])[CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:40][CH3:41])=[O:28])[O:33][N:32]=2)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CC(C)(Cc1ccccc1)C[C@H](CC(=O)N1CCOCC1)C(=O)O
Reactant: CCC(N)C(O)c1nc(-c2ccccc2)no1
Product: CCC(NC(=O)[C@@H](CC(=O)N1CCOCC1)CC(C)(C)Cc1ccccc1)C(=O)c1nc(-c2ccccc2)no1

Procedure:
It is similarly prepared (as mixture of diastereoisomers) according to general procedure given for example 10 above but using (R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-5-phenyl-pentanoic acid and 2-Amino-1-(3-phenyl-1,2,4-oxadiazol-5-yl)-butan-1-ol
Reaction SMILES: O.NN.CSCON1C(=O)C2=CC=CC=C2C1=O.Cl.[CH3:20][S:21][CH2:22][O:23][NH2:24].[CH:25]([NH:27][C:28]1[S:29][C:30]([Cl:40])=[C:31]([C:33](=O)[C:34]([O:36]CC)=[O:35])[N:32]=1)=[O:26].[OH-].[K+]>CO.O1CCCC1.N1C=CC=CC=1>[CH3:20][S:21][CH2:22][O:23][N:24]=[C:33]([C:31]1[N:32]=[C:28]([NH:27][CH:25]=[O:26])[S:29][C:30]=1[Cl:40])[C:34]([OH:36])=[O:35]
Reactant: CSCON
Reactant: CCOC(=O)C(=O)c1nc(NC=O)sc1Cl
Agent: CSCON1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: NN
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CSCON=C(C(=O)O)c1nc(NC=O)sc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of hydrazine hydrate (2.3 g) in methanol (2.3 g) was added to a mixture of N-(methylthiomethoxy) phthalimide (10.2 g) in tetrahydrofuran (30 ml) and stirred at ambient temperature for 30 minutes. 10% Hydrochloric acid (18 ml) was added to the reaction mixture under ice-cooling and the insoluble materials were filtered off to give a solution containing methylthiomethoxyamine. On the other hand, ethyl (2-formamido-5-chlorothiazol-4-yl)glyoxylate (10 g) was added to the 1 N aqueous potassium hydroxide (76.2 ml) at ambient temperature and the mixture was stirred for 10 minutes. The reaction mixture was adjusted to pH 2.0 with 10% hydrochloric acid under ice-cooling, thereto were added pyridine (10 g) and the above solution containing methylthiomethoxyamine, followed by stirring at ambient temperature for 3 hours. The aqueous solution was adjusted to pH 7.5 with 10% aqueous potassium hydroxide and washed with ethyl acetate. Ethyl acetate was added to the aqueous solution and the resulting mixture was adjusted to pH 1.7 with 10% hydrochloric acid, and the separated organic layer was washed with 3% hydrochloric acid and water, dried over magnesium sulfate and evaporated to give 2-methylthiomethoxyimino-2-(2-formamido-5-chlorothiazol-4-yl)acetic acid (syn isomer)(8.1 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:28])[C:7](=[O:27])[C:8]3[CH:18]=[C:17]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=4)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[CH3:29][O:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1>>[CH3:29][O:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH:36][C:2]2[CH:3]=[CH:4][C:5]3[N:6]([CH3:28])[C:7](=[O:27])[C:8]4[CH:18]=[C:17]([CH2:19][CH2:20][C:21]5[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=5)[CH:16]=[N:15][C:9]=4[N:10]([CH2:13][CH3:14])[C:11]=3[N:12]=2)=[CH:33][CH:32]=1
Reactant: COc1ccc(CN)cc1
Reactant: CCN1c2ncc(CCc3ccncc3)cc2C(=O)N(C)c2ccc(Cl)nc21
Product: CCN1c2ncc(CCc3ccncc3)cc2C(=O)N(C)c2ccc(NCc3ccc(OC)cc3)nc21
Temperature: 150 °C
Reaction time: 24 h
Yield: 26 %

Procedure:
A mixture of 2-chloro-5,11-dihydro-11-ethyl-8-[2-(4-pyridyl)ethyl]-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.285 g, 0.7 mmol) and 4-methoxybenzylamine (0.23 mL, 1.8 mmol) in 4 mL of xylenes was heated at 150° C. in a sealed tube. After 24 hours, additional amine (0.23 mL, 1.8 mmol) was added and the reaction temperature was increased to 250° C. Heat was removed after 2d, and the reaction mixture was washed with saturated aqueous ammonium chloride to remove excess amine. The organic layer was dried (magnesium sulfate) and concentrated. Purification by flash chromatography (elution with methanol-dichloromethane) afforded the title compound (0.09 g, 26%).
Reaction SMILES: COC1C=CC(C[S:8][C@H:9]2[CH2:13][N:12]([S:14]([C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=3)(=[O:16])=[O:15])[C@H:11]([C:27]([NH:29][NH2:30])=[O:28])[CH2:10]2)=CC=1>C(O)(C(F)(F)F)=O.C([SiH](C(C)C)C(C)C)(C)C>[SH:8][C@H:9]1[CH2:13][N:12]([S:14]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)(=[O:15])=[O:16])[C@H:11]([C:27]([NH:29][NH2:30])=[O:28])[CH2:10]1
Reactant: COc1ccc(CS[C@@H]2C[C@@H](C(=O)NN)N(S(=O)(=O)c3ccc4ccccc4c3)C2)cc1
Agent: CC(C)[SiH](C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: NNC(=O)[C@@H]1C[C@@H](S)CN1S(=O)(=O)c1ccc2ccccc2c1
Yield: 64.5 %

Procedure:
(step 9) 150 mg (0.3 mmol, 1.0 eq) (2S,4R)-4-(4-Methoxy-benzylsulfanyl)-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid hydrazide in 5 ml TFA and 0.65 ml triisopropylsilane were stirred for 3 d at RT. The solvent was evaporated and the residue redissolved in sat. NaHCO3 solution:ethyl acetate, the phases were separated and the inorganic one was extracted with ethyl acetate. The combined organic phases were washed with water and brine. Column chromatography yields 68 mg ( 61%) (2S,4R)-4-Mercapto-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid hydrazide as white foam, MS: 352 (MH+).
Reaction SMILES: Br[C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:11]([Sn](CCCC)(CCCC)C=C)[CH2:12]CC>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N+:8]([C:3]1[C:2]([CH:11]=[CH2:12])=[CH:7][CH:6]=[CH:5][N:4]=1)([O-:10])=[O:9]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=[N+]([O-])c1ncccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: CC#N
Product: C=Cc1cccnc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
3-Bromo-2-nitropyridine (1.015 g, 5.0 mmol), tetrabutylammonium chloride (1.390 g, 5.00 mmol), and bis(triphenylphosphine)palladium(II) chloride (0.351 g, 0.500 mmol) were combined. Mixture was suspended in acetonitrile (10 ml). The mixture was stirred at room temperature for 30 minutes while it was degassed by a flow of nitrogen. Tributyl(vinyl)tin (1.754 ml, 6.00 mmol) was added and the mixture was further degassed for 5 minutes. The vial was capped and heated at 90° C. for 4 hours. Solvents were removed from the mixture. The residue was dissolved with dichloromethane. Material was washed with brine and the aqueous phase was discarded. Organic layer was dried over Na2SO4, and filtered. Solvents were removed by roto-vap. Silica gel chromatography afforded the title compound as tan solid in 68% yield. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 8.39 (dd, J=4.58, 1.53 Hz, 1 H) 8.06 (dd, J=7.94, 1.53 Hz, 1 H) 7.55 (dd, J=7.93, 4.58 Hz, 1 H) 6.90 (dd, J=17.24, 11.14 Hz, 1 H) 5.82 (d, J=17.40 Hz, 1 H) 5.55 (d, J=10.99 Hz, 1 H).
Reaction SMILES: N#N.[CH2:3]([O:5][C:6](=[O:10])[C:7]([NH2:9])=[S:8])[CH3:4].[Cl:11][CH2:12][C:13](=O)[CH2:14]Cl.CCOC(C)=O>C1(C)C=CC=CC=1>[CH2:3]([O:5][C:6]([C:7]1[S:8][CH:14]=[C:13]([CH2:12][Cl:11])[N:9]=1)=[O:10])[CH3:4]
Reactant: CCOC(=O)C(N)=S
Reactant: O=C(CCl)CCl
Agent: N#N
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(CCl)cs1
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of amino-thioxo-acetic acid ethyl ester (2.50 g, 18.77 mmol) and 1,3-dichloro-propan-2-one (2.88 g, 21.59 mmol) in toluene (20.0 mL) was stirred for 2 h at reflux. EtOAc (20 mL) was added at rt and the mixture was washed with sat. aq. NaHCO3 (10 mL) followed by brine (20 mL). The organic layer was dried over MgSO4, filtered, and the solvent removed under reduced pressure. Purification of the residue by FC (4:1 hept-EA) gave the title compound as a light yellow oil. TLC:rf (4:1 hept-EA)=0.26. LC-MS-conditions 02: tR=0.89 min, [M+H]+=206.40.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][CH2:19][CH2:18][O:17][C:16]=3[CH:21]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.F[C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32]([NH2:34])=[O:33].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[N:20]([C:30]4[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=4[C:32]([NH2:34])=[O:33])[CH2:19][CH2:18][O:17][C:16]=3[CH:21]=2)(=[O:11])=[O:10])=[CH:27][CH:28]=1
Reactant: NC(=O)c1ccccc1F
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccccc2C(N)=O)cc1
Temperature: 90 °C
Yield: 71.7 %

Procedure:
To a solution of INTERMEDIate M (900 mg, 2.08 mmol) and 2-fluorobenzamide (293 mg, 2.08 mmol, Aldrich) in DMF (10 mL) was added cesium carbonate (1.01 g, 3.12 mmol). The reaction mixture was heated at 90° C. for 48 h. After completion, the reaction mixture was diluted with ethyl acetate (30 mL) and water (20 mL). The layers were separated and the organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain crude material which was purified by combi flash silica gel column chromatography (column size: 40 g, elution: 25% ethyl acetate in hexane) to provide 2-(7-(N-(4-methoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)benzamide (800 mg, 71.4%); LCMS (ESI) m/z; 537.12 (M+H).
Reaction SMILES: [C:1]([Si:5]([CH3:14])([CH3:13])[O:6][C@@H:7]1[CH2:11][CH2:10][C@H:9]([NH2:12])[CH2:8]1)([CH3:4])([CH3:3])[CH3:2].CN(C=O)C.Cl[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][N:22]=1.C([O-])([O-])=O.[K+].[K+]>[Pd].CO>[C:1]([Si:5]([CH3:14])([CH3:13])[O:6][C@@H:7]1[CH2:11][CH2:10][C@H:9]([NH:12][C:21]2[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][N:22]=2)[CH2:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H](N)C1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H](Nc2ccc(N)cn2)C1
Temperature: 75 °C
Reaction time: 60 h

Procedure:
To a 20 mL vial containing cis-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentylamine, prepared according to literature reference (see Chen, et al US 2004/0204427 A1), (580 mg, 2.69 mmol) was added DMF (10 mL), 2-chloro-5-nitro-pyridine (428 mg, 2.69 mmol), and TEA (1.5 mL). The vessel was purged with Ar, sealed, heated to 75° C. for 4.5 hr, cooled to room temperature and allowed to stir over the weekend (60 hr). The reaction mixture was heated again at 75° C. for an additional 6 hr and then allowed to cool to RT overnight (18 hr). The reaction mixture was concentrated and redissolved in DMF (10 mL). 2 eq of K2CO3 was added (744 mg) and heated to 70° C. for 1 hr. The reaction mixture was concentrated, supported on silica gel, and purified by flash chromatography using an Analogix with a 80 g Redisep silica gel column at 60 mL/min with increasing concentrations of Et2O in hexane (0-5 min: 0%, 5-25 min: 0-20%, 25-40 min: 30%, 40-65 min: 30-100%). The appropriate fractions were collected and dried producing a clear oil, 490.8, 54.0% (LCMS 4.23 min, 338 (M+H), calcd. C16H27N3O3Si (m/e) 337, 50-100% ACN in H2O/HCOOH, C18, APCI). The nitropyridyl compound was transferred to a PARR vessel with MeOH (10 mL), Pd/C (10%) was added and the vessel was pressurized with H2 at 54 psi. After 3 hr the reaction mixture was filtered through a bed of celite and concentrated to dryness twice from DCM. The purple black material was used immediately for amide coupling (LCMS 2.94 min, 308 (M+H), calcd. C16H27N3O3Si (m/e) 307, 10-100% ACN in H2O/HCOOH 0.3%, C18, APCI).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.Br[CH2:19][CH2:20][OH:21]>CN(C=O)C>[CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([CH2:19][CH2:20][OH:21])[CH2:4][CH2:3]1
Reactant: OCCBr
Reactant: CN1CCCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCCN(CCO)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
1-Methylhomopiperazine (2.00 g, 17.5 mmol) and DIPEA (3.0 mL, 18.4 mmol) were dissolved in DMF (25 mL). 2-bromethanol (1.3 mL, 18.4 mmol) was added slowly over 5 minutes. The reaction mixture was stirred at 100° C. for 2 hours and then at room temperature for 48 hours and then concentrated in vacuo. The residue was dissolved in EtOAc (−300 mL) and then washed sequentially with 1M aq Na2CO3 solution (5×200 mL), dried (MgSO4) and concentrated in vacuo to give 2-(4-methylhomopiperazin-1-yl)ethanol (2.77 g, 100%) as a brown oil which was used without further purification.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[F:13][C:14]1[CH:19]=[CH:18][C:17]([S:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=2[NH2:28])=[CH:16][CH:15]=1>>[F:13][C:14]1[CH:19]=[CH:18][C:17]([S:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=2[NH:28][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)=[CH:16][CH:15]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: Cc1ccc(Sc2ccc(F)cc2)c(N)c1
Product: Cc1ccc(Sc2ccc(F)cc2)c(Nc2ccnc3nc(C)ccc23)c1

Procedure:
The product from Example 1d (167 mg, 0.94 mmol) was reacted with the product from Example 49b (218 mg, 0.94 mmol) for 48 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the trifluoroacetic acid salt (224 mg, 49%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.37 (m, 3H) 2.77 (m, 3H) 6.29 (d, J=6.99 Hz, 1H) 7.10 (m, 2H) 7.32 (m, 5H) 7.80 (d, J=8.46 Hz, 1H) 8.41 (d, J=6.99 Hz, 1H) 8.95 (d, J=8.46 Hz, 1H) 11.04 (br. s., 1H) 14.43 (br. s., 1H); MS (ESI+) m/z 376 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[S:7][C:8]([C:14]([OH:16])=O)=[C:9]([O:10][CH:11]([CH3:13])[CH3:12])[C:5]=2[CH:4]=1.[NH2:19][C:20]1[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=1)[C:23]([O:25]CC)=[O:24]>>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[S:7][C:8]([C:14]([NH:19][C:20]3[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=3)[C:23]([OH:25])=[O:24])=[O:16])=[C:9]([O:10][CH:11]([CH3:12])[CH3:13])[C:5]=2[CH:4]=1
Reactant: COc1ccc2sc(C(=O)O)c(OC(C)C)c2c1
Reactant: CCOC(=O)c1cccc(N)c1
Product: COc1ccc2sc(C(=O)Nc3cccc(C(=O)O)c3)c(OC(C)C)c2c1
Yield: 84.8 %

Procedure:
Following a procedure analogous to Example 12, 5-methoxy-3-(1-methylethoxy)benzo[b]thiophene-2-carboxylic acid (7.0 g, 26 mmol) and ethyl 3-aminobenzoate (4.3 g, 26 mmol) provides 8.5 g (78%) of the intermediate ester. Saponification of the crude ester followed by recrystallization from aqueous ethanol gives 4.2 g (53%) of product; mp 197°-200° C. (dec).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9][CH2:10][C:11]#[CH:12].CC(C)=[O:15].OOS([O-])=O.[K+].O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9]([CH2:10][C:11]#[CH:12])=[O:15]
Reactant: CC(C)=O
Reactant: C#CCSc1cc(C)ccc1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S([O-])OO
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: O
Product: C#CCS(=O)c1cc(C)ccc1Br
Reaction time: 21 h
Yield: 93 %

Procedure:
To a solution of 1-bromo-4-methyl-2 prop-2-inylthiobenzene (62.18 g, 258 mmol), acetone (1.50 g, 25.8 mmol) and tetrabutylammonium bromide (4.16 g, 12.9 mmol) in ethyl acetate (750 ml), an aqueous solution of Oxone (166.6 g, 271 mmol) (750 ml) was added, and vigorously stirred for 21 hours. Water (250 ml) was added thereto to dissolve salts in the aqueous phase, and the aqueous phase was removed and the organic phase was washed with water (300 ml×3 times). The mixture was further washed twice with a mixture of saturated baking soda solution (100 ml) and water (200 ml), and was washed again with water (300 ml×2 times). After drying on magnesium sulfate, the solvent was evaporated to obtain 1-bromo-4-methyl-2-(prop-2-inylsulfinyl)benzene (63.37 g, 239 mmol (a value obtained by subtracting the weight of residual ethyl acetate from 1H NMR integrated ratio)). The yield was 93%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]([C:17]([NH2:19])=[O:18])[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:5]=[CH:6][CH:7]=1.[C:20]1([CH3:29])[CH:25]=[CH:24][CH:23]=[C:22]([N:26]=[C:27]=[O:28])[CH:21]=1>C1COCC1.C(OCC)(=O)C>[CH3:29][C:20]1[CH:21]=[C:22]([NH:26][C:27]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[N:9]([C:17]([NH2:19])=[O:18])[C:10]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH:5]=[CH:6][CH:7]=2)=[O:28])[CH:23]=[CH:24][CH:25]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: NC(=O)n1c(-c2cccc(N)c2)cc2ccccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cccc(NC(=O)Nc2cccc(-c3cc4ccccc4n3C(N)=O)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the solution of 2-(3-aminophenyl)-1H-indole-1-carboxamide (50.2 mg, 0.2 mmol, 1 eq) in anhydrous THF (2 mL) was added m-tolyl isocyanate (25 μL, 1 eq) and the reaction solution was stirred at room temperature for one hour. It was then diluted with ethyl acetate, washed with aqueous ammonium chloride, saturated aqueous sodium bicarbonate, brine, and lastly dried with anhydrous sodium sulfate. The upper solution was decanted, concentrated and the oily residue was treated with small amount of dichloromethane. The white solid appeared during this process was filtered to yield 2-[3-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]-1H-indole-1-carboxamide in amount of 36 mg.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:4]=2[O:3]1.Br[CH2:18][CH2:19][O:20][CH3:21].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:21][O:20][CH:19]([N:6]1[C:5]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:4]=2[O:3][C:2]([CH3:16])([CH3:1])[C:7]1=[O:8])[CH3:18]
Reactant: COCCBr
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2NC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(C)N1C(=O)C(C)(C)Oc2ccc([N+](=O)[O-])cc21
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 2,2-dimethyl-6-nitro-2H-1,4-benzoxazin-3(4H)-one (300 mg, 1.35 mmol, 1 equiv), 1-bromo-2-methoxyethane (0.32 mL, 3.38 mmol, 2.5 equiv.) and Cs2CO3 (880 mg, 2.70 mmol, 2.0 equiv.) in 6 mL of DMF was heated to 60° C. and stirred at this temperature overnight. The reaction mixture was then partitioned between EtOAc and water. The organic layer was separated and concentrated. The residue was purified by column chromatography using a mixture of EtOAC/hexane (1:4) as eluent to give the product as a clear oil (quantitative yield).
Reaction SMILES: [C:1]1([CH:7]2[O:16][C:15]3[C:10](=[N:11][C:12]([CH:17]=O)=[CH:13][CH:14]=3)[CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[C:21]1(C)C=CC=CC=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[C:1]1([CH:7]2[O:16][C:15]3[C:10](=[N:11][C:12]([CH:17]=[CH2:21])=[CH:13][CH:14]=3)[CH2:9][O:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccccc1
Reactant: O=Cc1ccc2c(n1)COC(c1ccccc1)O2
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: C=Cc1ccc2c(n1)COC(c1ccccc1)O2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In a two liter 3-neck, round bottom flask, fitted with a mechanical stirrer, a thermometer and a reflux condenser, a heterogeneous mixture of 2-phenyl-4H-1,3-dioxino[5,4-b]pyridine-6-carbaldehyde (24.1 g., 0.1 mole) sodium hydroxide (24.0 g., 0.6 mole) and methyltriphenylphosphonium bromide (71.5 g., 0.2 mole) in toluene (200 ml.) and water (600 ml.) was stirred at room temperature for 24 hours. The toluene layer was separated and the aqueous layer was washed with toluene (100 ml.). The combined toluene layers were dried over anhydrous magnesium sulfate. The toluene solution was then passed through a 10 mm. pad of silica gel which was then washed with 1 liter of ether/hexane solution (v/v 3:2). Evaporation of the solvents on a rotary evaporation in vacuo gave the crystalline 2-phenyl-6-vinyl-4H-1,3-dioxino [5,4-b]pyridine, 14.3 g. (59%); m.p. 54°-57° C.; mass spec (70 eV) m/e 211 (M+), 134, 133, 132, 106, 105, 104.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=[O:12])=[CH:5]2.[CH3:14][Si](C=[N+]=[N-])(C)C.C(O)(=O)C>CO.C(Cl)Cl>[OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:5]2
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1cc2cc(O)ccc2[nH]1
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cc2cc(O)ccc2[nH]1
Reaction time: 0.5 h
Yield: 99 %

Procedure:
5-Hydroxy-1H-indole-2-carboxylic acid (0.50 g, 2.82 mmol) was dissolved in MeOH:CH2Cl2 (1:1, 15 mL), trimethylsilyl diazomethane (2.0 M in hexanes, ˜5.0 mL) was added dropwise until a persistent yellow color formed and the reaction mixture was stirred for 0.5 h. To the solution was added acetic acid (0.5 mL) and the solvent was evaporated. Purification was accomplished by column chromatography (CH2Cl2: MeOH) to afford the title compound (0.55 g, 99%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.59 (br. s., 1H), 8.88 (dd, 1H), 7.23 (d, 1H), 6.85-6.96 (m, 2 H), 6.77 (dd, 1H), 3.81 (d, 3H). MS: m/z 192.2 (M+1).