Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[C:5]([NH:10][C:11]2[S:12][C:13]([C:16]#[N:17])=[CH:14][N:15]=2)[CH:4]=1.[Cl-].[CH3:19][NH:20][C:21]([N:23]1[CH2:28][CH2:27][NH2+:26][CH2:25][CH2:24]1)=[O:22].C(N(C(C)C)CC)(C)C>CS(C)=O>[CH3:19][NH:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH2:2][C:3]2[C:8]([CH3:9])=[CH:7][N:6]=[C:5]([NH:10][C:11]3[S:12][C:13]([C:16]#[N:17])=[CH:14][N:15]=3)[CH:4]=2)[CH2:25][CH2:24]1)=[O:22]
Reactant: Cc1cnc(Nc2ncc(C#N)s2)cc1CCl
Reactant: CNC(=O)N1CC[NH2+]CC1
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CNC(=O)N1CCN(Cc2cc(Nc3ncc(C#N)s3)ncc2C)CC1
Reaction time: 3.5 h

Procedure:
2-(4-Chloromethyl-5-methyl-pyridin-2-ylamino)-thiazole-5-carbonitrile (9-9, 0.204 g, 0.771 mmol) and 4-methylcarbamoyl-piperazin-1-ium chloride (4-3, 0.277 g, 1.54 mmol) were dissolved in 2 mL DMSO. Diisopropylethyl amine (0.537 mL, 3.08 mmol) was added and the reaction was stirred for 3.5 hours. The reaction mixture was then directly loaded onto a reverse phase purification system to afford the titled compound, 9-10, as the TFA salt. 1H NMR (CD3OD) δ 8.35 (s, 1H), 8.02 (s, 1H), 7.16 (s, 1H), 4.25 (s, 2H), 3.37 (bs, 4H), 3.24 (bs, 4H), 2.73 (s, 3H), 2.39 (s, 3H). MS [M+H]+=372.1. 4-(tert-Butyl-dimethyl-silanyloxymethyl)-2-chloro-3-methyl-pyridine (10-1)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1Br.[C:13]([Cu])#[N:14].CCOC(C)=O.[OH-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[C:13]#[N:14]
Reactant: N#C[Cu]
Reactant: COC(=O)c1cccc(Cl)c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(Cl)c1C#N
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-bromo-3-chlorobenzoic acid methyl ester (3.86 mmol) in 4 mL DMF was added CuCN (4.24 mmol) and the reaction mixture was heated to 90° C. overnight. After cooling to 10° C., 10 mL EtOAc and 3 mL 1M NaOH solution were added and stirring was continued at RT for 30 min. The aq. phase was separated and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification by preparative LC-MS (method L) gives the desired product as white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N:19]4[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]4)[CH:15]=3)[N:10]=[CH:9]2)[CH:7]=1.[CH:27]1[C:35]2[C:34]3[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=3[O:32][C:31]=2[C:30]([C:40](O)=[O:41])=[CH:29][CH:28]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[CH:27]1[C:35]2[C:34]3[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=3[O:32][C:31]=2[C:30]([C:40]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([N:8]3[C:17](=[O:18])[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([N:19]5[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]5)[CH:15]=4)[N:10]=[CH:9]3)[CH:7]=2)=[O:41])=[CH:29][CH:28]=1
Reactant: O=C(O)c1cccc2c1oc1ccccc12
Reactant: Cc1ccc(N)cc1-n1cnc2ccc(N3CCN(C)CC3)cc2c1=O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2cccc3c2oc2ccccc23)cc1-n1cnc2ccc(N3CCN(C)CC3)cc2c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
A solution of 3-(5-amino-2-methylphenyl)-6-(4-methylpiperazin-1-yl)-3,4-dihydroquinazolin-4-one (0.165 g) in DMF (0.5 ml) was added to a stirred mixture of dibenzofuran-4-carboxylic acid (0.1 g), diisopropyethylamine (0.164 ml), 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(V) (0.214 g) and DMF (0.5 ml) and the reaction mixture was stirred at ambient temperature for 16 hours. The mixture was diluted with water and the resultant solid was isolated, washed in turn with water and diethyl ether and dried under vacuum at 55° C. There was thus obtained the title compound (0.228 g); NMR Spectrum: (DMSOd6) 2.07 (s, 3H), 2,25 (s, 3H), 2.5-3.3 (m, 8H), 7.55 (m, 7H), 7.83 (m, 4H), 8.12 (s, 1H), 8.21 (d, 1H), 8.34 (d, 1H), 10.59 (s, 1H); Mass Spectrum: M+H+ 544.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]2[C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=[CH:10][C:4]=2[CH:3]=1.[Br:14]N1C(=O)CCC1=O>ClCCl.N(C(C)(CC(C)(OC)C)C#N)=NC(C)(CC(OC)(C)C)C#N>[Br:14][CH2:1][C:2]1[O:6][C:5]2[C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=[CH:10][C:4]=2[CH:3]=1
Reactant: Cc1cc2cccc([N+](=O)[O-])c2o1
Reactant: O=C1CCC(=O)N1Br
Agent: COC(C)(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)(C)OC
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc2cc(CBr)oc12
Yield: 85.8 %

Procedure:
A mixture of 2-methyl-7-nitrobenzo[b]furan (2.66 g), N-bromosuccinimide (3.21 g) and 2,2'-azobis-(2,4-dimethyl-4-methoxyvaleronitrile) (270 mg) in dichloromethane (30 ml) was refluxed for 1 hour. The reaction mixture was washed with aqueous saturated sodium bicarbonate and brine, dried over sodium sulfate and concentrated in vacuo. The residue was crystallized from diethyl ether to give 2-bromomethyl-7-nitrobenzo[b]furan (3.3 g).
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([C:8]2([N:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:15](=[O:18])[CH2:16][CH3:17])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:5][N:4]=1)[CH3:2].[CH2:25](Br)[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[Na+].[I-].C([O-])([O-])=O.[Na+].[Na+]>C(#N)C>[C:27]1([CH2:26][CH2:25][N:11]2[CH2:10][CH2:9][C:8]([C:6]3[O:7][C:3]([CH2:1][CH3:2])=[N:4][N:5]=3)([N:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:15](=[O:18])[CH2:16][CH3:17])[CH2:13][CH2:12]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCC(=O)N(c1ccccc1)C1(c2nnc(CC)o2)CCNCC1
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CCC(=O)N(c1ccccc1)C1(c2nnc(CC)o2)CCN(CCc2ccccc2)CC1

Procedure:
A mixture of 4-(ethyl-1,3,4-oxadiazolyl)-4-(N-phenylpropionamido)piperidine (900 mg, 2.74 mmol), phenethyl bromide (507 mg, 2.74 mmol, NaI (490 mg, 3.3 mmol), Na2CO3 (2.0 g) in acetonitrile (50 ml) was refluxed for 72 hours. It was filtered and concentrated in vacuo. The residue was treated with CH2Cl2 (100 ml) and filtered again. The filtrate was concentrated in vacuo and the resulting residue was chromatographed (SiO2, EtOAc/Hex 1:1) to give the product (904 mg, 2.1 mmol) as a colorless oil: IR (neat) 1660 cm-1 ; NMR (60 MHz, CDCl3) δ 0.87 (t, 3H, CH3CH2CON), 1.37 (t, 3H, oxadiazolyl CH3), 1.60-3.15 (m, 16H), 7.23 and 7.50 (2bs, 10H, phenyl H's). ##STR33##
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](I)=[CH:9][N:10]=2)[CH:7]=1.[N:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:15]3[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=3)=[CH:9][N:10]=2)[CH:7]=1
Reactant: OB(O)c1ccncc1
Reactant: Brc1ccc2ncc(I)n2c1
Product: Brc1ccc2ncc(-c3ccncc3)n2c1

Procedure:
The title compound, off-white solid (0.27 g, 45%), MS (ISP) m/z=274.4 [(M+H)+], mp 134° C., was prepared in accordance with the general method of intermediate E from commercially available 6-bromo-3-iodoimidazo[1,2-a]pyridine (0.7 g, 2.17 mmol) and commercially available pyridine-4-ylboronic acid (0.27 g, 2.17 mmol).
Reaction SMILES: O.N1CCCC1.C([O:10][C:11](=[O:44])[CH:12]([CH2:31][CH2:32][N:33]1[C:37](=[O:38])[C:36]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:35]2[C:34]1=[O:43])[N:13]([CH3:30])[S:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)(=[O:16])=[O:15])C=C.Cl>O1CCOCC1>[CH3:30][N:13]([S:14]([C:17]1[CH:18]=[CH:19][C:20]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:21][CH:22]=1)(=[O:15])=[O:16])[CH:12]([CH2:31][CH2:32][N:33]1[C:34](=[O:43])[C:35]2=[CH:42][CH:41]=[CH:40][CH:39]=[C:36]2[C:37]1=[O:38])[C:11]([OH:44])=[O:10]
Reactant: C=CCOC(=O)C(CCN1C(=O)c2ccccc2C1=O)N(C)S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: C1CCNC1
Product: CN(C(CCN1C(=O)c2ccccc2C1=O)C(=O)O)S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Yield: 94.8 %

Procedure:
Water (1.75 ml), tetrakis(triphenylphosphine)palldium(0) (8.2 mg. 0.007 mmol) and pyrrolidine (0.45 ml, 5.3 mmol) were successively added to a solution of (±)-N-methyl-N-(4-phenoxybenzenesulfonyl)-2-(2-phthalimidoethyl)glycine allyl ester (1.88 g, 3.5 mmol), the product of (3) above, in dioxane (33 ml) and the mixture was stirred at room temperature for 4 hours. The reaction mixture was acidified with hydrochloric acid (1N) and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crystalline residue was washed with diethyl ether to give the title compound (1.64 g, yield 94%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[S:10][C:11]=2[C:12](=[O:14])[CH3:13])=[CH:4][CH:3]=1.CO[CH:25](OC)[N:26]([CH3:28])[CH3:27]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[S:10][C:11]=2[C:12](=[O:14])/[CH:13]=[CH:25]/[N:26]([CH3:28])[CH3:27])=[CH:21][CH:22]=1
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Product: CN(C)/C=C/C(=O)c1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Yield: 90.5 %

Procedure:
A solution of 1-(4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazol-5-yl)ethanone (370 mg, 1.12 mmol) in 1,1-dimethoxy-N,N-dimethylmethanamine (10.0 mL, 75.3 mmol) was heated to 80 degrees for 6 hours. The reaction was cooled and concentrated in vacuo. The residue was purified by silica gel chromatography (EA/DCM=0/100→100/0) to give 389 mg (90% yield) of the title compound. as a yellow solid. LC/MS (FA) ES+ 384, 386. 1H NMR (300 MHz, CDCl3) δ: 8.70-8.68 (m, 2H), 7.81-7.75 (m, 3H), 7.36-7.33 (m, 2H), 7.26-7.24 (m, 2H), 5.41 (d, 1H, J=12.3 Hz), 4.55 (s, 2H), 3.16 (s, 3H), 2.88 (s, 3H).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[C:12]([NH:17][C:18]2[CH:33]=[CH:32][C:21]([O:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25](C(N)=O)[CH:24]=3)=[C:20]([F:34])[CH:19]=2)=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:35].[NH2:36]C1C=C(OC2C=CC(NC3N=CC=CC=3C(NC3C=CC(F)=CC=3F)=O)=CC=2F)C=CN=1>>[ClH:35].[ClH:35].[NH2:36][C:25]1[CH:24]=[C:23]([O:22][C:21]2[CH:32]=[CH:33][C:18]([NH:17][C:12]3[N:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:9]([NH:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])=[CH:19][C:20]=2[F:34])[CH:28]=[CH:27][N:26]=1
Reactant: Nc1cc(Oc2ccc(Nc3ncccc3C(=O)Nc3ccc(F)cc3F)cc2F)ccn1
Reactant: NC(=O)c1cc(Oc2ccc(Nc3ncccc3C(=O)NCc3ccccc3)cc2F)ccn1
Agent: Cl
Product: Nc1cc(Oc2ccc(Nc3ncccc3C(=O)NCc3ccccc3)cc2F)ccn1
Yield: 69 %

Procedure:
4-(4-(3-(Benzylcarbamoyl)pyridin-2-ylamino)-2-fluorophenoxy)picolinamide (0.068 g, 0.15 mmol) was converted to the title compound (0.051 g, 69%) in a manner similar to the preparation of 2-(4-(2-aminopyridin-4-yloxy)-3-fluorophenylamino)-N-(2,4-difluorophenyl)nicotinamide (Step E of Example 3). 1H NMR (DMSO-d6) δ 11.17 (s, 1H), 9.44 (t, 1H, J=5.7 Hz), 8.10-8.35 (m, 3H), 7.91 (d, 1H, J=7.2 Hz), 7.82 (br s, 2H), 7.15-7.42 (m, 7H), 6.90-6.94 (m, 1H), 6.65 (dd, 1H, J=7.2, 2.5 Hz), 6.12 (d, 1H, J=2.5 Hz), 4.45 (d, 2H, J=5.8 Hz); HRMS(ESI+), 430.1679 (M+H)+ calc, 430.1683 (M+H)+ found.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[NH:5][C:4](=[O:13])[CH:3]=1.[C:14]1([S:20]([CH2:23][CH2:24][CH2:25][CH2:26]Br)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:26][CH2:25][CH2:24][CH2:23][S:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:21])=[O:22])[CH:10]=2)[NH:5][C:4](=[O:13])[CH:3]=1
Reactant: Cc1cc(=O)[nH]c2ccc(O)cc12
Reactant: O=S(=O)(CCCCBr)c1ccccc1
Product: Cc1cc(=O)[nH]c2ccc(OCCCCS(=O)(=O)c3ccccc3)cc12

Procedure:
Prepared analogous to Example 140 from 4-methyl-6-hydroxy-carbostyril (m.p. 326°-330° C.) and 4-phenylsulfonyl-butyl-bromide.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:11])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[H-].[Na+].CO[C:16](=O)[CH:17]([CH2:38][C:39]1[CH:40]=[C:41]2[C:45](=[C:46]([CH3:48])[CH:47]=1)[NH:44][N:43]=[CH:42]2)[CH2:18][C:19](=[O:37])[N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[CH2:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[NH:28][C:27]2=[O:36])[CH2:22][CH2:21]1>O1CCCC1>[CH2:4]([C:3]1[N:11]=[C:16]([CH:17]([CH2:38][C:39]2[CH:40]=[C:41]3[C:45](=[C:46]([CH3:48])[CH:47]=2)[NH:44][N:43]=[CH:42]3)[CH2:18][C:19]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[NH:28][C:27]3=[O:36])[CH2:22][CH2:21]2)=[O:37])[O:1][N:2]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: N=C(Cc1ccccc1)NO
Reactant: COC(=O)C(CC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1)Cc1cc(C)c2[nH]ncc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(CC(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2nc(Cc3ccccc3)no2)cc2cn[nH]c12
Temperature: 65 °C
Yield: 27 %

Procedure:
To a solution of N-hydroxy-2-phenyl-acetamidine (0.27 mmol, 3 equiv, this and the other amidine intermediates of the present invention were prepared as described in J. Med. Chem. 1993, 1529-1538) in anhydrous tetrahydrofuran (4 mL) was added sodium hydride (0.27 mmol, 3 equiv) under nitrogen. The mixture was heated at 65° C. for 30 min before addition of a solution of (±)-2-(7-methyl-1H-indazol-5-ylmethyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butyric acid methyl ester (0.09 mmol, 1 equiv) in tetrahydrofuran (3 mL). The reaction mixture was heated at 65° C. overnight. Tetrahydrofuran was removed in vacuo and the reaction mixture was taken up in methylene chloride, washed with water (3×4 mL), dried over sodium sulfate and concentrated. Flash chromatography on silica gel using methanol/methylene chloride from 0 to 10% gave an impure product. The final product was obtained by preparative HPLC in 27% yield. LC/MS: tR=1.60 min, 590 (MH)+. 1H-NMR (400 MHz, CD3OD) δ 7.92 (1H, s), 6.90-7.25 (10H, m), 6.74 (1H, d, J=8.00 Hz), 4.32-4.57 (2H, m), 4.24-4.29 (2H, m), 3.79-4.06 (5H, m), 2.79-3.31 (5H, m), 2.57 (1H, m), 2.44 (3H, s), 1.50-1.82 (4H, m).
Reaction SMILES: [F:1][C:2]1[C:7]2[NH:8]C(=O)[O:10][C:11](=O)[C:6]=2[CH:5]=[C:4]([I:14])[CH:3]=1.[CH3:15][NH:16][CH3:17]>O1CCCC1>[NH2:8][C:7]1[C:2]([F:1])=[CH:3][C:4]([I:14])=[CH:5][C:6]=1[C:11]([N:16]([CH3:17])[CH3:15])=[O:10]
Reactant: O=c1[nH]c2c(F)cc(I)cc2c(=O)o1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc(I)cc(F)c1N
Temperature: 60 °C
Yield: 67 %

Procedure:
550 mg (1.79 mmol) of 8-fluoro-6-iodo-1H-benzo[d][1,3]oxazine-2,4-dione was combined with 4 mL tetrahydrofuran in a 15 mL-sized sealed tube. To the solution was added 1.79 mL (3.58 mmol) of a 2.0 M dimethylamine solution in tetrahydrofuran. The sealed tube was capped and heated in an oil bath at 60° C. for 48 hours. The solution was concentrated down and then purified by flash chromatography on silica gel. A gradient of ethyl acetate and hexanes was used to afford 368 mg (1.19 mmol, 67% yield) of 2-amino-3-fluoro-5-iodo-N,N-dimethyl-benzamide as a golden oil. 1H NMR (500 MHz, CDCl3) δ 7.29 (dd, 1H), 7.19 (s, 1H), 4.50 (s, br., 2H), 3.03 (s, br., 6H).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[Cl-].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[N:22]([CH3:23])[N:21]=[C:20]([C:24]([F:30])([F:29])[C:25]([F:28])([F:27])[F:26])[C:19]=2[C:31]([F:34])([F:33])[F:32])=[O:17])=[CH:11][C:10]=1[CH2:35][NH3+:36].N1C=CC=CC=1>C1COCC1>[C:1]([NH:36][CH2:35][C:10]1[CH:11]=[C:12]([NH:15][C:16]([C:18]2[N:22]([CH3:23])[N:21]=[C:20]([C:24]([F:29])([F:30])[C:25]([F:28])([F:26])[F:27])[C:19]=2[C:31]([F:32])([F:33])[F:34])=[O:17])[CH:13]=[CH:14][C:9]=1[Cl:8])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)Cl
Reactant: Cn1nc(C(F)(F)C(F)(F)F)c(C(F)(F)F)c1C(=O)Nc1ccc(Cl)c(C[NH3+])c1
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCC(=O)NCc1cc(NC(=O)c2c(C(F)(F)F)c(C(F)(F)C(F)(F)F)nn2C)ccc1Cl
Reaction time: 20 h
Yield: 73.1 %

Procedure:
Butanoyl chloride (24 mg, 0.23 mmol, 1.1 eq.) in THF (1.5 ml) was added to a solution of [2-chloro-5-({[1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazol-5-yl]carbonyl}amino)phenyl]methanaminium chloride (100 mg, 0.21 mmol) and pyridine (34 mg, 0.43 mmol, 2.1 eq.) in THF (3 ml). After 20 h at room temperature, the mixture was concentrated under reduced pressure and purified by column chromatography on silica gel (hexane/ethyl acetate) to give N-{3-[(butyrylamino)methyl]-4-chlorophenyl}-1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide (80 mg, 75%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][C:11]2[S:12][C:13]3[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:5][CH:4]=1)#[N:2]>C(O)(=O)C.[Fe]>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][S:10][C:11]2[S:12][C:13]3[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(CSc2nc3ccc([N+](=O)[O-])cc3s2)cc1
Agent: [Fe]
Solvent: CC(=O)O
Product: N#Cc1ccc(CSc2nc3ccc(N)cc3s2)cc1

Procedure:
A suspension of 1.0 g (3.05 mmol) of 2-[(4-cyanophenyl)methylthio]-6-nitro-benzothiazole is heated to boiling in 60 ml glacial acetic acid until a clear solution is formed. Then 2.0 g (36 mmol) of iron powder is added in two batches and the resulting mixture is refluxed for 5 minutes. It is filtered, and the filtrate is concentrated in vacuo. The crude product is made alkaline by the addition of conc. ammonia and purified by flash chromatography (silica gel, ethyl acetate/petroleum ether=20:80 to 35:65).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[CH:4][C:3]=1[C:10]1[C:19]2[C:14](=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:17][CH:18]=2)[N:13]=[CH:12][C:11]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl.N1C=CC=CC=1.Cl>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:10]1[C:19]2[C:14](=[C:15]([C:20]([F:23])([F:21])[F:22])[CH:16]=[CH:17][CH:18]=2)[N:13]=[CH:12][C:11]=1[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COc1ccc(F)c(-c2c(-c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Agent: Cl
Solvent: c1ccncc1
Product: Oc1ccc(F)c(-c2c(-c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Temperature: 200 °C
Yield: 64.1 %

Procedure:
4-(2-Fluoro-5-methoxyphenyl)-3-phenyl-8-(trifluoromethyl)quinoline (0.230 g, 0.578 mmol) was combined with pyridine-HCl (50 g) and raised to 200° C. in and oil bath for 2 hours. Upon cooling to a solid waxy solid, 2N HCl was added and the solid dissolved, poured into a separatory funnel and extracted with ethyl acetate. The combined organic phases were washed with sat. NaHCO3, water, brine, and dried with magnesium sulfate to afford 0.142 g (65%) of the title compound as a tan solid: mp 85° C.; Calcd. mass for C22H13NF4O 383 found by MS (ES) m/z 393.9.
Reaction SMILES: C([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[N:7][C:6]=1[Cl:12])C.[OH-].[Li+].Cl>O1CCCC1>[Cl:12][C:6]1[N:7]=[CH:8][C:9]([F:11])=[CH:10][C:5]=1[C:4]([OH:13])=[O:3]
Reactant: CCOC(=O)c1cc(F)cnc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cc(F)cnc1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 93.5 %

Procedure:
Ethyl-2-chloro-5-fluoro-nicotinoate (50.4 g, 0.247 mol) (see reference J. Med. Chem., 1993, 36(18), 2676–88) was dissolved in tetrahydrofuran (350 ml) and a 2 M aqueous solution of lithium hydroxide (247 ml, 0.495 mol) added. The reaction mixture was stirred at room temperature for 3 days. The pH of the solution was reduced to pH1 by addition of 6 N hydrochloric acid and then extracted with dichloromethane (3 fold). The combined extracts were dried over anhydrous magnesium sulphate and the solvent removed in vacuo to give a solid which was triturated with diethyl ether and then dried in vacuo to give 2-chloro-5-fluoro nicotinic acid (40.56 g) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ=8.20 (1H, s), 8.62 (1H, s) ppm. LRMS (electrospray): m/z [M+H]+ 174.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][CH2:24]O)[CH:18]=4)=[CH:16][C:9]=23)[C:5]([C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:37])[N:34]([CH3:36])[CH3:35])=[CH:28][CH:27]=2)=[N:4]1)[CH3:2].[CH3:38][CH2:39][N:40](CC)[CH2:41][CH3:42].N1CCCC1>C(Cl)Cl>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][CH2:24][N:40]5[CH2:41][CH2:42][CH2:38][CH2:39]5)[CH:18]=4)=[CH:16][C:9]=23)[C:5]([C:26]2[CH:27]=[CH:28][C:29]([NH:32][C:33](=[O:37])[N:34]([CH3:36])[CH3:35])=[CH:30][CH:31]=2)=[N:4]1)[CH3:2]
Reactant: CCN(CC)CC
Reactant: CCn1cc(-c2ccnc3[nH]c(-c4cccc(CCO)c4)cc23)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Solvent: ClCCl
Solvent: C1CCNC1
Product: CCn1cc(-c2ccnc3[nH]c(-c4cccc(CCN5CCCC5)c4)cc23)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 25 %

Procedure:
To a stirred solution of N′-[4-(1-ethyl-4-{2-[3-(2-hydroxyethyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)phenyl]-N,N-dimethylurea (210 mg, 0.42 mMol) in CH2Cl2 (15 mL) was added at 0° C. Et3N (120 uL, 0.86 mmol) and methanesulfonyl lchloride (40 uL, 0.52 mmol). After stirring for 3 h, pyrrolidine (2 mL, 24 mmol) was added. The reaction was allowed to warm to RT, stirred for 18 h, and evaporated to dryness under vacuum. Purification by Gilson HPLC provided the title compound (25%) as a pale yellow solid. ESMS [M+H]+: 548.4.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]=[O:18])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:19][O:20][C:21]([O:25][Si](C)(C)C)=[C:22]([CH3:24])[CH3:23]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([OH:18])[C:22]([CH3:24])([CH3:23])[C:21]([O:20][CH3:19])=[O:25])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=Cc1ccc2c(cnn2-c2ccc(F)cc2)c1
Reactant: COC(O[Si](C)(C)C)=C(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C(C)(C)C(O)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reaction time: 2 h
Yield: 49.1 %

Procedure:
To solution of 1-(4-fluorophenyl)-1H-indazol-5-carboxaldehyde (1.0 g, 4.16 mmol) and 1-methoxy-2-methyl-1-(trimethylsiloxy)propene (0.85 mL, 4.2 mmol) in 10 mL of dry DCM at 0° C. was added TiCl4 (0.8 mL of 1.0 M DCM solution, 0.8 mmol) The reaction was stirred 2 h and then quenched with aqueous sodium bicarbonate and extracted 2×EtOAc. The organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by SiO2 chromatography eluting with 1:2 EtOAc/hexane to give 700 mg (50% yield) of methyl 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-hydroxy-2,2-dimethylpropanoate. MS found: (M+H)+=343.
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[N:16]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:14]=[CH:13][C:9]=2[C:10](O)=[O:11])=[CH:5][CH:4]=1)#[N:2].[C:28]([O:32][C:33](=[O:39])[NH:34][CH2:35][CH2:36][CH2:37][NH2:38])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33](=[O:39])[NH:34][CH2:35][CH2:36][CH2:37][NH:38][C:10]([C:9]1[C:8]([O:7][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:27][CH:26]=2)=[N:16][C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)=[O:11])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: N#Cc1ccc(Oc2ccc(C(=O)O)c(Oc3ccc(C#N)cc3)n2)cc1
Product: CC(C)(C)OC(=O)NCCCNC(=O)c1ccc(Oc2ccc(C#N)cc2)nc1Oc1ccc(C#N)cc1
Yield: 62.1 %

Procedure:
Following the procedure of Example 5(c) 2,6-bis(4-Cyano phenoxy)-nicotinic acid 0.335 g (0.94 mmol) and (3-amino-propyl)-carbamic acid tert-butyl ester (0.163 g, 0.94 mmol) were used to afford 0.3 g of the required product. Percentage purity (LCMS): 78.7%, (M+1)=513.5+1.