Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[N:6]=1)=[O:4].O1CCOCC1.S(=O)(=O)(O)O>O>[CH3:13][O:12][C:10]([C:8]1[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:9]=1)=[O:11]
Reactant: COC(=O)c1cc(C(=O)OC)n(Cc2ccc(OC)cc2)n1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(C(=O)O)nn1Cc1ccc(OC)cc1
Temperature: 65 °C
Reaction time: 48 h

Procedure:
In a round bottom flask, 1-(4-methoxy-benzyl)-1H-pyrazole-3,5-dicarboxylic acid dimethyl ester (104, 28.5 g, 93.6 mmol) was combined with 100 mL of water and 20 mL of 1,4-dioxane. Sulfuric acid (5.5 mL, 100 mmol) and 2.0 mL of water were added and the reaction was stirred for 2 days at 60-70° C. The reaction was concentrated under vacuum until a precipitate formed. The solid was collected by filtration and washed with cold water several times to provide the desired compound. 1H NMR was consistent with the compound structure.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[O:14][C@H:13]([N:15]2[CH:22]=[C:21]([F:23])[C:19]([NH2:20])=[N:18][C:16]2=[O:17])[C@H:12]([OH:24])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:25][S:26](Cl)(=[O:28])=[O:27].CO>N1C=CC=CC=1.C1(C)C=CC=CC=1>[S:26]([O:24][C@@H:12]1[CH2:11][C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])[O:14][C@@H:13]1[N:15]1[CH:22]=[C:21]([F:23])[C:19]([NH2:20])=[N:18][C:16]1=[O:17])([CH3:25])(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1C[C@@H](O)[C@@H](n2cc(F)c(N)nc2=O)O1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC[C@H]1C[C@@H](OS(C)(=O)=O)[C@@H](n2cc(F)c(N)nc2=O)O1
Temperature: 0 °C
Yield: 68.1 %

Procedure:
A suspension of 19 (1.70 g, 4.73 mmol) in dry pyridine (80 mL) was stirred under argon and cooled to 0° C. Methanesulfonyl chloride (MsCl, 1.21 mL, 15.6 mmol) was added dropwise and the reaction mixture stirred at 0° C. for 5 h. Then the mixture was poured onto ice/water (300 mL) and extracted with chloroform (3×300 mL). Combined extracts were washed with a 5% aqueous sodium hydrogen carbonate solution (300 mL), with water (2×300 mL) and then dried over sodium sulphate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluent: stepwise gradient of methanol (8-12%) in toluene] to give pure 20 (1.41 g, 68% yield) as a white solid: mp 75-76 ° C.; UV (ethanol): λmax 243 nm (ε8100), 282 nm (ε7300), λmin 225 nm (ε6000), 265 nm (ε6000); 1H NMR (DMSO-d6): δ7.9-7.6 (br d, 2H, NH2), 7.85 (d, 1H, H-6, J6-F5=7.0 Hz), 6.08 (dd, 1H, H-1′, J1′-2′=5.2 Hz and J1′-F5=1.6 Hz), 5.4 (m, 1H, H-2′), 4.1 (m, 1H, H-4′), 3.9 (m, 1H, H-5′), 3.7 (m, 1H, H-5″), 3.11 (s, 3H, CH3SO2), 2.47 (m, 1H, H-3′), 2.0 (m, 1H, H-2″), 0.85 (s, 9H, (CH3)3C—Si), 0.05 (s, 6H, (CH3)2Si); MS (matrix GT): FAB>0 m/z 1312 (3M+H)+, 875 (2M+H)+, 438 (M+H)+, 309 (S)+, 130 (BH2)+; FAB<0 m/z 1310 (2M−H)−, 873 (2M−H)−, 436 (M−H)−, 128 (B)−, 95 (CH3SO3)−; [α]D20=−84 (c, 0.84 DMSO).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([OH:16])=[O:15].[C:17]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: COc1ccc2ncc(C(=O)O)c(Br)c2n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cnc2ccc(OC)nc2c1Br
Temperature: 25 °C
Reaction time: 72 h
Yield: 80 %

Procedure:
To a solution of 4-bromo-6-(methoxy)-[1,5]naphthyridine-3-carboxylic acid (for a synthesis see WO2004058144, Example 53(d)) (8.28 g, 29.3 mmol) in DMF (200 ml) was added K2CO3 (5.934 g, 43 mmol) and iodomethane (2.18 ml, 35 mmol) and the reaction was stirred at rt for 72 h. The reaction was partitioned between EtOAc and water. The organic phase was separated and washed twice more with water. The aqueous phases were re-extracted with EtOAc and this EtOAc phase separated and washed with water. The combined organic phases were dried and evaporated to give the desired product as a solid (7 g, 80%).
Reaction SMILES: S(Cl)(Cl)=O.CC1C=CC(C)=CC=1C(O)=O.CC1C=CC(C)=CC=1C(Cl)=O.[CH3:27][C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:29]=1[C:35]([N:37]=[C:38]=[S:39])=[O:36].[Cl:40][C:41]1[CH:42]=[C:43]([CH:45]=[CH:46][C:47]=1[O:48][C:49]1[C:58]2[C:53](=[CH:54][C:55]([O:61][CH3:62])=[C:56]([O:59][CH3:60])[CH:57]=2)[N:52]=[CH:51][CH:50]=1)[NH2:44]>C(O)C.C1(C)C=CC=CC=1>[Cl:40][C:41]1[CH:42]=[C:43]([NH:44][C:38]([NH:37][C:35](=[O:36])[C:29]2[CH:30]=[C:31]([CH3:34])[CH:32]=[CH:33][C:28]=2[CH3:27])=[S:39])[CH:45]=[CH:46][C:47]=1[O:48][C:49]1[C:58]2[C:53](=[CH:54][C:55]([O:61][CH3:62])=[C:56]([O:59][CH3:60])[CH:57]=2)[N:52]=[CH:51][CH:50]=1
Reactant: Cc1ccc(C)c(C(=O)N=C=S)c1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: Cc1ccc(C)c(C(=O)Cl)c1
Agent: Cc1ccc(C)c(C(=O)O)c1
Solvent: O=S(Cl)Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cc(C)ccc4C)cc3Cl)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 2,5-dimethylbenzoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 2,4-dimethyl-1-benzenecarbonyl isothiocyanate was prepared using the resultant 2,5-dimethyl-1-benzenecarbonyl chloride as a starting compound according to the description of the literature. 2,5-Dimethyl-1-benzenecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (74 mg, yield 94%).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([NH:8][C:9](=[O:15])[C:10](=[O:14])[NH:11]2)=[C:6]([CH2:16][NH:17][C:18](=[O:26])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2O)[CH:5]=1)([O-:3])=[O:2].[C:27]([O:30]CC)(=[O:29])[CH3:28].CO>>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([NH:8][C:9](=[O:15])[C:10](=[O:14])[NH:11]2)=[C:6]([CH2:16][NH:17][C:18](=[O:26])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:30][C:27](=[O:29])[CH3:28])[CH:20]=2)[CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(NCc1cc([N+](=O)[O-])cc2[nH]c(=O)c(=O)[nH]c12)c1ccccc1O
Reactant: CCOC(C)=O
Solvent: CO
Product: CC(=O)Oc1cccc(C(=O)NCc2cc([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c23)c1

Procedure:
N-(7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-ylmethyl)-(2-hydroxy)-benzoic acid amide, ESCl+ -MS: (M+H)+ =357; TLC: ethyl acetate/methanol (1:1+2% acetic acid) Rf 0.33.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([NH2:12])=[O:11])=[CH:4][CH:3]=1.[Cl:13][CH2:14][C:15]([CH2:17]Cl)=O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:13][CH2:14][C:15]1[N:12]=[C:10](/[CH:9]=[CH:8]/[C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[O:11][CH:17]=1
Reactant: O=C(CCl)CCl
Reactant: Cc1ccc(/C=C/C(N)=O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc(/C=C/c2nc(CCl)co2)cc1
Yield: 72.2 %

Procedure:
A mixture of (E)-3-(4-methylphenyl)-2-propenamide (8.06 g) and 1,3-dichloroacetone (6.98 g) in toluene (50 ml) were refluxed for 3 hours. After cooling, the reaction mixture was diluted with ethyl acetate, washed with water and saline, and dried over magnesium sulfate, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate-hexane 1:4) to yield the titled compound (8.44 g) as a white crystalline powder.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50].Cl>CN1C(=O)CCC1>[CH2:50]([O:14][C:13](=[O:15])[CH:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=1)[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH3:33]
Reactant: O=C(NC(Cc1ccc([N+](=O)[O-])cc1)C(=O)O)OCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CCCCCCCCCCCCCCCCCCOC(=O)C(Cc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccccc1
Temperature: 20 °C
Reaction time: 24 h
Yield: 62 %

Procedure:
To a mixture of 2-benzyloxycarbonylamino-3-(4-nitro-phenyl)-propionic acid (400 g), potassium carbonate (192.5 g) in NMP (1460 ml) maintained at 20° C., was added dropwise 1-Bromo octadecane (425 g). The reaction mixture was allowed to slowly come to room temperature and further stirred for 24 hours. The reaction mixture was then poured onto ice water and the pH was adjusted to 7 with dilute HCl. The solid was filtered, dried and purified by column chromatography using hexane:ethyl acetate (95:5) as an eluant to yield pure 2-benzyloxycarbonylamino-3-(4-nitro-phenyl)-propionic acid stearyl ester (430 g) as a white powder with a melting point of 56-59° C. The product was further characterized by IH NMR (CDCl3) δ 0.90 (t, 3H, CH3), 1.30 (m, 30H, 15X CH2), 1.60 (m, 2H, CH2), 3.05-3.25 (m, 2H, CH2), 4.20 (m, 2H, CH2), 4.65 (m, 1H, CH), 5.15 (m, 2H, CH2), 5.40 (d, 1H, NH), 7.30 (m, 54H, Ar), 7.45 (d, 2H, Ar), 8.15 (d, 2H, Ar)
Reaction SMILES: N([O-])=O.[Na+].[CH3:5][O:6][C:7]([CH2:9][C:10]1[CH:19]=[C:18](N)[C:17]([Cl:21])=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[O:8].COC(CC1C(Cl)=[C:35]([NH2:38])C=CC=1C(OC)=O)=O.[Cu]C#N.[C-]#N.[K+]>O.Cl.C(OCC)(=O)C>[CH3:5][O:6][C:7]([CH2:9][C:10]1[CH:19]=[C:18]([C:35]#[N:38])[C:17]([Cl:21])=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[O:8]
Reactant: COC(=O)Cc1c(C(=O)OC)ccc(N)c1Cl
Reactant: COC(=O)Cc1cc(N)c(Cl)cc1C(=O)OC
Agent: N#C[Cu]
Agent: Cl
Agent: O=N[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cc(C#N)c(Cl)cc1C(=O)OC
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 29 %

Procedure:
A solution of sodium nitrite (40 mg, 0.6 mmol) in water (0.25 mL) was added to a solution of a mixture (100 mg, 0.39 mmol) of methyl 2-methoxycarbonylmethyl-4-amino-5-chlorobenzoate and methyl 2-methoxycarbonylmethyl-4-amino-3-chlorobenzoate in 2N hydrochloric acid (0.5 mL) under the ice cold condition. The reaction solution was stirred at 0° C. for 1.5 hour. The resulting suspension was dissolved by adding water (0.1 mL) and ethyl acetate (0.2 mL). This solution was added to a suspension of copper (I) cyanide (45 mg, 0.5 mmol) and potassium cyanide (38 mg, 0.6 mmol) in a mixture of water (0.4 mL) and ethyl acetate (0.8 mL) at 0° C. The reaction solution was stirred at 0° C. for 1 hour. The resulting insoluble material was collected by Celite filtration, and washed with a mixed solvent of water and ethyl acetate (1:2). The filtrate and washing solution were combined together. The organic layer was separated, and dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give crude product. The crude product was purified by silica gel column chromatography using n-hexane-ethyl acetate (mixing ratio 10:1), and dried under reduced pressure to give a 0.7:1 mixture (30 mg, 29%) of the title compound and methyl 2-methoxycarbonylmethyl-4-cyano-3-chlorobenzoate.
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].[H-].[Na+].[C:7]([N:11]=[N:12][C:13]1([N:19]=[C:20]=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)([CH3:10])([CH3:9])[CH3:8].[N-]=C=O>O>[C:7]([N:11]=[N:12][C:13]1([NH:19][C:20]([O:4][CH:1]([CH3:3])[CH3:2])=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)O
Reactant: CC(C)(C)N=NC1(N=C=O)CCCCC1
Agent: [H-]
Agent: [N-]=C=O
Agent: [Na+]
Solvent: O
Product: CC(C)OC(=O)NC1(N=NC(C)(C)C)CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 50 ml of isopropanol in a 125 ml erlenmeyer flask stirred with a magnetic stirrer, was slowly added 2.1 grams (0.05 moles) of 57% sodium hydride. After the temperature came back to 25° C., 10.5 grams (0.05 moles) of 1-t-butylazo-1isocyanatocyclohexane was added dropwise over 5 minutes. After the addition was complete, the reaction was stirred an additional 30 minutes at room temperature. Gas chromatography indicated that the 1-t-butylazo-1-isocyanatocyclohexane had reacted almost immediately. The reaction mixture was poured into 300 ml water and the product extracted with 100 ml pentane. The pentane extract was separated, washed with water, 10% NaHCO3 solution, dried over anhydrous Na2SO4, filtered and the pentane evaporated under reduced pressure to leave 11.0 grams (81.5% crude yield) of a yellow liquid. The product had a strong carbonyl band at 1725 cm-1 and a sharp NH band at 3400 cm-1 in its infrared spectrum and the isocyanate band at 2225 cm-1 was absent.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH:11][C:12](=[O:27])[CH2:13][C:14]([NH:16][C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[C:26]=2[N:25]=[CH:24][CH:23]=[CH:22]3)=[O:15])[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH:31]([CH2:37][CH2:38][CH2:39][CH3:40])[C:32]([O:34][CH2:35][CH3:36])=[O:33]>CN(C=O)C.C1COCC1>[CH2:35]([O:34][C:32](=[O:33])[CH2:31][CH2:37][CH2:38][CH2:39][CH2:40][CH:13]([C:14](=[O:15])[NH:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[N:25]=[CH:24][CH:23]=[CH:22]2)[C:12](=[O:27])[NH:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:1]=[CH:2][CH:3]=[CH:4]2)[CH3:36]
Reactant: O=C(CC(=O)Nc1cccc2cccnc12)Nc1cccc2cccnc12
Reactant: CCCCC(Br)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)CCCCCC(C(=O)Nc1cccc2cccnc12)C(=O)Nc1cccc2cccnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
To a solution of N,N′-di-quinolin-8-yl-malonamide (10.3 g, 28.8 mmol) in dry DMF (200 mL) and dry THF (85 mL) at 0° C. was added NaH (60% disp./1.27 g, 31.7 mmol) portion-wise. The resultant solution was allowed to warm to RT for 10 min. The solution was cooled to 0° C. and ethyl bromohexanoate (5.6 mL, 31.7 mmol) was added dropwise. The mixture was stirred overnight. The solvent was removed, and the residue was diluted with EtOAc (250 mL), and washed with H2O (100 mL). The organic fraction was dried, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to yield the desired material (10 g, 69.6%). ESIMS calcd 499 (M++H), found 499 (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH:14]([F:16])[F:15])=[C:6]([CH:8]([CH2:11][OH:12])[C:9]#[N:10])[CH:7]=1.[OH:17][CH2:18][CH2:19]C#N>>[C:18]([O:12][CH2:11][CH:8]([C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[O:13][CH:14]([F:15])[F:16])[C:9]#[N:10])(=[O:17])[CH3:19]
Reactant: N#CC(CO)c1cc(Cl)ccc1OC(F)F
Reactant: N#CCCO
Product: CC(=O)OCC(C#N)c1cc(Cl)ccc1OC(F)F

Procedure:
This ester was prepared using the procedure described in Example 5, except 2-(5-chloro-2-(difluoromethoxy)phenyl)-3-hydroxypropanenitrile was used in place of 2-(2-chloro-5-(difluoromethoxy)phenyl)-3-hydroxypropanenitrile. The preparation of 2-5-chloro-2-(difluoromethoxy)phenyl)-3-hydroxypropanenitrile is described in Example 4. The recovered ester product was a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12](N(OC)C)=[O:13])=[CH:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1.CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[C:3]([CH:12]=[O:13])=[CH:4][C:5]([C:8]([F:9])([F:10])[F:11])=[N:6][CH:7]=1
Reactant: CON(C)C(=O)c1cc(C(F)(F)F)ncc1Br
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=Cc1cc(C(F)(F)F)ncc1Br
Temperature: -10 °C
Reaction time: 0.67 h
Yield: 76.9 %

Procedure:
To 5-bromo-N-methoxy-N-methyl-2-(trifluoromethyl)pyridine-4-carboxamide (21 g, 67.1 mmol) in THF (200 mL) was added DIBAL-H in toluene (1M, 73.8 mL, 73.8 mmol) through a syringe at −78° C. The reaction was stirred for 40 minutes while it was warmed to −10° C. The reaction was diluted with EtOAc (100 mL) and was quenched with 1N HCl solution (150 mL). The reaction mixture was filtered on a Celite and silica gel bed. The layers were separated and the organic layer was partitioned with saturated. NaHCO3 and then brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude reaction was purified by column chromatography to yield 5-bromo-2-(trifluoromethyl)pyridine-4-carbaldehyde (13.1 g, 51.6 mmol). 1H NMR (500 MHz, CDCl3) δ10.2 (s, 1H), 9.04 (s, 1H), 8.84 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]([N+:9]([O-])=O)[CH:5]=[CH:6][C:7]=1[F:8].Cl.[OH-].[Na+]>C(OCC)C>[NH2:9][C:4]1[C:3]([F:12])=[C:2]([Br:1])[C:7]([F:8])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: Nc1ccc(F)c(Br)c1F
Temperature: 60 °C
Yield: 90.5 %

Procedure:
A mixture of 31.2 g of 3-bromo-2,4-difluoronitrobenzene, 150 ml concentrated HCl and 150 g stannous chloride dihydrate was placed in a preheated oil bath at 60° C. A small quantity of diethyl ether was then added to bring about solution. After heating at 60° C. for 30 minutes, the mixture was cooled and then poured into 1500 ml ice/water. The solution was then basified to pH 13 using 30% aqueous sodium hydroxide while maintaining the temperature below 25° C. by external cooling. The mixture was extracted three times with chloroform and the combined organic extracts were washed with water. The organic phase was dried and evaporated to yield a white solid, m.p. 77°-78° C., yield 90.5% (24.7 g).
Reaction SMILES: [CH3:1][C@@H:2]1[CH:7]=[CH:6][CH2:5][C:4]([CH3:9])([CH3:8])[C@H:3]1[C:10](=[O:14])[CH:11]=[CH:12][CH3:13].B(F)(F)F>>[CH3:1][CH:2]1[CH:7]=[CH:6][CH2:5][C:4]([CH3:8])([CH3:9])[CH:3]1[C:10](=[O:14])[CH:11]=[CH:12][CH3:13]
Reactant: CC=CC(=O)[C@H]1[C@H](C)C=CCC1(C)C
Agent: FB(F)F
Product: CC=CC(=O)C1C(C)C=CCC1(C)C
Temperature: 130 °C
Reaction time: 1 h

Procedure:
To trans 1-(2,6,6-trimethyl-3-cyclohexen-1-yl)-2-buten-1-one (25 g; 130 mmol; trans:cis 98:2; purity≧99%) stirred under nitrogen at 20° C. was added BF3.(AcOH)2 (0.65 mmol) and [Ru(COD)(methallyl)2] (0.65 mmol) are added consecutively. The resulting solution was heated to 130° C. and stirred over 60 minutes at 130° C. under nitrogen. Then the resulting mixture is cooled to 20° C. and there was obtained a mixture comprising (% by weight of the final mixture, obtained by GC analysis):
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[C:16]([N:18]3[CH2:22][C@@H:21]([N:23]([CH2:37][C:38]4[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[C:40]([C:48]([F:51])([F:50])[F:49])[CH:39]=4)[C:24]4[N:29]=[CH:28][C:27]([N:30]5[CH2:34][CH2:33][N:32]([CH3:35])[C:31]5=[O:36])=[CH:26][N:25]=4)[CH2:20][C@H:19]3[CH2:52][CH3:53])[C:15]([Cl:54])=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].Cl>CCO>[F:47][C:44]([F:45])([F:46])[C:42]1[CH:43]=[C:38]([CH:39]=[C:40]([C:48]([F:49])([F:50])[F:51])[CH:41]=1)[CH2:37][N:23]([C:24]1[N:25]=[CH:26][C:27]([N:30]2[CH2:34][CH2:33][N:32]([CH3:35])[C:31]2=[O:36])=[CH:28][N:29]=1)[C@@H:21]1[CH2:22][N:18]([C:16]2[C:15]([Cl:54])=[CH:14][N:13]=[C:12]([N:9]3[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]3)[N:17]=2)[C@H:19]([CH2:52][CH3:53])[CH2:20]1
Reactant: CCOC(=O)C1CCN(c2ncc(Cl)c(N3C[C@@H](N(Cc4cc(C(F)(F)F)cc(C(F)(F)F)c4)c4ncc(N5CCN(C)C5=O)cn4)C[C@H]3CC)n2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(N3CCN(C)C3=O)cn2)CN1c1nc(N2CCC(C(=O)O)CC2)ncc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a mixture of 1-[4-((2R,4S)-4-{(3,5-bis-trifluoromethyl-benzyl)-[5-(3-methyl-2-oxo-imidazolidin-1-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidin-1-yl)-5-chloro-pyrimidin-2-yl]-piperidine-4-carboxylic acid ethyl ester (70 mg, 0.09 mmol) in EtOH (1 mL) is added 1N NaOH (0.45 mL, 0.45 mmol). The reaction mixture is stirred at room temperature for 1 hour. After quench with 1N HCl (0.45 mL, 0.45 mmol), the mixture is washed with brine and extracted with EtOAc. The combined organic layer is dried over MgSO4 then concentrated under reduced pressure to give 1-[4-((2R,4S)-4-{(3,5-bis-trifluoromethyl-benzyl)-[5-(3-methyl-2-oxo-imidazolidin-1-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidin-1-yl)-5-chloro-pyrimidin-2-yl]-piperidine-4-carboxylic acid (66 mg, 97%).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([CH:13]([CH3:15])[CH3:14])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=[O:4].C(=O)([O-])[O-:17].[Na+].[Na+].O>CN1CCCC1=O>[OH:17][CH2:2][C:3]([N:5]([CH:13]([CH3:15])[CH3:14])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=[O:4]
Reactant: CC(C)N(C(=O)CCl)c1ccc(F)cc1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)N(C(=O)CO)c1ccc(F)cc1
Reaction time: 2.5 h

Procedure:
In a suitable apparatus (500 ml flask), 23.0 g (0.1 mol) of N-chloroacetyl-N-isopropyl-4-fluoroaniline and 11.7 g (0.11 mol) of sodium carbonate are refluxed (100° C.) in a solution of 140 ml of water and 200 ml of N-methylpyrrolidone. After 2.5 hours, the solvent mixture is stripped off in vacuo and the residue distilled at 2 to 3 torr and 132° to 135° C. This gives 18.1 g (86% of theory) of N-hydroxyacetyl-N-isopropyl-(4-fluoroaniline) with a purity of 99.1% (GC).
Reaction SMILES: [CH:1]([N:4]1[C:9]2[N:10]=[C:11](S(C)=O)[N:12]=[CH:13][C:8]=2[CH:7]=[CH:6][C:5]1=[O:17])([CH3:3])[CH3:2].[CH2:18]([N:20]([CH2:31][CH3:32])[CH2:21][CH2:22][O:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)[CH3:19]>>[CH2:31]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([NH:28][C:11]2[N:12]=[CH:13][C:8]3[CH:7]=[CH:6][C:5](=[O:17])[N:4]([CH:1]([CH3:3])[CH3:2])[C:9]=3[N:10]=2)=[CH:29][CH:30]=1)[CH3:32]
Reactant: CCN(CC)CCOc1ccc(N)cc1
Reactant: CC(C)n1c(=O)ccc2cnc(S(C)=O)nc21
Product: CCN(CC)CCOc1ccc(Nc2ncc3ccc(=O)n(C(C)C)c3n2)cc1
Temperature: 175 °C
Yield: 47.5 %

Procedure:
To 8-isopropyl-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (126 mg, 0.50 mmol) was added 4-(2-diethylaminoethoxy)aniline (313 mg, 1.51 mmol). The reaction mixture was heated at 175° C. for 10 minutes then cooled to room temperature and partitioned between saturated sodium bicarbonate and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography eluting with 10% methanol in ethyl acetate. The fractions containing product were concentrated, and hexane was added. The resultant solid was collected by filtration to give 94 mg (47%) of 2-[4-(2-diethylaminoethoxy)-phenylamino]-8-isopropyl-8H-pyrido[2,3-d]pyrimidin-7-one, mp 84-85° C.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][C@H:13]([NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH2:12]3)O1.[OH:26]O>CO>[OH:26][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH2:14][C@H:13]([NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH2:12]2
Reactant: OO
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
Solvent: CO
Product: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(O)cc2C1
Reaction time: 8 h
Yield: 92.8 %

Procedure:
To a solution of N-[(2S)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide (32 g, 88 mmol, Description 2) in methanol (320 ml) at room temperature under nitrogen, hydrogen peroxide (30 weight % in water, 17.90 ml, 175 mmol) was added and the resulting pale yellow solution stirred overnight. The mixture was then evaporated under reduced pressure and the residue partitioned between EtOAc (500 ml) and water (300 ml). Aqueous phase was back extracted with EtOAc (300 ml) and the combined organics were washed with brine (100 ml)/water (100 ml), dried over Na2SO4 and evaporated to dryness. The resulting pale yellow solid was triturated with Et2O (100 ml)/n-hexane (100 ml) and dried at high vacuum to give N-[(2S)-5-hydroxy-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide (20.85 g) as a pale yellow solid.