Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:39])([F:38])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[C:40]([OH:47])(=[O:46])/[CH:41]=[CH:42]\[C:43]([OH:45])=[O:44]>CC(OC)(C)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:38])([F:39])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[C:40]([O-:47])(=[O:46])/[CH:41]=[CH:42]\[C:43]([O-:45])=[O:44]
Reactant: O=C(O)/C=C\C(=O)O
Agent: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc(C(F)(F)F)c2)cn1
Solvent: COC(C)(C)C
Product: O=C([O-])/C=C\C(=O)[O-]
Temperature: 5 °C
Reaction time: 8 h

Procedure:
Nilotinib base (0.300 g, 0.57 mmol) was dissolved in TFE (2 mL) at 40° C. to obtain a mixture. The mixture was stirred and added to a solution of maleic acid (0.033 g, 0.28 mmol) in TFE (1 mL) at 40° C. The resulting clear solution was stirred for about 4 h at 40° C. and subsequently cooled to 5° C. The mixture was kept at 5° C. overnight and then MTBE (1.5 v/v) was added to the mixture at room temperature leading to precipitation. The precipitate was filtered to give Nilotinib maleate form I.
Reaction SMILES: [Li]CCCC.CC1(C)CCCC(C)(C)N1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20]([OH:22])=[O:21].O=[C:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1>C1COCC1>[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:19]2[C:18]=1[C:27]1([CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1)[O:21][C:20]2=[O:22]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=C(O)c1cccc(Cl)c1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)OC(=O)c1cccc(Cl)c12
Temperature: -20 °C
Reaction time: 1 h
Yield: 12.9 %

Procedure:
2.5 M n-BuLi in hexanes (9.2 mL, 23 mmol) was added To a stirred solution of 2,2,6,6-tetramethylpiperidine (3.2 g, 23 mmol) in anhydrous THF (30 mL) at −20° C. under N2. The mixture was stirred for 1 h. at −20° C. and then cooled to −78° C. 3-Chlorobenzoic acid (1.8 g, 11.5 mmol) in anhydrous THF (20 mL) was slowly added dropwise and the mixture was stirred for 1 h at −78° C. The mixture was treated with tert-butyl 4-oxopiperidine-1-carboxylate (2.29 g, 11.5 mmol) and the resulting solution was warmed to rt and stirred overnight. The mixture was quenched with water and extracted with EtOAc (3×30 mL). The organic layers were combined, washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product, which was Purified by chromatography to give tert-butyl 7-chloro-3-oxo-3H-spiro[isobenzofuran-1,4′-piperidine]-1′-carboxylate (500 mg, 13%). 1H NMR (CD3OD): δ=1.45 (s, 9H), 2.60 (m, 2H), 3.20 (b, 2H), 4.20 (b, 2H), 7.48 (m, 1H), 7.55 (m, 1H), 7.75 (m, 1H).
Reaction SMILES: CN(C=O)C.CS(O[CH2:11][C:12]1[O:16][N:15]=[C:14]([C@@H:17]2[CH2:21][CH2:20][CH2:19][N:18]2[C:22](=[O:37])[C:23]([F:36])([F:35])[C:24]2([OH:34])[CH2:29][C:28]([CH3:31])([CH3:30])[CH2:27][C:26]([CH3:33])([CH3:32])[CH2:25]2)[CH:13]=1)(=O)=O.[N:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[OH:44].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[F:36][C:23]([F:35])([C:24]1([OH:34])[CH2:25][C:26]([CH3:32])([CH3:33])[CH2:27][C:28]([CH3:31])([CH3:30])[CH2:29]1)[C:22]([N:18]1[CH2:19][CH2:20][CH2:21][C@H:17]1[C:14]1[CH:13]=[C:12]([CH2:11][N:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]2=[O:44])[O:16][N:15]=1)=[O:37]
Reactant: Oc1ccccn1
Reactant: CC1(C)CC(C)(C)CC(O)(C(F)(F)C(=O)N2CCC[C@H]2c2cc(COS(C)(=O)=O)on2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: CC1(C)CC(C)(C)CC(O)(C(F)(F)C(=O)N2CCC[C@H]2c2cc(Cn3ccccc3=O)on2)C1
Temperature: 50 °C
Yield: 53.4 %

Procedure:
To a DMF (1.0 mL) solution of the compound (30 mg) obtained in Example 3-(5) and pyridin-2-ol (12 mg), K2CO3 (35 mg) was added and the mixture was stirred at 50° C. for an hour. To the reaction mixture, DMSO (1.0 ml) was added and after filtering off the insoluble matter, the filtrate was purified by reverse-phase preparative HPLC to give Compound 54 (2.0 mg, colorless oil) and Compound 60 (16.0 mg, colorless oil.)
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7].[F:15][C:16]([F:24])([F:23])[CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[C:9]1([S:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:20]2[CH2:21][CH2:22][CH:17]([C:16]([F:24])([F:23])[F:15])[CH2:18][CH2:19]2)(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=S(=O)(CCCCBr)c1ccccc1
Reactant: FC(F)(F)C1CCNCC1
Product: O=S(=O)(CCCCN1CCC(C(F)(F)F)CC1)c1ccccc1

Procedure:
Prepared from (4-bromobutane-1-sulfonyl)benzene and 4-trifluoromethylpiperidine by the method in Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[CH:5]=[O:6].S(=O)(=O)([OH:16])N.[O-]Cl=O.[Na+]>CC#N.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[C:5]([OH:16])=[O:6]
Reactant: NS(=O)(=O)O
Reactant: COc1cc(C=O)cc(Br)c1OC
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC#N
Product: COc1cc(C(=O)O)cc(Br)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
To a stirred solution of 3-bromo-4,5-dimethoxybenzaldehyde (5.0 g, 20.5 mmol, 1 eq.) in CH3CN (192 mL) at room temperature was added a solution of sulfamic acid (2.55 g, 26.3 mmol) in H2O (32 mL) followed by a dropwise addition of a solution of NaClO2 (3.03 g, 26.8 mmol, 1.3 eq.) in H2O (32 mL) over 20 min period. After stirring for 30 min at room temperature, the solvent was removed in vacuo. The residue was dissolved in 1.0 M aqueous HCl (300 mL) and extracted with EtOAc (3×100 mL). The combined organic layer was washed with brine (300 mL), dried over Na2SO4 and concentrated in vacuo to give 3-bromo-4,5-dimethoxybenzoic acid (5.0 g). The product was used without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(O)(=O)C.[Pd]>[CH2:17]([O:16][C:14]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:2]=1)=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=2)=[O:15])[CH3:18]
Reactant: CCOC(=O)c1cnc2cc(OC)ccc2c1Cl
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)c1cnc2cc(OC)ccc2c1
Yield: 88.1 %

Procedure:
4-Chloro-3-ethoxycarbonyl-7-methoxyquinoline (43 g, 162 mmol) was dissolved in acetic acid (250 ml), with 10% palladium on charcoal (1.5 g) and hydrogenated at atmospheric pressure during 8 hours. The catalyst was removed by filtration over a pad of celite and the solvent evaporated. The residue was diluted with water and the pH adjusted to 7–8 with a saturated solution of sodium hydrogen carbonate. The solid was collected by filtration, washed with water and dried under vacuum over phosphorus pentoxide to give 3-ethoxycarbonyl-7-methoxyquinoline (33 g, 88%) as a beige powder.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([OH:21])[C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:22]1[CH:27]=[CH:26][CH2:25][CH2:24][CH2:23]1.C1(C)C(S(O)(=O)=O)=CC=CC=1>ClCCl>[Si:1]([O:8][CH2:9][CH:10]([O:21][CH:23]1[CH2:24][CH2:25][CH2:26][CH2:27][O:22]1)[C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C(O)CO[Si](C)(C)C(C)(C)C)cc1
Reactant: C1=COCCC1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: ClCCl
Product: CC(C)(C)c1ccc(C(CO[Si](C)(C)C(C)(C)C)OC2CCCCO2)cc1
Reaction time: 2 h

Procedure:
1-Tert-butyldimethylsilyloxy-2-hydroxy-2-(4-tert-butylphenyl) ethane (0.5 g, 1.622 mmol) is dissolved in dichloromethane and to it is added dihydropyran (0.163 g,1.94 mmol) and toluenesulfonic acid (33 mg, 0.194 mmol). The reaction is stirred for 2 hours after which the mixture is washed with water and dried. The crude residue obtained after concentration is purified by flash chromatography (silica gel; ethyl acetate/hexanes) to obtain the product.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][CH:11]3[CH:6]([CH2:7][CH2:8][CH2:9][CH2:10]3)[C:5]=2[CH:4]=[CH:3][C:2]=1[O:14][CH2:15][C@H:16]1[O:20][C:19]([NH2:21])=[N:18][CH2:17]1.C1O[C@H]1CCl.[CH:27]1[C:39]2CC3C(CCCC3)[C:31]=2[CH:30]=C[C:28]=1[OH:40].C(OCC)(=O)C#CCC>C(O)C>[CH2:31]([C:39]1[N:18]2[CH2:17][C@@H:16]([CH2:15][O:14][C:2]3[CH:3]=[CH:4][C:5]4[CH:6]5[CH:11]([CH2:10][CH2:9][CH2:8][CH2:7]5)[CH2:12][C:13]=4[CH:1]=3)[O:20][C:19]2=[N:21][C:28](=[O:40])[CH:27]=1)[CH3:30]
Reactant: Oc1ccc2c(c1)CC1CCCCC21
Reactant: NC1=NC[C@@H](COc2ccc3c(c2)CC2CCCCC32)O1
Agent: CCC#CC(=O)OCC
Agent: ClC[C@H]1CO1
Solvent: CCO
Product: CCc1cc(=O)nc2n1C[C@@H](COc1ccc3c(c1)CC1CCCCC31)O2
Temperature: 25 °C

Procedure:
To a solution of (S)-5-(5,6,7,8,8a,9-hexahydro-4bH-fluoren-2-yloxymethyl)-4,5-dihydro-oxazol-2-ylamine (16 mg, 0.055 mmol), prepared in accordance with the procedures in Steps 1 and 2 of Example 1 and starting from R-epichlorohydrin and 5,6,7,8,8a,9-hexahydro-4bH-fluoren-2-ol (prepared by the same procedure as in Step 1 of Example 19), in ethanol (2 mL) was added ethyl 2-pentynoate (4.2 mg, 0.065 mmol). The reaction mixture was heated at reflux for 14 hrs and then cooled to room temperature. The reaction mixture was concentrated and then loaded onto a silica gel column, and eluted with 2-6% methanol/methylene chloride to afford 8 mg of (S)-5-ethyl-2-(5,6,7,8,8a,9-hexahydro-4bH-fluoren-2-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one.
Reaction SMILES: [C:1]12([NH:11][C:12](=[O:26])[C@@H:13]([CH3:25])[NH:14]C(OCC3C=CC=CC=3)=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C([NH-])(C)C>>[C:1]12([NH:11][C:12](=[O:26])[C@@H:13]([CH3:25])[NH2:14])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(=O)NC12CC3CC(CC(C3)C1)C2
Agent: CC(C)[NH-]
Product: C[C@@H](N)C(=O)NC12CC3CC(CC(C3)C1)C2

Procedure:
N-Benzyloxycarbonyl-D-alanine 1-adamantyl amide is hydrogenated by the precedure as described for the isopropyl amide.
Reaction SMILES: [CH2:1]1[C@@H:14]2[C@@:5]([C:15]([OH:17])=[O:16])([C:6]3[C:11]([CH2:12][CH2:13]2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:4][CH:3]=[CH:2]1.[CH3:18]OS(OC)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]1[CH:14]2[C:5]([C:15]([O:17][CH3:18])=[O:16])([C:6]3[C:11]([CH2:12][CH2:13]2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)[C@]12CC=CC[C@H]1CCc1ccccc12
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C12CCCCC1CCc1ccccc12
Reaction time: 8 h
Yield: 100.5 %

Procedure:
A solution of cis-1,9,10,10a-tetrahydro-4a(4H)-phenanthrenecarboxylic acid (25 g, 0.11 mole) and dimethylsulfate (11.4 ml, 0.12 mole) in 75 ml acetone was treated with potassium carbonate (20.7 g, 0.15 mole) and stirred overnight. An additional 5 ml dimethylsulfate was added and the reaction mixture was refluxed for 1 hour. After cooling the potassium carbonate was removed by filtration and the filtrate evaporated to give the title compound (27 g, quantitative).
Reaction SMILES: C[O:2][C:3](=[O:26])[C@@H:4]([N:12]1[CH2:16][C:15]([O:17][C:18]2[CH:19]=[N:20][C:21]([CH3:24])=[CH:22][CH:23]=2)=[CH:14][C:13]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1.O>[CH:6]1([CH2:5][C@H:4]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:19]=[N:20][C:21]([CH3:24])=[CH:22][CH:23]=3)=[CH:14][C:13]2=[O:25])[C:3]([OH:26])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2ccc(C)nc2)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(OC2=CC(=O)N([C@@H](CC3CCCCC3)C(=O)O)C2)cn1
Temperature: 23 °C
Reaction time: 2 h
Yield: 67.5 %

Procedure:
To a stirred solution of (S)-3-cyclohexyl-2-[4-(6-methyl-pyridin-3-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (490 mg, 1.36 mmol) in tetrahydrofuran-water (3:1, 10 mL) was added lithium hydroxide (172 mg, 4.1 mmol). The reaction mixture was stirred at 23° C. for 2 h. After this time, the mixture was concentrated and the reaction mixture was diluted with water. The reaction mixture was acidified with 2N hydrochloric acid, during which time precipitation occurred. The precipitate was removed by filtration, washed with cold water and dried in vacuo to obtain (S)-3-cyclohexyl-2-[4-(6-methyl-pyridin-3-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (316 mg, 67%) as a brown solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][C:9]([OH:11])=O)[CH:2]=1.[CH3:12][C:13]1(C)[O:20]C(=O)[CH2:17][C:15](=O)[O:14]1.CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[O:11]=[C:9]([CH2:8][CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:12][C:13]([O:14][CH2:15][CH3:17])=[O:20]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(O)CCc1cccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CCOC(=O)CC(=O)CCc1cccnc1
Reaction time: 4 h
Yield: 99.4 %

Procedure:
To a mixture of 3-(3-pyridyl)propionic acid (13.6 g, 0.09 mol), Meldrum's acid (13.0 g, 0.09 mol) and dimethylaminopyridine (11 g, 0.09 mol) was added 1,3-dicyclohexylcarbodiimide (18.54 g, 0.09 mol) and DCM (140 ml). The reaction was stirred for 4 h, filtered, concentrated, diluted with 200 ml ethanol and 25 ml 4M HCl/dioxane. The mixture was warmed to reflux 2 h, concentrated, combined with excess sodium carbonate, followed by 50% sodium hydroxide, then triturated with ethyl acetate, filtered, dried (Na2SO4), filtered, then concentrated to give A as an amber oil (19.8 g, 100%). LCMS m/z 222 (MH+)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][CH:13]=[N:14][C:7]=12.C(O[C@@H:19]1[O:31][C@H:30]([CH2:32][O:33]C(=O)C)[C@@H:25]([O:26]C(=O)C)[C@H:20]1[O:21]C(=O)C)(=O)C.ClCC(O)=O>N>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[N:12]([C@@H:19]3[O:31][C@H:30]([CH2:32][OH:33])[C@@H:25]([OH:26])[C@H:20]3[OH:21])[CH:13]=[N:14][C:7]=12
Reactant: c1csc(-c2ccnc3[nH]cnc23)c1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: N
Agent: O=C(O)CCl
Product: OC[C@H]1O[C@@H](n2cnc3c(-c4cccs4)ccnc32)[C@H](O)[C@@H]1O
Temperature: 200 °C
Yield: 29.2 %

Procedure:
A mixture of Compound 4 (80 mg, 0.4 mmol), tetra-O-acetyl-β-D-ribofuranose (130 mg, 0.4 mmol) and chloroacetic acid (2 mg) was heated at 200° C. for 5 minutes. The resulting dark syrup was treated with methanolic ammonia (40 ml) at room temperature for 18 hours. After the solvent was distilled off under reduced pressure, the residue was diluted with 30% aqueous CH3CN, and the product was purified by reversed-phase HPLC to give Compound 11 (39 mg, 29%, 2 steps).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([S:13][CH3:14])[N:5]=[N:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1.CCN(C(C)C)C(C)C.CCOC(C)=O>CN(C=O)C>[CH3:14][S:13][C:4]1[N:5]=[N:6][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:2]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[N:3]=1
Reactant: CCOC(=O)c1nnc(SC)nc1Cl
Reactant: Cc1ccc(N)cc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1nnc(SC)nc1Nc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl 5-chloro-3-(methylthio)-1,2,4-triazine-6-carboxylate (300 mg, 1.29 mmol) was dissolved in 10 mL dry DMF. To it was added p-toluidine (166 mg, 1.55 mmol) and then DIEA (0.45 mL, 2.58 mmol). The mixture was stirred at RT for 1 h. To the mixture were poured 200 mL EtOAc. The mixture was washed with brine twice, dried in MgSO4, and concentrated in vacuo to afford crude ethyl 3-(methylthio)-5-(p-tolylamino)-1,2,4-triazine-6-carboxylate. It was dissolved in 20 mL “7.0 N ammonia in methanol” (Acros, #133710010) and stirred for overnight. Solid slowly crashed out in the reaction flask and a slurry was yielded. The solid was isolated by filtration, washed with hexane and dried in vacuum oven. It was very pure 3-(methylthio)-5-(p-tolylamino)-1,2,4-triazine-6-carboxamide. Yield was 94 mg (26% for 2 steps).
Reaction SMILES: COC1C=CC(C[NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][CH:27]=[CH:28][C:21]=23)=[O:13])=CC=1.[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][C:33]=1[C:40]([F:43])([F:42])[F:41]>>[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][CH:27]=[CH:28][C:21]=23)=[O:13])=[CH:34][C:33]=1[C:40]([F:43])([F:42])[F:41]
Reactant: COc1ccc(CNCCNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)cc1
Reactant: O=Cc1ccc(Cl)c(C(F)(F)F)c1
Product: O=C(NCCNCc1ccc(Cl)c(C(F)(F)F)c1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid [2-(4-methoxy-benzylamino)-ethyl]-amide using 4-chloro-3-(trifluoromethyl)benzaldehyde instead of 4-methoxy benzaldehyde. LCMS (ESI) 494 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.52 (1H, br. s.) 10.28 (1H, s) 7.95-8.09 (2H, m) 7.81 (1H, s) 7.77 (1H, d, J=5.42 Hz) 7.56-7.64 (2H, m) 7.47 (1H, d, J=5.42 Hz) 7.29 (1H, dd, J=3.27, 2.64 Hz) 6.80 (1H, d, J=5.47 Hz) 6.42 (1H, dd, J=3.51, 1.90 Hz) 3.75 (2H, s) 3.34 (2H, d, J=5.95 Hz) 2.62 (2H, t, J=6.56 Hz)
Reaction SMILES: [CH2:1]([C:9]1[CH:25]=[CH:24][C:12]([CH2:13][NH:14][C:15](=[O:23])[NH:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(C1C=CC(NC(=O)NCCC(OCC)=O)=CC=1)CCCCCCC>>[CH2:1]([C:9]1[CH:10]=[CH:11][C:12]([CH2:13][NH:14][C:15](=[O:23])[NH:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:24][CH:25]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1ccc(CNC(=O)NCC(=O)OCC)cc1
Agent: CCCCCCCCc1ccc(NC(=O)NCCC(=O)OCC)cc1
Product: CCCCCCCCc1ccc(CNC(=O)NCC(=O)O)cc1
Yield: 87 %

Procedure:
When the product of Step A was substituted for ethyl 3-(3-(4-octylphenyl)ureido)propanoate in Example 11, Step B, the identical process afforded the title compound in 87% yield, as a colourless solid. 1H-NMR (CDCl3+CD3OD) 7.15 (d, 2H, J=8 Hz); 7.07 (d, 2H, J=8 Hz); 4.63 (CD3OH); 4.26 (s, 2H); 3.86 (s, 2H); 2.52 (t, 2H, J=7.8 Hz); 1.54 (m, 2H); 1.22 (m, 10H); 0.83 (t, 3H, J=7 Hz).
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:9][CH:8]([N:10]([CH:12]([CH3:14])[CH3:13])[CH3:11])[CH2:7][CH2:6][C@@H:5]1[N:15]1[CH2:19][CH2:18][C@H:17]([NH:20]C(=O)OCC2C=CC=CC=2)[C:16]1=[O:31])([CH3:3])[CH3:2]>CO.[OH-].[OH-].[Pd+2]>[NH2:20][C@H:17]1[CH2:18][CH2:19][N:15]([C@H:5]2[CH2:6][CH2:7][CH:8]([N:10]([CH:12]([CH3:13])[CH3:14])[CH3:11])[CH2:9][C@H:4]2[CH:1]([CH3:3])[CH3:2])[C:16]1=[O:31]
Reactant: CC(C)[C@@H]1CC(N(C)C(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)[C@@H]1CC(N(C)C(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Reaction time: 5 h
Yield: 91.8 %

Procedure:
Benzyl (S)-1-((1S,2S,4R/S)-2-isopropyl-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (160 mg) was dissolved in MeOH (6 mL) prior to the addition of 20% Pd(OH)2 (50 mg) in a Parr bottle. The bottle was evacuated and then back-filled with hydrogen; this was repeated three more times. The reaction was stirred under 60 psi of H2 for 5 h and then filtered and concentrated. The resulting residue was dissolved in MeOH (6 mL) prior to the addition of 20% Pd(OH)2 (75 mg) in a Parr bottle. The bottle was evacuated and then back-filled with hydrogen; this was repeated three more times. The reaction was stirred under 50 psi of H2 for 24 h and then filtered and concentrated to provide (S)-3-amino-1-((1S,2S,4R/S)-2-isopropyl-4-(isopropyl(methyl)amino)cyclohexyl)pyrrolidin-2-one (101 mg). MS (ES+)=296.3 (M+H)+.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:10]=[CH:9][S:8][C:7]=1[CH:11]=O.Cl.[NH2:14][OH:15].C(=O)([O-])O.[Na+]>C(O)C.O>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:10]=[CH:9][S:8][C:7]=1[CH:11]=[N:14][OH:15]
Reactant: NO
Reactant: O=Cc1sccc1C1OCCO1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=Cc1sccc1C1OCCO1

Procedure:
3-(1,3-Dioxolan-2-yl)thiophene-2-carbaldehyde (13.1 g, 71.11 mmol), prepared by a method described by Hibino (S. Hibino et al., J. Org. Chem. 1984, 49, 5006), was dissolved in ethanol (80 ml). At room temperature a solution of hydroxylamine hydrochloride (two equivalents) and sodium hydrogencarbonate (one equivalent) in water (130 ml) was added and the resultant mixture stirred at this temperature for two hours. The ethanol was removed under reduced pressure and the aqueous phase extracted with ethyl acetate (3×300 ml). The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation after filtration afforded 3-(1,3-dioxolan-2-yl)thiophene-2-carbaldehyde oxime as an off-white solid (quantitative). 1H NMR (2 isomers, 1:1) (CDCl3): δ 8.56 (1H, s), 8.45 (1H, s), 7.50 (1H, d, J 5.26), 7.25 (1H, d, J 5.2), 7.21 (1H, d, J 5.28), 7.12 (1H, d, J 5.2), 6.09 (1H, s), 5.99 (1H, s), 4.17–4.00 (2H, m).
Reaction SMILES: C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:20]([C:22]1[C:23]([N-:37][CH2:38][CH:39]([CH3:41])[CH3:40])=[C:24]([OH:36])[C:25]([F:35])=[C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:27]=1[CH3:28])#[N:21]>C(OCC)(=O)C>[F:35][C:25]1[C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:27]([CH3:28])[C:22]([C:20]#[N:21])=[C:23]2[C:24]=1[O:36][C:38]([CH:39]([CH3:41])[CH3:40])=[N:37]2
Reactant: Cc1c(C#N)c([N-]CC(C)C)c(O)c(F)c1-c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c(-c2ccccc2)c(F)c2oc(C(C)C)nc2c1C#N

Procedure:
Toluene (10 ml), p-toluenesulfonic acid monohydrate (5.3 mg, 28 μmol) were added to N-(5-cyano-2-fluoro-3-hydroxy-6-methylbiphenyl-4-yl)isobutylamide (I-51) (87 mg, 279 μmol), followed by refluxing with a Dean-Stark condenser for 3.5 hours. During the course, p-toluenesulfonic acid monohydrate (5.3 mg, 28 μmol) was added. Alter cooled, ethyl acetate (50 ml) was added to the reaction liquid, the organic layer was successively washed with saturated sodium bicarbonate water (30 ml), saturated brine (30 ml×2), then dried over anhydrous magnesium sulfate, concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1) to obtain the entitled compound (82 mg, quant.) as a colorless solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[NH:18][C:17](=[O:19])[NH:16][C:12]3=[N:13][C:14]=2[CH3:15])=[CH:5][CH:4]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>>[C:20]([NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[NH:18][C:17](=[O:19])[NH:16][C:12]3=[N:13][C:14]=2[CH3:15])=[CH:5][CH:4]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc2[nH]c(=O)[nH]c2cc1-c1ccc(N)cc1
Agent: Cl
Product: CC(=O)Nc1ccc(-c2cc3[nH]c(=O)[nH]c3nc2C)cc1
Yield: 90 %

Procedure:
[I; Ar 4-CH3CONHC6H4, R1 and R3 =H, R5 =CH3 ]was prepared from 1.73 g 6-(4-aminophenyl)-1,3-dihydro-5-methyl-2H-imidazo[4,5-b]pyridin-2-one hydrochloride and 0.65 ml acetic anhydride according to the procedure of Example 7, and was obtained in 90% yield as a colorless solid, m.p. above 300° C. when recrystallized from aqueous DMF.