Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]([CH2:20][CH2:21][CH2:22][NH:23]C(OC(C)(C)C)=O)[C:8]([C:10]1[C:11]([Cl:19])=[N:12][C:13]([S:17][CH3:18])=[N:14][C:15]=1[Cl:16])=[O:9]>C(OCC)(=O)C.Cl>[ClH:16].[F:38][C:2]([F:1])([F:39])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]([CH2:20][CH2:21][CH2:22][NH2:23])[C:8]([C:10]1[C:11]([Cl:19])=[N:12][C:13]([S:17][CH3:18])=[N:14][C:15]=1[Cl:16])=[O:9]
Reactant: CSc1nc(Cl)c(C(=O)N(CCCNC(=O)OC(C)(C)C)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(Cl)n1
Agent: Cl
Solvent: CCOC(C)=O
Product: CSc1nc(Cl)c(C(=O)N(CCCN)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(Cl)n1
Reaction time: 1 h
Yield: 199 %

Procedure:
3 mol/L hydrogen chloride-ethyl acetate (20 mL) was added to N-[3,5-bis(trifluoromethyl)benzyl]-N-[3-(t-butoxycarbonylamino)propyl]-4,6-dichloro-2-(methylthio)pyrimidine-5-carboxylic acid amide (Compound of Reference Example 4; 8.23 g) while the solution was chilled on an ice bath. The reaction mixture was stirred for 1 hour and then another 1 hour at room temperature. Subsequently, the solvent was removed to obtain N-[3,5-bis(trifluoromethyl)benzyl]-N-(3-aminopropyl)-4,6-dichloro-2-(methylthio)pyrimidine-5-carboxylic acid amide hydrochloride (7.35 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[CH:17]=[O:18])=[N:9]2)=[CH:4][CH:3]=1.CCO.[BH4-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH2:17][OH:18])[CH:19]=[CH:20][CH:21]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(OCc2ccc3ccc(Cl)cc3n2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: OCc1cccc(OCc2ccc3ccc(Cl)cc3n2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102 %

Procedure:
The aldehyde of Step 1 (46.64 g, 156.6 mmol) was dissolved in 300 mL of THF. At 0° C., 800 mL of EtOH was added, followed by NaBH4 (5.93 g, 157 mmol). The mixture was then stirred at r.t. (room temperature) for 1 h and poured into cold 25% aq (aqueous) NH4OAc. The organic solvents were evaporated and the title alcohol was extracted with toluene:THF 1:1, dried over Na2SO4 and filtered through silica to yield 47.9 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:15][CH2:14][C@H:13]([CH2:16]OS(C4C=CC(Br)=CC=4)(=O)=O)[O:12][C:8]3=2)[N:3]=1.[F:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][CH:33]=[C:32]2[CH2:38][CH:39]1[CH2:44][CH2:43][CH2:42][NH:41][CH2:40]1.C(N(CC)CC)C>CS(C)=O>[F:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][CH:33]=[C:32]2[CH2:38][CH:39]1[CH2:44][CH2:43][CH2:42][N:41]([CH2:16][CH:13]2[O:12][C:8]3=[C:9]4[C:4](=[CH:5][CH:6]=[C:7]3[O:15][CH2:14]2)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]4)[CH2:40]1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Reactant: Fc1ccc2[nH]cc(CC3CCCNC3)c2c1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1ccc2c3c(ccc2n1)OCC(CN1CCCC(Cc2c[nH]c4ccc(F)cc24)C1)O3

Procedure:
A solution of (2R)-4-bromobenzenesulfonic acid 8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl ester (0.090 g, 0.24 mmol), 5-fluoro-3-piperidin-3-ylmethyl-1H-indole (0.56 g, 0.24 mmol) and triethylamine (0.042 mL, 0.36 mmol) in dimethylsulfoxide (10 mL) was heated at 90° C. under nitrogen overnight. The reaction mixture was quenched with 1N sodium hydroxide and extracted with methylene chloride (3×50 mL). The organic layer was washed with water (3×50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum. The crude oil was column chromatographed on silica gel (5% methanol-75% ethyl acetate-20% hexane). The product-containing fractions were concentrated in vacuum to give 0.048 g (53%) of the (S)-enantiomer of the title compound as a brown oil. The dihydrochloride salt was prepared in ethyl acetate and collected as 0.037 g of a yellow solid, m.p. 68° C. (dec).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:30][CH2:31][CH3:32])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH:27]([F:29])[F:28])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[F:13])[CH2:4]1.[Si]([O:40][CH2:41][CH:42]=O)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[NH2:26][C:25]1[N:24]=[CH:23][N:22]=[C:21]2[N:17]([CH:15]([C:9]3[C:8]([O:30][CH2:31][CH3:32])=[C:7]([CH:5]4[CH2:6][N:3]([CH2:42][CH2:41][OH:40])[CH2:4]4)[C:12]([F:13])=[C:11]([Cl:14])[CH:10]=3)[CH3:16])[N:18]=[C:19]([CH:27]([F:29])[F:28])[C:20]=12
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: CCOc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(Cl)c(F)c1C1CNC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Product: CCOc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(Cl)c(F)c1C1CN(CCO)C1

Procedure:
This compound was prepared using procedures analogous to those for Example 1 step 8, with 1-[1-(3-azetidin-3-yl-5-chloro-2-ethoxy-4-fluorophenyl)ethyl]-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (racemic) and {[tert-butyl(dimethyl)silyl]oxy}acetaldehyde as starting materials. After reductive amination, tetrabutylammonium fluoride was added to remove the tert-butyl(dimethyl)silyl group. The product was isolated as a racemic mixture. LCMS calculated for C21H25ClF3N6O2 (M+H)+: m/z=485.2; Found: 485.2. 1H NMR (300 MHz, DMSO-d6): δ 8.23 (s, 1H), 7.38 (m, 2H), 6.29 (m, 1H), 3.78-3.67 (m, 4H), 3.53 (m, 1H), 3.12 (m, 2H), 2.99-2.87 (m, 2H), 2.34 (m, 2H), 1.68 (d, 3H), 1.22 (m, 3H) ppm.
Reaction SMILES: N#N.[Cl:3][CH2:4][C:5]1[N:6]=[C:7]([CH:10]([OH:12])[CH3:11])[S:8][CH:9]=1>C(C#N)(C)=O.O=[Mn]=O>[Cl:3][CH2:4][C:5]1[N:6]=[C:7]([C:10](=[O:12])[CH3:11])[S:8][CH:9]=1
Reactant: CC(O)c1nc(CCl)cs1
Agent: O=[Mn]=O
Agent: CC(=O)C#N
Agent: N#N
Product: CC(=O)c1nc(CCl)cs1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-(4-chloromethyl-thiazol-2-yl)-ethanol (1.09 g, 6.15 mmol) in AcCN (61.0 mL) was treated at rt with MnO2 (2.97 g, 30.76 mmol) and the reaction mixture was stirred for 16 h at rt before being filtered through Celite. The solvent was removed under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 02: tR=0.84 min, [M+H]+=176.41.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][N:2]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N1CCOCC1)C.[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][O:38][C:39]2[CH:47]=[CH:46][C:45]([CH:48]=[O:49])=[CH:44][C:40]=2[C:41](O)=[O:42])=[CH:33][CH:32]=1>CN(C)C=O>[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][O:38][C:39]2[CH:47]=[CH:46][C:45]([CH:48]=[O:49])=[CH:44][C:40]=2[C:41]([NH:7][C:4]2[CH:5]=[CH:6][N:1]=[N:2][CH:3]=2)=[O:42])=[CH:33][CH:32]=1
Reactant: O=Cc1ccc(OCc2ccc(F)cc2)c(C(=O)O)c1
Reactant: Nc1ccnnc1
Agent: CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=Cc1ccc(OCc2ccc(F)cc2)c(C(=O)Nc2ccnnc2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-Pyridazinamine (0.52 g, 5.47 mmol), EDC (0.84 g, 4.38 mmol), HOBT (0.89 g, 5.83 mmol) and N-ethylmorpholine (0.92 ml, 7.29 mmol) were added to a solution of 2-{[(4-fluorophenyl)methyl]oxy}-5-formylbenzoic acid (may be prepared by Description 105; 1 g, 3.65 mmol) in N,N-dimethylformamide (25 ml), and the mixture was stirred at room temperature for 4 hrs. The N,N-dimethylformamide was evaporated under reduced pressure on a buchi. Saturated aqueous sodium hydrogen carbonate (50 ml) and ethyl acetate (100 ml) were added to the residue and the mixture was stirred for 30 mins. The organics were separated and washed with water (50 ml), dried (MgSO4) and evaporated under reduced pressure to yield the title compound as a pale yellow solid. No further purification. No further purification carried out. 0.98 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[CH:9]([O:13][CH3:14])[C:10]([OH:12])=O.[NH2:15][CH2:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1>>[C:16]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH:22][C:10](=[O:12])[CH:9]([C:3]2[C:4]([OH:8])=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[O:13][CH3:14])=[CH:19][CH:18]=1)#[N:15]
Reactant: N#Cc1ccc(CN)cc1
Reactant: COC(C(=O)O)c1c(O)cccc1F
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1c(O)cccc1F

Procedure:
(RS)-(2-Fluoro-6-hydroxy-phenyl)-methoxy-acetic acid was reacted with 4-aminomethyl benzonitrile according to general procedure C to give (RS)-N-(4-cyano-benzyl)-2-(2-fluoro-6-hydroxy-phenyl)-2-methoxy-acetamide. Colorless solid. MS 315.1 ([M+H]+)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([C:24]4[N:25]=[N:26][N:27]([CH:29]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]5)[CH:28]=4)=[CH:23][C:18]=3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH:36]C(=O)C)[CH:10]=1.[CH:40]1([S:43](Cl)(=[O:45])=[O:44])[CH2:42][CH2:41]1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([C:24]4[N:25]=[N:26][N:27]([CH:29]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]5)[CH:28]=4)=[CH:23][C:18]=3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH:36][S:43]([CH:40]2[CH2:42][CH2:41]2)(=[O:45])=[O:44])[CH:10]=1
Reactant: CC(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cn(C5CCN(C)CC5)nn4)ccc32)c1
Reactant: O=S(=O)(Cl)C1CC1
Product: CN1CCC(n2cc(-c3ccc4c(c3)ncn4-c3cc(NS(=O)(=O)C4CC4)cc(-c4ccc(F)cc4F)c3)nn2)CC1

Procedure:
The compound was prepared from the compound of Example 164 using the procedures of Example 165 and cyclopropane sulfonyl chloride. LC-MS (ESI): Calculated mass: 553.61; Observed mass: 554.2 [M+H]+ (rt: 0.57 min).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](O)[CH:5]=[CH:6][C:7]=1[C:8](=[O:18])[CH:9]([CH3:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[F:20][C:21]1[CH:22]=[C:23]([C:36]2[CH:41]=[CH:40][C:39]([C:42]([OH:44])=[O:43])=[CH:38][CH:37]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>>[F:1][C:2]1[CH:3]=[C:4]([C:37]2[CH:38]=[C:39]([C:42]([OH:44])=[O:43])[CH:40]=[CH:41][C:36]=2[C:23]2[CH:24]=[CH:25][C:26]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[C:21]([F:20])[CH:22]=2)[CH:5]=[CH:6][C:7]=1[C:8](=[O:18])[CH:9]([CH3:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1F
Reactant: CCCCCCCC(C)C(=O)c1ccc(O)cc1F
Product: CCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2-c2ccc(C(=O)C(C)CCCCCCC)c(F)c2)cc1F

Procedure:
The same procedure as in Example 20 was repeated, except that (+)-3-fluoro-4-(2-methylnonanoyl) phenol was used instead of (+)-3-fluoro-4-(2-methyloctanoyl) phenol in Example 20 and 3'-fluoro-4'-octyloxybiphenyl-4-carboxylic acid was used instead of 3-fluoro-4-heptyloxy benzoic acid in Example 20, to obtain an objective compound having the aforementioned physical and chemical properties.
Reaction SMILES: [P:1]([O:8][CH2:9][CH3:10])([O:5]CC)[O:2][CH2:3][CH3:4].Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].BrCC>>[CH2:9]([O:8][P:1]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])([O:2][CH2:3][CH3:4])=[O:5])[CH3:10]
Reactant: CCOC(=O)CBr
Reactant: CCOP(OCC)OCC
Solvent: CCBr
Product: CCOC(=O)CP(=O)(OCC)OCC
Temperature: 100 °C
Yield: 95 %

Procedure:
100 parts by weight of triethyl phosphite and 100 parts by weight of ethyl bromoacetate were put into a reactor equipped with a distillation tube, and the inside of the reactor was substituted by nitrogen. Subsequently, the reactor was heated at 100° C. to start a reaction. Since bromoethane as a by-product began to distill out immediately, the reaction was maintained until the distillation-out of bromoethane slowed down. When the distillation-out of bromoethane became moderate, the reactor was further heated at 150° C. to continue the reaction for 3 hours. The reaction mixture was distilled at 180° C. under a normal pressure to obtain an achromatic transparent liquid (yield of 95%, boiling point of 177° C./760 mmHg).
Reaction SMILES: CO[C:3]1[C:4](=[O:22])[N:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:6][CH2:7][C:8]=1[C:9](=O)[CH2:10][CH3:11].Cl.Cl.[CH:25]1([NH:30][NH2:31])[CH2:29][CH2:28][CH2:27][CH2:26]1>O1CCCC1>[CH:25]1([N:30]2[C:3]3[C:4](=[O:22])[N:5]([CH2:13][C:14]4[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=4)[CH2:6][CH2:7][C:8]=3[C:9]([CH2:10][CH3:11])=[N:31]2)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CCC(=O)C1=C(OC)C(=O)N(Cc2ccc(OC)cc2)CC1
Reactant: NNC1CCCC1
Agent: Cl
Solvent: C1CCOC1
Product: CCc1nn(C2CCCC2)c2c1CCN(Cc1ccc(OC)cc1)C2=O
Temperature: 88 °C

Procedure:
3-Methoxy-1-(4-methoxybenzyl)-4-propionyl-5,6-dihydro-1H-pyridin-2-one (14.471 kg, 47.76 moles) was dissolved in tetrahydrofuran (10.5 gal, 39.7 L) in a clean and dry 100 gallon tank. Cyclopentylhydrazine dihydrochloride (7.664 kg, 44.3 moles) was added and the reaction mixture warmed slowly to 88° C. while nitrogen was swept over the reaction to remove methanol, THF, and HCl. The reaction was monitored by HPLC until the conversion was complete which required heating overnight in most cases. The pot reaction product was a thick dark oil. A sample of 1-cyclopentyl-3-ethyl-6-(4-methoxybenzyl)-1,4,5,6-tetrahydropyrazolo[3,4-c]pyridin-7-one was isolated for characterization.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[CH2:18]([OH:21])[CH2:19][OH:20].[OH-].[Na+]>O>[OH:20][CH2:19][CH2:18][O:21][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Reactant: OCCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(OCCO)c(C(F)(F)F)c1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
27 g of 4-chloro-5-trifluoromethyl-1,3-dinitrobenzene are initially introduced into 37 g of ethylene glycol, and 11.4 g of 50 percent strength aqueous sodium hydroxide solution are added dropwise at 45° C. in the course of 20 minutes. The mixture is subsequently stirred at 45° C. for 1 hour, a further 1.5 g of sodium hydroxide solution are added, the mixture is subsequently stirred at 45° C. for 1 hour, a furthere 1.5 g of sodium hydroxide solution are added, the mixture is subsequently stirred at 45° C. for a further hour and 200 ml of water are then added. The oil which has separated out is separated off, washed twice with 30 ml of water each time and dissolved in 75 ml of ethyl acetate and the solution is washed again with water. The ethyl acetate phase is then dried and concentrated.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Br.[F:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2.[H-].[Na+].O>CN(C=O)C>[CH2:1]([N:12]1[C:13]2[C:9](=[CH:8][C:7]([F:6])=[CH:15][CH:14]=2)[CH:10]=[CH:11]1)[CH:3]1[O:5][CH2:4]1
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: BrCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc2c(ccn2CC2CO2)c1
Temperature: 60 °C
Yield: 87.2 %

Procedure:
Epibromohydrin (1.4 ml, 16.5 mmole) was added to a stirred solution of 5-fluoroindole (2.0 g, 15 mmole) and sodium hydride (0.66 g, 16.5 mmole) in anhydrous DMF (20 ml), and the mixture was heated at 60° C. under nitrogen for 15 hours. Water (100 ml) was added and the product extracted into CH2Cl2 (3×35 ml). The combined organics were washed with water (25 ml), brine (25 ml) and dried over anhydrous sodium sulfate. Filtration and concentration in vacuo gave the crude product as a viscous yellow colored oil (2.7 g). This was purified by flash silica gel chromatography (30% ethyl acetate in hexane) to afford the titled product as a viscous oil (2.5 g, 89% yield).
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH:8](P(OCC)(OCC)=O)[CH3:9])=[O:7].[CH2:18]([C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[C:22]([O:34][CH2:35][O:36][CH3:37])=[C:23]([O:32][CH3:33])[CH:24]=[C:25]2[CH:30]=O)[CH3:19].O>CN(C)C=O>[CH2:18]([C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[C:22]([O:34][CH2:35][O:36][CH3:37])=[C:23]([O:32][CH3:33])[CH:24]=[C:25]2/[CH:30]=[C:8](\[CH3:9])/[C:6]([O:5][CH2:4][CH3:3])=[O:7])[CH3:19]
Reactant: CCc1cccc2c(C=O)cc(OC)c(OCOC)c12
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C(C)=C/c1cc(OC)c(OCOC)c2c(CC)cccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
36 g of 60% sodium hydride was suspended in 500 ml of N,N-dimethylformamide and 268 g of triethyl 2-phosphonopropionate was added at ice bath temperature. After stirring at room temperature for 1 hour, a solution of 206 g of 5-ethyl-3-methoxy-4-methoxymethoxy-1-naphthalenecarbaldehyde was added. After stirring at room temperature for 15 minutes, ice cooled water was gradually added at ice bath temperature. The mixture was extracted with ethyl acetate and the combined organic layer was washed with brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the residue was purified by silica gel column chromatography (10% ethyl acetate/hexane) to obtain 262.4 g of the titled compound as a yellow oil (containing a small amount of Z isomer).
Reaction SMILES: [S:1](=[O:15])(=[O:14])([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][CH2:12][CH3:13])[NH2:2].[CH3:16][O:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([NH:26][C:27](=O)[O:28]C2C=CC=CC=2)[N:19]=1.N12CCCN=C1CCCCC2>C(#N)C>[CH3:25][O:24][C:22]1[CH:23]=[C:18]([O:17][CH3:16])[N:19]=[C:20]([NH:26][C:27](=[O:28])[NH:2][S:1]([O:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:10][CH2:11][CH2:12][CH3:13])(=[O:14])=[O:15])[N:21]=1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Reactant: CCCOc1ccccc1OS(N)(=O)=O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCCOc1ccccc1OS(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.4 %

Procedure:
1.74 g (0.008 mol) of 2-propoxyphenyl sulfamate are added at room temperature to 2.32 g (0.0084 mol) of phenyl N-(4,6-dimethoxypyrimidin-2-yl)carbamate, dissolved in 100 ml of acetonitrile. After 1.33 g (0.0088 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) have been added, the reaction mixture is stirred at room temperature for 18 hours, concentrated, diluted with H2O and acidified using 2N hydrochloric acid to give a pH of 3-4. After the solids have been filtered off with suction and dried, 2.85 g (86% of theory) of 3-(4,6-dimethoxypyrimidin-2-yl)- 1-(2-propoxyphenoxysulfonyl)urea of melting point 108°-109° C. are obtained.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([C:9]2[N:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]3=[N:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1.[NH2:18][C:19]1[CH:20]=[C:21]([CH:30]=[CH:31][CH:32]=1)[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23].[H-].[Na+]>CN(C)C=O>[C:22]([C:21]1[CH:20]=[C:19]([CH:32]=[CH:31][CH:30]=1)[NH:18][C:3]1[N:8]=[C:7]([C:9]2[N:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]3=[N:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1)(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cccc(C(=O)c2ccccc2)c1
Reactant: CSc1nccc(-c2cnc3ccccn23)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)c1cccc(Nc2nccc(-c3cnc4ccccn34)n2)c1
Temperature: 130 °C
Yield: 11.9 %

Procedure:
To a solution of 2-methylsulfanyl-4-(imidazo-[1,2-a]pyridin-3-yl)pyrimidine (0.146 g, 0.60 mmol) and 3-aminobenzophenone (0.238 g, 1.21 mmol) in N,N-dimethylformamide (2.5 mL) was added sodium hydride (0.061 g, 1.52 mmol) and the mixture was heated at 130° C. for 4 hours. The mixture was allowed to cool to room temperature and the solvent was removed. The residue was dissolved in water and the resulting solid was washed with water and chloroform. The organic phase was dried over MgSO4 and the solvent was evaporated. The crude product was purified by column chromatography on silica gel using chloroform/ethanol, 9:1, as the eluent affording 0.028 g (12% yield) of the title compound as a yellow solid: mp (decomp.) 237-246° C.; MS (TSP) m/z 392 (M+1); 1H NMR (400 MHz, DMSO-d6) δ 10.25 (d, J=6.3 Hz, 1 H), 10.15 (s, 1 H), 8.74 (s, 1 H), 8.55 (d, J=5.4 Hz, 1 H), 8.29 (s, 1 H), 8.25 (d, J=8.1 Hz, 1 H), 7.87 (m, 3 H), 7.78 (t, J=7.4 Hz, 1 H), 7.67 (m, 2 H), 7.60 (m, 2 H), 7.55 (d, J=5.4 Hz, 1 H), 7.44 (d, J=7.5 Hz, 1 H), 7.20 (m, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][OH:13].Cl.[O-:15][C:16]#N.[K+]>O>[OH:13][CH2:12][CH2:11][CH2:10][N:9]1[C:3]2[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[NH:1][C:16]1=[O:15]
Reactant: N#C[O-]
Reactant: Cc1ccc(NCCCO)c(N)c1
Agent: Cl
Agent: [K+]
Solvent: O
Product: Cc1ccc2c(c1)[nH]c(=O)n2CCCO
Temperature: 25 °C
Reaction time: 24 h
Yield: 31 %

Procedure:
To a stirred and cooled solution of 54 parts of 3-[(2-amino-4-methylphenyl)amino]-1-propanol in 30 parts of hydrochloric acid solution 10% and 200 parts of water is added dropwise a solution of 28 parts of potassium cyanate in 50 parts of water at a temperature below 10° C. Upon completion, stirring is continued first for 1 hour at room temperature and further for 24 hours at reflux temperature. After cooling to room temperature, the product is extracted with trichloromethane. The extract is washed with a hydrochloric acid solution 5%, dried, filtered and evaporated. The residue is crystallized from 4-methyl-2-pentanone, yielding 19.5 parts (31%) of 1,3-dihydro-1-(3-hydroxypropyl)-5-methyl-2H-benzimidazol-2-one; mp. 114.1° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([O:14]CC2C=CC=CC=2)=[C:9]([CH2:22][CH3:23])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]>C1COCC1.C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:24])[C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([OH:14])=[C:9]([CH2:22][CH3:23])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1cc(C(=O)OC(C)(C)C)cc(C)c1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1cc(C(=O)OC(C)(C)C)cc(C)c1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 109.3 %

Procedure:
To a solution of 4-benzyloxy-3-ethyl-5-methyl-benzoic acid tert-butyl ester (9.02 g, 27.6 mmol) in THF (50 mL) and ethanol (50 mL), Pd/C (400 mg, 10% Pd) is added. The slurry is stirred at rt for 24 h under 1 bar of H2. The catalyst is removed by filtration and the filtrate is concentrated, dissolved again in THF (50 mL) and ethanol (50 mL), and again treated with Pd/C (400 mg, 10% Pd). The slurry is stirred at rt for 24 h under 1 bar of H2. The catalyst is again removed by filtration and the filtrate is concentrated and dried to give 3-ethyl-4-hydroxy-5-methyl-benzoic acid tert-butyl ester as a pale yellow oil (7.13 g). LC-MS: tR=1.01 min; 1H NMR (CDCl3): δ 1.28 (t, J=7.8 Hz, 3H), 1.61 (s, 9H), 2.30 (s, 3H), 2.67 (q, J=7.5 Hz, 2H), 5.13 (br s, 1H), 7.67 (s, 1H), 7.69 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][CH:12]=[N:11][C:10]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[I:29]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C1COCC1.CCOC(C)=O>[I:29][C:12]1[O:13][C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:11]=1
Reactant: CCOC(=O)c1ncoc1-c1ccc(OC)cc1
Reactant: II
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S([O-])([O-])=S
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(I)oc1-c1ccc(OC)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
To a solution of ethyl 5-(4-methoxyphenyl)oxazole-4-carboxylate (2.75 g, 11.1 mmol) in anhydrous THF (20 mL) under an N2 atmosphere at −78° C. was added 1M lithium bis(trimethylsilyl)amide in THF (18 mL, 18 mmol), dropwise. The reaction mixture was stirred at −78° C. for one hour. A solution of iodine (5.0 g, 19.7 mmol) in anhydrous THF (10 mL) was added dropwise and the reaction stirred at −78° C. for a further 1 hour. The mixture was then warmed to −10° C. and 10% sodium thiosulfate solution and EtOAc was added. The aqueous phase was extracted with EtOAc and the combined organic phase was washed with brine, dried over MgSO4 and the solvent removed in vacuo. The residue was purified by silica gel column chromatography using a 10-40% EtOAc in hexanes gradient to afford ethyl 2-iodo-5-(4-methoxyphenyl)oxazole-4-carboxylate (3.33 g, 8.9 mmol, 80%) as a white solid. 1H NMR (CDCl3) 1.40 (3H, t), 3.87 (3H, s), 4.41 (2H, q), 6.98 (2H, d), 8.01 (2H, d). LCMS (1) Rt: 2.13 min; m/z (ES+) 374.