Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:22])[C@H:10]([NH:14]C(=O)OC(C)(C)C)[CH2:11][O:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([NH-])C1C=CC=CC=1.Cl>ClCCl>[NH2:14][C@H:10]([CH2:11][O:12][CH3:13])[C:9]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:22]
Reactant: COC[C@@H](NC(=O)OC(C)(C)C)C(=O)NCc1ccccc1
Agent: Cl
Agent: [NH-]Cc1ccccc1
Solvent: ClCCl
Product: COC[C@@H](N)C(=O)NCc1ccccc1
Temperature: 25 °C
Yield: 88.6 %

Procedure:
To a cold solution (5° C.) of 3.36 g of Intermediate 5, benzylamide in 40 mL of dichloromethane was added 6.02 mL of 36% HCl. The reaction mixture was stirred at room temperature until no starting material was observed by TLC. The organic phase was washed with 1N HCl (2×30 mL) and the combined aqueous phase basified to 10-12 with 25% NaOH. After saturating the aqueous phase with sodium chloride, it was extracted with dichloromethane (3×30 mL). The organic phase was dried and concentrated under vacuum yielding 2.01 g of a pale yellow oil.
Reaction SMILES: C([O:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[C:10]([Br:15])[C:11]2=[O:14])=[CH:7][CH:6]=1)(=O)C.C(OC1C=C2C(C(C3C=CC=CC=3)=C(Br)C2=O)=CC=1)(=O)C>>[Br:15][C:10]1[C:11](=[O:14])[C:12]2[C:8]([C:9]=1[C:16]1[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=1)=[CH:7][CH:6]=[C:5]([OH:4])[CH:13]=2
Reactant: CC(=O)Oc1ccc2c(c1)C(=O)C(Br)=C2c1ccc(C(F)(F)F)cc1
Agent: CC(=O)Oc1ccc2c(c1)C(=O)C(Br)=C2c1ccccc1
Product: O=C1C(Br)=C(c2ccc(C(F)(F)F)cc2)c2ccc(O)cc21
Reaction time: 7 h
Yield: 67 %

Procedure:
The procedure of Step 5 of Example 1 was repeated except for using 2-bromo-3-(4-(trifluoromethyl)phenyl)-1-oxo-1H-inden-6-yl acetate obtained in Step 4 as a starting material instead of 2-bromo-1-oxo-3-phenyl-1H-inden-6-yl acetate and being stirred for 7 h to obtain the title compound (67%).
Reaction SMILES: [NH2:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][CH:17]([CH2:22][S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:18][C:19]([OH:21])=[O:20])=[O:15])=[CH:6][CH:5]=1.[CH2:32](O)[CH3:33].Cl>O1CCOCC1>[NH2:1][N:2]=[CH:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][CH:17]([CH2:22][S:23]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)(=[O:24])=[O:25])[CH2:18][C:19]([O:21][CH2:32][CH3:33])=[O:20])=[O:15])=[CH:8][CH:9]=1
Reactant: CCO
Reactant: NN=Cc1ccc(CCCCC(=O)NC(CC(=O)O)CS(=O)(=O)c2ccccc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)CC(CS(=O)(=O)c1ccccc1)NC(=O)CCCCc1ccc(C=NN)cc1
Reaction time: 2 h

Procedure:
(±)-3-[[5-[4-(Aminoiminomethyl)phenyl]-1-oxopentyl]amino]-4-(phenylsulfonyl)butanoic acid (2.5 g) was added to dry ethanol (50 ml) and 4N HCl in dioxane (10 ml) . This mixture was left to stir for 2 h. After complete reaction the solvent was removed under reduced pressure and the oily mass was purified by reverse phase chromatography (water/acetonitrile) and lyophilized to give 1.6 g of the title compound as a white solid: 1H NMR (d6 -DMSO) δ1.15 (t, 3H, J=7.5 Hz), 1.48 (m, 2H), 1.56 (m, 2H), 1.75 (m, 2H), 2.10 (m, 2H), 2.41 (m, 2H), 2.68 (m, 2H), 3.9 (m, 1H), 4.0 (q, 2H, J=7.5 Hz), 4.02 (m, 2H), 7.35 (m, 9H), 7.7 (bd, 1H, J=7.9 Hz), 9.05 (bs, 2H), 9.3 (bs, 2H)MS (FAB) m/e 474.1 (M+H+)
Reaction SMILES: [NH3:1].[F:2][C:3]([F:15])([F:14])[C:4]1[CH:5]=[C:6](F)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11]>O>[N+:10]([C:9]1[CH:8]=[CH:7][C:6]([NH2:1])=[CH:5][C:4]=1[C:3]([F:15])([F:14])[F:2])([O-:12])=[O:11]
Reactant: N
Reactant: O=[N+]([O-])c1ccc(F)cc1C(F)(F)F
Solvent: O
Product: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1

Procedure:
A solution of ammonia in water (100 cm3, s.g. 0.88) was added to 3-trifluoromethyl-4-nitrofluorobenzene (5 g) and the mixture was heated in a bomb at 150° for 2 hours. Solvent was removed in vacuo to yield a yellow solid. Recrystallization of this solid from hexane/ethyl acetate afforded yellow crystals of 4-nitro-3-trifluoromethylaniline, m.p. 134°, (3.5 g).
Reaction SMILES: C([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH3:27])(=[N:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:20])[CH:14]=2)=[CH:5][C:4]=1[N:28]=[CH:29][N:30](C)[CH3:31])#N.[CH:33]1([NH2:37])[CH2:36][CH2:35][CH2:34]1.CCCCCC.ClCCl.CO>CO>[CH:33]1([NH:37][C:31]2[C:3]3[C:4](=[CH:5][C:6]([O:11][CH2:12][C:13]4[CH:14]=[C:15]([S:19]([CH3:27])(=[N:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:20])[CH:16]=[CH:17][CH:18]=4)=[C:7]([O:9][CH3:10])[CH:8]=3)[N:28]=[CH:29][N:30]=2)[CH2:36][CH2:35][CH2:34]1
Reactant: CCOC(=O)N=S(C)(=O)c1cccc(COc2cc(N=CN(C)C)c(C#N)cc2OC)c1
Reactant: NC1CCC1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CO
Product: CCOC(=O)N=S(C)(=O)c1cccc(COc2cc3ncnc(NC4CCC4)c3cc2OC)c1
Yield: 74 %

Procedure:
According to GWP 5, the reaction of N′-(2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonimidoyl]benzyloxy}-4-methoxyphenyl)-N,N-dimethylformimidamide (72 mg, 0.16 mmol) with cyclobutylamine (16 μL, 0.19 mmol) and chromatographic purification (silica gel, amino column, hexane, dichloromethane/methanol: 0→5% methanol) gives the desired product in 74% yield (56 mg).
Reaction SMILES: C(Cl)CCl.[C:5]([C:8]1[CH:9]=[CH:10][C:11]2[NH:17][CH:16]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:15](=[O:23])[N:14]([CH:24]([CH3:26])[CH3:25])[CH2:13][C:12]=2[CH:27]=1)([OH:7])=O.Cl.Cl.[NH2:30][CH2:31][C:32]1[NH:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1.C1C=CC2N(O)N=NC=2C=1.O.C(N(C(C)C)CC)(C)C>CN(C=O)C.CO.CCOC(C)=O>[CH:24]([N:14]1[CH2:13][C:12]2[CH:27]=[C:8]([C:5]([NH:30][CH2:31][C:32]3[NH:36][C:35]4[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=4[N:33]=3)=[O:7])[CH:9]=[CH:10][C:11]=2[NH:17][CH:16]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:15]1=[O:23])([CH3:26])[CH3:25]
Reactant: NCc1nc2ccccc2[nH]1
Reactant: COC(=O)CC1Nc2ccc(C(=O)O)cc2CN(C(C)C)C1=O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CC1Nc2ccc(C(=O)NCc3nc4ccccc4[nH]3)cc2CN(C(C)C)C1=O
Reaction time: 20 h
Yield: 81.6 %

Procedure:
EDC (173 mg, 0.90 mmol) was added to a stirred solution of methyl (±)-7-carboxy-4-isopropyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (240.3 mg, 0.75 mmol), 2-(aminomethyl)benzimidazole dihydrochloride (198 mg, 0.90 mmol), HOBT.H2O (122 mg, 0.90 mmol), and diisopropylethylamine (0.52 mL, 3.0 mmol) in anhydrous DMF (4 mL) at RT. After 20 h, the reaction was concentrated on the rotavap (high vacuum), and the residue was diluted with H2O (5 mL) to afford a gummy precipitate. EtOAc (3 mL) was added and the mixture was stirred briskly. The precipitate remained gummy, but changed in form so that it was suspended as a mass in the solvents. The solvents were drawn off with a pipet and the residue was suspended in MeOH (3 mL) and EtOAc (6 mL). The mixture was stirred briskly at RT for several min, then was cooled in ice and filtered. The filter pad was washed with EtOAc and dried in high vacuum to leave the title compound (275.1 mg, 82%) as an off-white powder: 1H NMR (250 MHz, 20% CD3OD/CDCl 3) δ 7.45-7.70 (m, 4H), 7.15-7.35 (m, 2H), 6.56 (d, J=9.1 Hz, 1H), 5.22 (d, J=16.9 Hz, 1H), 5.13 (app t, 1H), 4.72-4.92 (m, 1H), 4.72 (s, 2H), 4.03 (d, J=16.9 Hz, 1H), 3.74 (s, 3H), 3.00 (d, J=16.4, 7.7 Hz, 1H), 2.67 (dd, J=16.4, 6.0 Hz, 1H), 1.21 (d, J=6.7 Hz, 3H), 1.03 (d, J=6.8 Hz, 3H); MS (ES) 450.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[C:29]([NH2:34])[CH:28]=[CH:27]2.CCN(CC)CC.[CH2:42]([N:44]=[C:45]=[O:46])[CH3:43]>CN(C=O)C>[CH2:42]([NH:44][C:45]([NH:34][C:29]1[CH:28]=[CH:27][C:26]2[C:31](=[CH:32][CH:33]=[C:24]([O:23][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][CH2:16][N:17]5[CH2:22][CH2:21][O:20][CH2:19][CH2:18]5)=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)[CH:25]=2)[CH:30]=1)=[O:46])[CH3:43]
Reactant: COc1cc2c(Oc3ccc4cc(N)ccc4c3)ccnc2cc1OCCCN1CCOCC1
Reactant: CCN=C=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1ccc2cc(Oc3ccnc4cc(OCCCN5CCOCC5)c(OC)cc34)ccc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 6-[6-methoxy-7-(3-morpholin-4-ylpropoxy)-4-quinolyloxy]-2-naphthylamine (prepared similar to that described in Example 1, Step c) (46.0 mg, 0.1 mmol) in anhydrous DMF (5 mL, Aldrich) was added Et3N (50.5 mg, 0.5 mmol, Aldrich) and ethyl isocyanate (35.5 mg, 0.5 mmol, Aldrich) at RT. The reaction was stirred at RT for 16 h, then was quenched with saturated aqueous solution of NaHCO3 (20 mL) and extracted with EtOAc (2×30 mL). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (FPNH-25S, Biotage, EtOAc) to give the title compound as white solid. MS (ESI, pos. ion) m/z: 531.3 (M+1); 529.3 (M−1). Calc'd for C30H33N4O5−530.25.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[S:5][C:6]=1[C:7](OCC)=[O:8].[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[CH3:1][C:2]1[N:3]=[C:4]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[S:5][C:6]=1[CH2:7][OH:8]
Reactant: CCOC(=O)c1sc(Oc2ccccc2)nc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(Oc2ccccc2)sc1CO
Temperature: 0 °C
Reaction time: 2 h
Yield: 78.9 %

Procedure:
To a solution of ethyl 4-methyl-2-(phenyloxy)-1,3-thiazole-5-carboxylate (X-2a) (0.18 g, 0.687 mmol) in THF (3 mL) at 0° C. was added a solution of 1M LAH in THF (2.10 mL, 2.10 mmol). The mixture was stirred at 0° C. for 2 h. Water was added (1 mL) followed by a solution of 1M NaOH (1 mL) and water (1 mL). The mixture was filtered through a pad of Celite, and the Celite was washed with EtOAc. The filtrate was concentrated, and the crude material was purified by chromatography (EtOAc/hexanes) to give the title compound as a colorless oil (0.12 g, 80%). 1H NMR (400 MHz, CDCl3) δ 7.40 (t, J=8.0 Hz, 2H), 7.25 (m, 3H), 4.66 (s, 2H), 2.26 (s, 3H).
Reaction SMILES: C([O:8][C:9]1[CH:25]=[CH:24][C:12]([CH2:13][NH:14][C:15]2[C:20](Cl)=[C:19]([CH3:22])[N:18]=[C:17]([CH3:23])[N:16]=2)=[CH:11][C:10]=1[O:26][CH2:27][CH:28]1[CH2:30][CH2:29]1)C1C=CC=CC=1.[H][H]>CO.C(O)(=O)C>[CH:28]1([CH2:27][O:26][C:10]2[CH:11]=[C:12]([CH2:13][NH:14][C:15]3[CH:20]=[C:19]([CH3:22])[N:18]=[C:17]([CH3:23])[N:16]=3)[CH:24]=[CH:25][C:9]=2[OH:8])[CH2:30][CH2:29]1
Reactant: [H][H]
Reactant: Cc1nc(C)c(Cl)c(NCc2ccc(OCc3ccccc3)c(OCC3CC3)c2)n1
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(NCc2ccc(O)c(OCC3CC3)c2)nc(C)n1

Procedure:
A solution of 2.0 g (4.7 mmol) of (4-benzyloxy-3-cyclopropylmethoxybenzyl)(5-chloro-2,6-dimethyl-pyrimidin-4-yl)amine (from example A5) in 50 ml of methanol and 20 ml of glacial acetic acid is admixed with 250 mg of Pd-on-carbon catalyst (type 38H, Johnson Matthey) and hydrogenated by circulation with hydrogen until about 2 equivalents of hydrogen (about 350 ml) have been taken up. After filtration to remove the catalyst, the solution is concentrated and the residue is chromatographed on silica gel (mobile phase: toluene/dioxane/ammonia=2:1:0.05). The fractions with Rf=0.15 are collected and concentrated. The residue (1.5 g), which is of poor solubility, is reacted further without additional purification (see example 7).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)=[CH:5][N:4]=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:8]([NH:9][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:7][C:6]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)=[CH:5][N:4]=1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1N
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
2-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine (940 mg, 3.76 mol) was dissolved in 20 mL pyridine. The mixture was submitted to three vacuum-argon cycles and was cooled at 0° C. with an ice bath. Methanesulfonyl chloride (600 μl, 7.75 mol) was added dropwise and the reaction mixture was stirred overnight. The solvent was concentrated and the residue was partitioned between dichloromethane and a saturated sodium bicarbonate solution. The organic phase was dried over sodium sulphate and evaporated under reduced pressure. The semi-solid was crystallized with diethyl ether and isopropyl ether to obtain a solid that was filtered and dried in the oven to give 720 mg (58% yield) of the final compound as a mixture of boronic acid and boronate. Purity 100%.
Reaction SMILES: [CH3:1][C:2]1[CH:28]=[CH:27][C:5]([NH:6][C:7]2[CH:15]=[C:14]([C:16]([OH:18])=O)[C:13]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)=[CH:12][C:8]=2[C:9](O)=[O:10])=[CH:4][CH:3]=1>CO>[CH3:1][C:2]1[CH:28]=[CH:27][C:5]2[NH:6][C:7]3[C:8]([C:9](=[O:10])[C:4]=2[CH:3]=1)=[CH:12][C:13]1[NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=2[C:16](=[O:18])[C:14]=1[CH:15]=3
Reactant: Cc1ccc(Nc2cc(C(=O)O)c(Nc3ccc(C)cc3)cc2C(=O)O)cc1
Solvent: CO
Product: Cc1ccc2[nH]c3cc4c(=O)c5cc(C)ccc5[nH]c4cc3c(=O)c2c1
Temperature: 85 °C
Yield: 95 %

Procedure:
Example 5 was repeated using 25 g per minute of 2,5-di(4-methylanilino)terephthalic acid and 51 g per minute of polyphosphoric acid at a processor temperature of 160° C., followed by drowning with 100 g per minute of methanol (initial temperature of 25° C.) heated to 85° C. 2,9-Dimethylquinacridone was obtained in greater than 95% yield.
Reaction SMILES: [OH-].[Na+].[C:3]([C:5]1[C:10]2[N:11]=[C:12]([NH:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])[O:13][C:9]=2[C:8]([N:23]2[CH2:27][CH2:26][C@H:25]([N:28]([CH3:30])[CH3:29])[CH2:24]2)=[C:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:6]=1[CH3:37])#[N:4].Cl>C(O)C>[C:3]([C:5]1[C:10]2[N:11]=[C:12]([NH:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])[O:13][C:9]=2[C:8]([N:23]2[CH2:27][CH2:26][C@H:25]([N:28]([CH3:29])[CH3:30])[CH2:24]2)=[C:7]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:6]=1[CH3:37])#[N:4]
Reactant: CCOC(=O)CCCNc1nc2c(C#N)c(C)c(-c3ccccc3)c(N3CC[C@H](N(C)C)C3)c2o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(NCCCC(=O)O)nc2c1C#N
Temperature: 25 °C
Reaction time: 15 h
Yield: 68.8 %

Procedure:
With cooling with ice, aqueous 1 N sodium hydroxide solution (536 μl, 0.536 mmol) was added to an ethanol (3.5 ml) solution of ethyl 4-({4-cyano-7-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-5-methyl-6-phenyl-1,3-benzoxazol-2-yl}amino)butanoate (I-281) (170 mg, 0.357 mmol), followed by stirring at room temperature for 15 hours. With cooling with ice, aqueous 1 N hydrochloric acid solution (536 μl, 0.536 mmol) was added to the reaction liquid, followed by concentration under reduced pressure. The resulting residue was purified by preparative TLC (eluent, chloroform:methanol=5:1, v/v) to obtain the entitled compound (110 mg, 69%) as a pale brown foamy substance.
Reaction SMILES: [OH:1][C:2]([C:4](F)(F)F)=O.OC(C(F)(F)F)=O.OC(C(F)(F)F)=O.[CH3:22][N:23]([CH2:25][C:26]1[CH:27]=[C:28]([C:32]2[NH:61][C:35]3=[N:36][CH:37]=[CH:38][C:39]([C:40]4[C:41]([C:49]5[CH:54]=[CH:53][C:52]([NH:55][C:56](=[O:60])[N:57]([CH3:59])[CH3:58])=[CH:51][CH:50]=5)=[N:42][N:43]([CH2:45][CH2:46][NH:47][CH3:48])[CH:44]=4)=[C:34]3[CH:33]=2)[CH:29]=[CH:30][CH:31]=1)[CH3:24].[OH-].[Na+].CC(OC(C)=O)=O>CO.O>[CH3:58][N:57]([CH3:59])[C:56]([NH:55][C:52]1[CH:51]=[CH:50][C:49]([C:41]2[C:40]([C:39]3[CH:38]=[CH:37][N:36]=[C:35]4[NH:61][C:32]([C:28]5[CH:29]=[CH:30][CH:31]=[C:26]([CH2:25][N:23]([CH3:22])[CH3:24])[CH:27]=5)=[CH:33][C:34]=34)=[CH:44][N:43]([CH2:45][CH2:46][N:47]([CH3:48])[C:2](=[O:1])[CH3:4])[N:42]=2)=[CH:54][CH:53]=1)=[O:60]
Reactant: O=C(O)C(F)(F)F
Reactant: CNCCn1cc(-c2ccnc3[nH]c(-c4cccc(CN(C)C)c4)cc23)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N(C)CCn1cc(-c2ccnc3[nH]c(-c4cccc(CN(C)C)c4)cc23)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Temperature: 25 °C
Yield: 90 %

Procedure:
To N′-(4-{4-(2-{3-[(dimethylamino)methyl]phenyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1-[2-(methylamino)ethyl]-1H-pyrazol-3-yl}phenyl)-N,N-dimethylurea-3TFA (300 mg, 0.34 mMol) in MeOH (10 mL) was added with stirring at RT, aq. 1 N NaOH and Ac2O (40 uL, 0.42 mMol). After stirring for 30 min. the reaction was diluted with water, basified with aq. 1 N NaOH (0.4 mL), extracted with (9:1) CHCl3/iPrOH, dried (Na2SO4), filtered, and evaporated to dryness under vacuum. Trituration with (1:1) Et2O and petroleum ether, filtration and drying under vacuum gave the title compound (177 mg, 90%) as an off-white solid. ESMS [M+H]+: 579.7.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[C:8]1[C:13]([C:14]([O:16]C)=O)=[CH:12][N:11]=[CH:10][CH:9]=1.O1CCC[CH2:19]1>O.[OH-].[Na+]>[CH3:19][C:10]1[N:11]=[CH:12][C:13]([CH2:14][OH:16])=[CH:8][CH:9]=1
Reactant: C1CCOC1
Reactant: COC(=O)c1cnccc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: Cc1ccc(CO)cn1

Procedure:
To a slurry of lithium aluminum hydride (500 mg, 13.2 mmol) in anhydrous tetrahydrofuran (45 mL) at 0° C. under nitrogen was added dropwise a solution of methyl 4-methylnicotinate (15, 1.0 g, 6.6 mmol) in anhydrous tetrahydrofuran (5 mL). After 1.5 h the suspension was diluted with water (1 mL) and 6 N NaOH solution (5 mL). The precipitate was removed by vacuum filtration and the filtrate was dried over Na2SO4, filtered, and the solvent was removed under reduced pressure to provide the title compound as a light yellow oil: 1H NMR (300 MHz) 8.34 (s, 1H), 7.60 (d, J=7.9 Hz, 1H), 7.12 (d, J=7.9 Hz, 1H), 4.65 (s, 2H), 4.18-4.10 (bs, 1H), 2.51 (s, 3H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:11](=[CH:14]/[C:15]2[O:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-])=O)[CH:21]=3)=[CH:18][CH:19]=2)/[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]>[Zn].C(O)(=O)C>[NH2:26][C:22]1[CH:21]=[C:20]([C:17]2[O:16][C:15](/[CH:14]=[C:11](/[C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)\[C:12]#[N:13])=[CH:19][CH:18]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: COc1ccc(/C(C#N)=C/c2ccc(-c3cccc([N+](=O)[O-])c3)o2)cc1OC
Agent: [Zn]
Solvent: CC(=O)O
Product: COc1ccc(/C(C#N)=C/c2ccc(-c3cccc(N)c3)o2)cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 20 %

Procedure:
Acetic acid (300 mL) was added to Compound 21 (1.00 g) to form suspension. Zinc powder (3.47 g) was added to the suspension, followed by stirring at room temperature for 4 hours. The reaction mixture was subjected to filtration by use of a celite pad, and the celite pad was washed with chloroform. The filtrate (acetic acid-chloroform solution) was evaporated to dryness. The residue was purified by silica gel column chromatography (chloroform-methanol), to thereby yield the target product (yield: 184 mg, 24%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=1.C([Li])CCC.[CH3:20][C:21]1([O:24][CH2:23]1)[CH3:22]>O1CCCC1>[Cl:8][C:6]1[CH:5]=[C:4]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:3]=[C:2]([CH2:1][CH2:20][C:21]([CH3:23])([OH:24])[CH3:22])[N:7]=1
Reactant: Cc1nc(Cl)cc(N2CCOCC2)n1
Reactant: CC1(C)CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(O)CCc1nc(Cl)cc(N2CCOCC2)n1
Temperature: -78 °C
Yield: 43.4 %

Procedure:
2-Methyl-4-chloro-6-morpholino-pyrimidine (10.7 g.; 50 mmol) was dissolved in tetrahydrofuran (200 mL). The reaction was chilled to −78° C. under an inert atmosphere. A solution of n-butyllithium in hexanes (25 mL, 2.5M, 62.50 mmol) was added, and the reaction mixture was stirred for thirty minutes. A solution of isobutylene oxide 6.6 mL, 75 mmol) was added, and the reaction was allowed to warm to room temperature while stirring overnight. The solvent was removed under reduced pressure, and the crude material was dissolved in methylene chloride (200 mL) and washed with saturated ammonium chloride (2×50 mL), dried with sodium sulfate, and evaporated to dryness. The compound was purified by column chromatography to give 4-(4-chloro-6-morpholin-4-yl-pyrimidin-2-yl)-2-methyl-butan-2-ol (6.2 g., 21.7 mmol).
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:27])=[C:6]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[C:7]2[N:8]([N:10]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[N:12]=2)[CH:9]=1)(=[O:3])[CH3:2].CO[CH:30](OC)[N:31]([CH3:33])[CH3:32].CCOC(C)=O>C1(C)C=CC=CC=1>[CH3:30][N:31]([CH3:33])[CH:32]=[CH:2][C:1]([C:4]1[C:5]([CH3:27])=[C:6]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[C:7]2[N:8]([N:10]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[N:12]=2)[CH:9]=1)=[O:3]
Reactant: CC(=O)Nc1nc2c(-c3cccc(C(F)(F)F)c3)c(C)c(C(C)=O)cn2n1
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nc2c(-c3cccc(C(F)(F)F)c3)c(C)c(C(=O)C=CN(C)C)cn2n1
Temperature: 100 °C

Procedure:
A suspension of N-[6-acetyl-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-acetamide (Int. 24, 732 mg, 1.947 mmol) and dimethylformamide dimethylacetal (4 mL) in toluene (10 mL) was heated at 100° C. for 2 hrs. The reaction mixture was cooled then EtOAc (50 mL) was added and the resultant precipitate was collected by filtration to afford the title compound as a white solid (508 mg).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:34][CH:35]([C:39]2[CH:44]=[CH:43][C:42]([S:45]([CH3:48])(=[O:47])=[O:46])=[C:41]([C:49]([F:52])([F:51])[F:50])[CH:40]=2)[C:36]([OH:38])=O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:53][C:54]1[S:55][CH:56]=[CH:57][N:58]=1>C(Cl)Cl>[CH:28]1([CH2:34][CH:35]([C:39]2[CH:44]=[CH:43][C:42]([S:45]([CH3:48])(=[O:46])=[O:47])=[C:41]([C:49]([F:51])([F:52])[F:50])[CH:40]=2)[C:36]([NH:53][C:54]2[S:55][CH:56]=[CH:57][N:58]=2)=[O:38])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Nc1nccs1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCCC2)C(=O)O)cc1C(F)(F)F
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCCC2)C(=O)Nc2nccs2)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28.8 %

Procedure:
A solution of triphenylphosphine (279 mg, 1.06 mmol) in methylene chloride (5 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (188.7 mg, 1.06 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with a solution of 3-cyclohexyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionic acid (237 mg, 0.626 mmol) in methylene chloride (4 mL). The clear solution was stirred for 15 min at 0° C. and then allowed to warn to 25° C. where it was stirred for 2 h. The reaction mixture was then treated with 2-aminothiazole (188 mg, 1.88 mmol), and the resulting suspension was stirred for 15 h at 25° C. The reaction mixture was concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (50 mL) and a 1N aqueous hydrochloric acid solution (50 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×30 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 4/1 to 2/1 hexanes/ethyl acetate) afforded 3-cyclohexyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-thiazol-2-yl-propionamide (83 mg, 29%) as an amorphous solid: EI-HRMS m/e calcd for C20H23F3N2O3S2 (M+) 460.1102, found 460.1100.