Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:13])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[H][H]>[Pd].CO>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([OH:13])[C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: O=C(O)C(=O)Cc1ccc(O)cc1
Agent: [Pd]
Solvent: CO
Product: O=C(O)C(O)Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
10 g of 3-(4-hydroxyphenyl)pyruvic acid and 50 ml of methanol were charged to a pressure reactor to form a solution, and 0.5 g of 5% palladium on charcoal was added thereto. The atmosphere was displaced with hydrogen, and the mixture was stirred at 25° C. under a hydrogen pressure of 5 kg/cm2 for 2 hours. After completion of the reaction, the reaction mixture was filtered to remove the catalyst, and the filtrate was concentrated under reduced pressure to give 10.1 g of 3-(4-hydroxyphenyl)lactic acid as colorless crystals.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][C:12]3[O:13][C@:14]4([CH2:22][N:23]=3)[CH:19]3[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]3)[CH2:15]4)=[N:10][C:5]2=[N:4][CH:3]=1.Cl>CO>[S:8]1[C:6]2=[N:7][CH:2]=[CH:3][N:4]=[C:5]2[N:10]=[C:9]1[NH:11][C:12]1[O:13][C@:14]2([CH2:22][N:23]=1)[CH:19]1[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]1)[CH2:15]2
Reactant: Brc1cnc2nc(NC3=NC[C@@]4(CN5CCC4CC5)O3)sc2n1
Agent: Cl
Solvent: CO
Product: c1cnc2sc(NC3=NC[C@@]4(CN5CCC4CC5)O3)nc2n1
Yield: 67.6 %

Procedure:
(R)—N-(6-Bromothiazolo[5,4-b]pyrazin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (44 mg, 0.111 mmol) was suspended in MeOH (50 mL) and 3N HCl was added until all solids had dissolved (˜10 ml). The reaction flask was flushed with nitrogen and then 10% palladium on carbon (35 mg) was added, and the flask was fitted with a hydrogen balloon. The mixture was allowed to react overnight, at which time TLC showed consumption of the starting material. The flask was flushed with nitrogen, filtered through celite and washed with methanol. The combined filtrates were concentrated by ˜90% to remove most of the methanol, and the solution was made basic by the addition of a saturated solution of sodium bicarbonate. The basic aqueous phase was extracted with chloroform (4×). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The mixture was purified by silica gel chromatography (2-40% [9:1 methanol:ammonium hydroxide]-chloroform). The product fractions were combined and concentrated in vacuo to afford (R)—N-(thiazolo[5,4-b]pyrazin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (24 mg, 0.075 mmol, 67.5% yield). 1H NMR (400 MHz, CDCl3) δ ppm 9.50 (br. s., 1H) 8.41 (d, J=2.76 Hz, 1H) 8.27 (d, J=2.76 Hz, 1H) 4.06 (d, J=9.79 Hz, 1H) 3.72 (d, J=9.79 Hz, 1H) 3.43 (dd, J=15.06, 1.76 Hz, 1H) 2.74-3.09 (m, 5H) 2.12-2.25 (m, 2H) 1.71-1.86 (m, 1H) 1.49-1.67 (m, 2H). MS (LC/MS) R.T.=0.75; [M+H]+=317.13.
Reaction SMILES: Br[C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:12])[CH:3]=1.C([Li])CCC.[CH3:18][N:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1.[Cl-].[NH4+]>O1CCCC1.CCCCCC.O>[F:12][C:4]1[CH:3]=[C:2]([C:22]2([OH:25])[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]2)[C:10]([F:11])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1cc(F)c(Br)cc1F
Reactant: CN1CCC(=O)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN1CCC(O)(c2cc(F)c(C(=O)O)cc2F)CC1
Temperature: -30 °C
Reaction time: 0.33 h

Procedure:
A solution of 1.19 g (5 mmoles) of 4-bromo-2,5-difluorobenzoic acid in 20 ml of tetrahydrofuran at -75° C. was treated with 4.2 ml of 2.4 M n-butyl lithium in hexane. The mixture was stirred 20 minutes, treated with a solution of 0.58 g (5.1 mmoles) of 1-methyl-4-piperidone in 5 ml tetrahydrofuran, stirred a further 1.5 hours, let warm to -30° C., and treated with a solution of 0.55 g (10.3 mmoles) ammonium chloride in 20 ml water. The product, the title compound, crystallized on standing.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:16]([O:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:4]([CH:3]=1)[C:12]([O:14][CH3:15])=[O:13])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(OCc2ccccc2)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
To a solution of dimethyl 5-hydroxyisophthalate (50.0 g, 238 mmol) in N,N-dimethylformamide (500 mL), benzyl bromide (29.5 mL, 248 mmol) was added dropwise in the presence of potassium carbonate (42.4 g, 307 mmol), and the reaction mixture was stirred for 2 hours at room temperature, followed by addition of water thereto. The resultant mixture was extracted with diethyl ether. The resultant organic layer was washed sequentially with water and saturated brine and dried over sodium sulfate anhydrate. The solvent was removed under reduced pressure, to thereby yield a solid. The solid was crystallized from diethyl ether, to thereby yield 68.9 g of dimethyl 5-benzyloxyisophthalate as colorless needles (yield 96%).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]([Cl:14])=[CH:12][C:8]([C:9](Cl)=[O:10])=[C:7]([O:15][CH3:16])[CH:6]=1)(=[O:3])[CH3:2].[N-:17]=[N+:18]=[N-:19].[Na+]>CC(C)=O>[C:1]([NH:4][C:5]1[C:13]([Cl:14])=[CH:12][C:8]([C:9]([N:17]=[N+:18]=[N-:19])=[O:10])=[C:7]([O:15][CH3:16])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cc(NC(C)=O)c(Cl)cc1C(=O)Cl
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1cc(NC(C)=O)c(Cl)cc1C(=O)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 209.7 %

Procedure:
An acetone solution of 4-acetylamino-5-chloro-2-methoxy-benzoyl chloride (e6) (2.0 g) was added to a stirred aqueous solution of sodium azide (2.0 g) and the suspension stirred at room temperature for 30 minutes. Extraction with ethyl acetate gave 4-acetylamino-5-chloro-2-methoxy-benzoyl azide (e7) (4.3 g) as a white crystalline solid on trituration under petrol, m.p. 135°-140°. [I.R.ν(N3)=2140 cm-1 and ν(C=O)=1645, 1705 cm-1 ]
Reaction SMILES: [CH:1]1([S:4][C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[CH2:7][NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH2:3][CH2:2]1.[C:19](=O)([O-])[O-].[K+].[K+].CI>CC#N.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:1]1([S:4][C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[CH2:7][N:8]([CH3:19])[C:9](=[O:14])[C:10]([F:11])([F:12])[F:13])[CH2:3][CH2:2]1
Reactant: O=C(NCc1ccccc1SC1CC1)C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CN(Cc1ccccc1SC1CC1)C(=O)C(F)(F)F
Temperature: 25 °C

Procedure:
To 1C (1.68 g, 5.47 mmol) in CH3CN (55 mL) was added potassium carbonate (1.13 g, 8.20 mmol), tetrabutylammonium bromide (88 mg, 0.27 mmol) and methyl iodide (3.40 mL, 54.7 mmol) and the reaction was heated to reflux overnight. After cooling to rt and concentrating, the remaining residue was dissolved in ethyl acetate and washed with water (3×) and brine. The organic layer was dried (MgSO4), filtered and concentrated to provide ID (1.50 g) as a yellow oil. LC-MS: 321.95 (M+H)+.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[C:10]([CH2:20][OH:21])([CH2:18][OH:19])[C:9]1=[O:22])=O)(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O>C1COCC1>[Cl:17][C:14]1[CH:15]=[C:16]2[C:11]([C:10]([CH2:18][OH:19])([CH2:20][OH:21])[C:9](=[O:22])[NH:8]2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)C(CO)(CO)c2ccc(Cl)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: O=C1Nc2cc(Cl)ccc2C1(CO)CO
Temperature: 20 °C
Reaction time: 5 h
Yield: 189.3 %

Procedure:
A mixture of 6-chloro-3,3-bis-hydroxymethyl-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (1.9 g, 5.8 mmol), DCM (50 mL) and TFA (10 mL) was stirred at 20° C. for 5 h then evaporated in vacuo to give a semi-solid. Azeotrope with THF was performed to give the title compound (2.5 g). MS: [M+H]+=228.
Reaction SMILES: [NH2:1][C:2]1C=CC=C2[C:11]=1C(O)=CC=C2.C[CH2:14][CH2:15][CH2:16][C:17](=[O:24])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>C(O)C>[CH:11]1[C:18]2[C:19]3[C:14]([CH:15]=[CH:16][C:17]=2[O:24][NH:1][CH:2]=1)=[CH:23][CH:22]=[CH:21][CH:20]=3
Reactant: CCCCCCC(=O)CCCC
Reactant: Nc1cccc2cccc(O)c12
Solvent: CCO
Product: C1=Cc2c(ccc3ccccc23)ON1
Yield: 35.9 %

Procedure:
With 6.3 g of 8-amino-1-naphthol and 20 ml of ethanol, 8.1 g of 5-undecanone was mixed. The mixture was refluxed for 3 hours. The reaction mixture was condensed, and purified in a column chromatography (silica gel, n-hexane/ethyl acetate=1/6) to obtain 2.6 g of naphthooxazinine.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([C:23]1[S:27][C:26]2=[N:28][C:29]([C:31]([OH:33])=[O:32])=[CH:30][N:25]2[CH:24]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[CH2:34]([O:42][C:43]1[CH:48]=[CH:47][C:46](O)=[CH:45][CH:44]=1)[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>CN(C)C1C=CN=CC=1.ClCCl>[CH2:16]([C:23]1[S:27][C:26]2=[N:28][C:29]([C:31]([O:33][C:46]3[CH:47]=[CH:48][C:43]([O:42][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:44][CH:45]=3)=[O:32])=[CH:30][N:25]2[CH:24]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCOc1ccc(O)cc1
Reactant: CCCCCCCc1cn2cc(C(=O)O)nc2s1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCOc1ccc(OC(=O)c2cn3cc(CCCCCCC)sc3n2)cc1

Procedure:
1.2 g of N,N'-dicyclohexylcarbodiimide are added in portions to a solution of 1.3 g of 2-heptylimidazo[2,1-b]-thiazole-6-carboxylic acid, 1 g of 4-octyloxyphenol and 0.1 g of 4-(dimethylamino)pyridine in 25 ml of dichloromethane within 10 minutes while stirring. The mixture is stirred overnight at room temperature and then filtered. The filtrate is diluted with dichloromethane, washed with two portions of 50 ml each of saturated sodium carbonate solution and then with water, dried over magnesium sulphate and filtered, and the filtrate is evaporated. Recrystallization of the residue from ethyl acetate/cyclohexane gives 4-octyloxyphenyl 2-heptylimidazo[2,1-b]thiazole-6-carboxylate, m.p.(C/SA): 112.6° C., c.p.(SA /I): 151.4° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH2:12][S:13]([CH3:15])=[O:14])=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH2:17]([O:19][CH2:20][CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[NH:31][CH:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][C:40]2([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:44][CH2:43][NH:42][CH2:41]2)[CH2:34][CH2:33]1)[CH3:18]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH2:12][S:13]([CH3:15])=[O:14])=[CH:8][C:4]=1[C:5]([N:42]1[CH2:43][CH2:44][C:40]([CH2:39][CH2:38][N:35]2[CH2:36][CH2:37][CH:32]([NH:31][C:23]3[N:22]([CH2:21][CH2:20][O:19][CH2:17][CH3:18])[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[N:24]=3)[CH2:33][CH2:34]2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:41]1)=[O:7]
Reactant: COc1ccc(CS(C)=O)cc1C(=O)O
Reactant: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Agent: Cl
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(CS(C)=O)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 59.1 using 2-methoxy-5-(methylsulfinylmethyl)benzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=2[C:6]1=O)=O.Cl.[NH2:19][C:20]([NH2:22])=[NH:21].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:22][C:20]1[N:21]=[C:3]([OH:2])[C:5]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=3[C:6]=2[N:19]=1
Reactant: N=C(N)N
Reactant: COC(=O)C1CCCCc2ccccc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(O)c2c(n1)-c1ccccc1CCCC2
Temperature: 25 °C

Procedure:
A mixture of Example 20A (1.49 g, 6.4 mmol), guanidine hydrochloride (2.1 g, 22 mmol) and K2CO3 (3.26 g, 24 mmol) in anhydrous DMF (20 mL) was heated at 120° C. for 8 hours under a nitrogen atmosphere. The mixture was cooled to room temperature and partitioned between EtOAc (200 mL) and H2O (150 mL). The aqueous layer was extracted with EtOAc three times. The organic layers were combined, washed with brine, dried (MgSO4), filtered and concentrated to provide a residue. The residue was chromatographed on silica gel eluting with MeOH:EtOAc:CHCl3 (10:45:45) to provide the title compound.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH:5]([C:7]([O:9][CH2:10][CH:11]1[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[NH2:6]>ClCCl.C([O-])(O)=O.[Na+]>[CH:13]1[C:12]2[CH:11]([CH2:10][O:9][C:7]3[O:8][C:1](=[O:2])[NH:6][N:5]=3)[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)Cl
Reactant: NNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=c1[nH]nc(OCC2c3ccccc3-c3ccccc32)o1
Reaction time: 0.25 h

Procedure:
2 equivalents of phosgene (1.89M in toluene; 4.2 ml) are added to a solution of 3.91 mmol of 9H-fluoren-9-ylmethyl hydrazinecarboxylate in 40 ml of dichloromethane and 40 ml of saturated aqueous NaHCO3 solution. The mixture is stirred for 15 minutes and then worked up as usual, giving 5-(9H-fluoren-9-ylmethoxy)-3H-[1,3,4]oxadiazol-2-one (“AB”)
Reaction SMILES: Br[CH:2]1[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=O.[NH2:11][C:12]([NH2:14])=[S:13]>CCO>[NH2:14][C:12]1[S:13][C:2]2[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=2[N:11]=1
Reactant: O=C1CCCCC(=O)C1Br
Reactant: NC(N)=S
Solvent: CCO
Product: Nc1nc2c(s1)C(=O)CCCC2

Procedure:
To a solution of 2-bromocycloheptane-1,3-dione (45.17 mmol) in abs. EtOH (100 mL) was added thiourea (3.61 g, 47.43 mmol). The reaction mixture was stirred at room temperature overnight at which point the EtOH was removed under reduced pressure and the resulting dark orange residue was triturated with DCM. The residue was recrystallized from EtOH to afford 26z as an off white solid (6 g, 50% overall crude yield from cycloheptane-1,3-dione). 1H NMR (300 MHz, DMSO-d6): δ 8.87 (br s, 2H), 2.87 (t, J=6 Hz, 2H), 2.64 (t, J=6 Hz, 2H), 1.89-1.85 (m, 2H), 1.81-1.77 (m, 2H);
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:29][OH:30])[C:5]([CH2:21][O:22]C2CCCCO2)=[C:6]2[C:10]=1[N:9]([S:11]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:8]=[CH:7]2.C(N(C(C)C)C(C)C)C.[CH3:40][Si:41]([CH2:44][CH2:45][O:46][CH2:47]Cl)([CH3:43])[CH3:42]>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:29][O:30][CH2:47][O:46][CH2:45][CH2:44][Si:41]([CH3:43])([CH3:42])[CH3:40])[C:5]([CH2:21][OH:22])=[C:6]2[C:10]=1[N:9]([S:11]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:8]=[CH:7]2
Reactant: C[Si](C)(C)CCOCCl
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(COC4CCCCO4)c(CO)cc(C)c32)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3c(CO)c(COCOCC[Si](C)(C)C)cc(C)c32)cc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a solution (±)-(7-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-tosyl-1H-indol-5-yl)methanol (200 mg, 0.466 mmol) and iPr2EtN (0.16 mL, 0.93 mmol) in CH2Cl2 (2 mL) was added SEMCl (0.124 mL, 0.69 mmol), and then the mixture was stirred at 40° C. for 1 hr. The reaction mixture was concentrated (during the concentration, the THP group was partially removed) and then purified by SiO2 column chromatography (heptane/EtOAc=1/0 to 1/3) to give the title compound. 1H NMR (400 MHz, ACETONITRILE-d3) δ 7.81 (d, J=3.79 Hz, 1H), 7.58 (d, J=8.30 Hz, 2H), 7.32 (d, J=8.30 Hz, 2H), 7.08 (s, 1H), 6.99 (d, J=3.79 Hz, 1H), 4.79 (d, J=5.81 Hz, 2H), 4.68 (s, 2H), 4.67 (s, 2H), 3.54-3.63 (m, 2H), 3.05 (t, J=5.80 Hz, 1H), 2.54 (s, 3H), 2.35 (s, 3H), 0.82-0.96 (m, 2H), 0.01 (s, 9H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9](=O)[C:10]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1.C(OCC)(=O)C.O>O1CCCC1>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([CH:11]=[C:10]([C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)[CH2:9][OH:8])[CH:17]=[CH:16][C:15]=1[O:18][CH3:19]
Reactant: COC(=O)C(=Cc1ccc(OC)c(OC)c1)c1ccc(OC)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(C(=Cc2ccc(OC)c(OC)c2)CO)cc1
Reaction time: 1 h
Yield: 54.7 %

Procedure:
In a 100 mL round bottom flask lithium aluminium hydride WAIN (0.28 g, 7.2 mmol) in tetrahydrofuran (THF) was taken and cooled to 0-5° C., to which methyl-3-(3,4-dimethoxyphenyl)-2-(4-methoxyphenyl)prop-2-enoate (2 g, 6.09 mmol) dissolved in THF (15 mL) was added drop wise using dropping funnel. The reaction mixture was stirred for 1 hour at same temperature and the reaction was monitored by TLC. Upon the completion of reaction, added ethyl acetate (50 mL) drop wise followed by cold water (50 mL). The organic layer was separated and the aqueous layer further extracted with ethyl acetate (50 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give pure compound (1 g, 55%).
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[C:15](CC(C)C)[C:14]([CH3:24])=[C:13]([CH3:25])[N:12]=1>O1CCCC1>[CH3:24][C:14]1[C:15]([NH:12][CH2:13][CH:14]([CH3:24])[CH3:15])=[C:16]([N+:17]([O-:19])=[O:18])[C:11]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[N:12][C:13]=1[CH3:25]
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(CC(C)C)c1C
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCC(C)C)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 216.2 %

Procedure:
Sodium hydride (19.8 g of a 60% dispersion in mineral oil, 0.495 mol) in tetrahydrofuran (THF) (450 mL) was cooled to 0° C.; a solution of phenol (77.7 g, 0.826 mol) in THF (150 mL) was added slowly over a period of 30 minutes. The reaction was stirred at ambient temperature for 30 minutes, and a solution of 2-chloro-5,6-dimethyl-4-(2-methylpropyl)-3-nitropyridine (60.78 g, 0.236 mol) in THF (350 mL) was added. The reaction was heated to 70° C., heated at 50° C. overnight, allowed to cool to ambient temperature, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (800 mL). The resulting solution was washed sequentially with 1 N aqueous sodium hydroxide (1×800 mL), brine (3×400 mL), 1 N aqueous sodium hydroxide (1×400 mL), brine (1×400 mL), 1 N aqueous sodium hydroxide (1×400 mL), and deionized water (1×400 mL); dried over magnesium sulfate; filtered through a layer of CELITE filter agent; concentrated under reduced pressure; and further dried overnight under high vacuum to provide 80.46 g of 5,6-dimethyl-N-(2-methylpropyl)-3-nitro-2-phenoxypyridin-4-amine as an orange-red solid containing some mineral oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1>O.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([C:11]([F:12])([F:13])[F:14])=[CH:8][CH:7]=3)[N:1]=2)=[CH:18][CH:17]=1
Reactant: NC(=O)c1ccc(C(F)(F)F)cc1N
Reactant: O=Cc1ccc(Cl)cc1
Agent: Cl[Fe](Cl)Cl
Solvent: O
Product: O=c1[nH]c(-c2ccc(Cl)cc2)nc2cc(C(F)(F)F)ccc12
Temperature: 25 °C

Procedure:
To a stirred suspension of 2-amino-4-(trifluoromethyl)benzamide (33.6 g, 0.16 mol) in water (750 mL) was added dropwise 4-chlorobenzaldehyde. Iron trichloride hexahydrate (133 g) was then added in portions. The reaction mixture was then heated at reflux for 24 h. After allowing the suspension to cool to room temperature, the precipitate was isolated by vacuum filtration washing with water (3×500 mL) and dried under vacuum (10 mbar, 50° C.). Yield=50 g, 94%; HPLC-mass spectrometry (LC-MS): 3.7 min, 325 (M+).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6]C(C)(C)C)=[O:5].FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[CH:11][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1cc(Oc2ccccc2)ccc1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Oc2ccccc2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
To a solution of tert-butyl 2-methyl-4-phenoxybenzoate (150 mg, 0.53 mmol) in dichloromethane (10 mL) was added 2,2,2-trifluoroacetic acid (2 mL). The mixture was stirred at room temperature for 0.5 hour, and then concentrated to give 2-methyl-4-phenoxybenzoic acid (100 mg, 84% yield) as a white solid.
Reaction SMILES: [N:1]1[CH:2]=[C:3]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[S:6][C:5]([C:13]([OH:15])=O)=[CH:4]2.ON1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.[C:36]([O:40][C:41]([N:43]1[CH2:48][CH2:47][CH:46]([CH2:49][NH2:50])[CH2:45][CH2:44]1)=[O:42])([CH3:39])([CH3:38])[CH3:37].C(=O)([O-])O.[Na+]>C(#N)C.C(N(CC)CC)C>[C:36]([O:40][C:41]([N:43]1[CH2:48][CH2:47][CH:46]([CH2:49][NH:50][C:13]([C:5]2[S:6][C:7]3[N:12]4[C:3](=[CH:2][N:1]=[C:11]4[CH:10]=[CH:9][CH:8]=3)[CH:4]=2)=[O:15])[CH2:45][CH2:44]1)=[O:42])([CH3:39])([CH3:38])[CH3:37]
Reactant: O=C(O)C1=Cc2cnc3cccc(n23)S1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)C2=Cc3cnc4cccc(n34)S2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
While 26.48 g (121.3 mM) of 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid and 15.4 g (133 mM) of N-hydroxysuccinimide were stirred together in 250 ml of acetonitrile, 25.6 g (133 mM) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added and the mixture was stirred at room temperature for 6 hours. To this reaction mixture was added 20.3 ml (146 mM) of triethylamine as well as 27.3 g (127 mM) of 1-(tert-butoxycarbonyl)piperidin-4-ylmethylamine and the mixture was stirred at room temperature overnight. This reaction mixture was poured in aqueous solution of sodium hydrogen carbonate and extracted with 3 portions of ethyl acetate. The organic layers were pooled and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate to ethyl acetate-methanol=9:1) to provide crude N-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide. To this crude N-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide was added 30 ml of concentrated hydrochloric acid and the mixture was stirred at room temperature for one hour. To this reaction mixture was added ethanol, followed by stirring, and the resulting precipitate was recovered by filtration and rinsed serially with ethanol and diethyl ether to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:12])[CH2:9][O:10][CH3:11])=[CH:4][CH:3]=1.Cl.[O-:14][C:15]#[N:16].[K+].C(=O)(O)[O-].[Na+]>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([NH:12][C:15]([NH2:16])=[O:14])[CH2:9][O:10][CH3:11])=[CH:6][CH:7]=1
Reactant: N#C[O-]
Reactant: COCC(N)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Product: COCC(NC(N)=O)c1ccc(F)cc1
Temperature: 80 °C

Procedure:
To a microwave vial equipped with a stir bar was added 1-(4-fluorophenyl)-2-methoxyethanamine (1.2 g, 7.09 mmol) and water (10 mL). To this mixture was added HCl (1N, 7.23 mL, 7.23 mmol) and potassium cyanate (2.88 g, 35.5 mmol). The mixture was heated in a microwave reactor to 80° C. for 1 h. Saturated sodium bicarbonate was added and the products extracted into EtOAc (×4). The organic layers were combined, washed with brine (×2), and dried over MgSO4. The material was concentrated in vacuo while loading onto silica gel. Purification by flash chromatography (0-10% EtOAc-Hexanes) gave 1-(1-(4-fluorophenyl)-2-methoxyethyl)urea. MS ESI calc'd. for C10H13FN2O2 [M+1]+ 213. found 213.