Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].O=[C:10]1[CH2:15][CH2:14][N:13](C([O-])=O)[CH2:12][CH2:11]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[ClH:33]>ClCCCl.CO.O>[ClH:33].[F:1][C:2]1[CH:3]=[C:4]([NH:5][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(F)c1
Reactant: O=C1CCN(C(=O)[O-])CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClCCCl
Solvent: O
Product: Fc1cccc(NC2CCNCC2)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
3-Fluoroaniline (28.38 ml, 0.296 mol) was added to a solution of 4-oxo-1-piperidine carboxylate (60 g, 0.302 mol) in 1,2-DCE (600 ml) and the mixture stirred for 15 minutes. Sodium tri(acetoxy)borohydride (83 g, 0.392 mol) was added gradually over 5 minutes and the mixture stirred for 5.5 h, then poured into a mixture of 2M HCl (100 ml), water (200 ml) and ice (1 l). The phases were separated and the aqueous phase extracted with DCM (200 ml). The combined organic phases were dried over MgSO4 and concentrated to give a pale yellow solid which was dissolved in MeOH (400 ml) and treated with 2M HCl (100 ml). The resulting solution was stirred at 60° C. overnight. 5M HCl (100 ml) was added and heating continued for a further 7 h. The reaction mixture was concentrated in vacuo to give a yellow oily solid. This was re-crystallized from MeOH/EtOAc to give two batches of the title compound (42.6 g & 17.0 g). These batches were then re-crystallized from IMS/EtOAc and the resulting batches were dried in vacuo at 50° C. to give the title compound (49.0 g total). δH (CD3OD, 250 MHz) 7.54 (1H, q), 7.24 (2H, m), 7.15 (1H, t), 3.89 (1H, m), 3.54 (2H, d), 3.11 (2H, t), 2.24 (2H, d), 2.01 (2H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]23[CH2:16][CH2:15][CH2:14][CH:13]2[CH2:12][S:11][C:10]([NH2:17])=[N:9]3)=[CH:4][C:3]=1[O:18]C.B(Br)(Br)Br>C(Cl)Cl.O>[NH2:17][C:10]1[S:11][CH2:12][CH:13]2[CH2:14][CH2:15][CH2:16][C@:8]2([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([OH:18])[CH:4]=2)[N:9]=1
Reactant: COc1cc([C@]23CCCC2CSC(N)=N3)ccc1F
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: NC1=N[C@@]2(c3ccc(F)c(O)c3)CCCC2CS1
Temperature: 0 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
To a −78° C. solution of (7aS)-7a-(4-fluoro-3-methoxyphenyl)-4,4a,5,6,7,7a-hexahydrocyclopenta[d][1,3]thiazin-2-amine (0.717 g, 2.56 mmol) in CH2Cl2 (15 mL) is added boron tribromide 11.20 g, 7.67 mmol). The reaction is warmed to 0° C. and is stirred for 2 hr. The reaction is diluted with water and the pH is adjusted to 7. The aqueous is extracted three times with EtOAc (some MeOH is added to help dissolve some solids during the extraction). The organic layer is dried over Na2SO4 and the solvent is removed under reduced pressure. The crude product is purified with a 10 g SCX column using 4:1 CH2Cl2:MeOH and then 2:1 CH2Cl2:7 N NH3 in MeOH to elute the product and give the title compound (0.56 g, 82%). ES/MS m/e: 267 (M+1).
Reaction SMILES: [BH4-].[Na+].C(O)(C)C.COS([O-])(=O)=O.[CH3:13][N+:14]1[N:15]([CH3:31])[C:16]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:17][C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O>[CH3:31][N:15]1[CH:16]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:17][CH:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:14]1[CH3:13]
Reactant: Cn1c(-c2ccccc2)cc(-c2ccccc2)[n+]1C
Agent: COS(=O)(=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CN1C(c2ccccc2)CC(c2ccccc2)N1C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Sodium borohydride (19 g, 0.5 mole) is added portionwise to an isopropanol (1 liter) solution of 1,2-dimethyl-3,5-diphenylpyrazolium methyl sulfate (40.1 g, 0.25 mole). The reaction is allowed to stir at room temperature for 3 days; then additional sodium borohydride (9 g, 0.25 mole) is added, and the reaction is heated to reflux with stirring and maintained there for 7 hours. The reaction mixture is cooled to room temperature and water (100 ml) is added over a 11/2-hour period. After stirring for 2 hours, the isopropanol is removed on a rotary evaporator, and the resulting paste slurried in water and extracted with diethyl ether. Evaporation of the ether layer gives the pyrazolidine as a viscous oil; 48.3 g, 72%, and analyzed as its HCl salt.
Reaction SMILES: [F:1][CH:2]([F:39])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH2:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:5]=2[N:4]=1.[Cl:40][CH2:41][S:42](Cl)(=[O:44])=[O:43].C([O-])([O-])=O.[K+].[K+].Cl>C(Cl)Cl.CO>[ClH:40].[Cl:40][CH2:41][S:42]([N:30]1[CH2:31][CH2:32][CH:27]([N:20]([C:10]2[N:9]=[C:8]([N:7]3[C:6]4[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:5]=4[N:4]=[C:3]3[CH:2]([F:1])[F:39])[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=2)[CH2:21][CH2:22][CH2:23][N:24]([CH3:25])[CH3:26])[CH2:28][CH2:29]1)(=[O:44])=[O:43]
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(CCCN(C)C)C2CCNCC2)n1
Reactant: O=S(=O)(Cl)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(CCCN(C)C)C2CCN(S(=O)(=O)CCl)CC2)n1
Yield: 44 %

Procedure:
Reaction of N1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N3,N3-dimethyl-N1-(4-piperidinyl)-1,3-propanediamine (Example 21) with chloromethanesulfonyl chloride and K2CO3 in CH2Cl2, followed by conversion to the hydrochloride salt with 1.25 M HCl in methanol gave N1-{1-[(chloromethyl)sulfonyl]-4-piperidinyl}-N1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N3,N3-dimethyl-1,3-propanediamine hydrochloride in 44% yield: mp (MeOH) 222-225° C.; 1H NMR (DMSO-d6) δ 9.89 (br, 1H), 7.90 (d, J=8.4 Hz, 1H), 7.71 (t, JHF=53.0 Hz, 1H), 7.47-7.41 (m, 1H), 7.00 (d, J=8.2 Hz, 1H), 5.17 and 5.11 (2s, 2H), 4.74-4.71 and 4.66-4.53 (2m, 1H), 3.98 (s, 3H), 3.92-3.82 (m, 6H), 3.71 (m, 4H), 3.60-3.51 (m, 2H), 3.16-3.04 (m, 4H), 2.75 and 2.70 (2s, 6H), 2.02-1.80 (m, 6H); Anal. Calcd. for C27H39Cl2F2N9O4S.0.5; H2O: C, 46.1; H, 5.7; N, 17.9; Cl, 10.1. Found: C, 46.1; H, 5.8; N, 17.9; Cl, 9.7%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[CH:12]([CH2:13][CH2:14]Cl)[O:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:16]=1.[Cl:19][C:20]1[CH:21]=[C:22]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1>C(O)CO.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[CH:12]([CH2:13][CH2:14][N:29]3[CH2:28][CH2:27][N:26]([C:22]4[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[CH:21]=4)[CH2:31][CH2:30]3)[O:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:16]=1
Reactant: COc1cc2c(cc1OC)C(CCCl)OCCC2
Reactant: Clc1cccc(N2CCNCC2)c1
Solvent: OCCO
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1OC)C(CCN1CCN(c3cccc(Cl)c3)CC1)OCCC2
Yield: 34.2 %

Procedure:
A mixture of 2.00 g (7.39 mmol) of 2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzoxepin-1-yl)]ethyl chloride and 2.8 g (14.5 mmol) of 1-(3-chlorophenyl)piperazine is stirred at 85° for 36 hours in 1 ml of ethylene glycol and 10 ml of toluene. Excess toluene is added and the solids are removed by filtration from the warm solution. The organic phase is concentrated. The product was recrystallized from CH2Cl2 and toluene to give 1.09 g of product, m.p. 125°-126°.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:30])[C:10]([NH:12][C:13]1[CH:28]=[CH:27][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20](C(N)=O)[CH:19]=2)=[C:15]([F:29])[CH:14]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[N:32]1C=CC=CC=1.FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=O>CN(C=O)C.C(OCC)(=O)C>[NH2:32][C:20]1[CH:19]=[C:18]([O:17][C:16]2[CH:27]=[CH:28][C:13]([NH:12][C:10](=[O:11])[C:9]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:30])=[CH:14][C:15]=2[F:29])[CH:23]=[CH:22][N:21]=1
Reactant: NC(=O)c1cc(Oc2ccc(NC(=O)C(=O)NCc3ccccc3)cc2F)ccn1
Reactant: c1ccncc1
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(Oc2ccc(NC(=O)C(=O)NCc3ccccc3)cc2F)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 4-(4-(2-(benzylamino)-2-oxoacetamido)-2-fluorophenoxy)picolinamide (41 mg, 0.10 mmol) in DMF (0.5 mL), water (5 μL, 0.26 mmol), and pyridine (32 μL, 0.39 mmol) was added [bis(trifluoroacetoxy)iodo]benzene (60 mg, 0.14 mmol, Aldrich). After stirring at rt for 2 h, the reaction was diluted with ethyl acetate (20 mL), washed with 10% aqueous lithium chloride solution (2×10 mL) followed by brine (10 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (EtOAc/0-5% MeOH) to give the title compound as a white solid. The solid was suspended in ethyl acetate (3 mL) and 0.5 mL of 1 N HCl in ether was added. The mixture was concentrated in vacuo and the residue was lyophilized from acetonitrile (1 mL)/water (3 mL) to give the HCl salt of the title compound (25 mg, 60%) as a white solid. 1H NMR (DMSO-d6) δ 11.05 (s, 1H), 9.57 (t, 1H, J=6 Hz), 7.96 (dd, 1H, J=12.8, 2 Hz), 7.91 (d, 1H, J=7.2 Hz), 7.81 (br s, 2H), 7.76 (d, 1H, J=8.8 Hz), 7.43 (t, 1H, J=8.8 Hz), 7.29-7.17 (m, 5H), 6.64 (dd, 1H, J=7.2, 2.8 Hz), 6.10 (d, 1H, J=2 Hz), 4.34 (d, 2H, J=6.4 Hz); MS (ESI+) m/z 381.24 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1I)[O:5][CH2:6][CH2:7][N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]#[CH:31])=[N:28][CH:29]=2)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]#[C:31][C:15]3[CH:14]=[CH:13][C:4]([O:5][CH2:6][CH2:7][N:8]4[CH2:12][CH2:11][CH2:10][CH2:9]4)=[CH:3][C:2]=3[F:1])=[N:28][CH:29]=2)=[CH:22][CH:23]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: Fc1cc(OCCN2CCCC2)ccc1I
Product: Fc1cc(OCCN2CCCC2)ccc1C#Cc1ccc(-c2ccc(Cl)cc2)cn1

Procedure:
Prepared according to general working method I from 1-[2-(3-fluoro-4-iodo-phenoxy)-ethyl]-pyrrolidine (500 mg, 0.75 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (159 mg, 0.75 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]([OH:24])[CH2:17][C:18]([CH2:22]C)([CH2:20]C)[CH3:19])=[N:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCOCC1.[O-2].[O-2].[Mn+4]>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16](=[O:24])[CH2:17][C:18]([CH3:22])([CH3:20])[CH3:19])=[N:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(C)(CC)CC(O)c1ccc(CNC(=O)OC(C)(C)C)cn1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: CC(C)(C)CC(=O)c1ccc(CNC(=O)OC(C)(C)C)cn1
Temperature: 70 °C
Yield: 88.6 %

Procedure:
Add manganese dioxide (472 mg, 5.429 mmol) to a solution of 5-tert-butoxycarbonylaminomethyl-2-(1-hydroxy-3,3-diethyl-butyl)-pyridine (118 mg, 0.383 mmol) in anhydrous 1,4-dioxane (5 mL) at room temperature. Heat the reaction mixture at 70° C. overnight. Filter the reaction mixture over Celite® and concentrate in vacuo to obtain the desired intermediate (104 mg, 89%).
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([C:14]3[NH:19][C:18]4[CH:20]=[CH:21][C:22](I)=[CH:23][C:17]=4[S:16](=[O:26])(=[O:25])[N:15]=3)=[C:10]([OH:27])[C:9]3=[CH:28][CH:29]=[CH:30][N:8]23)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:38]1[S:39](=[O:44])(=[O:43])[CH2:40][CH2:41][CH:42]=1)CCC>CN(C)C=O.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>[O:43]=[S:39]1(=[O:44])[CH2:40][CH2:41][CH:42]=[C:38]1[C:22]1[CH:21]=[CH:20][C:18]2[NH:19][C:14]([C:11]3[C:12](=[O:13])[N:7]([CH2:6][C:5]4[CH:31]=[CH:32][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]4[CH:30]=[CH:29][CH:28]=[C:9]4[C:10]=3[OH:27])=[N:15][S:16](=[O:26])(=[O:25])[C:17]=2[CH:23]=1
Reactant: O=c1c(C2=NS(=O)(=O)c3cc(I)ccc3N2)c(O)c2cccn2n1Cc1ccc(F)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCCS1(=O)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: O=c1c(C2=NS(=O)(=O)c3cc(C4=CCCS4(=O)=O)ccc3N2)c(O)c2cccn2n1Cc1ccc(F)cc1
Temperature: 90 °C
Yield: 48.5 %

Procedure:
1-(4-Fluoro-benzyl)-4-hydroxy-3-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-pyrrolo[1,2-b]pyridazin-2-one (Example 9b, 0.207 g, 0.371 mmol), tributyl-(1,1-dioxo-4,5-dihydro-1H-1λ6-thiophen-2-yl)-stannane (Example 11a, 0.181 g, 0.442 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.025 g, 0.020 mmol) were dissolved in N,N-dimethylformamide (8 mL) at 25° C. The mixture was heated to 90° C. for 24 h, then was allowed to cool to 25° C. and filtered through Celite. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm, 0→7% methanol in dichloromethane) to afford a brown solid. This material was re-chromatographed (Merck silica gel 60, 40-63 μm, 40→100% ethyl acetate in hexanes, followed by 100% ethyl acetate, followed by 0→7% methanol in dichloromethane) to afford the desired product, 3-[7-(1,1-dioxo-4,5-dihydro-1H-1λ6-thiophen-2-yl)-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl]-1-(4-fluoro-benzyl)-4-hydroxy-pyrrolo[1,2-b]pyridazin-2-one (0.100 g, 0.180 mmol, 48.6% yield). LC-MS (ESI) calcd for C25H19FN4O6S2 554.07. found 555.00 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([CH:11]2[CH2:16][NH:15][CH2:14][CH2:13][N:12]2[C:17]2[C:18]3[N:26]=[C:25](Cl)[CH:24]=[CH:23][C:19]=3[N:20]=[CH:21][N:22]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:28][O:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[CH:32][C:31]=1[OH:45].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([CH:11]2[CH2:16][NH:15][CH2:14][CH2:13][N:12]2[C:17]2[C:18]3[N:26]=[C:25]([C:34]4[CH:33]=[CH:32][C:31]([OH:45])=[C:30]([O:29][CH3:28])[CH:35]=4)[CH:24]=[CH:23][C:19]=3[N:20]=[CH:21][N:22]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Reactant: O=C(Nc1cccc(Cl)c1)C1CNCCN1c1ncnc2ccc(Cl)nc12
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(-c2ccc3ncnc(N4CCNCC4C(=O)Nc4cccc(Cl)c4)c3n2)ccc1O
Temperature: 25 °C
Yield: 53.9 %

Procedure:
To a solution of 4-[(N-3-chloro-phenylcarbamoyl)-piperazin-1-yl]-6-chloro-pyrido[3,2-d]pyrimidine (0.51 mmole) in 1,4-dioxane (15 ml) and water (5 ml) was added 2-methoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (0.51 mmole), potassium carbonate (1.53 mmole) and tetrakis(triphenylphosphine)palladium(0) (0.02 mmole). The reaction mixture was refluxed for two hours, cooled down to room temperature and the solvents were evaporated in vacuo. The residue was purified by silica gel column chromatography (the mobile phase being an acetone/dichloromethane mixture in a ratio of 20:80), affording the title compound as a pure white powder (135 mg, yield 54%) which was characterized by its mass spectrum as follows: MS (m/z): 492 ([M+H]+, 100).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:16]=[C:15]([C:17]([N:19]4[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]4)=[O:18])[CH:14]=[CH:13][CH:12]=3)[S:10][C:3]=12.[CH3:26][C:27]1[NH:28][C:29]2[C:34]([CH:35]=1)=[CH:33][C:32]([NH2:36])=[CH:31][CH:30]=2>>[CH3:26][C:27]1[NH:28][C:29]2[C:34]([CH:35]=1)=[CH:33][C:32]([NH:36][C:2]1[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[C:9]([C:11]4[N:16]=[C:15]([C:17]([N:19]5[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]5)=[O:18])[CH:14]=[CH:13][CH:12]=4)[S:10][C:3]=13)=[CH:31][CH:30]=2
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: CN1CCN(C(=O)c2cccc(-c3cc4nccc(Cl)c4s3)n2)CC1
Product: Cc1cc2cc(Nc3ccnc4cc(-c5cccc(C(=O)N6CCN(C)CC6)n5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from [6-(7-chloro-thieno[3,2-b]pyridin-2-yl)-pyridin-2-yl]-(4-methyl-piperazin-1-yl)-methanone and 2-methyl-5-aminoindole by the procedure analogous to example 148(c) above. 1H NMR (400 MHz, CD3OD) δ8.06 (d, 1H), 7.90 (m, 3H), 7.58 (d, 1H), 7.30 (m, 2H), 6.93 (d, 1H), 6.62 (d, 1H), 6.10 (s, 1H), 3.77 (m, 2H), 3.59 (m, 2H), 2.55 (m, 2H), 2.40 (m, 2H), 2.40 (s, 3H), 2.31 (s, 3H); RP18-HPLC RT: 3.92 minutes; API MS: 483 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[CH:7][N:6]=[C:5](O)[C:4]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:2].O(Cl)[Cl:16].[OH-].[Na+]>O>[Cl:16][C:5]1[C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:3]([CH2:1][CH3:2])[N:8]=[CH:7][N:6]=1
Reactant: CCOC(=O)c1c(O)ncnc1CC
Reactant: ClOCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)c1c(Cl)ncnc1CC
Temperature: 90 °C
Reaction time: 3 h
Yield: 43.8 %

Procedure:
Ethyl 6-ethyl-4-hydroxypyrimidine-5-carboxylate (7.30 g, 37.21 mmol) was stirred under ice-cooling. Phophorus oxychloride (11.41 g, 74.41 mmol) was added dropwise to it. After the addition, the mixture was stirred at 90° C. for 3 hours. After cooling to room temperature, the mixture was poured into ice-cooled water and adjusted to pH 10 with an aqueous solution of sodium hydroxide. The resulting mixture was extracted with methylene chloride and dried over magnesium sulfate, and the solvent was evaporated. The residue was purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (=8/2) to give the desired ethyl 4-chloro-6-ethylpyrimidine-5-carboxylate (3.50 g, 44%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:6]([C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)=[CH:5]2.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C[Si]([N-:45][Si](C)(C)C)(C)C.[Li+].C(OCC)(=O)C>O.[OH-].[Na+].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N+:25]([C:22]1[CH:21]=[CH:20][C:19]([C:6]2[N:7]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([NH2:45])=[CH:10][CH:9]=3)=[CH:24][CH:23]=1)([O-:27])=[O:26]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: O=[N+]([O-])c1ccc(-c2cc3cc(Br)ccc3n2CCN2CCCCC2)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ccc2c(c1)cc(-c1ccc([N+](=O)[O-])cc1)n2CCN1CCCCC1
Temperature: 25 °C
Yield: 62.3 %

Procedure:
Compound 16 (0.5 g, 1.167 mmol) and tris(dibenzylideneacetone)dipalladium (0) (53.4 mg, 0.058 mmol) were charged to an argon-purged flask fitted with a magnetic stirbar and condenser. Anhydrous tetrahydrofuran (15 mL) was added and stirring begun. Tri-tert-butylphosphine, 10 wt % in hexanes (0.358 mL, 0.1167 mmol) and lithium bis(trimethylsilyl)amide solution (3.501 mL, 3.501 mmol, 1.0 M in THF) were added and the mixture heated to reflux for 2 hours. The solution was cooled to room temperature overnight, diluted with water (15 mL) and 3M sodium hydroxide solution added to adjust pH to 9. Ethyl acetate added and the mixture was transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were washed with H2O, brine, dried over magnesium sulphate, filtered, concentrated and the crude residue purified twice via chromatography on silica gel (2M NH3 in methanol:CH2Cl2, 2.5:97.5) to afford orange solid 17 (265 mg, 62.4%); 1H NMR (DMSO-d6) δ 8.31 (d, 2H, J=8.9 Hz), 7.89 (d, 2H, J=8.9 Hz), 7.25 (d, 1H, J=8.6 Hz), 6.71 (d, 1H, J=1.9 Hz), 6.63 (dd, 1H, J=2.0, 8.5 Hz), 6.47 (s, 1H), 4.64 (brs, 2H), 4.22 (t, 2H, J=6.6 Hz), 2.43 (t, 2H, J=6.5 Hz), 2.17 (m, 4H), 1.30 (m, 6H); ESI-MS (m/z, %): 365 (M+1, 100%).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:7]([OH:9])=[O:8])[NH2:3].[CH2:14]([O:16][C:17](=[O:26])[C:18]([C:24]#[N:25])=[C:19](OCC)[CH3:20])[CH3:15].C(N(CC)CC)C>C(O)C>[CH2:14]([O:16][C:17]([C:18]1[C:19]([CH3:20])=[N:3][N:2]([C:4]2[CH:5]=[C:6]([C:7]([OH:9])=[O:8])[CH:10]=[CH:11][C:12]=2[CH3:13])[C:24]=1[NH2:25])=[O:26])[CH3:15]
Reactant: Cc1ccc(C(=O)O)cc1NN
Reactant: CCOC(=O)C(C#N)=C(C)OCC
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C)nn(-c2cc(C(=O)O)ccc2C)c1N
Temperature: 65 °C
Yield: 87.9 %

Procedure:
To a stirred solution of 3-hydrazino-4-methylbenzoic acid hydrochloride (Example 3A, 353 mg, 1.74 mmol, 1.0 eq) in 15 mL of ethanol were added 2-cyano-3-ethoxy-but-2-enoic acid ethyl ester (prepared as described by Xia et al., J. Med. Chem., 1997, 40, 4372) (319 mg, 1.746 mmol, 1.0 eq) and triethylamine (242 μL, 1.74 mmol, 1.0 eq) and the mixture was heated at 65° C. overnight. The mixture was cooled to room temperature and concentrated. The crude residue was purified by flash chromatography on silica gel (loaded with CH2Cl2, and packed and eluted with gradient from 6/4 hexanes/EtOAc to elute byproducts followed by 8/2 EtOAc/hexanes and 8/2 EtOAc/MeOH to elute product) to provide the product as a brown solid (464 mg, 68%). HPLC (4 minute 10-95 gradient) tR1.97 min; MS m/z 304.1 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[N:15][NH2:16])[C:4]=2[CH:3]=1>O1CCCC1.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[N+:15]=[N-:16])[C:4]=2[CH:3]=1
Reactant: NN=C1c2ccccc2-c2ccc(Cl)cc21
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: [N-]=[N+]=C1c2ccccc2-c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.9 %

Procedure:
A mixture of (19) (5.3 g, 23.2 mmoL) and activated manganese dioxide (20 g, 232.5 mmoL, 10 eq) in tetrahydrofuran (500 mL) was stirred at room temperature for 18 h. The mixture was then filtered through celite and concentrated to provide 5.3 g (100%) of product (20) as a red solid: mp 102°-108° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:10][CH:9]([C:11]([NH:13][C:14]3[CH:33]=[CH:32][C:17]([O:18][CH:19]4[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]4)=[CH:16][CH:15]=3)=[O:12])[CH2:8]2)[CH:2]=1.FC(F)(F)C(O)=O>ClCCl>[NH:22]1[CH2:23][CH2:24][CH:19]([O:18][C:17]2[CH:16]=[CH:15][C:14]([NH:13][C:11]([CH:9]3[CH2:10][N:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH2:8]3)=[O:12])=[CH:33][CH:32]=2)[CH2:20][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC(=O)C3CN(c4cccnc4)C3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(OC2CCNCC2)cc1)C1CN(c2cccnc2)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
tert-Butyl 4-(4-(1-(pyridin-3-yl)azetidine-3-carboxamido)phenoxy)piperidine-1-carboxylate (3.82 g, 8.44 mmol) was dissolved in 60 ml dichloromethane, cooled to 0° C. and treated with trifluoroacetic acid (10 ml). The mixture was allowed to warm to room temperature and was stirred for 2 hours. Removal of the solvent under vacuum provided the title compound.