Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]#N)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:33][O-:34].[Na+].C[OH:37]>>[C:27]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([O:34][CH3:33])=[O:37])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: N#Cc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Reactant: C[O-]
Reactant: CO
Agent: [Na+]
Product: COC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of 6-[(2,2-diphenylethyl)amino]-9-tetrahydro-2H-pyran-2-yl-9H-purine-2-carbonitrile (Preparation 3) (1.00 g, 2.36 mmol) in methanol (20 ml) was treated with sodium methoxide (0.14 g, 2.59 mmol) and the resulting mixture was heated at reflux under a nitrogen atmosphere for 20 hours. TLC analysis showed that some starting material still remained therefore further sodium methoxide (64 mg, 1.18 mmol) was added and the mixture was heated at reflux under a nitrogen atmosphere for a further hour. The mixture was then cooled to room temperature and the solvent was removed under reduced pressure. Tetrahydrofuran (30 ml) and water (10 ml) were added to the residue and the pH was adjusted to 4 by addition of acetic acid (1 ml). This mixture was heated at reflux for 1 hour. TLC analysis showed that some starting material still remained and therefore further acetic acid (0.5 ml) was added and heating at reflux continued for 18 hours. The reaction was cooled to room temperature and partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogen carbonate. The organic phase was separated, washed with brine, dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol (98.5:1.5 by volume) to afford the title compound (521 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:25]=[CH:24][C:15]([C:16]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:17])=[CH:14][CH:13]=2)=[N:2]1.C(OC([NH:33][C:34]([CH3:39])([CH3:38])[C:35](O)=[O:36])=O)(C)(C)C.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN1CCOCC1.Cl.CO>CO>[NH2:33][C:34]([CH3:39])([CH3:38])[C:35]([N:21]1[CH2:22][CH2:23][N:18]([C:16](=[O:17])[C:15]2[CH:14]=[CH:13][C:12](/[CH:11]=[CH:10]/[C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][N:2]=3)=[CH:25][CH:24]=2)[CH2:19][CH2:20]1)=[O:36]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: O=C(c1ccc(/C=C/c2n[nH]c3ccccc23)cc1)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CO
Solvent: O
Product: CC(C)(N)C(=O)N1CCN(C(=O)c2ccc(/C=C/c3n[nH]c4ccccc34)cc2)CC1
Temperature: 60 °C
Yield: 0 %

Procedure:
The product obtained using Compound 18 (300 mg, 0.90 mmol), 2-(tert-butoxycarbonyl)amino-2-methylpropionic acid (153 mg, 0.75 mmol), 1-hydroxybenzotriazole monohydrate (132 mg, 0.98 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (202 mg, 1.05 mmol) and N-methylmorpholine (0.16 mL, 1.50 mmol) in a similar manner to Example 5, was dissolved in methanol (2.00 mL), and the solution was added with 4 moL/L hydrogen chloride-methanol solution (1.50 mL), followed by heating under reflux at 60° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from acetone to obtain Compound 131 (0.10 mg, 23%).
Reaction SMILES: [CH3:1][Si:2]([CH3:18])([C:12]#[C:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11]>C(O)C.C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[CH3:18][Si:2]([CH3:1])([CH2:12][CH2:13][Si:14]([CH3:15])([CH3:16])[CH3:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11]
Reactant: C[Si](C)(C)C#C[Si](C)(C)CCCCCCCCO
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CC[Si](C)(C)CCCCCCCCO
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A suspension of compound 15 (15.21 g, 0.0535 mol) and palladium hydroxide on charcoal (1.85 g, 1.60 mmol) in ethanol and ethyl acetate (120 ml, 1:1) was stirred under an atmosphere of hydrogen for 24 h at room temperature. The reaction mixture was filtered (celite) and the solvent roved in vacuo to yield a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]([OH:14])=[O:13])[C:6](=[CH:10][CH:11]=1)[C:7]([OH:9])=O.C(OC(=O)C)(=O)C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:12](=[O:13])[O:14][C:7](=[O:9])[C:6]2=[CH:10][CH:11]=1
Reactant: COc1ccc(C(=O)O)c(C(=O)O)c1
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2c(c1)C(=O)OC2=O
Temperature: 25 °C

Procedure:
4-Methoxyphthalic acid (959 gm., 5.06 m) and acetic anhydride (2 l.) were mixed together and warmed to reflux. After 2 hours at reflux the solution was filtered while hot. The filtrate was cooled to room temperature and then it was cooled at -70° C. overnight. The solid precipitate was recovered by suction filtration, washed with petroleum either (40°-60°) and air dried. wt.=649 gm., m.p. 89°-94° C.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:15][C:14]2[C:6](=[CH:7][C:8]3[CH2:12][CH2:11][O:10][C:9]=3[CH:13]=2)[CH2:5][CH2:4]1.[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[CH2:16]([N:2]=[C:3]1[CH2:15][C:14]2[C:6](=[CH:7][C:8]3[CH2:12][CH2:11][O:10][C:9]=3[CH:13]=2)[CH2:5][CH2:4]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1ccccc1
Reactant: NC1CCc2cc3c(cc2C1)OCC3
Agent: Cl
Solvent: CCO
Product: c1ccc(CN=C2CCc3cc4c(cc3C2)OCC4)cc1

Procedure:
10 g of the compound of Example 2 are brought to reflux in 200 ml of ethanol in the presence of 2.8 g of benzaldehyde. A sample is removed, concentrated and recrystallized in ethanol.
Reaction SMILES: Cl.O1CCOCC1.C(O)(C(F)(F)F)=O.C(OC([N:22]1[C@H:27]([C:28]2[NH:32][C:31]3[CH:33]=[CH:34][C:35]([C:37]4[CH:38]=[C:39]5[C:44](=[CH:45][CH:46]=4)[CH:43]=[C:42]([C:47]4[NH:51][C:50]([C@@H:52]6[CH2:57][C@@H:56]7[C@@H:54]([CH2:55]7)[N:53]6C(OC(C)(C)C)=O)=[N:49][CH:48]=4)[CH:41]=[CH:40]5)=[CH:36][C:30]=3[N:29]=2)[CH2:26][C@@H:25]2[C@H:23]1[CH2:24]2)=O)(C)(C)C>C(Cl)Cl>[C@@H:54]12[CH2:55][C@@H:56]1[CH2:57][C@@H:52]([C:50]1[NH:49][CH:48]=[C:47]([C:42]3[CH:43]=[C:44]4[C:39](=[CH:40][CH:41]=3)[CH:38]=[C:37]([C:35]3[CH:34]=[CH:33][C:31]5[N:32]=[C:28]([C@@H:27]6[CH2:26][C@@H:25]7[C@@H:23]([CH2:24]7)[NH:22]6)[NH:29][C:30]=5[CH:36]=3)[CH:46]=[CH:45]4)[N:51]=1)[NH:53]2
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1ncc(-c2ccc3cc(-c4ccc5[nH]c([C@@H]6C[C@H]7C[C@H]7N6C(=O)OC(C)(C)C)nc5c4)ccc3c2)[nH]1
Agent: Cl
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cc2cc(-c3c[nH]c([C@@H]4C[C@H]5C[C@H]5N4)n3)ccc2cc1-c1ccc2nc([C@@H]3C[C@H]4C[C@H]4N3)[nH]c2c1
Reaction time: 0.5 h
Yield: 75.7 %

Procedure:
4M HCl in dioxane (10 mL, 40.0 mmol) was added to a stirred solution of a TFA salt of (1R,3S,5R)-tert-butyl 3-(5-(6-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-5-yl)naphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (151 mg) in DCM (3 mL). Precipitate formed immediately. The suspension was agitated for 30 min. The volatile components were evaporated under vacuum. The crude residue was taken in DCM (3 mL) and TFA (2 mL) was added. The solution was agitated for 1 h. The volatile components were evaporated under reduced pressure. The residue was taken into MeOH and filtered through a Strata XC MCX cartridge. The cartridge was washed with methanol and the compound was release from the cartridge by eluting with a solution of 2M of ammonia/methanol. The ammonia/methanol filtrate was evaporated under reduced pressure to yield 6-(6-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-4-yl)naphthalen-2-yl)-2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazole (79 mg, 0.17 mmol) as yellow solid. LC-MS retention time 1.130 min; m/z 473.35 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5u C18 4.6×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where Solvent A was 10% MeOH/90% H2O/0.1% TFA and Solvent B was 10% H2O/90% MeOH/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (500 MHz, MeOD) δ ppm 8.19 (s, 1H), 8.07 (s, 1H), 7.92 (dd, J=8.6, 5.8 Hz, 2H), 7.88 (s, 1H), 7.82 (dd, J=5.8, 1.5 Hz, 2H), 7.61-7.66 (m, 2H), 7.51 (s, 1H), 4.24-4.35 (m, 2H), 3.11 (td, J=6.1, 2.4 Hz, 1H), 3.06 (td, J=6.0, 2.6 Hz, 1H), 2.40-2.53 (m, 2H), 2.18-2.33 (m, 2H), 1.69-1.76 (m, 1H), 1.62-1.69 (m, 1H), 0.88 (ddd, J=6.6, 4.3, 2.6 Hz, 1H), 0.79-0.84 (m, 1H), 0.61-0.68 (m, 1H), 0.55-0.60 (m, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]1.[OH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][N:22]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[OH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:13][CH:10]2[CH2:9][CH2:8][N:7]([C:2]3[N:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:12][CH2:11]2)=[O:26])=[CH:23][N:22]=1
Reactant: NC1CCN(c2ncccn2)CC1
Reactant: O=C(O)c1ccc(-c2ccccc2O)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NC1CCN(c2ncccn2)CC1)c1ccc(-c2ccccc2O)nc1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
1-pyrimidin-2-ylpiperidin-4-amine (45 mg, 0.25 mmol) was added to a solution of 6-(2-hydroxyphenyl)nicotinic acid (50 mg, 0.23 mmol) in DMF (0.25 ml) and triethylamine (0.176 ml, 1.26 mmol). O-(1H-Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (125 mgs, 0.33 mmol) in DMF (0.5 ml) was then added and the reaction sealed. The reaction was shaken at 50° C. for 16 hours. The reaction was then evaporated to dryness in vacuo. Dichloromethane (2 ml) and saturated aqueous sodium hydrogen carbonate (0.5 ml) were added, the sealed reaction was shaken vigorously for 2 h. After this time the plates were opened and the biphasic mixture filtered through an Isolute SPE phase separation tube. The organic layer (filtrate) was evaporated to dryness in vacuo. DMSO (1 ml) was then added and the plate sealed and shaken at 50° C. until all the residue had dissolved then purified by reverse phase preparative HPLC using method B as defined below. R.T. 3.06 MS ES m/z 376 [M+H]+. This gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH:10]([CH3:12])[CH2:9][C:8](=[O:13])[N:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.CI.[C:23](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:23])[CH:10]([CH3:12])[CH2:9][C:8](=[O:13])[N:7]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:6]=2[CH:20]=1
Reactant: O=C([O-])[O-]
Reactant: CC1CC(=O)N(c2ccccc2)c2cc(Cl)ccc2N1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CC1CC(=O)N(c2ccccc2)c2cc(Cl)ccc2N1C

Procedure:
28.6 g of 8-chloro-4-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-one in 100 ml dimethylformamide is stirred with 18 g methyl iodide and 14 g anhydrous potassium carbonate for 2 hours on a boiling water bath. The reaction mixture is poured into 500 ml water and extracted with ether several times. The ethereal extracts are washed with water and dried over sodium sulfate. Upon distilling off the solvent, the crystalline residue is recrystallized from acetic acid ethyl ester. The yield is 24.5 g having an m.p.=113° C.-114° C. (82% of the theory).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[CH2:10][C:11]([F:14])([F:13])[F:12].[NH2:15][OH:16].Cl.CC([O-])=O.[Na+]>C(O)C.O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:15][OH:16])=[CH:4][C:3]=1[CH2:10][C:11]([F:14])([F:13])[F:12]
Reactant: NO
Reactant: O=Cc1ccc(Br)c(CC(F)(F)F)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=Cc1ccc(Br)c(CC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 4-bromo-3-(2,2,2-trifluoroethyl)benzaldehyde (700 mg, 2.62 mmol, 1.00 equiv) in ethanol:H2O (20:5 mL), NH2OH. hydrogen chloride (235 mg, 3.41 mmol, 1.30 equiv), NaOAc (279 mg, 3.40 mmol, 1.30 equiv). The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3×20 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×20 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 700 mg (crude) of N-[[4-bromo-3-(2,2,2-trifluoroethyl)phenyl]methylidene]hydroxylamine as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH:13]([CH3:15])[CH3:14])=[CH:9][CH:10]=2)[C:5]([OH:16])=[C:4]([C:17]([OH:19])=O)[N:3]=1.Cl.C([O:25][C:26](=[O:35])[C@H:27]([NH2:34])[CH2:28][O:29]C(C)(C)C)(C)(C)C>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH:13]([CH3:14])[CH3:15])=[CH:9][CH:10]=2)[C:5]([OH:16])=[C:4]([C:17]([NH:34][C@H:27]([CH2:28][OH:29])[C:26]([OH:35])=[O:25])=[O:19])[N:3]=1
Reactant: CC(C)Oc1ccc2c(Cl)nc(C(=O)O)c(O)c2c1
Reactant: CC(C)(C)OC[C@@H](N)C(=O)OC(C)(C)C
Agent: Cl
Product: CC(C)Oc1ccc2c(Cl)nc(C(=O)N[C@H](CO)C(=O)O)c(O)c2c1

Procedure:
Prepared in analogy to Example A-2 e) and f) from 1-chloro-4-hydroxy-6-isopropoxy-isoquinoline-3-carboxylic acid (can be obtained according to U.S. Pat. No. 6,093,730, October 1998, Weidmann et al.) and (R)-2-amino-3-tert-butoxy-propionic acid tert-butyl ester hydrochloride; MS-(+)-ion: M+1=369.0 amu.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]([CH2:19][C:20]([N:22]2[CH2:42][CH2:41][C:25]3[C:26]4[C:27]([N:32]([CH2:33][C:34]5[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=5)[C:24]=3[CH2:23]2)=[N:28][CH:29]=[CH:30][CH:31]=4)=[O:21])[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])C1C=CC=CC=1.[H][H]>[C].[Pd].CO.C1COCC1>[F:40][C:36]1[CH:35]=[C:34]([CH:39]=[CH:38][CH:37]=1)[CH2:33][N:32]1[C:27]2=[N:28][CH:29]=[CH:30][CH:31]=[C:26]2[C:25]2[CH2:41][CH2:42][N:22]([C:20](=[O:21])[CH2:19][C:17]3[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([OH:8])[CH:18]=3)[CH2:23][C:24]1=2
Reactant: [H][H]
Reactant: COC(=O)c1ccc(CC(=O)N2CCc3c(n(Cc4cccc(F)c4)c4ncccc34)C2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(CC(=O)N2CCc3c(n(Cc4cccc(F)c4)c4ncccc34)C2)cc1O
Yield: 93.9 %

Procedure:
To 1.24 mL of a methanol/THF (1:1) solution of the compound (70 mg) produced in Example 63 was added 5% palladium carbon (7 mg, 10 wt %), and the mixture was stirred at room temperature for 3 hours under the hydrogen atmosphere. After the reaction solution was filtered with Celite, the solvent was concentrated under reduced pressure. The resulting residue was purified by silica gel column (hexane/ethyl acetate=70:30-40:60) to obtain the title compound (55.2 mg) having the following physical property values.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[S:24]1[CH2:28][CH2:27][NH:26][CH2:25]1.O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>C1COCC1>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:16]=[CH:17][C:18]([C:19]([N:26]2[CH2:27][CH2:28][S:24][CH2:25]2)=[O:21])=[CH:22][CH:23]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: C1CSCN1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N2CCSC2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.4 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65 mmol) and thiazolidine (0.65 mmol) in THF (6 mL) at 0° C. were added 1-hydroxybenzotriazole hydrate (100.8 mg, 0.65 mmol), N-ethyldiisopropylamine (281.7 μl, 1.613 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidazole hydrochloride (126.2 mg, 0.65 mmol). The resulting reaction mixture was stirred overnight at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=3:1 to 1:4) afforded the title compound (68 mg, 28%) which was obtained as a white solid. MS: m/e=382.2 [M+H]+.
Reaction SMILES: [CH:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:7][CH:8]([CH2:11][CH3:12])[CH:9]=O>>[CH:1](=[O:6])[CH:2]=[CH:3][CH2:4][CH2:5][CH2:12][CH2:11][CH:8]([CH3:9])[CH3:7]
Reactant: CCC(C)C=O
Reactant: CCCCC=O
Product: CC(C)CCCCC=CC=O

Procedure:
This example describes the process of the invention for the co-aldol condensation of n-pentanal and 2-methylbutanal (2-MBA) to give an isodecenal consisting of the isomers 2-propyl-4-methylhexenal (1+2) and -propylheptenal (1+1) using the cosolvent diethylene glycol (DEG). 400 kg/h of catalyst were passed through the reactor (as described in Example 3) at a tempera ture of 110° at the autogenous pressure of the reactants.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][O:5][CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[C:16]1[CH:21]=[CH:20][N:19]=[C:18](SC)[N:17]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[NH2:35][CH:36]1[CH2:41][CH2:40][CH:39]([N:42]([CH3:47])[S:43]([CH3:46])(=[O:45])=[O:44])[CH2:38][CH2:37]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:47][N:42]([CH:39]1[CH2:40][CH2:41][CH:36]([NH:35][C:18]2[N:17]=[C:16]([N:11]3[C:12]4[C:8](=[C:7]([CH2:6][O:5][CH2:4][CH2:3][S:2][CH3:1])[CH:15]=[CH:14][CH:13]=4)[CH:9]=[CH:10]3)[CH:21]=[CH:20][N:19]=2)[CH2:37][CH2:38]1)[S:43]([CH3:46])(=[O:44])=[O:45]
Reactant: CN(C1CCC(N)CC1)S(C)(=O)=O
Reactant: CSCCOCc1cccc2c1ccn2-c1ccnc(SC)n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CSCCOCc1cccc2c1ccn2-c1ccnc(NC2CCC(N(C)S(C)(=O)=O)CC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.9 %

Procedure:
4-(2-Methylsulfanyl-ethoxymethyl)-1-(2-methylsulfanyl-pyrimidin-4-yl)-1H indole (196 mg, 0.36 mmol) was dissolved in DCM, cooled on an ice bath, and MCPBA (635 mg, 2.83 mmol) was added and the mixture was stirred at RT overnight. The mixture was then diluted with DCM, washed with 5% NaHCO3, dried over sodium sulfate, filtered, concentrated in vacuo, and the residue dissolved in NMP and added to a suspension of N-(4-amino-cyclohexyl)-N-methyl-methanesulfonamide (409 mg, 1.98 mmol), 0.39 mL DIEA (2.27 mmol) and molecular sieves (previously stirred at RT for 1 h). The mixture was stirred at 120° C. for 1 h, cooled to RT, the mixture decanted into water, stirred for 30 min, filtered, and the precipitate purified by flash chromatography, eluting with DCM:MeOH 97:3. The product was then stirred in ether, filtered, and the solvent removed in vacuo overnight to yield N-methyl-N-(4-{4-[4-(2-methylsulfanyl-ethoxymethyl)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexyl)-methanesulfonamide (47 mg).
Reaction SMILES: C([N:9]1[CH2:14][CH2:13][C:12]2([CH2:19][C:18](=[O:20])[C:17]3[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=3[S:15]2)[CH2:11][CH2:10]1)(=O)C1C=CC=CC=1.[ClH:25]>C(O)C>[NH:9]1[CH2:14][CH2:13][C:12]2([CH2:19][C:18](=[O:20])[C:17]3[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=3[S:15]2)[CH2:11][CH2:10]1.[ClH:25]
Reactant: O=C1CC2(CCN(C(=O)c3ccccc3)CC2)Sc2ccccc21
Agent: Cl
Solvent: CCO
Product: O=C1CC2(CCNCC2)Sc2ccccc21
Reaction time: 18 h
Yield: 92 %

Procedure:
A solution of product from Step C (3.2 g, 0.0095 mol) in ethanol (50 ml) and 6 N HCl (50 ml) was heated at reflux. After 18 hours, the reaction was concentrated to dryness and the residue crystallized from ethanol to yield 2.9 g (92%) of product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[NH2:40][CH:37]1[CH2:38][CH2:39][N:34]([S:31]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:6]2[CH:5]=[CH:4][C:3]([C:17]3[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=3)=[C:2]([F:1])[CH:7]=2)(=[O:33])=[O:32])[CH2:35][CH2:36]1
Reactant: NC1CCN(S(=O)(=O)c2ccccc2Br)CC1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)N3CCC(N)CC3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 1-((2-bromophenyl)sulfonyl)piperidin-4-amine. MS (ESI): mass calcd. for C21H22FN5O2S, 427.15; m/z found, 428.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.36 (s, 1H), 8.25-8.23 (d, J=1.4, 1H), 8.11-8.08 (m, 1H), 7.96 (m, 1H), 7.74-7.69 (m, 1H), 7.65-7.60 (m, 1H), 7.45-7.41 (m, 1H), 7.32-7.29 (m, 1H), 7.28 (s, 1H), 3.47-3.40 (m, 2H), 3.18-3.08 (m, 1H), 2.57-2.43 (m, 2H), 1.91-1.84 (m, 2H), 1.51-1.39 (m, 2H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=2[CH3:21])[CH:9]=[CH:10][C:11]=1[CH:12]=[O:13])[CH2:2][CH2:3][CH3:4].Br[CH2:23][C:24]1[N:28]([C:29]2[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:36])[N:27]=[CH:26][C:25]=1[CH:37]([CH3:39])[CH3:38].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:23][C:24]3[N:28]([C:29]4[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:30]=4[Cl:36])[N:27]=[CH:26][C:25]=3[CH:37]([CH3:39])[CH3:38])=[CH:16][C:15]=2[CH3:21])[CH:9]=[CH:10][C:11]=1[CH:12]=[O:13])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc(-c2ccc(O)cc2C)ccc1C=O
Reactant: CC(C)c1cnn(-c2c(Cl)cccc2Cl)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOc1cc(-c2ccc(OCc3c(C(C)C)cnn3-c3c(Cl)cccc3Cl)cc2C)ccc1C=O
Temperature: 70 °C
Reaction time: 2 h
Yield: 32.6 %

Procedure:
A solution of 3-butoxy-4′-hydroxy-2′-methyl-biphenyl-4-carbaldehyde (0.198 g, 0.696 mmol) and 5-bromomethyl-4-isopropyl-1-(2,6-dichloro-phenyl)-1H-pyrazole (0.242 g, 0.696 mmol) in DMF (2.0 mL) is treated with K2CO3 (0.192 g, 1.39 mmol). The mixture is stirred at 70° C. for 2 hours. The mixture is cooled to room temperature and quenched with water (10 mL). The mixture is extracted with ethyl acetate (20 mL×2), and the combined organic layers are dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by silica gel chromatography eluting with 20% ethyl acetate in hexanes to give 3-butoxy-4′-[2-(2,6-dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2′-methyl-biphenyl-4-carbaldehyde (0.125 g, 33%). ES/MS m/e 551.0; 553.0 (M+1).