Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([O:18][C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[C:28]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])(=[O:31])[NH:29][NH2:30].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>ClCCl>[C:33]([O:32][C:28]([NH:29][NH:30][C:23](=[O:24])[C:22]1[CH:21]=[CH:20][C:19]([O:18][C@H:15]2[CH2:16][CH2:17][C@H:12]([C:10]([N:7]3[CH2:6][CH2:5][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:9][CH2:8]3)=[O:11])[CH2:13][CH2:14]2)=[CH:27][CH:26]=1)=[O:31])([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](Oc3ccc(C(=O)O)cc3)CC2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](Oc3ccc(C(=O)NNC(=O)OC(C)(C)C)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 420 mg (0.93 mmol) of trans-4-[4-(4-Isopropyl-piperazine-1-carbonyl)-cyclohexyloxy]-benzoic acid, 156 mg (1.18 mmol) of tert-butyl carbazate, 272 mg (1.42 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 192 mg (1.42 mmol) of 1-hydroxybenzotriazole, and 574 mg (5.67 mmol) of N-methylmorpholine in 10 ml of dichloromethane was stirred for 3 h at room temperature. After evaporation, the mixture was diluted with AcOEt, washed with water and saturated NaHCO3 solution, dried over Na2SO4, and evaporated. The residue was purified by column chromatography on silica eluting with dichloromethane and methanol=from 98:2 to 19:1. The combined product fractions were evaporated to dryness to yield 0.46 g (quant.) of the title compound. MS (m/e): 489.4 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:6]C(=O)N[C:3]1=[O:8].[OH-:17].[Na+].Cl>O>[CH3:1][C@@:2]([C:3]([OH:17])=[O:8])([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH2:6]
Reactant: CC1(CCc2ccccc2)NC(=O)NC1=O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: C[C@](N)(CCc1ccccc1)C(=O)O

Procedure:
54.6 g 5-methyl-5-phenethyl-hydantoin (0.25 Mol) are reacted with 30 g sodium hydroxide (0.75 Mol) and 150 ml water for 3.5 hours in an autoclave at an oil bath temperature of 180° C. After cooling, 350 ml H2O are added and the clear, light brown solution adjusted with hydrochloric acid to pH 7.0. The white precipitate is suctioned off, washed with 20 mg H2O and dried in a vacuum drying cabinet at 65° C. The produce is recrystallized twice from water.
Reaction SMILES: S([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19]C)=[O:18])[CH:15]=2)[C:10]([CH3:21])=[N:9]1)(C(F)(F)F)(=O)=O.C(=O)([O-])[O-].[K+].[K+].Cl>CO.O>[CH3:21][C:10]1[C:11]2[C:16](=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][CH:12]=2)[NH:8][N:9]=1
Reactant: COC(=O)c1ccc2c(C)nn(S(=O)(=O)C(F)(F)F)c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1n[nH]c2cc(C(=O)O)ccc12
Temperature: 25 °C
Yield: 98.6 %

Procedure:
A solution of methyl 1-triflyl-3-methyl-indazole-6-carboxylate (0.668 g, Reference Example 46) in a mixture of methanol and water (3:1, 80 ml) was treated with potassium carbonate (1.15 g). The mixture was heated at reflux for 5 hours then cooled to room temperature then poured into 1N hydrochloric acid (50 ml). The mixture was extracted three times with ethyl acetate (50 ml). The combined extracts were dried over sodium sulphate then evaporated. The residue was washed with a mixture of hexane and ether to give the title compound (0.360 g).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH3:7])[C:4]([OH:6])=[O:5].[C:10](OC(=O)C)(=[O:12])[CH3:11].[C:17](O)(=[O:19])[CH3:18]>>[C:10]([O:1][CH2:2][C:3]([CH2:8][O:9][C:17](=[O:19])[CH3:18])([CH3:7])[C:4]([OH:6])=[O:5])(=[O:12])[CH3:11]
Reactant: CC(=O)O
Reactant: CC(=O)OC(C)=O
Reactant: CC(CO)(CO)C(=O)O
Product: CC(=O)OCC(C)(COC(C)=O)C(=O)O

Procedure:
268 g (2 moles) of 2,2-bis-hydroxymethyl propionic acid are refluxed for 10 hours in 800 ml of glacial acetic acid and 416 ml (4.4 moles) of acetic acid anhydride. The reaction solution is freed from the solvent in vacuo. The oily residue is stirred with 1500 ml of petroleum ether, the carboxylic acid ester is crystallizing out. It is filtered off under suction and washed with petroleum ether. Yield 420 g (96% of the theoretical); Mp. 85° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21].[Cl-].[Al+3].[Cl-].[Cl-].COC1C=C(C(C2C=CC(OC)=CC=2)=CC#N)C=CC=1OC>C(Cl)Cl>[CH3:12][O:13][C:14]1[CH:19]=[C:18]([C:6]([C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:7])[CH:17]=[CH:16][C:15]=1[O:20][CH3:21]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: COc1ccccc1OC
Agent: COc1ccc(C(=CC#N)c2ccc(OC)c(OC)c2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cccc(C(=O)c2ccc(OC)c(OC)c2)c1
Yield: 110 %

Procedure:
3-methoxybenzoyl chloride (2.06 ml, 14.65 mmol), 1,2-dimethoxybenzene (1.87 ml, 14.65 mmol) in anhydrous methylene chloride (25 ml), and aluminum chloride (2.15 g, 16.12 mmol) were treated in the same manner as described above for the synthesis of 3-(3,4-dimethoxy-phenyl)-3-(4-methoxy-phenyl)-acrylonitrile. The crude was purified via flash column chromatography (20% EtOAc in hexane) to give (3,4-dimethoxy-phenyl)-(3-methoxy-phenyl)-methanone as a yellow oil (4.39 g, 100%); 1HNMR (CDCl3) δ 7.50 (d, J=1 Hz, 1H, Ar), 7.42-7.30 (m, 4H, Ar), 7.14-7.09 (m, 1H, Ar), 6.90 (d, J=8 Hz, 1H, Ar), 3.96 (s, 3H, OCH3), 3.95 (s, 6H, 2OCH3), 3.86 (s, 3H, OCH3); 13C NMR (CDCl3) δ 195.4, 159.6, 153.1, 149.1, 139.7, 130.3, 129.2, 125.6, 122.5, 118.3, 114.4, 112.3, 109.9, 56.2, 56.2, 55.6; Anal. Calcd. For C16H16O4: C, 70.58; H, 5.92. Found: C, 70.38; H, 5.99; N, <0.05. The product was carried over to the next step.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.[C:11](=O)([O-])[O-].[K+].[K+].S([O:21][CH3:22])(OC)=O>>[CH3:11][O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:21][CH3:22])=[O:7])=[CH:4][CH:3]=1
Reactant: COS(=O)OC
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc(O)cc1
Agent: [K+]
Product: COC(=O)c1ccc(OC)cc1
Temperature: 100 °C
Yield: 110 %

Procedure:
To a 100 ml three-necked flask equipped for reflux and fitted with a mechanical stirrer was added 2.0 g (0.014 mol) of p-hydroxybenzoic acid, 1.0 g. (0.007 mol) of potassium carbonate, and 5.0 ml (0.059 mol) of dimethyl sulfite. The mixture was heated at 100° C. for four hours and then quenched with 15 ml of water. The organics were taken up with methylene chloride and washed sequentially with 12% caustic solution and water. The extracts were concentrated in vacuo to give 1.28 g of methyl p-methoxybenzoate.
Reaction SMILES: C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)[C:8](=[O:19])[NH:9][C:10]2[S:11][CH:12]=[C:13](CC(O)=O)[N:14]=2)CCCC1.[CH:30]1([CH2:34][NH:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[C:38]([F:43])[CH:37]=2)[CH2:33][CH2:32][CH2:31]1.C([O:46][C:47](=[O:56])[CH2:48][S:49]C1SC(N)=NC=1)C>>[CH:30]1([CH2:34][N:35]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[C:38]([F:43])[CH:37]=2)[C:8](=[O:19])[NH:9][C:10]2[S:11][C:12]([S:49][CH2:48][C:47]([OH:56])=[O:46])=[CH:13][N:14]=2)[CH2:31][CH2:32][CH2:33]1
Reactant: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Reactant: Fc1ccc(NCC2CCC2)cc1F
Reactant: CCOC(=O)CSc1cnc(N)s1
Product: O=C(O)CSc1cnc(NC(=O)N(CC2CCC2)c2ccc(F)c(F)c2)s1

Procedure:
The title compound was prepared via {2-[3-cyclbutylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclobutylmethyl-(3,4-difluorophenyl)-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:30]=[CH:31][CH:32]=2)[CH2:23][CH2:22]1.C(N(CC)CC)C>C1COCC1>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:33][C:34](=[O:38])[CH:35]([CH3:36])[CH3:37])[CH:30]=[CH:31][CH:32]=3)[CH2:23][CH2:22]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccccc3)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 67 %

Procedure:
A mixture of 2,2-diphenylacetyl chloride (0.300 mmol, 69.2 mg), N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide (0.250 mmol, 75.8 mg) and triethylamine (0.500 mmol, 50.5 mg) was dissolved in THF (2.00 mL) and the mixture was shaken on an Orbital J-KEM Shaker at room temperature for 12 h. The reaction mixture was concentrated in vacuo, and the residue was purified by preparative TLC [silica, CH2Cl2: ammonia (2.0 M in methanol) 100:5] to afford the desired product (83.3 mg, 62% yield): 1H NMR (400 MHz, CDCl3) δ 7.51 (s, 1H), 7.33–7.21 (m, 13H), 6.94 (m, 2H), 4.88 (s, 1H), 3.39 (t, 2H, J=5.6 Hz), 2.93 (d, 2H, J=11.3 Hz), 2.52–2.36 (m, 4H), 1.97 (t, 2H, J=11.3 Hz), 1.83–1.58 (m, 6H), 1.24 (d, 6H, J=7.6 Hz); Anal. Calcd for C32H39N3O2+HCl+0.19CHCl3: C, 69.44; H, 7.27; N, 7.55. Found: C, 69.44; H, 7.43; N, 7.43; ESMS m/e: 498.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH:12]=[CH2:13].C1C=C(Cl)C=C(C(OO)=[O:22])C=1>C(Cl)Cl>[Cl:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:13][O:22]1
Reactant: C=Cc1ccc2c(c1Cl)COC2=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C1OCc2c1ccc(C1CO1)c2Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-chloro-5-ethenyl-2-benzofuran-1(3H)-one (1.1 g, 5.7 mmol) in DCM (40 mL) was added mCPBA (1.9 g, 8.5 mmol). The solution was allowed to stir at RT for 16 hours. Analysis by TLC and LC showed formation of the desired product. The reaction was diluted with DCM (200 mL), washed with aqueous Na2S2O3 and Na2CO3, dried over sodium sulfate, concentrated, and purified by silica gel flash chromatography to afford title compound. 1H-NMR (500 MHz, CDCl3) δ ppm 7.86 (d, J=8.0 Hz, 1H), 7.48 (d, J=8.0 Hz, 1H), 5.34 (s, 2H), 4.33 (m, 1H), 3.33 (m, 1H), 2.75 (m, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([OH:7])=O.S(Cl)(Cl)=O.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1>CN(P(N(C)C)(N(C)C)=O)C.C(#N)C>[C:29]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[NH:22][S:19]([C:16]1[CH:17]=[CH:18][C:13]([N:12]2[CH2:2][CH2:3][CH2:4][C:5]2=[O:7])=[CH:14][CH:15]=1)(=[O:21])=[O:20])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Nc1ccc(S(=O)(=O)Nc2ccccc2C(=O)c2ccccc2)cc1
Reactant: O=C(O)CCCBr
Solvent: O=S(Cl)Cl
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC#N
Product: O=C(c1ccccc1)c1ccccc1NS(=O)(=O)c1ccc(N2CCCC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 474 mg (2.84 mmol) of 4-bromo-butanoic acid in 6 mL of 5:1 HMPA/acetonitrile was cooled to 0 deg and thionyl chloride (0.207 mL, 2.84 mmol) was added. The reaction mixture was warmed to room temperature, and transferred to a flask containing 250 mg (0.709 mmol) of neat 4-amino-N-(2-benzoylphenyl)benzenesulfonamide. The solution was allowed to stir overnight. The reaction was quenched w/saturated sodium bicarbonate and diluted with EtOAc (˜100 mL), washed with water (3×20 mL) and brine (1×20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via flash chromatography (15% to 75% EtOAc/hexanes)to provide the title compound. LC/MS (ES MS, M+H+ found: 457).
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](=[S:14])[NH2:13])=[CH:8]2.Br[CH:24]([CH:27]=O)[CH:25]=[O:26].CN(C)C(=O)C>O>[OH:26][CH2:25][C:24]1[S:14][C:12]([C:9]2[NH:10][C:11]3[C:7]([CH:8]=2)=[CH:6][CH:5]=[CH:4][C:3]=3[N:2]([CH3:1])[S:15]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)(=[O:17])=[O:16])=[N:13][CH:27]=1
Reactant: O=CC(Br)C=O
Reactant: CN(c1cccc2cc(C(N)=S)[nH]c12)S(=O)(=O)c1cccs1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN(c1cccc2cc(-c3ncc(CO)s3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 80 °C
Reaction time: 3 h
Yield: 37.3 %

Procedure:
A mixture of 7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (1.00 g), bromomalonaldehyde (0.86 g) and N,N-dimethylacetamide (8 ml) was stirred at 80° C. for 3 hr. Water was added to the reaction mixture, and the resulting crystals were collected by filtration, washed with water, and dried. The obtained crystals were dissolved in tetrahydrofuran (8 ml) and methanol (8 ml), sodium borohydride (63 mg) was added at 0° C., and the mixture was stirred at 0° C. for 1 hr. The reaction mixture was concentrated, 10% aqueous citric acid solution was added, and the resulting crystals were collected by filtration, washed with water, and dried. The crystals were subjected to silica gel column chromatography to give the title compound (0.43 g, yield 39%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (3:1, volume ratio). melting point 201-202° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]3[N:16]4[N:17]=[C:18]([C:21]#[N:22])[CH:19]=[CH:20][C:15]4=[N:14][CH:13]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-:23].[Na+].Cl.[C:26](Cl)(=O)[C:27](Cl)=O.C(N)C>CO>[CH2:26]([NH:22][C:21]([C:18]1[CH:19]=[CH:20][C:15]2[N:16]([C:12]([CH2:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)=[CH:13][N:14]=2)[N:17]=1)=[O:23])[CH3:27]
Reactant: [OH-]
Reactant: O=C(Cl)C(=O)Cl
Reactant: N#Cc1ccc2ncc(Cc3ccc4ncccc4c3)n2n1
Agent: CCN
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCNC(=O)c1ccc2ncc(Cc3ccc4ncccc4c3)n2n1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
3-Quinolin-6-ylmethyl-imidazo[1,2-b]pyridazine-6-carbonitrile (Example 208; 43 mg, 0.15 mmol) in a 1 M aqueous solution of NaOH (1.8 mL, 1.8 mmol) was heated under microwave irradiation at 200° C. for 30 min. The RM was quenched with a 2 M aqueous solution of HCl (0.9 mL, 1.8 mmol) and diluted with MeOH and filtered over Celite. The filtrate is evaporated and dry under vacuo. The residue was suspended in DCM (3 mL) and cooled at 0° C. Were added DMF (0.01 mL) and, slowly, oxalyl chloride (0.055 mL, 0.65 mmol). The RM was allowed to reach rt and stirred at this temperature for 45 min. The RM was dropped in a 2 M solution of ethylamine in MeOH (6 mL). The RM was stirred at rt for 5 min before being evaporated to dryness and the residue quenched with aqueous saturated NaHCO3 and diluted with EtOAc. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine and dried over Na2SO4, filtered and evaporated. The residue was purified by preparative HPLC with acetonitrile and water (+0.1% TFA) to yield the title compound as light yellow solid (tR 1.96 min (conditions 8), MH+=332).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].[Cl:12][C:13]1[N:14]=[C:15](Cl)[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[S:19][C:17]=2[N:18]=1>>[Cl:12][C:13]1[N:14]=[C:15]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:16]2[CH:21]=[C:20]([C:22]([F:24])([F:25])[F:23])[S:19][C:17]=2[N:18]=1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: FC(F)(F)c1cc2c(Cl)nc(Cl)nc2s1
Product: O=[N+]([O-])c1cccc(CNc2nc(Cl)nc3sc(C(F)(F)F)cc23)c1

Procedure:
Following the procedure of Example 1, the reaction of 3-nitrobenzylamine with 2,4-dichloro-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-6-trifluoromethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [O:1]1[CH2:4][CH:3]([OH:5])[CH2:2]1.[Br:6][C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(OCC)(=O)C>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([O:5][CH:3]2[CH2:4][O:1][CH2:2]2)=[CH:9][CH:8]=1
Reactant: OC1COC1
Reactant: Oc1ccc(Br)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Brc1ccc(OC2COC2)cc1
Temperature: 110 °C
Reaction time: 17 h
Yield: 52.7 %

Procedure:
To oxetan-3-ol (112 mg, 1.5 mmol) in THF (5 mL) was added 4-bromophenol (200 mg, 1.16 mmol), polymeric triphenylphosphine (0.5 g, 1.5 mmol) and DIAD (305 mg, 1.5 mmol). The reaction mixture was degassed with nitrogen for 2 min and stirred at 110° C. for 17 hours. The cooled reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue, which was dissolved in ethyl acetate (50 mL) and washed with 2 M NaOH (3×15 mL) and brine (2×20 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo to give a residue, which was purified by flash chromatography on silica gel eluting with EtOAc/petroleum ether (1:10) to give 3-(4-bromophenoxy)oxetane (140 mg, 53%) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 7.37 (d, 2H), δ 6.55 (d, 2H), 5.19-5.13 (m, 1H), 4.97-4.94 (m, 2H), 4.76-4.73 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:15]([O:17]C)=[O:16])[C:5]2[C:6]([Cl:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[OH-].[Na+]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]([C:15]([OH:17])=[O:16])[C:5]2[C:6]([Cl:14])=[CH:7][N:8]([CH:11]([CH3:12])[CH3:13])[C:9]=2[CH:10]=1
Reactant: COC(=O)c1cc(Br)cc2c1c(Cl)cn2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)n1cc(Cl)c2c(C(=O)O)cc(Br)cc21
Temperature: 55 °C
Yield: 56 %

Procedure:
To a solution of methyl 6-bromo-3-chloro-1-(1-methylethyl)-1H-indole-4-carboxylate (1.2 g, 3.63 mmol) in THF (2.368 ml) and MeOH (14.21 ml) was added 3 N NaOH (1.573 ml, 4.72 mmol). The resulting mixture was heated at 55° C. for 4 h. The reaction was removed from the heat and the solvent removed in-vacuo. The remaining residue was dissolved with water (12 ml) and made acidic dropwise with 1 N HCl. The product precipitated and the slurry became too thick to stir and was diluted with water (10 ml). After the precipitation halted no more acid was added. The solid was collected by vacuum filtration, washed with water, and air dried under vacuum overnight to give 6-bromo-3-chloro-1-(1-methylethyl)-1H-indole-4-carboxylic acid (650 mg, 2.033 mmol, 56.0% yield over 2 steps) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 13.22 (s, 1H), 8.09 (d, J=1.77 Hz, 1H), 7.89 (s, 1H), 7.45 (d, J=1.77 Hz, 1H), 4.88 (quin, J=6.63 Hz, 1H), 1.43 (d, J=6.57 Hz, 6H). MS(ES) [M+H]+ 316.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[N:30]=[C:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:32][C:33]=1[CH3:34])[CH2:6][O:7][C:8]1[C:12]([CH2:13][C:14]([O:16]C)=[O:15])=[CH:11][N:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:9]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[N:30]=[C:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:32][C:33]=1[CH3:34])[CH2:6][O:7][C:8]1[C:12]([CH2:13][C:14]([OH:16])=[O:15])=[CH:11][N:10]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:9]=1
Reactant: COC(=O)Cc1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(COc2nn(-c3ccccc3)cc2CC(=O)O)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
A mixture of methyl [3-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1-phenyl-1H-pyrazol-4-yl]acetate (496 mg), 1 N aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml) and ethanol (4 ml) was stirred at room temperature for 1 hr. 1N Hydrochloric acid (2 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to give [3-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1-phenyl-1H-pyrazol-4-yl]acetic acid (438 mg, yield 90%), which was then recrystallized from ethanol-water. melting point: 147–148° C.
Reaction SMILES: CC[C:3]([C:5]1[C:6]2([CH2:11][CH:12]=[CH:13][C:14]=1[CH3:15])[CH2:10][CH2:9][CH2:8][CH2:7]2)=[O:4].[Li+].CC([N-][CH:21]([CH3:23])[CH3:22])C.C(=[O:26])C>CCCCCC.CC(OC)(C)C>[OH:26][CH:21]([CH3:22])[CH2:23][C:3]([C:5]1[C:6]2([CH2:11][CH:12]=[CH:13][C:14]=1[CH3:15])[CH2:10][CH2:9][CH2:8][CH2:7]2)=[O:4]
Reactant: CC=O
Reactant: CCC(=O)C1=C(C)C=CCC12CCCC2
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: COC(C)(C)C
Solvent: CCCCCC
Product: CC1=C(C(=O)CC(C)O)C2(CC=C1)CCCC2
Yield: 68 %

Procedure:
Prepared in 68% yield after FC (300 g SiO2, hexane/MTBE 4:1 to 3:1) from methyl 1-(7-methylspiro[4.5]deca-6,8-dien-6-yl)ethanone (2.25 g, 11.8 mmol), LDA, acetaldehyde as described in Example 10.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].N1C=CN=C1.C(OCC)C>CN(C)C=O.O>[C:1]1([CH2:7][CH2:8][C:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(O)CCc1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC(=O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Dissolve 3-phenylpropionic acid (1.5 g, 10 mmol) in dimethylformamide (5 mL) and add t-butyldimethylsilyl chloride (7.5 g, 50 mmol) and imidazole ( 6.8 g, 0.1 mol). Stir for 48 hours at room temperature, pour into ethyl ether and water and separate the organic phase. Dry (MgSO4 ) and evaporate the solvent in vacuo to give 3-phenylpropionic acid, t-butyldimethylsilyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5](Br)[N:4]([CH3:8])[N:3]=1.[Cl:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:6]=[C:5]([C:11]2[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=2[Cl:9])[N:4]([CH3:8])[N:3]=1
Reactant: OB(O)c1ccc(F)cc1Cl
Reactant: Cn1nc(Br)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cn1nc(Br)cc1-c1ccc(F)cc1Cl
Temperature: 90 °C

Procedure:
A mixture of 3,5-dibromo-1-methyl-1H-pyrazole (i.e. the product of Step B) (2.00 g, 8.33 mmol) in toluene (40 mL) was sparged with a stream of argon for 45 minutes, and then 2-chloro-4-fluorophenylboronic acid (1.59 g, 9.11 mmol), potassium phosphate tribasic (5.30 g, 25.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.48 g, 0.41 mmol) were added. The reaction mixture was heated at 90° C. for 3 h, and then cooled to room temperature and diluted with ethyl acetate (250 mL). The mixture was washed with water (25 mL) and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting material was purified by silica gel chromatography (5 to 40% gradient of ethyl acetate in hexanes as eluant) to provide the title compound as a white solid (620 mg).