Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][NH:6][C:7]([C:9]1[CH:10]=[CH:11][C:12]([C:15](O)=[O:16])=[N:13][CH:14]=1)=[O:8].[Cl:22]C1C=C(C=CC=1Cl)CNC(C1SC(C(O)=O)=CC=1)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][NH:6][C:7]([C:9]1[CH:10]=[CH:11][C:12]([C:15]([Cl:22])=[O:16])=[N:13][CH:14]=1)=[O:8]
Reactant: O=C(O)c1ccc(C(=O)NCc2ccc(Cl)c(Cl)c2)s1
Reactant: O=C(NCc1ccc(Cl)c(Cl)c1)c1ccc(C(=O)O)nc1
Product: O=C(NCc1ccc(Cl)c(Cl)c1)c1ccc(C(=O)Cl)nc1

Procedure:
Compound (13(b)) was treated in an analogous manner to compound (12(b)) in Example 12 to give 5(3,4-dichlorobenzylcarbamoyl)pyridine-2-carbonylchloride (13(c)) which was used crude in the next reaction.
Reaction SMILES: [F:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][N:7]=1)([F:5])[CH2:3]I.[N-:13]=[N+:14]=[N-:15].[Na+]>CS(C)=O>[N:13]([CH2:3][C:2]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][N:7]=1)([F:5])[F:1])=[N+:14]=[N-:15]
Reactant: Cc1ccc(C(F)(F)CI)nc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1ccc(C(F)(F)CN=[N+]=[N-])nc1
Temperature: 90 °C
Reaction time: 48 h
Yield: 92.5 %

Procedure:
A solution of 2-(1,1-Difluoro-2-iodo-ethyl)-5-methyl-pyridine (3.8 g, 13.43 mmol), as prepared in the previous step, was dissolved into DMSO (6 mL), treated with NaN3 (1.0 g, 16.12 mmol, 1.2×) and heated to 90° C. After 2 days, the reaction was partitioned between EtOAc (125 mL) and H2O (2×50 mL). The organic phase was dried over Na2SO4 and concentrated to afford the product as a clear oil (2.46 g, 12.42 mmol, 93% crude yield). 1H NMR (300 Hz, CDCl3) δ 8.49 (s, 1H), 7.63 (m, 2H), 4.01 (t, J=13.2 Hz), 2.41 (s, 3H); LC/MS (m/z) [M+1−N2]+ 171.1 (calculated for C8H9F2N2, 171.2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[Cl-].[Li+].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[CH:25]([CH3:28])[CH:26]=[O:27].O>C1COCC1>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[CH:25]([CH3:28])[CH:26]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=1)[OH:27]
Reactant: COc1ccc(Cl)c(C(C)C=O)c1
Reactant: Clc1cc(I)ccn1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Cl)c(C(C)C(O)c2ccnc(Cl)c2)c1
Reaction time: 1.5 h

Procedure:
2-Chloro-4-iodopyridine (1.03 g, CAS Reg. No. 153034-86-7) was dissolved in THF (50 mL) and a solution of isopropylmagnesiumchloride-lithium chloride complex (14% in THF, 3.13 mL) was added at RT over 3 minutes. The mixture was cooled in an ice bath and 2-(2-chloro-5-methoxy-phenyl)-propionaldehyde (710 mg) dissolved in THF (20 mL) was added drop wise over a period of 10 minutes. Stirring was continued for 1.5 hours. The reaction mixture was poured into water, extracted with ethyl acetate and the organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (silica gel, gradient of ethyl acetate in heptane) to give the desired compound as a yellow oil (734 mg). MS (m/e)=312.0 (MH+).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:20]=[CH:19][C:8]2[N:9]=[C:10](SC)[C:11]3[C:12](=[CH:14][S:15][CH:16]=3)[NH:13][C:7]=2[CH:6]=1)(=[O:4])=[O:3].O.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C(O)(=O)C>[CH3:1][S:2]([C:5]1[CH:20]=[CH:19][C:8]2[N:9]=[C:10]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[C:11]3[C:12](=[CH:14][S:15][CH:16]=3)[NH:13][C:7]=2[CH:6]=1)(=[O:3])=[O:4]
Reactant: CSC1=Nc2ccc(S(C)(=O)=O)cc2Nc2cscc21
Reactant: C1CNCCN1
Solvent: O
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc2c(c1)Nc1cscc1C(N1CCNCC1)=N2

Procedure:
A solution of 6-methylsulfonyl-10-(methylthio)-4H-thieno[3,4-b][1,5]benzodiazepine in excess piperazine and glacial acetic acid is heated in a bomb at 150° C. for 2 days. The solution is poured into water and the product is collected.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.CO[C:24](OC)([N:26]([CH3:28])[CH3:27])[CH3:25]>C1(C)C=CC=CC=1>[Br:8][C:6]1[N:7]=[C:2]([N:1]=[C:24]([N:26]([CH3:28])[CH3:27])[CH3:25])[C:3]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]2)=[N:4][CH:5]=1
Reactant: COC(C)(OC)N(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)nc2N)CC1
Solvent: Cc1ccccc1
Product: CC(=Nc1nc(Br)cnc1N1CCN(C(=O)OC(C)(C)C)CC1)N(C)C

Procedure:
A 100 mL round bottom flask was charged with tert-butyl 4-(3-amino-5-bromopyrazin-2-yl)piperazine-1-carboxylate (1.0 g, 2.8 mmol), N,N-dimethylacetamide dimethyl acetal (0.44 g, 3.3 mmol) and toluene (20 mL). The mixture was heated at reflux for 11 h. Work-up: the solvent was evaporated to dryness. The product was used in the next step without further purification.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:10])[CH2:4]/[CH:5]=[CH:6]/[C:7](O)=[O:8].C(Cl)(=O)C([Cl:14])=O>C(#N)C.CN(C=O)C>[ClH:14].[CH3:2][N:3]([CH3:10])[CH2:4]/[CH:5]=[CH:6]/[C:7]([Cl:1])=[O:8]
Reactant: CN(C)C/C=C/C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: CC#N
Solvent: CN(C)C=O
Product: CN(C)C/C=C/C(=O)Cl
Temperature: 60 °C

Procedure:
To (E)-4-(dimethylamino)but-2-enoic acid hydrochloride (110 mg, 0.664 mmol) in acetonitrile (1.5 mL) was added oxalyl dichloride (75.9 mg, 0.598 mmol) followed by one drop of DMF. After heating to 60° C. for 30 minutes, the mixture was cooled to room temperature and concentrated to 0.5 mL total volume. The resulting solution was used without further purification.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:3]1[CH3:15].[H-].[Na+].Cl[C:19]1[N:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=1>C1COCC1.O>[CH3:15][C@H:3]1[C@H:2]([O:1][C:19]2[N:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=2)[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: C[C@H]1[C@H](O)CCCN1C(=O)OC(C)(C)C
Reactant: FC(F)(F)c1cnc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H]1[C@H](Oc2ncc(C(F)(F)F)cn2)CCCN1C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 72.3 %

Procedure:
To (2S,3R)-tert-butyl 3-hydroxy-2-methylpiperidine-1-carboxylate (670 mg, prepared according to J. Org. Chem. 2008, 73, 2898) in THF (15 mL) at 0° C. was added NaH (60 wt %, 188 mg). After 15 min, 2-chloro-5-(trifluoromethyl)pyrimidine (570 mg) was added and the reaction allowed to proceed at rt overnight. The reaction was diluted with H2O and extracted with DCM. The organic layers were dried (MgSO4). Purification via silica gel chromatography (0-40% EtOAc in heptane) gave the title compound (813 mg, 72%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)=[O:4].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:38][CH2:39][C:40]1[CH:41]=[CH:42][C:43]([F:54])=[C:44]([C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([CH2:52][OH:53])[CH:47]=2)[CH:45]=1.C(N(CC)CC)C>C(Cl)Cl>[F:54][C:43]1[C:44]([C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([CH2:52][OH:53])[CH:47]=2)=[CH:45][C:40]([CH2:39][NH:38][C:8]([C:7]2[CH:6]=[C:5]([CH:13]=[CH:12][CH:11]=2)[C:3]([O:2][CH3:1])=[O:4])=[O:10])=[CH:41][CH:42]=1
Reactant: NCc1ccc(F)c(-c2cccc(CO)c2)c1
Reactant: COC(=O)c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CO)c3)c2)c1
Reaction time: 8 h

Procedure:
To 3-[(methyloxy)carbonyl]benzoic acid (0.18 g, 1 mmol) in CH2Cl2 (25 mL) was added HBTU (0.379 g, 1 mmol), followed by [5′-(aminomethyl)-2′-fluoro-3-biphenylyl]methanol (0.231 g, 1 mmol), and triethylamine (0.278 mL, 2 mmol). The mixture was stirred under argon overnight. The reaction mixture was then concentrated to dryness, and taken up in EtOAc and H2O. The organic phase was washed 2× with H2O, 1× with brine, dried and concentrated. The residue was absorbed on Isolute® Sorbent, and CombiFlashed on a 12 g column eluted with 0-100% EtOAc/hexane to afford the title compound as a white solid. LC-MS m/z 393.8 (M+H)+, 1.98 min (ret time); analytical HPLC shows 97.2% purity, (ret time 7.205 min).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13](/[CH:14]=[C:15]4/[C:16](=[O:21])[NH:17][C:18](=[O:20])[NH:19]/4)=[C:9]3[N:8]=[C:7](S(C)(=O)=O)[N:6]=2)[CH2:3][CH2:2]1.C1(NC2N3N=CC(/C=C4/C(=O)NC(=O)N/4)=C3N=C(S(C)=O)N=2)CC1.[Cl:50][C:51]1[CH:52]=[C:53]([CH:55]=[CH:56][CH:57]=1)[NH2:54].CO>CN1C(=O)CCC1>[Cl:50][C:51]1[CH:52]=[C:53]([NH:54][C:7]2[N:6]=[C:5]([NH:4][CH:1]3[CH2:3][CH2:2]3)[N:10]3[N:11]=[CH:12][C:13](/[CH:14]=[C:15]4/[C:16](=[O:21])[NH:17][C:18](=[O:20])[NH:19]/4)=[C:9]3[N:8]=2)[CH:55]=[CH:56][CH:57]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CS(=O)(=O)c1nc(NC2CC2)n2ncc(/C=C3\NC(=O)NC3=O)c2n1
Agent: CS(=O)c1nc(NC2CC2)n2ncc(/C=C3\NC(=O)NC3=O)c2n1
Solvent: CO
Solvent: CN1CCCC1=O
Product: O=C1NC(=O)/C(=C/c2cnn3c(NC4CC4)nc(Nc4cccc(Cl)c4)nc23)N1
Temperature: 120 °C

Procedure:
A (1:1) mixture of (Z)-5-((4-(cyclopropylamino)-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione and (Z)-5-((4-(cyclopropylamino)-2-(methylsulfinyl)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione (15 mg) was mixed with 3-chloroaniline (0.1 ml) in NMP (0.2 ml) and the mixture heated in a microwave oven at 120° C. for 15 min. Methanol was added and the resulting solid filtered and dried to provide (Z)-5-((2-(3-chlorophenylamino)-4-(cyclopropylamino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione as a solid (7 mg). LCMS (ES): >95% pure, m/z 411 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][CH:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([OH:14])=[CH:9][CH:10]=2)[O:5]1)[CH3:2].S(OC)(O[CH3:19])(=O)=O.[OH-].[Na+].O>CO>[CH2:1]([O:3][CH:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:19])=[CH:9][CH:10]=2)[O:5]1)[CH3:2]
Reactant: CCOC1CCc2ccc(O)cc2O1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOC1CCc2ccc(OC)cc2O1
Reaction time: 1 h
Yield: 94.1 %

Procedure:
The above-obtained 2-ethoxy-7-hydroxychroman (10.9 g) was dissolved in 60 ml of methanol, and 10.6 g of dimethyl sulfate and 13.5 g of a 25% sodium hydroxide aqueous solution were added thereto at room temperature. The mixture was stirred at this temperature for 1 hour. After 30 ml of water was added thereto, the methanol was removed by distillation in vacuo, and the residue was extracted twice with 50 ml of toluene. The toluene layer was washed with water, and the toluene was removed by distillation in vacuo. The resulting residue was purified by distillation to obtain 11.0 g of a desired colorless liquid (yield 94%).
Reaction SMILES: [F:1][C:2]1[C:11]2[CH:12]([CH2:14][NH:15][CH2:16][CH2:17][C@H:18]3[O:22][C:21](=[O:23])[N:20]([C:24]4[CH:25]=[CH:26][C:27]5[O:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=5[CH:34]=4)[CH2:19]3)[CH2:13][N:9]3[C:10]=2[C:5]([CH:6]=[CH:7][C:8]3=[O:35])=[CH:4][CH:3]=1>CO.CC(O)=O.[Pd]>[F:1][C:2]1[C:11]2[CH:12]([CH2:14][NH:15][CH2:16][CH2:17][C@@H:18]3[O:22][C:21](=[O:23])[N:20]([C:24]4[CH:25]=[CH:26][C:27]5[O:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=5[CH:34]=4)[CH2:19]3)[CH2:13][N:9]3[C:10]=2[C:5]([CH2:6][CH2:7][C:8]3=[O:35])=[CH:4][CH:3]=1
Reactant: O=C1COc2ccc(N3C[C@@H](CCNCC4Cn5c(=O)ccc6ccc(F)c4c65)OC3=O)cc2N1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: O=C1COc2ccc(N3C[C@H](CCNCC4CN5C(=O)CCc6ccc(F)c4c65)OC3=O)cc2N1
Yield: 75 %

Procedure:
A solution of the compound of Example 2 (60 mg) in MeOH/AcOH (1:1, 2 mL) was hydrogenated over Pd/C (133 mg) overnight. The catalyst was filtered off and thoroughly washed with MeOH and MeOH/DCM. The filtrate was concentrated under reduced pressure. The residue was taken up in water and 28% aq. NH4OH, filtered, washed with water and TBME and dried under reduced pressure, affording an off-white foam (45 mg; 75% yield).
Reaction SMILES: [NH2:1][C:2]1[N:12]2[C:13]3[N:8]([C:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)=[CH:10][CH2:11]2)[N:7]=[CH:6][C:5]=3[C:4](=[O:24])[N:3]=1.CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.[Cl:41][CH2:42][C:43](Cl)=[O:44].O>O1CCCC1>[Cl:41][CH2:42][C:43]([NH:1][C:2]1[N:12]2[C:13]3[N:8]([C:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)=[CH:10][CH2:11]2)[N:7]=[CH:6][C:5]=3[C:4](=[O:24])[N:3]=1)=[O:44]
Reactant: Nc1nc(=O)c2cnn3c2n1CC=C3c1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)CCl
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: O
Solvent: C1CCOC1
Product: O=C(CCl)Nc1nc(=O)c2cnn3c2n1CC=C3c1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A 500 mg amount of 5-amino-8-[3-(trifuoromethyl)phenyl]-3H,6H-1,4,5a,8a-tetraazaacenaphthylen-3-one (prepared as described in Example 29) was suspended and stirred in 30 ml of dry tetrahydrofuran, then 1 equivalent (0.322 g) of [1,8-bis(dimethylamino)-naphthalene,N,N,N',N'-tetramethyl-1,8-naphthalenediamine] (Proton Sponge® was added followed by 1.1 equivalents (0.187 g) of chloroacetyl chloride. The reaction mixture was heated at reflux for 16 hours, then allowed to cool to room temperature. The mixture was poured into 200 ml of water and the resulting precipitate was collected by filtration to give 423 mg of the product of the example as a brown solid, m.p. 189°-192° C. (dec).
Reaction SMILES: [OH:1][C:2]1[CH:44]=[CH:43][C:5]([CH2:6][NH:7][C:8]2[N:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:11]=[C:10]([NH:20][C:21]3[CH:42]=[CH:41][C:24]([C:25]([NH:27][CH2:28][C:29]([CH3:40])([CH3:39])[CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:26])=[CH:23][N:22]=3)[CH:9]=2)=[CH:4][CH:3]=1.[Cl:45][CH2:46][C:47]([CH2:49]Cl)=[CH2:48].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.CCOC(C)=O>[Cl:45][CH2:46][C:47](=[CH2:48])[CH2:49][O:1][C:2]1[CH:44]=[CH:43][C:5]([CH2:6][NH:7][C:8]2[N:13]=[C:12]([O:14][CH2:15][C:16]([F:17])([F:18])[F:19])[N:11]=[C:10]([NH:20][C:21]3[CH:42]=[CH:41][C:24]([C:25]([NH:27][CH2:28][C:29]([CH3:39])([CH3:40])[CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:26])=[CH:23][N:22]=3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: C=C(CCl)CCl
Reactant: CC(C)(CNC(=O)OC(C)(C)C)CNC(=O)c1ccc(Nc2cc(NCc3ccc(O)cc3)nc(OCC(F)(F)F)n2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: C=C(CCl)COc1ccc(CNc2cc(Nc3ccc(C(=O)NCC(C)(C)CNC(=O)OC(C)(C)C)cn3)nc(OCC(F)(F)F)n2)cc1
Yield: 43.7 %

Procedure:
A suspenssion of tert-butyl (3-(6-((6-((4-hydroxybenzyl)amino)-2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)amino)nicotinamido)-2,2-dimethylpropyl)carbamate (90 mg), 3-chloro-2-(chloromethyl)prop-1-ene (27.2 mg) and K2CO3 (40.1 mg) in acetone (6 mL) was heated to reflux for 16 hours. The mixture was diluted with EtOAc (200 mL), washed with water (30 mL), brine (30 mL), dried over MgSO4 and concentrated. The residue was purified by preparative HPLC to give desired product tert-butyl 3-(6-(6-(4-(2-(chloromethyl)allyloxy)benzylamino)-2-(2,2,2-trifluoroethoxy)pyrimidin-4-ylamino)nicotinamido)-2,2-dimethylpropylcarbamate (45 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:6]([N+:17]([O-])=O)[C:5]=1[CH3:20]>C1COCC1.CO.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:6]([NH2:17])[C:5]=1[CH3:20]
Reactant: COC(=O)c1ccc(NC2CCCCC2)c([N+](=O)[O-])c1C
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(NC2CCCCC2)c(N)c1C
Yield: 78.7 %

Procedure:
4-Cyclohexylamino-2-methyl-3-nitrobenzoic acid methyl ester (150 mg) was dissolved in THF/MeOH (30 mL, 1:2 ratio) and stirred in the presence of H2 (1 atm) and a catalytic amount of Pd(OH)2 (20 mg) at room temperature for 14 h. The reaction mixture was then filtered, evaporated to dryness and purified by flash column chromatography, using 25% EtOAc in hexane with 0.2% NH4OH as the eluent, to give the pure aniline (106 mg).
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][C:6]([NH2:13])=[CH:5][N:4]=1)#[N:2].[C:14](Cl)(Cl)=[S:15]>O>[N:13]([C:6]1[CH:7]=[C:8]([C:9]([F:12])([F:10])[F:11])[C:3]([C:1]#[N:2])=[N:4][CH:5]=1)=[C:14]=[S:15]
Reactant: N#Cc1ncc(N)cc1C(F)(F)F
Reactant: S=C(Cl)Cl
Solvent: O
Product: N#Cc1ncc(N=C=S)cc1C(F)(F)F
Yield: 74 %

Procedure:
A solution of 2-hydroxy-3-(trifluoromethyl)pyridine C in a mixture of N-iodosuccinimide (NIS), acetonitrile, and dimethylformamide (DMF) is heated at 80° C. for 2 hours to produce 2-hydroxy-3-trifluoromethyl-5-(iodo)pyridine I (greater than 80% yield). The 2-hydroxy-3-trifluoromethyl-5-(iodo)pyridine I is then mixed with POCl3 in DMF and heated to 130° C. in a microwave for 20 minutes to produce 2-chloro-3-trifluoromethyl-5-(iodo)pyridine J (yield of 50 to 55%). The 2-chloro-3-trifluoromethyl-5-(iodo)pyridine K is reacted in a solution of pMBnNH2, palladium(II) acetate, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP), triethylamine, and cesium carbonate in toluene to produce 5-((4-methoxyphenyl))methylamino)-2-chloro-3-(trifluoromethyl)pyridine K (yield of 40%). The 5-((4-methoxyphenyl))methylamino)-2-chloro-3-(trifluoromethyl)pyridine K is reacted in a solution of zinc cyanide, tris(dibenzylideneacetone)dipalladium (Pd2(dba)3), and 1,1′-bis(diphenylphosphino)ferrocene (dppf) in DMF to provide 5-(4-methoxybenzylamine)-2-cyano-3-(trifluoromethyl)pyridine K (yield of 92%). The 5-(4-methoxybenzylamine)-2-cyano-3-(trifluoromethyl)pyridine K is reacted in a solution of dichloromethane and trifluoroacetic acid to provide 2-cyano-3-trifluoromethyl-5-(amino)pyridine H (yield greater than 95%). The 2-cyano-3-trifluoromethyl-5-(amino)pyridine H is reacted with thiophosgene in water at 25° C. for 2 hours to provide 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile A (yield of 74% to 95%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:28](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([C@H:14]2[CH2:19][CH2:18][C@H:17]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH2:15]2)[CH3:28])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)cc(N[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)c1C
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CI
Product: COC(=O)c1cc(Br)cc(N(C)[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)c1C
Temperature: 80 °C

Procedure:
To a stirred solution of trans-methyl 5-bromo-3-((4-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-2-methylbenzoate (3 g, 6.81 mmol) in acetonitrile (40 mL), cesium carbonate (4.4 g, 13.62 mmol) and methyl iodide (4.83 g, 34.05 mmol) were added; the resulting reaction mixture was heated at 80° C. for 7 h. Upon completion, the reaction mixture was cooled to room temperature and filtered, the residue was washed with ethyl acetate and filtrate was concentrated to afford desired crude compound which then purified by column chromatography giving the desired compound (1.3 g, 43%).
Reaction SMILES: [N+:1](=[CH2:3])=[N-:2].[CH2:4]([O:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[N:10][C:9]=1[C:14]#[CH:15])[CH3:5].C(O)(=O)C>C(OCC)C>[CH2:4]([O:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[N:10][C:9]=1[C:14]1[CH:15]=[CH:3][NH:1][N:2]=1)[CH3:5]
Reactant: C#Cc1ncccc1C(=O)OCC
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)c1cccnc1-c1cc[nH]n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An excess of diazomethane in diethylether at 0° is added to 3.91 g of 2-ethynylnicotinic acid ethyl ester and the solution allowed to warm to RT and let stand overnight. Acetic acid is added until no further gas evolves and the mixture is extracted with brine, dried over MgSO4, filtered and the solvent removed by evaporation under vacuum to yield the title compound as an oil.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][C:10]=1[CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]1>C(Cl)Cl>[F:8][C:9]1[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][C:10]=1[CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCCC(CCCOCc2cc(Br)ccc2F)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1ccc(Br)cc1COCCCC1CCCNC1
Temperature: 0 °C

Procedure:
In a 100 ml round bottom flask, 1-[2-fluoro-5-bromobenzyloxy]-3-[1-(t-butoxycarbonyl)piperidin-3-yl]propane (0.395 g) was dissolved in methylene chloride (4.2 ml). The solution was cooled to 0° C. and trifluoroacetic acid (0.8 ml) was slowly added dropwise. The resulting mixture was stirred at 0° C. for thirty minutes, followed by stirring at ambient temperature for thirty minutes. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between 1 M potassium carbonate and methylene chloride. The aqueous fraction was back extracted with methylene chloride. The organic fractions were combined, and dried over sodium sulfate. The solvents were removed in vacuo. The desired title intermediate was further purified by liquid chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[C:30]([C:34]([O:36]CC)=[O:35])=[CH:29][CH:28]=[CH:27]4)=[CH:20][CH:19]=2)=[C:14]([CH:39]([CH3:41])[CH3:40])[O:13][N:12]=1.C(O)C.[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[C:30]([C:34]([OH:36])=[O:35])=[CH:29][CH:28]=[CH:27]4)=[CH:22][CH:23]=2)=[C:14]([CH:39]([CH3:41])[CH3:40])[O:13][N:12]=1
Reactant: CCOC(=O)c1cccc2cc(-c3ccc(OCc4c(CCc5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)c1onc(CCc2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3c(C(=O)O)cccc3c2)cc1
Temperature: 100 °C
Yield: 84 %

Procedure:
A solution of ethyl 6-[4-({[3-[2-(2,6-dichlorophenyl)ethyl]-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthalenecarboxylate (0.110 g, 0.187 mmol) in tetrahydrofuran (2 mL) was placed in a microwave reaction tube. Ethanol (1 mL) was added followed by 1 N sodium hydroxide (0.36 mL, 0.36 mmol). The tube was sealed and heated in a microwave reactor to 100° C. for 500 seconds. Additional sodium hydroxide solution (0.2 mL, 0.2 mmol) was added and the solution was heated in a microwave reactor to 100° C. for another 500 seconds. The solution was neutralized and concentrated. The residue was partitioned between water and ethyl acetate. The organic layer was concentrated to yield the title compound as a white solid (0.088 g, 83.8%). 1H NMR (DMSO-d6): δ 13.14 (s, 1H), 8.91 (d, J=9 Hz, 1H), 8.27 (d, J=1 Hz, 1H), 8.20 (d, J=8 Hz, 1H), 7.96 (dd, J=2, 9 Hz, 2H), 7.80 (d, J=9 Hz, 2H), 7.58 (m, 1H), 7.43 (d, J=8 Hz, 2H), 7.26 (m, 1H), 7.15 (d, J=9 Hz, 2H), 4.98 (s, 2H), 3.35 (septet, J=7 Hz, overlapping H2O, 1H), 3.25-3.20 (m, 2H), 2.89-2.85 (m, 2H), 1.25 (d, J=7 Hz, 6H).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]1[N:9]=[N:10][C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=12.C(N(CC)CC)C.[N:31]1([C:37](Cl)=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH3:1][C@H:2]1[N:3]([C:8]2[C:13]3[CH:14]=[N:15][CH:16]=[CH:17][C:12]=3[C:11]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[N:10][N:9]=2)[CH2:4][CH2:5][N:6]([C:37]([N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:38])[CH2:7]1
Reactant: O=C(Cl)N1CCCCC1
Reactant: C[C@@H]1CNCCN1c1nnc(-c2ccccc2)c2ccncc12
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(C(=O)N2CCCCC2)CCN1c1nnc(-c2ccccc2)c2ccncc12

Procedure:
Using methods described in Example 18, and starting with (R)-4-(2-methylpiperazin-1-yl)-1-phenylpyrido[4,3-d]pyridazine 16 (125 mg, 409 μmol, triethylamine (80 μl, 614 μmol), and piperidine-1-carbonyl chloride (67 μl, 532 μmol) afforded (R)-(3-methyl-4-(1-phenylpyrido[4,3-d]pyridazin-4-yl)piperazin-1-yl)(piperidin-1-yl)methanone 38. MS 416.2 (calc'd) 417.3 (M+H, found).