Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:25]=[CH:24][C:12]([C:13]([O:15][CH:16]([CH3:23])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:14])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[OH:8][C:9]1[CH:25]=[CH:24][C:12]([C:13]([O:15][CH:16]([CH3:23])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:14])=[CH:11][CH:10]=1
Reactant: CCCCCCC(C)OC(=O)c1ccc(OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCCCC(C)OC(=O)c1ccc(O)cc1

Procedure:
The compound obtained in (1) above was dissolved in 15 ml of ethanol, and 0.36 g of 10 % palladium-on-carbon was added to the solution to conduct hydrogenation in a hydrogen atmosphere to obtain 1.29 g of the titled compound.
Reaction SMILES: Cl[CH:2]([C:13](=O)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[C:20]([NH2:23])(=[S:22])[CH3:21]>>[CH3:21][C:20]1[S:22][C:2]([CH2:3][C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=2)=[C:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:23]=1
Reactant: CC(N)=S
Reactant: CCCCCC(=O)C(Cl)Cc1ccc([N+](=O)[O-])cc1
Product: CCCCCc1nc(C)sc1Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
An equimolar mixture (19.6 mmol) of 2-chloro-1-(4-nitrophenyl)octan-3-one and thioacetamide is heated at 60° C. for 24 hours. After cooling to room temperature, the reaction mixture is concentrated and taken up in isopropyl ether to give 1.7 g of 2-methyl-5-(4-nitrobenzyl)-4-pentylthiazole, which is a pale yellow solid melting at 57° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:17]([OH:19])=O)[CH:13]([CH2:15][CH3:16])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C:21]1[S:22][CH:23]=[N:24][N:25]=1>>[CH2:1]([O:8][C:9]([NH:11][CH:12]([C:17]([NH:20][C:21]1[S:22][CH:23]=[N:24][N:25]=1)=[O:19])[CH:13]([CH2:15][CH3:16])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nncs1
Reactant: CCC(C)C(NC(=O)OCc1ccccc1)C(=O)O
Product: CCC(C)C(NC(=O)OCc1ccccc1)C(=O)Nc1nncs1
Yield: 56.6 %

Procedure:
26.5 g of N-benzyloxycarbonyl-DL-isoleucine and 10 g of 2-amino-1,3,4-thiadiazole were reacted in the same manner as in Example 3(i) to obtain 19.5 g (yield: 56%) of 2-(N-benzyloxycarbonyl-DL-isoleucylamino)-1,3,4-thiadiazole as white crystals having a melting point of 149° C.
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](OS(C(F)(F)F)(=O)=O)=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.[CH2:25]([OH:28])[C:26]#[CH:27]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:27]#[C:26][CH2:25][OH:28])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: C#CCO
Reactant: O=S(=O)(Oc1ccc2c(ccn2-c2ccc(F)cc2)c1)C(F)(F)F
Product: OCC#Cc1ccc2c(ccn2-c2ccc(F)cc2)c1

Procedure:
In analogy to example 5.2, Trifluoro-methanesulfonic acid 1-(4-fluoro-phenyl)-1H-indol -5-yl ester and propargylalcohol were converted to yield 3-[1-(4-Fluoro-phenyl)-1H-indol -5-yl]-prop-2-yn-1-ol as light brown solid, 85-88° C., MS: 265 (M).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2[OH:20])=[N:6][C:7]=1[CH2:8][CH3:9].[CH:23]1(C2N=C(N[C@@H]3C4C(=CC=CC=4)C[C@@H]3O)C(CC)=NC=2)CC1>>[Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2[OH:20])=[N:6][C:7]=1[CH:8]1[CH2:23][CH2:9]1
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Reactant: CCc1ncc(C2CC2)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Product: CCc1nc(Br)c(C2CC2)nc1N[C@@H]1c2ccccc2C[C@@H]1O

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting (1R,2S)-1-[(6-cyclopropyl-3-ethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.93–1.09, 1.28–1.39, 2.35–2.43, 2.60–2.67, 2.99–3.05, 3.22–3.29, 4.70, 5.04, 5.44–5.49, 7.23–7.32; MS (ESI+) for C18H20BrN3O m/z 374 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:36]=[CH:35][C:5]([C:6]([NH:8][C:9]2[N:13]([C@@H:14]3[CH2:19][CH2:18][C@H:17]([C:20]([O:22]C)=[O:21])[CH2:16][CH2:15]3)[C:12]3[CH:24]=[C:25]([CH2:28][N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)[CH:26]=[CH:27][C:11]=3[N:10]=2)=[O:7])=[CH:4][CH:3]=1.CO.[OH-].[Na+].[ClH:41]>CCOCC>[ClH:41].[F:1][C:2]1[CH:36]=[CH:35][C:5]([C:6]([NH:8][C:9]2[N:13]([C@@H:14]3[CH2:19][CH2:18][C@H:17]([C:20]([OH:22])=[O:21])[CH2:16][CH2:15]3)[C:12]3[CH:24]=[C:25]([CH2:28][N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)[CH:26]=[CH:27][C:11]=3[N:10]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H]1CC[C@@H](n2c(NC(=O)c3ccc(F)cc3)nc3ccc(CN4CCCCC4)cc32)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Product: O=C(Nc1nc2ccc(CN3CCCCC3)cc2n1[C@H]1CC[C@@H](C(=O)O)CC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A round bottom flask under nitrogen atmosphere was charged with cis-methyl 4-(2-(4-fluorobenzamido)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate (0.10 g, 0.203 mmol), MeOH (2.90 mL) and 1N aqueous NaOH (3.05 mL, 3.05 mmol) and stirred at RT overnight. The reaction mixture was adjusted to a pH of approximately 2 by treatment with 6N HCl and was extracted with DCM (3×50 mL). The organic layers were combined, dried over sodium sulfate and concentrated under vacuum to afford an off-white solid. Trituration with ether afforded cis-4-(2-(4-fluorobenzamido)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylic acid hydrochloride as a white solid (0.095 g, 91% yield). MS m/z=479.2 [M+H]. Calc'd for C27H31N4O3: 478.2.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH2:2][CH2:3][CH3:4].[CH3:7][N:8]([CH3:31])[C:9]1(C#N)[CH2:14][CH2:13][CH:12]([CH:15]([O:23][CH:24]([O:26][CH2:27][CH3:28])[CH3:25])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:11][CH2:10]1.O.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([C:9]1([N:8]([CH3:31])[CH3:7])[CH2:14][CH2:13][CH:12]([CH:15]([O:23][CH:24]([O:26][CH2:27][CH3:28])[CH3:25])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:11][CH2:10]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(C)OC(Cc1ccccc1)C1CCC(C#N)(N(C)C)CC1
Reactant: CCCC[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCC1(N(C)C)CCC(C(Cc2ccccc2)OC(C)OCC)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A 2 M solution of n-butylmagnesium chloride in tetrahydrofuran (4.62 ml, 9.25 mmol) was added dropwise to a solution of 1-dimethylamino-4-[1-(1-ethoxy-ethoxy)-2-phenylethyl]cyclohexanecarbonitrile (1.06 g, 3.1 mmol) in tetrahydrofuran (15 ml), while cooling with ice and under an argon atmosphere. The mixture was stirred at room temperature for 48 h and thereafter water and saturated ammonium chloride solution (10 ml of each) were added. The phases were separated and the aqueous phase was extracted with diethyl ether (3×10 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=O)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([CH2:31]P(=O)(OCC)OCC)=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].CC(C)([O-])C.[K+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4](/[CH:10]=[CH:31]/[C:28]2[CH:27]=[CH:26][C:25]([N:22]3[CH2:21][CH2:20][N:19]([C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[CH2:24][CH2:23]3)=[CH:30][CH:29]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(Br)cc1C=O
Reactant: CCOP(=O)(Cc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ncc(Br)cc1/C=C/c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Yield: 82.6 %

Procedure:
To 5-bromo-2-methoxypyridine-3-carbaldehyde (1.5 g, 6.95 mmol) and diethyl (4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)methylphosphonate (2.39 g, 5.79 mmol) in anhydrous THF (50 mL) under nitrogen was added potassium tert-butoxide (1.30 g, 11.6 mmol) at rt over 5 min. After 3 h a further portion of the aldehyde (160 mg, 0.74 mmol) was added. After a further 30 min the reaction was concentrated and the residue purified by column chromatography (30% EtOAc in PE) to give the title compound (2.27 g, 83%) as a yellow oil. 1H NMR (CDCl3) 1.51 (9H, s), 3.24 (4H, t), 3.68 (4H, t), 4.00 (3H, s), 7.02 (2H, d), 7.11 (2H, m), 7.49 (2H, d), 7.89 (1H, s), 8.07 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[CH2:7][C:8](=[O:12])[NH:9][CH:10]=[CH:11][C:5]=2[CH:4]=1>C(O)C.C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[CH2:7][C:8](=[O:12])[NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)NC=C2
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1OC)CC(=O)NCC2
Reaction time: 22 h

Procedure:
At ambient temperature, 35 g (159.6 mmol) of 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one are dissolved in a mixture of 525 mL of ethanol and 175 mL of ethyl acetate. There are then added 7 g (20% by weight) of palladium-on-carbon 10% and hydrogenation is carried out at 65° C. and 3.5 bars for 22 hours. The catalyst is filtered off over Celite; rinsing with a mixture of ethanol/ethyl acetate and evaporation to dryness are carried out to yield the desired product.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[S:18][C:17]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[O:19][C:20]3[CH:32]=[CH:31][C:23]4[C:24]([C:28]([OH:30])=O)=[C:25]([CH3:27])[O:26][C:22]=4[CH:21]=3)[CH:11]=2)=[O:9])[CH2:4]1.C(Cl)(=O)C(Cl)=O.[NH2:39][CH2:40][CH2:41][OH:42]>>[OH:42][CH2:41][CH2:40][NH:39][C:28]([C:24]1[C:23]2[CH:31]=[CH:32][C:20]([O:19][C:16]3[CH:15]=[CH:14][N:13]=[C:12]4[CH:11]=[C:10]([C:8]([N:5]5[CH2:6][CH2:7][CH:3]([O:2][CH3:1])[CH2:4]5)=[O:9])[S:18][C:17]=34)=[CH:21][C:22]=2[O:26][C:25]=1[CH3:27])=[O:30]
Reactant: COC1CCN(C(=O)c2cc3nccc(Oc4ccc5c(C(=O)O)c(C)oc5c4)c3s2)C1
Reactant: NCCO
Agent: O=C(Cl)C(=O)Cl
Product: COC1CCN(C(=O)c2cc3nccc(Oc4ccc5c(C(=O)NCCO)c(C)oc5c4)c3s2)C1

Procedure:
This material was prepared from 6-[2-(3-methoxypyrrolidine-1-carbonyl)-thieno[3,2-b]pyridin-7-yloxy]-2-methyl-benzofuran-3-carboxylic acid 89e by treatment with oxalyl chloride and 2-aminoethanol in a manner as previously described for example 16d. 1H NMR (DMSO-d6) δ 8.57 (1H, d, J=5.6 Hz), 8.06 (1H,s), 8.00 (1H, t, J=5.3 Hz), 7.82 (1H, d, J=8.6 Hz), 7.66 (1H, d, J=2.3 Hz), 7.26 (1H, dd, J=8.3, 2.3 Hz), 6.72 (1H, d, J=5.3 Hz), 4.76(1H, m), 4.10–3.82 (3H, m), 3.67–3.59 (2H, m), 3.55 (2H, t, J=6.1 Hz), 3.37 (2H, t, J=6.1 Hz), 3.27, 3.24 (3H, 2s), 2.63 (3H, s), 2.06 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][C:7]([CH3:13])([CH3:12])[C:6]3[C:14]([C:18]([O:20]CC)=[O:19])=[N:15][N:16]([CH3:17])[C:5]=3[C:4]=2[N:3]=1.[OH-].[K+:24]>C(O)C>[K+:24].[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][C:7]([CH3:13])([CH3:12])[C:6]3[C:14]([C:18]([O-:20])=[O:19])=[N:15][N:16]([CH3:17])[C:5]=3[C:4]=2[N:3]=1
Reactant: CCOC(=O)c1nn(C)c2c1C(C)(C)Cc1cnc(N)nc1-2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cn1nc(C(=O)[O-])c2c1-c1nc(N)ncc1CC2(C)C
Yield: 84 %

Procedure:
A suspension of ethyl 8-amino-1,4,4-trimethyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate (20.00 g, 66.368 mmol) in anhydrous ethanol (250 mL), 1.5M potassium hydroxide in ethanol (150 mL) was added under good stirring and the mixture was heated to reflux for 1.5 hours. After cooling in an ice bath, a solid was formed; that was filtered washing with ethanol, dried at 40° C. under vacuum to yield 17.34 g (yield 84%) of white solid compound.
Reaction SMILES: [C:1]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[CH:9]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C([Li])CCC.C(Br)C[Br:24]>O1CCCC1>[C:1]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[C:9]=1[Br:24])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: COc1cc(NC(=O)C(C)(C)C)ccc1Cl
Reactant: BrCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1c(Cl)ccc(NC(=O)C(C)(C)C)c1Br
Temperature: 0 °C
Reaction time: 3 h
Yield: 5.7 %

Procedure:
To solution of N-pivaloyl-4-chloro-3-methoxyaniline (5.0 g, 21 mmol) in tetrahydrofuran (60 mL) at −60° C. was added n-butyl lithium (2.5M, 44 mmol). The solution was allowed to warm to 0° C. and stir for 3 hours. Ethylene dibromide (9.9 g, 53 mmol) was added and the solution stirred for 18 hours before being quenched with with ammonium chloride (saturated solution, 20 mL) and extracted with ethyl ether (2×50 mL). The combined extracts were washed with brine, dried (sodium sulfate) and concentrated. The residure was purified by chromatography (10% ethyl acetate/hexanes) to give N-pivaloyl-2-bromo-4-chloro-3-methoxyaniline (3.7 g, 1.2 mmol): LC/MS (m/z=320).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]([OH:22])=O)[N:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:23][CH:24]([C:26]1[O:30][N:29]=[C:28]([CH2:31][NH2:32])[CH:27]=1)[CH3:25]>>[CH:24]([C:26]1[O:30][N:29]=[C:28]([CH2:31][NH:32][C:20]([C:10]2[N:11]=[N:12][C:13]([O:14][CH2:15][C:16]([F:19])([F:17])[F:18])=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:9]=2)=[O:22])[CH:27]=1)([CH3:25])[CH3:23]
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nn1
Reactant: CC(C)c1cc(CN)no1
Product: CC(C)c1cc(CNC(=O)c2cc(-c3ccc(Cl)cc3)c(OCC(F)(F)F)nn2)no1

Procedure:
The title compound was synthesized in analogy to Example 41, using 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylic acid (example M) and 5-(1-methylethyl)-3-isoxazolemethanamine (CAS Registry No. 154016-49-6) as starting materials; LC-MS (UV peak area/ESI) 99.1%, 455.2 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][C:8]3[CH:14]=[C:13]([CH:15]([CH3:21])[C:16]([O:18]CC)=[O:17])[CH:12]=[CH:11][C:9]=3[S:10][C:2]=12.[OH-].[Na+]>C(O)C.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][C:8]3[CH:14]=[C:13]([CH:15]([CH3:21])[C:16]([OH:18])=[O:17])[CH:12]=[CH:11][C:9]=3[S:10][C:2]=12
Reactant: CCOC(=O)C(C)c1ccc2c(c1)Cc1cccnc1S2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C(=O)O)c1ccc2c(c1)Cc1cccnc1S2
Yield: 88.3 %

Procedure:
A mixture of 3 g of ethyl 2-(5H-[1]benzothiopyrano[2,3-b]pyridin-7-yl)propionate and 0.48 g of sodium hydroxide is dissolved in a mixture of 25 ml of ethanol and 5 ml of water, and the solution is heated under reflux for 1.5 hours. The ethanol is distilled off under reduced pressure, and water is added to the residue. The mixture is made acid with acetic acid, and the crystalline precipitate is filtered off and recrystallized from aqueous dioxane to give 2.4 g of 2-(5H-[1]benzothiopyrano[2,3-b]pyridin-7-yl)propionic acid melting at 203°-204°C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8](=[N:13][OH:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][CH:7]=1.Br[CH2:16][CH2:17][O:18][CH2:19][CH2:20]Br.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[F:10][C:9]([F:12])([F:11])[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([N:1]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:3]=1)=[N:13][OH:14]
Reactant: BrCCOCCBr
Reactant: Nc1cccc(C(=NO)C(F)(F)F)c1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: ON=C(c1cccc(N2CCOCC2)c1)C(F)(F)F
Yield: 89.3 %

Procedure:
A mixture of 1-(3-aminophenyl)-2,2,2-trifluoroethanone oxime (1.7 g), bromoethyl ether (2.246 g), and i-Pr2NEt (2.57 g) in toluene (20 mL) was refluxed for 4 hours. After cooling, the reaction mixture was quenched with water. The aqueous layer was extracted with dichloromethane, and the combined organic layers were dried over magnesium sulphate, filtered and concentrated in vacuo. The crude product was purified by silica gel flash chromatography (50% ethyl acetate in hexane) to give the title compound as an oil (2.04 g).
Reaction SMILES: [CH:1]1([C:6](Cl)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:9][C:10]1[N:34]=[CH:33][C:13]2[N:14]=[CH:15][N:16]=[C:17]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)=[C:21]([CH3:32])[CH:20]=3)[C:12]=2[CH:11]=1.CCN(CC)CC>C(Cl)Cl>[CH:1]1([C:6]([N:29]2[CH2:28][CH2:27][CH:26]([O:25][C:22]3[CH:23]=[CH:24][C:19]([NH:18][C:17]4[C:12]5[CH:11]=[C:10]([F:9])[N:34]=[CH:33][C:13]=5[N:14]=[CH:15][N:16]=4)=[CH:20][C:21]=3[CH3:32])[CH2:31][CH2:30]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CCCC1
Reactant: Cc1cc(Nc2ncnc3cnc(F)cc23)ccc1OC1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(Nc2ncnc3cnc(F)cc23)ccc1OC1CCN(C(=O)C2CCCC2)CC1
Yield: 69.5 %

Procedure:
Cyclopentane carbonyl chloride (0.187 g, 1.41 mmol) was added to a solution of (6-Fluoro-pyrido[3,4-d]pyrimidin-4-yl)-[3-methyl-4-(piperidin-4-yloxy)-phenyl]-amine (T) (0.50 g, 1.28 mmol) and NEt3 (0.38 g, 3.84 mmol) in CH2Cl2 (15 mL After 1 h the reaction was quenched with water, the layers were separated and the organic layer was washed with 1N NaOH and water, dried over Na2SO4, and concentrated. Purification by flash column chromatography (CH2Cl2/MeOH, 97/3) afforded the title compound as a yellow solid (0.40 g, 70%). LRMS: 450.3 (MH+); 1H NMR (DMSO-d6, 400 MHz): δ 9.90 (s, 1H), δ 8.86 (s, 1H), δ 8.58 (s, 1H), δ 8.19 (s, 1H), δ 7.54-7.56 (m, 2H), δ 7.04 (d, J=9.56 Hz, 1H) δ 4.58-4.61 (m, 1H), δ 3.70-3.72 (m, 2H), δ 3.33-3.44 (m, 2H), δ 2.93-3.008 (m, 1H), δ 2.17 (s, 3H), δ 1.46-1.94 (m, 12H).
Reaction SMILES: [NH2:1][C:2]1([C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([O:23][CH3:24])[CH:17]=3)=[CH:13][CH:14]=2)=[O:7])[CH2:5][CH2:4][CH2:3]1.Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH3:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:12]2[N:11]=[CH:10][C:9]([N:8]3[C:6](=[O:7])[C:2]4([CH2:5][CH2:4][CH2:3]4)[NH:1][C:26]3=[O:28])=[CH:14][CH:13]=2)=[CH:17][C:18]=1[O:23][CH3:24]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc(Oc2ccc(NC(=O)C3(N)CCC3)cn2)ccc1C
Solvent: ClCCl
Product: COc1cc(Oc2ccc(N3C(=O)NC4(CCC4)C3=O)cn2)ccc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 179.5 %

Procedure:
To a solution of 1-amino-N-(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)cyclobutanecarboxamide (Intermediate 102, 60 mg) in dry dichloromethane (2 mL) TEA (0.128 mL, 0.916 mmol) was added. The reaction mixture was cooled in an ice-bath, then a solution of triphosgene (24.47 mg, 0.082 mmol) in dry dichloromethane (0.500 mL) was added dropwise. The mixture was stirred at 0° C. for 30 minutes. The reaction was maintained at 0° C. and quenched with water (10 mL). The mixture was extracted with dichloromethane (3×4 mL). The combined organic layers were dried over sodium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using a 25 g SNAP column and using as eluents cyclohexane/ethylacetate from 100:0 to 50:50. This afforded the title compound (52 mg) as a white solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@H:12]([NH:16][C:17](=[O:30])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([C:28]#[N:29])[CH:19]=2)[CH2:13][CH2:14][OH:15])=[CH:7][CH:6]=1)=O.[NH2:31][C:32]1[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][N:33]=1.C([O-])(O)=O.[Na+]>CC(O)C>[C:28]([C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[O:24][CH:25]([CH3:27])[CH3:26])[C:17]([NH:16][C@@H:12]([CH2:11][C:8]1[CH:7]=[CH:6][C:5]([C:3]2[N:31]=[C:32]3[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][N:33]3[CH:2]=2)=[CH:10][CH:9]=1)[CH2:13][CH2:14][OH:15])=[O:30])#[N:29]
Reactant: Cc1cccnc1N
Reactant: CC(C)Oc1ccc(C(=O)N[C@H](CCO)Cc2ccc(C(=O)CBr)cc2)cc1C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1cccn2cc(-c3ccc(C[C@@H](CCO)NC(=O)c4ccc(OC(C)C)c(C#N)c4)cc3)nc12
Reaction time: 7 h
Yield: 70.3 %

Procedure:
To a solution of N-((1S)-1-{[4-(bromoacetyl)phenyl]methyl}-3-hydroxypropyl)-3-cyano-4-[(1-methylethyl)oxy]benzamide (300 mg, 0.634 mmol) in i-PrOH (6 mL) was added 2-amino-3-picoline (Aldrich, 69 mg, 0.634 mmol) followed by solid NaHCO3 (64 mg, 0.761 mmol). The resultant suspension was heated to 80° C. After 7 h, a majority of the i-PrOH was removed under reduced pressure and the residue was dissolved in 3% MeOH/EtOAc (30 mL) and washed with water (10 mL) and brine (10 mL). The combined aqueous layers were extracted with 3% MeOH/EtOAc (30 mL) and the combined extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (MeCN/H2O with 0.1% TFA) and the clean fractions were adjusted to pH ˜8 with saturated aqueous NaHCO3 and extracted with 3% MeOH/EtOAc (3×30 mL). The extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to give 215 mg (70%) of the title compound as a pale yellow solid. LC/MS (ES) m/e 483.2 (M+H)+.
Reaction SMILES: O=[C:2]([CH3:15])[CH2:3][S:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1.Cl.[F:17][C:18]1[CH:19]=[C:20]([NH:24]N)[CH:21]=[CH:22][CH:23]=1>>[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:19]=1[C:3]([S:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1)=[C:2]([CH3:15])[NH:24]2
Reactant: NNc1cccc(F)c1
Reactant: CC(=O)CSc1cccc(CC(=O)O)c1
Agent: Cl
Product: Cc1[nH]c2cccc(F)c2c1Sc1cccc(CC(=O)O)c1

Procedure:
Prepared according to the procedure described in Example 2, Step 1, using the following starting materials: [3-(2-oxo-propylsulfanyl)-phenyl]-acetic acid and 3-fluorophenylhydrazine hydrochloride.
Reaction SMILES: N[C:2]([C:21]([F:24])([F:23])[F:22])=[C:3]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:4]([C:6]1[CH:11]=[CH:10][C:9]([S:12][CH3:13])=[CH:8][CH:7]=1)=[O:5].Cl.CC[O:28]CC>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH:3]([C:2](=[O:28])[C:21]([F:24])([F:23])[F:22])[C:4]([C:6]2[CH:11]=[CH:10][C:9]([S:12][CH3:13])=[CH:8][CH:7]=2)=[O:5])=[CH:15][CH:16]=1
Reactant: CSc1ccc(C(=O)C(=C(N)C(F)(F)F)c2ccc(F)cc2)cc1
Reactant: CCOCC
Agent: Cl
Product: CSc1ccc(C(=O)C(C(=O)C(F)(F)F)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of 4.0 g of product of step 1, 40 mL of ether, and 40 mL of 6 N hydrochloric acid was stirred at room temperature for 4 days. The ether layer was dried over magnesium sulfate and concentrated in vacuo to give 4.0 g of crude 2-(4-fluorophenyl)-1-[4-(methylthio)phenyl]-4,4,4-trifluoro-1,3-butandione. A mixture of 0.22 g (0.59 mmol)of this product, 0.09 g of phenylhydrazine, and 10 mL of glacial acetic acid was heated at 80 ° C. for 18 hours and poured into water. The insoluble solid was purified by HPLC (10% ethyl acetate-hexane) to give 8 mg of 4-(4-fluorophenyl)-3-[4-(methylthio)phenyl]-1-phenyl-5-(trifluoromethyl)pyrazole and 140 mg of 4-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-1-phenyl-3-(trifluoromethyl)pyrazole.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:12])=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2.O.C(=O)(O)[O-].[Na+].[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[C:19]([NH:1][C:2]1[C:3]([Cl:12])=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2)(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1c(Cl)ccc2ccncc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(=O)Nc1c(Cl)ccc2ccncc12

Procedure:
8-Amino-7-chloroisoquinoline is refluxed in excess acetic anhydride for two hours or until the reaction is complete. The mixture is then poured into water, neutralized with 10% aqueous sodium bicarbonate solution and extracted with chloroform. The chloroform extract is washed with water, dried over sodium sulfate and concentrated to give 8-acetamido-7-chloroisoquinoline.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1[CH:8]=[O:9].[C:10]([OH:13])(=O)[CH3:11]>C1COCC1.O>[CH3:1][C:2]1[C:6]([CH2:5][N:4]2[CH2:11][CH2:10][O:13][CH2:2][CH2:3]2)=[C:5]([CH3:7])[NH:4][C:3]=1[CH:8]=[O:9]
Reactant: CC(=O)O
Reactant: Cc1cc(C)c(C=O)[nH]1
Solvent: C1CCOC1
Solvent: O
Product: Cc1[nH]c(C=O)c(C)c1CN1CCOCC1
Temperature: 92.5 °C
Yield: 36 %

Procedure:
A mixture of 3,5-dimethyl-1H-pyrrole-2-carbaldehyde (1.85 g, 15 mmol), di-morpholine-methane (5 mL, 27 mL) in THF (40 mL), water (15 mL) and acetic acid (4 mL) was heated to reflux (oil bath 90-95° C.) for 6 hours. The reaction was concentrated to a volume of 20 mL, basified with Na2CO3 and extracted with ethyl acetate (3×75 mL). The combined extracts were dried, concentrated and the residue was purified on a silica gel column to give 2 g (36%) of the titled compound as a solid.