Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH2:10][C:11]([OH:13])=O)[C:6]=2[C:14]=1[F:15].[NH2:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH3:29])([CH3:28])[C:26]#[N:27])=[C:21]([CH3:30])[CH:20]=1)[CH3:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH2:10][C:11]([NH:16][CH:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([C:26]#[N:27])([CH3:29])[CH3:28])=[C:21]([CH3:30])[CH:20]=3)[CH3:18])=[O:13])[C:6]=2[C:14]=1[F:15]
Reactant: O=C(O)Cn1cnc2ccc(F)c(F)c21
Reactant: Cc1cc(C(C)N)ccc1C(C)(C)C#N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(C(C)NC(=O)Cn2cnc3ccc(F)c(F)c32)ccc1C(C)(C)C#N
Yield: 67 %

Procedure:
To a solution of (6,7-difluoro-1H-benzimidazol-1-yl)acetic acid (500 mg, 2.36 mmol) prepared according to scheme 2, 2-{4-[1-aminoethyl]-2-methylphenyl}-2-methylpropanenitrile (477 mg, 2.36 mmol) prepared according to scheme 16 and DMAP (570 mg, 4.71 mmol) stirred in anhydrous DMF (4.0 mL) is added HATU (896 mg, 2.36 mmol) after 18 hours of stirring, the mixture is diluted with EtOAc (100 mL). The organic phase is washed with distilled water, dried over anhydrous MgSO4. The mixture is filtered and concentrated. The product is purified on a preparative LCMS system equipped with a Synergi Polar (4u) 21.2×50 mm column, mobile phase: A=water (0.1% TFA), B=MeCN using a short 40 to 60% B 10 min. gradient method. The pure fractions are combined the TFA neutralized with a 4N NaOH solution and then extracted with ethyl acetate which is separated dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide the expected product (+) and (−)-2-(6,7-difluoro-1H-benzimidazol-1-yl)-N-{1-[4-(1-cyano-1-methylethyl)-3-methylphenyl]ethyl}acetamide (627 mg, 67%) as a white solid. 1H NMR (400 MHz, METHANOL-D4) δ ppm 1.48 (d, J=7.03 Hz, 3 H) 1.75 (s, 6H) 2.61 (s, 3H) 4.99 (q, J=7.03 Hz, 1H) 5.12 (s, 2H) 7.12-7.25 (m, 3H) 7.33 (d, J=8.20 Hz, 1H) 7.42 (ddd, J=8.89, 3.61, 1.17 Hz, 1H) 8.13 (s, 1H), MS [M+H], calcd: 397.2. found: 397.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]([CH3:15])[CH3:14])=[C:11]([NH2:16])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[C:19]([C:30]([F:33])([F:32])[F:31])=[N:20][N:21]([CH:24]([CH2:28][CH3:29])[C:25](O)=[O:26])[C:22]=1[CH3:23].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[Cl:17][C:18]1[C:19]([C:30]([F:32])([F:31])[F:33])=[N:20][N:21]([CH:24]([CH2:28][CH3:29])[C:25]([NH:16][C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:12]=2[CH:13]([CH3:14])[CH3:15])=[O:26])[C:22]=1[CH3:23]
Reactant: CC(C)c1c(N)cnn1-c1ccc(F)cc1
Reactant: CCC(C(=O)O)n1nc(C(F)(F)F)c(Cl)c1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C(=O)Nc1cnn(-c2ccc(F)cc2)c1C(C)C)n1nc(C(F)(F)F)c(Cl)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a solution of 1-(4-fluorophenyl)-5-isopropylpyrazol-4-amine (0.03 g, 0.14 mmol) in DMF (1.0 mL) was added 2-[4-chloro-5-methyl-3-(trifluoromethyl)pyrazol-1-yl]butanoic acid (0.037 g, 0.14 mmol), followed by diisopropylethylamine (0.042 g, 0.32 mmol) and HATU (0.057 g, 0.15 mmol). After stirring at room temperature for 1 h, the reaction was diluted with water and the aqueous layer was extracted with ethyl acetate (2×5 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting crude product was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.020 g, 0.042 mmol, 31%). 1H NMR (400 MHz, CDCl3) δ 8.47 (s, 1H), 8.04 (s, 1H), 7.35-7.24 (m, 2H), 7.21-7.11 (m, 2H), 4.80 (dd, J=8.7, 6.5 Hz, 1H), 2.98 (m, 1H), 2.42-2.29 (m, 5H), 1.26 (d, J=7.2 Hz, 3H), 1.10 (d, J=7.1 Hz, 3H), 0.92 (t, J=7.3 Hz, 3H); MS: (ES) m/z calculated for C21H22ClF4N5O [M+H]+ 472.1, found 471.9.
Reaction SMILES: [ClH:1].Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:14]3[N:13]=[C:12]2[CH2:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:6][CH:5]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C.CS(O[CH2:45][CH2:46][C:47]1[S:48][CH:49]=[CH:50][CH:51]=1)(=O)=O>O>[ClH:1].[ClH:1].[F:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][N:11]2[C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:14]3[N:13]=[C:12]2[CH2:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:45][CH2:46][C:47]3[S:48][CH:49]=[CH:50][CH:51]=3)[CH2:23][CH2:22]2)=[CH:8][CH:9]=1
Reactant: CS(=O)(=O)OCCc1cccs1
Reactant: Fc1ccc(Cn2c(CC3CCNCC3)nc3cccnc32)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: Fc1ccc(Cn2c(CC3CCN(CCc4cccs4)CC3)nc3cccnc32)cc1
Yield: 76 %

Procedure:
A mixture of 7.9 parts of 3-[(4-fluorophenylmethyl)-2-(4-piperidinylmethyl)-3H-imidazo[4,5-b]pyridine dihydrochloride, 8.5 parts of sodium carbonate and 120 parts of 4-methyl-2-pentanone was stirred and refluxed for 30 minutes using a water separator. 7.8 Parts of 2-thiopheneethanol methanesulfonate (ester) were added and the whole was stirred and refluxed for 4 hours using a water separator. After cooling, the salts were filtered off, washed with 4-methyl-2-pentanone and the filtrate was washed with water. The organic layer was dried, filtered and evaporated. The residue was converted into the hydrochloride salt in 2-propanol and 2-propanone. The salt was filtered off and dried in vacuo at 60° C., yielding 8.0 parts (76%) of 3-[(4-fluorophenyl)methyl]-2-[[1-[2-(2-thienyl)ethyl]-4-piperidinyl]methyl]-3H-imidazo[4,5-b]pyridine dihydrochloride. monohydrate; mp. 210.8° C. (117).
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[N:16][C:8]=3[NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:5]2=[N:4][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O)C.C(=O)(O)[O-].[Na+].CC1(C)C(C)(C)OB([C:42]2[CH:47]=[CH:46][C:45]([C@@H:48]([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])[CH3:49])=[CH:44][CH:43]=2)O1>C1(C)C=CC=CC=1>[C:20]1([C:3]2[N:4]=[C:5]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[NH:9][C:8]4[N:16]=[CH:17][CH:18]=[CH:19][C:7]=4[N:6]3[C:2]=2[C:42]2[CH:43]=[CH:44][C:45]([C@@H:48]([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])[CH3:49])=[CH:46][CH:47]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Brc1c(-c2ccccc2)nc2n1-c1cccnc1Nc1ccccc1-2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(-c2c(-c3ccccc3)nc3n2-c2cccnc2Nc2ccccc2-3)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 30.7 %

Procedure:
To a suspension of 3-bromo-2-phenyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepine (0.60 g, 1 eq.) in a mixture of toluene (10 mL), ethanol (10 mL), and saturated sodium bicarbonate (3 mL) was added (S)-tert-butyl (1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)carbamate (1.31 g, 2.45 eq.). The reaction was degassed (nitrogen) for 5 minutes and tetrakis(triphenylphosphine)palladium(0) added (0.3 g). The reaction was again degassed for 5 minutes and stirred at 100° C. overnight. The reaction mixture was cooled to room temperature and poured onto water (50 mL). The aqueous phase was extracted with dichloromethane (2×50 mL) and the organic extracts were combined and washed with water (1×50 mL), brine (1×50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (25-75% ethyl acetate in hexanes) gave the product which was triturated with ether to give (S)-tert-butyl (1-(4-(2-phenyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-3-yl)phenyl)ethyl)carbamate (0.251 g, 31%). LCMS: 530 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.[C:27]([O-:30])(=O)[CH3:28].[Na+].O>C(OC(=O)C(CCC)CCC)(=O)C(CCC)CCC>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([C:27](=[O:30])[CH:28]([CH2:9][CH2:4][CH3:5])[CH2:3][CH2:2][CH3:11])[C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:25])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Reactant: CC(=O)[O-]
Agent: CCCC(CCC)C(=O)OC(=O)C(CCC)CCC
Agent: [Na+]
Solvent: O
Product: CCCC(CCC)C(=O)n1c(=O)n(-c2ccc(C(C)(C)C#N)cc2)c2c3cc(Br)ccc3ncc21
Temperature: 25 °C

Procedure:
A mixture of 2-(4-(8-Bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 1, 25 mg, 0.06 mmol) and sodium acetate (5 mg, 0.06 mmol) was heated at 110-120° C. in valproic anhydride (1 ml) for four hours. Reaction mixture was cooled to RT. Water was added and extracted with ethyl acetate. Ethyl acetate layer was washed with brine, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound. Yield: 12 mg (38%); 1H NMR (CDCl3, 300 MHz): δ 9.849 (s, 1H), 7.98-8.01 (d, 1H, J=9 Hz), 7.78-7.81 (d, 2H, J=8.7 Hz), 7.63-7.67 (dd, 1H, J=9, 2.1 Hz), 7.54-7.57 (d, 2H, J=8.1 Hz), 7.02-7.03 (d, 1H, J=1.8 Hz), 2.38 (m, 1H), 1.84 (s, 6H), 1.67 (m, 4H), 1.49 (m, 4H), 0.9 (m, 6H); MS: m/z 533 (M+).
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.Cl.[Br:10][C:11]1[CH:12]=[C:13]([CH2:18][NH2:19])[CH:14]=[CH:15][C:16]=1[F:17].C(N(C(C)C)CC)(C)C>C1COCC1>[Br:10][C:11]1[CH:12]=[C:13]([CH2:18][NH:19][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8])[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: O=C1CCCC(=O)O1
Reactant: NCc1ccc(F)c(Br)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)CCCC(=O)NCc1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
A mixture of glutaric anhydride (342 mg, 3 mmol), [(3-bromo-4-fluorophenyl)methyl]amine hydrochloride salt (721.5 mg, 3 mmol), and diisopropyl ethyl amine (2 mL) in THF (50 mL) was stirred at room temperature for 1 hour. It was concentrated, mixed with 4% HCl (50 mL) and extracted with EtOAc (50 mL, 2×). The combined organic extracts were dried and concentrated to provide the captioned product (920 mg).
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)[C:3]([OH:5])=[O:4].[C:12](#N)[CH3:13]>>[CH:7]1([CH2:6][CH:2]([N:1]2[CH2:13][C:12]3[C:2](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:3]2=[O:4])[C:3]([OH:5])=[O:4])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: NC(CC1CCCC1)C(=O)O
Reactant: CC#N
Product: O=C(O)C(CC1CCCC1)N1Cc2ccccc2C1=O
Temperature: 25 °C
Yield: 83 %

Procedure:
A mixture of 2-Amino-3-cyclopentyl-propionic acid (0.800 g; 5.09 mmol) and phthalic dicarboxaldehyde (0.684 g; 5.10 mmol) in acetonitrile (30 mL) was refluxed for 3 h under nitrogen. The mixture was allowed to cool to room temperature and the solid was filtered off and washed once with cold acetonitrile (5 mL) to give 1.16 g (83%) of 3-Cyclopentyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid as a white solid: EI-HRMS m/e calcd for C16H19NO3 (M+) 273.1365, found 273.1374.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18]C)[CH:16]=[CH:17][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1>Br.C(O)(=O)C>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Agent: Br
Solvent: CC(=O)O
Product: Oc1ccc(-c2cc3ccc(O)cc3s2)cc1
Yield: 75.1 %

Procedure:
2-(4-Methoxyphenyl)-6-methoxybenzo[b]thiophene (10 g, 35.5 mmol) was suspended in 50 mL of 48% aqueous hydrobromic acid and 100 mL of glacial acetic acid. The reaction was heated to reflux under a nitrogen atmosphere for 120 hours. The reaction was allowed to cool and filtered. The solid product was washed with water and dried to yield 6.46 g of the title compound. 1H NMR: (CDCl3 -d6DMSO):δ 7.54 (d, 1H), 7.48 (d, 2H), 7.27 (s, 1H), 7.24 (m, 1H), 6.92 (d, 1H), 6.85 (d, 2H). MS(FD): m/e=242 (M+).
Reaction SMILES: C([O:4][C@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@@H:6]1[O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:32]=[C:33]([CH2:37][C:38]([O:40][CH3:41])=[O:39])[CH:34]=[CH:35][CH:36]=1)(=O)C.C[O-].[Na+].C(Cl)(Cl)Cl>CO>[C@H:6]1([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[CH:32]=[C:33]([CH2:37][C:38]([O:40][CH3:41])=[O:39])[CH:34]=[CH:35][CH:36]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@@H:5]1[OH:4]
Reactant: COC(=O)Cc1cccc(-c2ccccc2O[C@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]2OC(C)=O)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)Cc1cccc(-c2ccccc2O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
Methyl 3-(2-(2,3,4,6-tetra-O-acetyl-α-D-mannopyranosyloxy)phenyl)phenylacetate (3.96 g, 6.9 mmol, from Part E, EXAMPLE 2) was dissolved in methanol (50 ml), sodium methoxide (100 mg) was added and the solution stirred at room temperature for two hours. The reaction mixture was neutralized with Dowex-50W ion exchange resin (H+ form), filtered and concentrated in vacuo. Chromatography (silica, 9:1 CHCl3 :methanol) gave methyl 3-(2-(α-D-mannopyranosyloxy)phenyl)phenylacetate (2.8 g, quantitative yield (~100%)).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH3:18])[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:11]2[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>O1CCOCC1.C(O)(C)(C)C.CCCCCCC.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:22][S:19]([C:12]1[C:13]([CH3:18])=[N:14][C:15]2[C:10]([C:11]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:9][C:8]([N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)=[CH:17][CH:16]=2)(=[O:21])=[O:20]
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccccc2)c1S(C)(=O)=O
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CC(C)(C)O
Solvent: C1COCCO1
Solvent: CCCCCCC
Product: Cc1nc2ccc(N3CCCCC3)cc2c(-c2ccccc2)c1S(C)(=O)=O
Temperature: 120 °C
Yield: 398.5 %

Procedure:
A tube placed under argon was charged with tris(dibenzylideneacetone)dipalladium chloroform complex (3 mg), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (3 mg) and cesium carbonate (121 mg, 0.37 mmol). 6-Bromo-3-methanesulfonyl-2-methyl-4-phenyl-quinoline (compound of example 2) (100 mg, 0.26 mmol) in dioxane/tert.-butanol 1:1 (15 ml) was added, followed by piperidine (0.027 ml, 0.031 mmol). The tube was sealed and heated at 120° C. for 2 h. The reaction mixture was cooled to 20° C., diluted with heptane, filtered through dicalite and purified directly by flash chromatography on silica gel in heptane/ethyl acetate 40:60 to give a yellow solid (47 mg, 46%). MS: m/z=381 (M+H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][CH2:6][C:7]#[C:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][N:13]=[C:12]2Cl)=[O:4].[CH3:20][C:21]1[CH:22]=[C:23]([NH2:34])[CH:24]=[CH:25][C:26]=1[O:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1>CC(O)(C)C.ClCCCl>[Cl:1][CH2:2][C:3]([NH:5][CH2:6][C:7]#[C:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][N:13]=[C:12]2[NH:34][C:23]1[CH:24]=[CH:25][C:26]([O:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)=[C:21]([CH3:20])[CH:22]=1)=[O:4]
Reactant: O=C(CCl)NCC#Cc1ccc2ncnc(Cl)c2c1
Reactant: Cc1cc(N)ccc1Oc1cccnc1
Solvent: CC(C)(C)O
Solvent: ClCCCl
Product: Cc1cc(Nc2ncnc3ccc(C#CCNC(=O)CCl)cc23)ccc1Oc1cccnc1
Yield: 88.8 %

Procedure:
A mixture of 2-Chloro-N-[3-(4-chloro-quinazolin-6-yl)-prop-2-ynyl]-acetamide (0.90 g, 3.05 mmol) and 3-Methyl-4-(pyridin-3-yloxy)-phenylamine (0.61 g, 3.05 mmol) in tBuOH/DCE (5.0/5.0 mL) was refluxed under nitrogen for 40 minutes and concentrated. The residue was dissolved in MeOH (2.0 mL) and added to EtOAc with vigorous stirring to precipitate the HCl salt product as tan solid which was collected by vacuum-filtration, rinsed with EtOAc, and further dried to give 1.24 g (82%) of 2-Chloro-N-(3-{4-[3-methyl-4-(pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-acetamide: 1H NMR (CD3OD) δ 2.27 (s, 3H), 4.09 (s, 2H), 4.29 (s, 2H), 7.07 (d, 1H), 7.51 (m, 2H), 7.60 (d, 1H), 7.70 (s, 1H), 7.78 (d, 1H), 8.05 (d, 1H), 8.32 (m, 2H), 8.67 (s, 1H), 8.75 (s, 1H); MS m/z (MH+) 458.0.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[S:11][C:10](=[O:12])[N:9]([CH3:13])[C:8]=1[CH3:14])=O.[N+]([O-])(O)=O.[N:20]1([C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33]([NH2:35])=[NH:34])=[CH:28][CH:27]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[CH3:13][N:9]1[C:8]([CH3:14])=[C:7]([C:5]2[CH:4]=[CH:3][N:35]=[C:33]([NH:32][C:29]3[CH:28]=[CH:27][C:26]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:31][CH:30]=3)[N:34]=2)[S:11][C:10]1=[O:12]
Reactant: N=C(N)Nc1ccc(N2CCOCC2)cc1
Reactant: Cc1c(C(=O)C=CN(C)C)sc(=O)n1C
Solvent: O=[N+]([O-])O
Product: Cc1c(-c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)sc(=O)n1C

Procedure:
Condensation between 5-(3-dimethylamino-acryloyl)-3,4-dimethyl-3H-thiazol-2-one and N-(4-morpholin-4-yl-phenyl)-guanidine nitrate afforded the title compound. Anal. RP-HPLC: tR=17.5 min (0-60% MeCN in 0.1% aq CF3COOH over 20 min, 1 mL/min, purity>95%). 1H-NMR (DMSO-d6) δ: 2.48 (3H, s, CH3), 3.03 (4H, m, 2×morph-NCH2), 3.08 (3H, s, CH3), 3.72 (4H, m, 2×morph-OCH2), 6.85 (1H, d, J=5.2, pyrim-H), 6.89 (2H, d, J=9.2, 2×ArH), 7.57 (2H, d, J=9.2, 2×ArH), 8.36 (1H, d, J=5.2, pyrim-H) and 9.35 (1H, s, NH). MS (ESI+) m/z 384[M+H]+ (C19H21N5O2S requires 383.5).
Reaction SMILES: C(O)(C(F)(F)F)=O.[O:8]=[C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:16]=2)[CH:12]=[CH:11][N:10]1[CH2:28][C:29]1[CH:37]=[C:36]2[C:32]([CH:33]=[CH:34][N:35]2C(OC(C)(C)C)=O)=[CH:31][CH:30]=1.C([O-])(O)=O.[Na+].CC#N>ClCCl>[NH:35]1[C:36]2[C:32](=[CH:31][CH:30]=[C:29]([CH2:28][N:10]3[CH:11]=[CH:12][C:13]([C:15]4[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH:22]5[CH2:27][CH2:26][O:25][CH2:24][CH2:23]5)[N:16]=4)=[CH:14][C:9]3=[O:8])[CH:37]=2)[CH:33]=[CH:34]1
Reactant: CC(C)(C)OC(=O)n1ccc2ccc(Cn3ccc(-c4ccnc(NC5CCOCC5)n4)cc3=O)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: O=c1cc(-c2ccnc(NC3CCOCC3)n2)ccn1Cc1ccc2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.6 %

Procedure:
TFA (2 mL) was added to a solution of tert-butyl 6-((2-oxo-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-1(2H)-yl)methyl)-1H-indole-1-carboxylate (70 mg, 0.14 mmol) in dichloromethane (3 mL) at 20° C. The mixture was stirred at room temperature for 2 hours. LC-MS showed the tert-butyl 6-((2-oxo-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-1(2H)-yl)methyl)-1H-indole-1-carboxylate had disappeared. The reaction mixture was adjusted with a saturated NaHCO3 solution to a pH of around 8-9, then extracted with dichloromethane, and dried with Na2SO4. The organic phase was evaporated, and the residue was purified with prep-HPLC (A: H2O including 0.5% NH3HCO3, B: CH3CN) to afford 1-((1H-indol-6-yl)methyl)-4-(2-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-4-yl)pyridin-2(1H)-one (11 mg, 20% yield). 1H NMR (500 MHz, (CD3)2SO) δ 11.10 (s, 1H), 8.41 (d, J=5.0 Hz, 1H), 7.92 (d, J=7.0 Hz, 1H), 7.50 (d, J=8 Hz, 1H), 7.40-7.32 (m, 3H), 7.15-7.11 (m, 2H), 7.03 (d, J=8 Hz, 1H), 6.85 (d, J=7 Hz, 1H), 6.39 (s, 1H), 5.22 (s, 2H), 3.98 (m, 1H), 3.89-3.85 (m, 2H), 3.45-3.36 (m, 2H), 1.86-1.83 (m, 2H), 1.60-1.45 (m, 2H); LCMS (ESI) m/z: 402.2 [M+H+].
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14](S(N2CCC(C3C4C(=CC=C(F)C=4)N(S(CC[Si](C)(C)C)(=O)=O)C=3)CC2)(=O)=O)[CH:13]([C:45]([OH:47])=O)[CH2:12]1)=O)C1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.[NH2:54]O.CO>C(Cl)Cl.CN(C=O)C>[NH:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH:13]1[C:45]([NH2:54])=[O:47]
Reactant: NO
Reactant: C[Si](C)(C)CCS(=O)(=O)n1cc(C2CCN(S(=O)(=O)N3CCN(C(=O)OCc4ccccc4)CC3C(=O)O)CC2)c2cc(F)ccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: NC(=O)C1CNCCN1
Temperature: 25 °C
Reaction time: 14 h
Yield: 483.9 %

Procedure:
To a solution of 4-benzyloxycarbonyl-1-(4-[5-fluoro-1-(2-trimethylsilylethane-sulfonyl)indol-3-yl]piperidine-1-sulfonyl)piperazine-2-(RS)-carboxylic acid(288 mg, 0.40 mmol), [prepared as described in Step 6 above] in methylene chloride (5 ml) at 0° C. were added a few drops of DMF and oxalyl chloride (89 ml, 1.0 mmol). The reaction mixture was warmed to RT over 1 h, and stirring was continued for an additional 14 h. The reaction mixture was concentrated in vacua, redissolved in methylene chloride (5 ml) and cooled to 0° C. N,O-bis-trithylsilyl hydroxylamine (0.304 ml, 1.42 mmol) added, the reaction was warmed to RT, stred for 3 h, and then recooled to 0° C. After adding methanol (3 ml), the mixture was stirred for an additional 30 min., and then concentrated in vacuo. The residue was partitioned between methylene chloride (50 ml) and aqueous 2.4 M HCl (10 ml), the organic layer was separated and washed with saturated aqueous sodium bicarbonate, dried over MgSO4, and concentrated in vacuo to afford N-hydroxy-4-benzyloxycarbonyl-1-j4-[5-fluoro-1-2-trmethylsilylethanesulfonyl)-indol-3-yl]-piperidine-1-sulfonyl ) piperazine-2-(RS)-carboxamide as a yellow foam (250 mg, 86%). The residue was used without further purification.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[CH:15]2.[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C>[C:21]1([S:27]([N:17]2[C:18]3[C:14](=[CH:13][C:12]([F:11])=[CH:20][CH:19]=3)[CH:15]=[CH:16]2)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Fc1ccc2[nH]ccc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1ccc2cc(F)ccc21
Reaction time: 0.17 h
Yield: 74 %

Procedure:
KHMDS (0.5 M in toluene, 23 mL, 11.65 mmol) was added at 0° C. to a solution of 5-fluoroindole (1.5 g, 11.09 mmol) in DMF (23 mL). After stirring for 10 minutes, benzenesulfonyl chloride (1.55 mL, 12.209 mmol) was added. The ice-bath was removed and the mixture was stirred at room temperature for 4 hours. A saturated solution of NH4Cl was added to the reaction, and the resulting mixture was extracted with EtOAc. The combined organic extracts were washed with water and brine; dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was recrystallized from toluene to afford 2.26 g (74% yield) of 1-benzenesulfonyl-5-fluoro-1H-indole as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:22])[C@H:4]([N:6]([S:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]#[C:20][CH3:21])=[CH:13][CH:12]=1)(=[O:10])=[O:9])[CH3:7])[CH3:5].O.[OH-].[Li+].Cl>C1COCC1.CO>[CH2:18]([O:17][C:14]1[CH:13]=[CH:12][C:11]([S:8]([N:6]([CH3:7])[CH:4]([CH3:5])[C:3]([OH:22])=[O:2])(=[O:9])=[O:10])=[CH:16][CH:15]=1)[C:19]#[C:20][CH3:21]
Reactant: CC#CCOc1ccc(S(=O)(=O)N(C)[C@H](C)C(=O)OC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC#CCOc1ccc(S(=O)(=O)N(C)C(C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.9 %

Procedure:
To a solution of 0.273 g (0.840 mmol) of (2R)-2-[(4-but-2-ynyloxy-benzenesulfonyl)-methyl-amino]-propionic acid methyl ester in 6 mL of THF/methanol (1/1) was added 0.123 g (2.94 mmol) of lithium hydroxide monohydrate and the resulting solution was stirred at room temperature for 3 h. The reaction was then acidified with 5% HCl solution and extracted with chloroform. The combined organics were dried over MgSO4, filtered and concentrated in vacuo to give 0.256 g of 2-[(4-but-2-ynyloxy-benzenesulfonyl)-methyl-amino]-propionic acid as a white solid. Electrospray Mass Spec 310.2 (M−H)−.