Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:11]2[CH2:12][CH2:13][C:14]3([CH3:18])[O:16][O:17][C@:10]42[C@H:5]([C@@H:6]([CH3:20])[C@@H:7]([OH:19])[O:8][C@@H:9]4[O:15]3)[CH2:4][CH2:3]1.[CH2:21](OC(OCC)OCC)[CH3:22].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C(O)C>[CH3:21][CH2:22][O:19][C@H:7]1[O:8][C@@H:9]2[O:15][C:14]3([CH3:18])[O:16][O:17][C@@:10]42[C@@H:5]([CH2:4][CH2:3][C@@H:2]([CH3:1])[C@@H:11]4[CH2:12][CH2:13]3)[C@H:6]1[CH3:20]
Reactant: C[C@H]1[C@@H](O)O[C@@H]2OC3(C)CC[C@H]4[C@H](C)CC[C@@H]1[C@@]24OO3
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: CCO[C@H]1O[C@@H]2OC3(C)CC[C@H]4[C@H](C)CC[C@@H]([C@H]1C)[C@@]24OO3
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
Dihydroartemisinin (50 mg) was dissolved in dry ethanol (3 ml). Add 2 ml of triethylorthoformate and (25 mg) of p-toluenesulphonic acid. The reaction mixture was stirred at room temperature (20° C.) for 30 min. 50 ml of water was added in the reaction mixture The reaction product was extracted by dichloromethane (30 mil×3). The dichloromethane extract was dried over anhydrous sodium sulphate and evaporation of solvent under vacuum at 40° C. and yielded the arteether (52 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C@@H:13]1[CH2:18][CH2:17][C@H:16]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:26]=[C:27]([C:35]([OH:37])=[O:36])[CH:28]=[C:29]4[C:34]=3[N:33]=[CH:32][CH:31]=[CH:30]4)[CH2:21][CH2:20]2)[CH2:15][CH2:14]1)#[N:2].[CH3:38]O>C1(C)C=CC=CC=1.CCO>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C@@H:13]1[CH2:18][CH2:17][C@H:16]([N:19]2[CH2:20][CH2:21][N:22]([C:25]3[CH:26]=[C:27]([C:35]([O:37][CH3:38])=[O:36])[CH:28]=[C:29]4[C:34]=3[N:33]=[CH:32][CH:31]=[CH:30]4)[CH2:23][CH2:24]2)[CH2:15][CH2:14]1)#[N:2]
Reactant: Cn1cc([C@H]2CC[C@@H](N3CCN(c4cc(C(=O)O)cc5cccnc45)CC3)CC2)c2cc(C#N)ccc21
Reactant: CO
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(N2CCN([C@H]3CC[C@@H](c4cn(C)c5ccc(C#N)cc54)CC3)CC2)c2ncccc2c1
Temperature: 23 °C
Reaction time: 12 h

Procedure:
To 50 mg (0.1 mmol) of 8-[4-[(cis)-4-(5-cyano-1-methyl-1H-indole-3-yl)cyclohexyl]-1-piperazinyl]-6-quinolinecarboxylic acid in 1 mL of MeOH and 3 mL of C6H5CH3 at 23° C. was added 0.9 mL (0.39 mmol) of a 10% solution of (CH2)3SiCHN2 in hexanes. After stirring at 23° C. for 12 hours, the volatiles were removed by rotary evaporation. The crude product was chromatographed on silica gel eluting with 20:1 CH2Cl2:MeOH. The product fractions were pooled, stripped, and treated with 5 mg (0.05 mmol) of (CO2H)2 in absolute EtOH to give 20 mg (0.04 mmol, a 40% yield) of the oxalate salt of the title compound as a tan crystalline solid. mp: 153-155° C.; MS (ES) m/z: 599 (MH)+.
Reaction SMILES: [C:1]1([P:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:14]1C(O)=C[CH:17]=[C:16]([CH3:21])[CH:15]=1.C(O)C>>[C:1]1([P:7]([O:11][C:12]2[CH:14]=[CH:15][C:16]([CH3:21])=[CH:17][CH:13]=2)[O:8][CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOP(OCC)c1ccccc1
Reactant: Cc1ccc(O)cc1
Solvent: CCO
Product: CCOP(Oc1ccc(C)cc1)c1ccccc1
Temperature: 130 °C
Yield: 90 %

Procedure:
18.8 g (0.6 mol) of diethyl phenylphosphonite and 64.9 g (0.6 mol) of p-cresol were mixed and heated at 300 to 500 mbar to 130° C. Ethanol distilled off via a small column. The temperature was increased to 165° C. stepwise, and the vacuum was simultaneously increased to 100 mbar. In total, 21 g (0.458 mol) of ethanol distilled off. The reaction mixture was then distilled. After a first fraction which contained the unreacted starting materials, 107 g were obtained having a boiling point of 118° to 120° C. at 0.1 mbar. At a 76% conversion rate, the yield was approximately 90% of theory.
Reaction SMILES: O[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](O)=[CH:4][C:3]=1O.CN(C1C=CC=CN=1)C.C(Cl)(=O)C=C>ClCCl>[CH:9]1[C:8]2[C:7](=[O:17])[C:6]3[C:15](=[CH:2][CH:3]=[CH:4][CH:5]=3)[C:14](=[O:16])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: O=C1c2ccccc2C(=O)c2c(O)c(O)cc(O)c21
Agent: C=CC(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)c2ccccc21

Procedure:
Twenty-five parts of 1,2,4-trihydroxy-anthraquinone, 45 parts of dimethylaminopyridine and 0.01 part of methoquinone were dissolved in 1000 parts of dried dichloromethane and the obtained solution was cooled with ice in a nitrogen atmosphere. Then, 25 parts of acryloyl chloride was dropped into the resulting solution. After the completion of the dropping, the obtained mixture was stirred under reflux for 8 hours. The reaction mixture thus obtained was washed with water, dried and distilled to remove the solvent. Thus, a yellow polymerizable anthraquinone dye C was obtained. The anthraquinone dye C is represented by the below chemical formula (IV). ##STR4##
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.[N:21]1[C:25]2[CH:26]=[CH:27][C:28]([NH2:30])=[CH:29][C:24]=2[NH:23][CH:22]=1>>[N:21]1[C:25]2[CH:26]=[CH:27][C:28]([NH:30][C:4]3[N:9]=[CH:8][C:7]4=[CH:10][CH:11]=[C:12]([C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=5[O:19][CH3:20])[N:6]4[N:5]=3)=[CH:29][C:24]=2[NH:23][CH:22]=1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc4nc[nH]c4c3)nn12

Procedure:
Following the synthetic and purification procedures described in Example 1293d, 2-methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (75.4 mg, 0.262 mmol) was coupled to 3H-benzimidazol-5-ylamine (60.0 mg, 0.45 mmol) at 105° C. for 86 h to afford the title compound. Yield of TFA salt: 62 mg (50%) of brown powder. LC/MS: 357 (M+H); HPLC: 95% pure, RT=2.38 min; 1H NMR: (DMSO, δ) 9.77 (s, 1H), 9.38 (s, 1H), 9.02 (s, 1H), 8.04 (s, 1H), 7.93 (d, J=9.2, 1H), 7.85 (d, J=7.5, 1H), 7.65 (d, J=9.2, 1H), 7.47 (t, J=8.2, 1H), 7.25 (d, J=8.2, 1H), 7.17 (t, J=7.5, 1H), 7.01 (d, J=4.8, 1H), 6.98 (d, J=4.8, 1H), 3.81 (s, 3H)-benzimidazole NH presumably underwent rapid exchange with residual water.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][N:6]=[CH:5]2.C([Li])(C)(C)C.[C:17](=[O:19])=[O:18]>>[F:11][C:10]1[CH:9]=[C:8]2[C:4]([CH:5]=[N:6][NH:7]2)=[CH:3][C:2]=1[C:17]([OH:19])=[O:18]
Reactant: Fc1cc2[nH]ncc2cc1Br
Reactant: O=C=O
Agent: [Li]C(C)(C)C
Product: O=C(O)c1cc2cn[nH]c2cc1F

Procedure:
This compound was prepared in a manner similar to that shown in Scheme 3, using 5-bromo-6-fluoro-1H-indazole (88d), which was treated with t-butyl lithium and carbon dioxide to yield 6-fluoro-1H-indazole-5-carboxylic acid. This compound in turn was treateded with thiosemicarbazide and polyphosphoric acid to form 5-(6-fluoro-1H-indazol-5-yl)-1,3,4-thiadiazol-2-amine. MS (API-ES) m/z (%): 236 (100%, M++1).
Reaction SMILES: [F:1][C:2]([F:49])([F:48])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:21]=3[N:31]([CH2:34][C@H:35]3[CH2:40][CH2:39][C@H:38]([CH2:41][C:42]([O:44]CC)=[O:43])[CH2:37][CH2:36]3)[CH2:32][CH3:33])[C@H:14]2[CH3:47])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH-].[K+]>CCO>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([O:26][C:27]([F:29])([F:30])[F:28])[CH:23]=[CH:22][C:21]=3[N:31]([CH2:34][C@H:35]3[CH2:36][CH2:37][C@H:38]([CH2:41][C:42]([OH:44])=[O:43])[CH2:39][CH2:40]3)[CH2:32][CH3:33])[C@H:14]2[CH3:47])[CH:4]=[C:3]([C:2]([F:1])([F:49])[F:48])[CH:8]=1
Reactant: CCOC(=O)C[C@H]1CC[C@H](CN(CC)c2ccc(OC(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCN(C[C@H]1CC[C@H](CC(=O)O)CC1)c1ccc(OC(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl (trans-4-{[[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethoxy)phenyl](ethyl)amino]methyl}cyclohexyl)acetate (29 mg, 0.0407 mmol) in EtOH (1 mL) was added 4 M KOH (100 μL). The reaction was stirred at room temperature for 30 minutes and 4 M KOH (100 μL) was added. After an additional 30 minutes 4 M KOH (100 μL) was added. After 30 min the reaction was quenched with 1 N HCl (1.5 mL) and then neutralized with saturated NaHCO3 solution. The mixture was extracted with EtOAc (2×20 mL) and washed with brine. The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by PTLC (EtOAc+1% AcOH) afforded (trans-4-{[[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethoxy)phenyl](ethyl)amino]methyl}cyclohexyl)acetic acid. Rf=0.94 (EtOAc+1% AcOH). LCMS=685.3 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.91 (s, 1H), 7.80 (s, 2H), 7.20-7.12 (m, 3H), 5.76 (d, J=8.1 Hz, 1H), 4.74 (d, J=16.3 Hz, 1H), 4.59 (d, J=16.3 Hz, 1H), 4.04-4.00 (m, 1H), 2.97-2.75 (m, 4H), 1.81-0.88 (m, 15H), 0.66 (d, J=6.5 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:4]=[C:3]1[CH2:15][C:16]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]
Reactant: Nc1ccccc1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cn1c(CC(=O)Nc2ccccc2)nc(N2CCOCC2)cc1=O
Yield: 39.8 %

Procedure:
The product is prepared according to the procedure described in example 5, using 200 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 1 of example 68, 134 mg of aniline, and 180 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.12 ml of pyridine and 2.5 ml of N,N-dimethylformamide. 95 mg of 2-[1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]-N-phenylacetamide are obtained in the form of a purple solid, the characteristics of which are the following:
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:3]=1[O:4][CH2:5][C:6]#N.[CH2:13]([NH:16][CH2:17][CH2:18][NH2:19])[CH:14]=[CH2:15].[Na+].S.[ClH:22]>>[ClH:22].[CH2:13]([N:16]1[CH2:17][CH2:18][N:19]=[C:6]1[CH2:5][O:4][C:3]1[CH:8]=[CH:9][CH:10]=[C:11]([CH3:12])[C:2]=1[CH3:1])[CH:14]=[CH2:15]
Reactant: Cc1cccc(OCC#N)c1C
Reactant: C=CCNCCN
Agent: Cl
Agent: S
Agent: [Na+]
Product: C=CCN1CCN=C1COc1cccc(C)c1C

Procedure:
4.84 g (30 mmol) of 2,3-dimethylphenoxy-acetonitrile, 3.3 g (33 mmol) of N-allyl-ethylenediamine and 260 mg of sodium polysulfide (Na2S4) are stirred together at 50° C. for 4 hours. The excess amine is then stripped off under a high vacuum, ethanolic hydrochloric acid is added to the residue and the hydrochloride is precipitated by addition of ether.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[C:4]([CH3:11])[N:3]=1>[Pd].CCO>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH3:11])[N:3]=1
Reactant: Cc1nc(N)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1nc(N)ccc1N
Reaction time: 18 h
Yield: 99.5 %

Procedure:
A mixture of 2-amino-5-nitro-6-methylpyridine (5.42 g, 0.0354 mol) (E. D. Parker and W. Shive, J. Amer. Chem. Soc., 69:63 (1947)), absolute EtOH (150 ml) and 10% palladium-on-carbon catalyst (0.488 g) was hydrogenated at an initial pressure of 40 p.s.i. for 18 hours. The catalyst was removed by filtration through celite and the filtrate was concentrated to give 4.34 g of the titled product.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][CH:32]=[CH:31][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][C:22]=3[C:27]#[N:28])[C:17]([O:29][CH3:30])=[CH:16][N:15]=2)=[N:6]1.[OH-:35].[Na+].OO>CS(C)=O>[F:1][C:2]1[CH:34]=[CH:33][CH:32]=[CH:31][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][C:22]=3[C:27]([NH2:28])=[O:35])[C:17]([O:29][CH3:30])=[CH:16][N:15]=2)=[N:6]1
Reactant: COc1cnc(-c2nn(Cc3ccccc3F)c3ccccc23)nc1Nc1ccncc1C#N
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cnc(-c2nn(Cc3ccccc3F)c3ccccc23)nc1Nc1ccncc1C(N)=O
Temperature: 63 °C
Reaction time: 3 h

Procedure:
54 mg of 4-({2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methoxypyrimidin-4-yl}amino)pyridine-3-carbonitrile (24-1, 0.12 mmol, 1. eq.) were dissolved in 1.6 ml of dimethyl sulfoxide under nitrogene atmosphere. 42 μl of 3 M aqueous sodium hydroxide solution (0.126 mmol, 1.05 eq.) were added. The mixture was oilbath heated to 63° C. bath temperature. At this temperature 302 μl hydrogen peroxide (30% in water) (9.87 mmol, 82.2 eq.) were added dropwise. The reaction mixture was stirred at 65° C. bath temperature for 3 hours and at room temperature for 24 hours. After stirring the mixture one hour with ice-water it was extracted three times with dichloromethane/isopropanol 4:1. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative TLC (dichloromethane/methanol 9:1) to yield 12.0 mg (0.02 mmol, 20.5%) of the analytically pure target compound.
Reaction SMILES: [F:1][C:2]([F:34])([C:8]1[CH:9]=[C:10]2[CH2:33][C@@:15]3([C:23]4[C:18](=[N:19][CH:20]=[CH:21][CH:22]=4)[N:17]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:16]3=[O:32])[CH2:14][C:11]2=[N:12][CH:13]=1)[C:3](OCC)=[O:4].[Cl-].[Ca+2].[Cl-].[BH4-].[Na+]>CO>[F:34][C:2]([C:8]1[CH:9]=[C:10]2[CH2:33][C@@:15]3([C:23]4[C:18](=[N:19][CH:20]=[CH:21][CH:22]=4)[N:17]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[C:16]3=[O:32])[CH2:14][C:11]2=[N:12][CH:13]=1)([F:1])[CH2:3][OH:4]
Reactant: CCOC(=O)C(F)(F)c1cnc2c(c1)C[C@@]1(C2)C(=O)N(COCC[Si](C)(C)C)c2ncccc21
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CO
Product: C[Si](C)(C)CCOCN1C(=O)[C@]2(Cc3cc(C(F)(F)CO)cnc3C2)c2cccnc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (S)-ethyl 2,2-difluoro-2-(2′-oxo-1′-((2-(trimethylsilyl)ethoxy)methyl)-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-3-yl)acetate (0.542 g, 1.11 mmol) in MeOH (10 mL) at ambient temperature was added calcium chloride (0.184 g, 1.66 mmol) and sodium borohydride (0.128 g, 3.32 mmol). After stirring at ambient temperature for 24 h, the reaction was quenched with a saturated solution of sodium chloride (5 mL), partitioned between water (20 mL) and EtOAc (100 mL). The organic layer was removed and the aqueous phase was extracted further with EtOAc (30 mL). The combined organic extracts were washed with brine, then dried over sodium sulfate, filtered, and concentrated to dryness in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH—100:0 to 93:7, to give the title compound. MS: m/z=448.1 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:21])[CH:4]([NH:8][C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)[CH:5]([CH3:7])[CH3:6]>C(OC(=O)C)(=O)C>[CH:5]([CH:4]1[C:3](=[O:2])[O:21][C:9]([C:10]2[CH:11]=[CH:12][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:14][CH:15]=2)=[N:8]1)([CH3:6])[CH3:7]
Reactant: COC(=O)C(NC(=O)c1ccc(C(F)(F)F)cc1)C(C)C
Solvent: CC(=O)OC(C)=O
Product: CC(C)C1N=C(c2ccc(C(F)(F)F)cc2)OC1=O
Temperature: 95 °C

Procedure:
3-Methyl-2-(4-trifluoromethyl-benzoylamino)-butyric acid methyl ester (4.75 g, 16.42 mmol) is dissolved in acetic anhydride (25 mL) and heated to 95° C. for 3 hr. The mixture is concentrated in vacuo and the residue is partitioned between aqueous saturated sodium hydrogen carbonate (100 mL) and ethyl acetate (100 mL) the layers are separated, the organic phase is washed with water and brine (100 mL each), dried over anhydrous magnesium sulfate, filtered, concentrated in vacuo, and purified over silica gel eluting with 9:1 hexanes:ethyl acetate to afford 4-Isopropyl-2-(4-trifluoromethyl-phenyl)-4H-oxazol-5-one as a colorless oil which solidifies to a white crystalline solid on standing, 4.14 g, 93%. MS (M++1) 272.
Reaction SMILES: Cl[C:2]1[C:3]([N+:12]([O-])=O)=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.CN(C)[CH:17]=[S:18]>>[CH3:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]2[N:12]=[CH:17][S:18][C:2]=2[CH:7]=1
Reactant: CN(C)C=S
Reactant: Cc1cc(Cl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Product: Cc1cc2scnc2cc1[N+](=O)[O-]
Temperature: 120 °C

Procedure:
A mixture of 1.6 g of 5-chloro-2,4-dinitrotoluene and 20 mL of N,N-dimethyl-thioformamide is heated to 120° C. for 16 hours. After cooling to room temperature, the mixture is purified by flash column chromatography on silica gel, eluting with 3% to 10% ethyl acetate/hexanes to provide 0.78 g of 6-methyl-5-nitrobenzothiazole as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:24][C:25]=1[CH3:26])[CH2:6][O:7][C:8]1[N:15]=[CH:14][CH:13]=[CH:12][C:9]=1[C:10]#N.C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[NH4+].C(OCC)(=[O:54])C>CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[O:24][C:25]=1[CH3:26])[CH2:6][O:7][C:8]1[N:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=[O:54]
Reactant: COc1cc(COc2ncccc2C#N)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: CCOC(C)=O
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COc1cc(COc2ncccc2C=O)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-[3-methoxy-4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]nicotinonitrile (4.25 g) and toluene (150 mL) was dropwise added a solution (0.95 M, 23.0 mL) of diisobutylaluminum hydride in hexane at −78° C. After stirring for 1 hr the reaction mixture was warmed to room temperature and the mixture was further stirred for 1 hr. A saturated aqueous ammonium chloride solution (35 mL) was dropwise added to the mixture and the mixture was stirred at room temperature for 30 min. To the mixture was added ethyl acetate and the insoluble materials were filtered off. The filtrate was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give 2-[3-methoxy-4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]nicotinaldehyde as crystals from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless crystals (710 mg, 17%). melting point: 99-100° C.
Reaction SMILES: [OH:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][N:8]2[CH2:21][C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[CH:4][C:3]=1[O:34][CH3:35].Br[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>>[CH2:41]([O:40][C:38](=[O:39])[CH2:37][O:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][N:8]2[CH2:21][C:22](=[O:23])[NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:4][C:3]=1[O:34][CH3:35])[CH3:42]
Reactant: COc1cc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)ccc1O
Reactant: CCOC(=O)CBr
Product: CCOC(=O)COc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)cc1OC

Procedure:
prepared by reaction of 2-[1-(4-hydroxy-3-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with ethyl bromoacetate
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([O:18]C)=[O:17])=[CH:15][C:10]=3[N:9]=[CH:8]2)=[CH:4][CH:3]=1.[Li+].[OH-].Cl>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:10]=3[N:9]=[CH:8]2)=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccc2c(c1)ncn2Cc1ccc(Br)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc2c(c1)ncn2Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of methyl 1-(4-bromobenzyl)-1H-benzo[d]imidazole-5-carboxylate (650 mg, 1.88 mmol) and LiOH (150 mg, 3.76 mmol) in Methanol (10 mL) and 1120 (5 mL) was stirred at RT overnight. Then the methanol was removed under the reduced pressure to get a residue, pH was adjusted to 7 with 3N HCl to give a large number of precipitation, then filtered and the filter cake was washed by water (5 mL×2), dried under vacuum to give the titled compound.
Reaction SMILES: [C:1]([N:9]=[C:10]=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:12]1[CH:16]=[CH:15][C:14]2[CH:17]([NH2:21])[CH2:18][CH2:19][CH2:20][C:13]1=2>C(Cl)Cl>[C:1]([NH:9][C:10]([NH:21][CH:17]1[C:14]2[CH:15]=[CH:16][S:12][C:13]=2[CH2:20][CH2:19][CH2:18]1)=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=NC(=O)c1ccccc1
Reactant: NC1CCCc2sccc21
Solvent: ClCCl
Product: O=C(NC(=O)c1ccccc1)NC1CCCc2sccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 2.94 g sample of benzoyl isocyanate in 5 ml of CH2Cl2 is added to 3.04 g of 4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine in 50 ml of CH2Cl2 under N2 atmosphere. After stirring overnight at room temperature, the reaction mixture is evaporated to dryness in vacuo. The residue is then stirred in 100 ml of Et2O and filtered to afford 1-benzoyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea, m.p. 189° C. to 194° C. Substitution of trichloroacetyl isocyanate for benzoyl isocyanate affords 1-trichloroacetyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea. Use of 4,5,6,7-tetrahydrobenzo[b]thien-4-ylisocyanate and acetamide in the above manner affords 1-acetyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:54])[C@@H:4]([NH:21][C:22]([C@@H:24]1[CH2:33][C:32]2[CH:31]=[C:30]3[O:34][CH2:35][C@H:36]([C:38]4[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]5[CH:51]=[CH:50][C:49]([Cl:52])=[C:48]([Cl:53])[CH:47]=5)=[CH:40][CH:39]=4)[O:37][C:29]3=[CH:28][C:27]=2[CH2:26][NH:25]1)=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[C:14]=2[CH3:20])=[CH:8][CH:7]=1.[N:55]([CH:58]1[CH2:61][CH2:60][CH2:59]1)=[C:56]=[O:57]>>[CH3:1][O:2][C:3](=[O:54])[C@@H:4]([NH:21][C:22]([C@@H:24]1[CH2:33][C:32]2[CH:31]=[C:30]3[O:34][CH2:35][C@H:36]([C:38]4[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]5[CH:51]=[CH:50][C:49]([Cl:52])=[C:48]([Cl:53])[CH:47]=5)=[CH:40][CH:39]=4)[O:37][C:29]3=[CH:28][C:27]=2[CH2:26][N:25]1[C:56](=[O:57])[NH:55][CH:58]1[CH2:61][CH2:60][CH2:59]1)=[O:23])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[C:14]=2[CH3:20])=[CH:10][CH:11]=1
Reactant: COC(=O)[C@H](Cc1ccc(Oc2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: O=C=NC1CCC1
Product: COC(=O)[C@H](Cc1ccc(Oc2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)NC1CCC1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-2-({(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester (30 mg) was reacted with Isocyanato-cyclobutane according to General Procedure AD and I to give (S)-2-({(3S,8S)-7-cyclobutylcarbamoyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester. This ester was hydrolyzed according to General Procedure B to give the title compound (12 mg). LCMS (m/z): 852.