Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7]([CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:13]=3[I:22])=[N:8]2)=[C:4]([NH2:23])[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].S(C1C=CC(C)=CC=1)(O[CH2:34][CH2:35][CH2:36][C:37]#[CH:38])(=O)=O>CN(C=O)C>[F:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:13]=3[I:22])[N:8]2[CH2:38][CH2:37][CH2:36][C:35]#[CH:34])=[C:4]([NH2:23])[N:3]=1
Reactant: COc1cc(I)c(Cc2nc3nc(F)nc(N)c3[nH]2)cc1OC
Reactant: C#CCCCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C#CCCCn1c(Cc2cc(OC)c(OC)cc2I)nc2c(N)nc(F)nc21

Procedure:
A solution of 2-fluoro-8-(2-iodo-4,5-dimethoxy-benzyl)adenine (12 mg, 0.028 mmol), Cs2CO3 (9 mg, 0.028 mmol), pent-4-ynyl tosylate (8.6 mg, 7 L, 0.036 mmol) in anhydrous DMF (80 L) was stirred at 50° C. for 1 h. Following solvent removal, the product (13.7 mg, 99%) was collected through silica gel column purification (CHCl3:EtOAc:hexanes:i-PrOH at 20:10:20:1). 1H NMR (400 MHz, CDCl3) 7.27 (s, 1H), 6.65 (s, 1H), 5.94 (bs, 2H), 4.29 (s, 2H), 4.13 (t, J=7.3 Hz, 2H), 3.87 (s, 3H), 3.73 (s, 3H), 2.26-2.22 (m, 2H), 2.00 (t, J=2.6 Hz, 1H), 1.97-1.90 (m, 2H); 13C NMR (100 MHz, CDCl3) 156.5, 153.2, 151.3, 150.0, 149.1, 130.9, 121.9, 112.6, 88.5, 82.5, 70.0, 56.4, 56.2, 42.6, 39.2, 28.4, 16.1; MS m/z 496.2 (M+H)+. HPLC: (a) 99.9% (60% water-40% acetonitrile); (b) 96.8% (35% to 55% acetonitrile).
Reaction SMILES: [C:1]([Mg]Br)#[CH:2].[CH2:5]1COC[CH2:6]1.C([O:12][C:13]1[CH2:31][CH2:30][C@H:29]2[C:15](=[CH:16][CH2:17][C@@H:18]3[C@@H:28]2[CH2:27]C[C@@:23]2([CH2:24]C)[C@H:19]3[CH:20]=[CH:21][C:22]2=[O:32])[CH:14]=1)C.Cl>CC1OCCC1.CCO>[C:23]([C@:22]1([OH:32])[CH:21]=[CH:20][C@H:19]2[C@H:18]3[C@H:28]([CH2:27][CH2:1][C@:2]12[CH2:5][CH3:6])[C@@H:29]1[C:15](=[CH:14][C:13](=[O:12])[CH2:31][CH2:30]1)[CH2:16][CH2:17]3)#[CH:24]
Reactant: C#C[Mg]Br
Reactant: C1CCOC1
Reactant: CCOC1=CC2=CC[C@@H]3[C@H](CC[C@]4(CC)C(=O)C=C[C@@H]34)[C@H]2CC1
Agent: Cl
Solvent: CCO
Solvent: CC1CCCO1
Product: C#C[C@]1(O)C=C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21CC
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
A 0.5 M solution of ethynylmagnesium bromide in THF (200 ml, 100 mmol) was added under a nitrogen atmosphere to a solution of 3-ethoxy-18-methyl-estra-3,5,15-trien-17-one (20 g, 64.1 mmol) in 2-MeTHF (40 ml) without exceeding 25° C. The mixture was stirred at room temperature for 2 h, cooled to 7° C. and EtOH (10 ml) was added. The mixture was stirred for 10 min, 3N aqueous hydrochloric acid solution was then added, and the mixture was stirred at a temperature below 10° C. for 2 h. The organic layer was separated and the aqueous layer was extracted with 2-MeTHF. The organic layers were combined and successively washed with 10% aqueous sodium chloride solution, 10% aqueous sodium hydrogencarbonate solution and 10% aqueous sodium chloride solution. 1-butanol (40 ml) was added to the organic layer and THF and 2-MeTHF were evaporated under vacuum at a temperature below 50° C. The remaining mixture in 1-butanol was cooled to 5° C. The precipitate was filtered, washed with water and dried under vacuum to afford crude 17α-ethynyl-17β-hydroxy-18-methyl-estra-4,15-dien-3-one (14.9 g, yield: 75%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=1[CH2:17][CH2:18][CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH2:20].C(NCC)C>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13](=[S:20])[NH2:14])=[CH:11][C:10]=1[CH2:17][CH2:18][CH3:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: S
Reactant: CCCc1cc(C#N)ccc1OCc1ccccc1
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CCCc1cc(C(N)=S)ccc1OCc1ccccc1
Temperature: 60 °C

Procedure:
Through a solution of 4-(benzyloxy)-3-propylbenzonitrile (1.23 g, 4.91 mmol) (Example 30) in DMF (35 mL) was passed H2S for 30 min at rt. Diethyl amine (0.76 mL, 7.36 mmol) was added and the solution was heated to 60° C. for 4 h. The mixture was cooled to rt, and the residual H2S was removed by passing argon through the solution for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was filtered through a plug of silica and washed with EtOAc. Concentration of the filtrate under reduced pressure resulted in a yellow solid which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[C]=O.[O:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1>>[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH:3]=[CH:2][C:1]([O:5][CH3:6])=[O:4]
Reactant: c1ccoc1
Reactant: C=CC(=O)OC
Agent: [C]=O
Product: COC(=O)C=Cc1ccco1
Reaction time: 7 h
Yield: 39 %

Procedure:
Charged in a shaking type stainless steel autoclave having an inner capacity of 100 ml, were 30 ml of furan, 1.083 g of methyl acrylate and 0.04 g of Rh4 (CO)12, followed by supply of carbon monoxide under 25 kg/cm2. Reaction was carried out at 220° C. for 7 hours. After completion of the reaction, the obtained reddish orange reaction solution was concentrated under reduced pressure and separated and purified by silica gel column chromatography. From a fraction eluted with benzene/hexane (3/2 to 4/1) was obtained 0.74 g of methyl β-(2-furyl)acrylate (1) (the yield was 39% based on methyl acrylate).
Reaction SMILES: C(O)(=O)C.O=[CH:6][CH2:7][CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].[NH2:17][C@:18]12[CH2:53][CH2:52][C@@H:51]([C:54]([CH3:56])=[CH2:55])[C@@H:19]1[C@@H:20]1[C@@:33]([CH3:36])([CH2:34][CH2:35]2)[C@@:32]2([CH3:37])[C@@H:23]([C@:24]3([CH3:50])[C@@H:29]([CH2:30][CH2:31]2)[C:28]([CH3:39])([CH3:38])[C:27]([C:40]2[CH:49]=[CH:48][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][CH:41]=2)=[CH:26][CH2:25]3)[CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CCO.O1CCOCC1>[C:12]([O:11][C:10]([NH:9][CH2:8][CH2:7][CH2:6][NH:17][C@:18]12[CH2:53][CH2:52][C@@H:51]([C:54]([CH3:56])=[CH2:55])[C@@H:19]1[C@@H:20]1[C@@:33]([CH3:36])([CH2:34][CH2:35]2)[C@@:32]2([CH3:37])[C@@H:23]([C@:24]3([CH3:50])[C@@H:29]([CH2:30][CH2:31]2)[C:28]([CH3:38])([CH3:39])[C:27]([C:40]2[CH:41]=[CH:42][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:48][CH:49]=2)=[CH:26][CH2:25]3)[CH2:22][CH2:21]1)=[O:16])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)NCCC=O
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Solvent: CC(=O)O
Product: C=C(C)[C@@H]1CC[C@]2(NCCCNC(=O)OC(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
Acetic acid (0.013 mL, 0.221 mmol) and tert-butyl 3-oxopropylcarbamate (38.2 mg, 0.221 mmol) were added to a solution of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (40 mg, 0.074 mmol) in EtOH (1 mL) and dioxane (1.0 mL) and the mixture was stirred for 2 h at rt. Sodium triacetoxyborohydride (78 mg, 0.368 mmol) was added and the reaction mixture was stirred at 20° C. for two hours. The reaction was quenched with a saturated aqueous solution of sodium bicarbonate (3 mL), washed with 0.1N HCl (5 mL) and brine (5 mL) and extracted with DCM (3×5 mL). All the extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound as pale yellow oil (28 mg, 54%). LCMS: m/e 701.51 (M+H)+, 4.0 min (method 10).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][Si](C(C)C)(C(C)C)C(C)C)[N:10]([C:30]([C:32]3[C:37]([F:38])=[CH:36][C:35]([F:39])=[CH:34][C:33]=3[F:40])=[O:31])[N:9]=2)=[CH:4][CH:3]=1.FC1C=CC(C2SC(C3C=CC=C(OC)C=3O[Si](C(C)C)(C(C)C)C(C)C)N(C(C3C(F)=CC(F)=CC=3F)=O)N=2)=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Br[CH2:102][C:103]1[O:104][CH:105]=[CH:106][C:107]=1[C:108]([O:110][CH3:111])=[O:109]>>[CH3:111][O:110][C:108]([C:107]1[CH:106]=[CH:105][O:104][C:103]=1[CH2:102][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH:11]1[N:10]([C:30](=[O:31])[C:32]2[C:37]([F:38])=[CH:36][C:35]([F:39])=[CH:34][C:33]=2[F:40])[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[S:12]1)=[O:109]
Reactant: COC(=O)c1ccoc1CBr
Reactant: CC(C)[Si](Oc1ccccc1C1SC(c2ccc(F)cc2)=NN1C(=O)c1c(F)cc(F)cc1F)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: COc1cccc(C2SC(c3ccc(F)cc3)=NN2C(=O)c2c(F)cc(F)cc2F)c1O[Si](C(C)C)(C(C)C)C(C)C
Agent: [F-]
Product: COC(=O)c1ccoc1COc1ccccc1C1SC(c2ccc(F)cc2)=NN1C(=O)c1c(F)cc(F)cc1F
Reaction time: 0.25 h

Procedure:
[5-(4-Fluoro-phenyl)-2-(2-triisopropylsilanyloxy-phenyl)-[1,3,4]thiadiazol-3-yl]-(2,4,6-trifluoro-phenyl)-methanone (0.67 mmol), prepared as described for [5-(4-fluoro-phenyl)-2-(3-methoxy-2-triisopropylsilanyloxy-phenyl)-[1,3,4]thiadiazol-3-yl]-(2,4,6-trifluoro-phenyl)-methanone in example 3, is treated with tetrabutylammonium fluoride (1.0 M in THF) (1.3 mmol) at room temperature. After 15 minutes, methyl 2-(bromomethyl)-3-furoate (0.74 mmol) is added and the mixture is stirred for an additional 12 hours. The solvent is removed in vacuo and the residue is purified on silica to yield 2-{2-[5(4-fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxymethyl}-furan-3-carboxylic acid methyl ester as a yellow solid: LC/MS (ES+): 571.1 (M+1)+.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])[C:16]=3[N:17]=[C:18]([CH3:20])[N:19]=2)[CH2:4][CH2:3]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][N:31]([C:37](=[O:38])[CH2:36][O:35][CH3:34])[CH2:32][CH2:33]4)=[O:26])[C:16]=3[N:17]=[C:18]([CH3:20])[N:19]=2)[CH2:3][CH2:4]1
Reactant: Cc1ccc(OCC2CC2)c(-c2nc(C)nc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(C)ccc4OCC4CC4)nc(C)nc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methylphenyl]-2,6-dimethyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f57) and commercially available available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([NH:11][CH2:12][CH2:13][C:14]([OH:16])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(C1NC=CN=1)(C1NC=CN=1)=O.C([Mg]Cl)(C)C.C(O)(=O)[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37]>C1COCC1>[CH2:39]([O:38][C:36](=[O:37])[CH2:35][C:14](=[O:16])[CH2:13][CH2:12][NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH3:40]
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Reactant: CCOC(=O)CC(=O)O
Agent: CC(C)[Mg]Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CCNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Cbz-β-Alanine (5.0 g, 21.6 mmol) is dissolved in THF (10 mL). To this is added dropwise a solution of carbonyl diimidazole (3.5 g, 21.6 mmol) in THF (50 mL) and allowed to stir 16 hrs. This solution is then reduced to ˜30 mL by rotary evaporation. In a separate flask (oven dried), isopropyl magnesium chloride in THF (2M) (16.2 mL, 32 mmol) is added and cooled to 0° C. and hydrogen ethyl malonate (4.28 g, 32.4 mmol) is added dropwise. The contents are allowed to stir at 0° C. for 30 min, allowed to warm to 25° C. and continue stirring for another 30 min, and finally warmed to 40° C. for 30 min. The contents are then cooled to 0° C. and the contents of the first flask are added dropwise. The reaction is allowed to gradually come to 25° C. and continue stirring for 4 hrs. The reaction is poured into 100 mL of ice cold 1 N H3PO4 and allowed to stir for 30 min. The contents are extracted (3×100 mL) with ethyl acetate. The combined organic layers are then washed (3×100 mL) with saturated sodium bicarbonate followed by (3×100 mL) with brine. The organic layer is dried over MgSO4, filtered and reduced to an oil by rotary evaporation to provide 5-benzyloxycarbonylamino-3-oxo-pentanoic acid ethyl ester. The product is used as is without further purification. 1H NMR (300 MHz, CDCl3) δ 7.32 (s, 5H), 5.25 (bm, 1H), 5.06 (s, 2H), 4.17 (q, 2H), 3.42 (m, 5H), 2.78 (t, 2H), 1.25 (t, 3H); MS (ion spray) 294 (M+H)+.
Reaction SMILES: [NH2:1][C:2]([CH3:17])([CH2:5][N:6]1[N:10]=[C:9]2[CH:11]=[C:12]([CH3:16])[C:13]([Cl:15])=[CH:14][C:8]2=[N:7]1)[C:3]#[N:4].[F:18][C:19]([F:30])([F:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[S:25])=[CH:22][CH:21]=1>>[Cl:15][C:13]1[C:12]([CH3:16])=[CH:11][C:9]2=[N:10][N:6]([CH2:5][C:2]([NH:1][C:24](=[S:25])[C:23]3[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:29])[F:30])=[CH:28][CH:27]=3)([C:3]#[N:4])[CH3:17])[N:7]=[C:8]2[CH:14]=1
Reactant: Cc1cc2nn(CC(C)(N)C#N)nc2cc1Cl
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Product: Cc1cc2nn(CC(C)(C#N)NC(=S)c3ccc(C(F)(F)F)cc3)nc2cc1Cl

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(5-chloro-6-methyl-2H-benzotriazol-2-yl)-2-methylpropionitrile (90 mg, described in Example 9) and 4-trifluoromethylthiobenzoyl chloride (0.1 mL), the title compound was isolated as a white solid (152 mg, 93%). Rf=0.6 (1:1 EA/heptane). MS (ES): M/Z [M+H]=454. 1H NMR: (400 MHz, DMSO-d6): 1.73 (s, 3H), 2.46 (s, 3H), 5.38 (d, J=13.4 Hz, 1H), 5.45 (d, J=13.4 Hz, 1H), 7.87 (d, J=8.5 Hz, 2H), 7.91 (d, J=8.6 Hz, 2H), 7.96 (s, 1H), 8.13 (s, 1H) and 9.00 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −41.93 (s, 3F).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH3:21])[N:10]=2)[N:3]=1.[CH3:22][O-:23].[Na+].CO.[Na]>C(Cl)(Cl)Cl.O>[CH3:22][O:23][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH3:21])[N:10]=2)[N:3]=1
Reactant: Cc1cc(Cl)nc(-c2cccc(-c3ccccc3C)n2)n1
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cc(C)nc(-c2cccc(-c3ccccc3C)n2)n1
Reaction time: 0.5 h
Yield: 96 %

Procedure:
To 4-chloro-6-methyl-2-(6-o-tolyl-2-pyridinyl)pyrimidine (2 g) was added sodium methoxide prepared from methanol (10 ml) and metallic sodium (0.19 g). After the mixture was left to stand at room temperature for 30 minutes, water (30 ml) and chloroform (100 ml) was added thereto, and then extracted. After the extract was dried over anhydrous magnesium sulfate, it was concentrated under reduced pressure to obtain 4-methoxy-6-methyl-2-(6-o-tolyl-2-pyridinyl)pyrimidine (1.9 g, yield 96%).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.O1CCCC1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1.O1C2C=CC=CC=2N=C1>O>[F:24][C:23]([F:25])([F:26])[C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:2]2[O:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)=[CH:18][CH:19]=1
Reactant: Clc1nc2ccccc2o1
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: c1ccc2ocnc2c1
Solvent: O
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(Nc2nc3ccccc3o2)cc1
Temperature: 25 °C

Procedure:
To a solution of 15.4 g. (0.1 mole) of 2-chlorobenzoxazole in 200 ml. of tetrahydrofuran was added dropwise a solution of 16.1 g. (0.1 mole) of p-aminobenzotrifluoride in 100 ml. of tetrahydrofuran with vigorous agitation. Following the addition, the reaction mixture was heated on a steam bath under reflux for 16 hours. Then the reaction mixture was cooled to about 25° C., and about 500 ml. of water was added. The tetrahydrofuran solvent was removed by distillation under vacuum, leaving an aqueous slurry of the reaction product. The solids were filtered off and dried. The dried residue was dissolved in a minimum amount of warm benzene. Then about 200 ml. of hexane was added to the benzene solution to crystallize the reaction product. The crystals were filtered off and dried, yielding 19.2 g. of 2-[4-trifluoromethyl)anilino]benzoxazole having a melting point of 180°-182° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][C:11](Cl)=[N:12][OH:13])=[N:2]1.[NH3:15]>C(Cl)(Cl)Cl.C(O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][C:11](=[N:12][OH:13])[NH2:15])=[N:2]1
Reactant: ON=C(Cl)Cc1noc2ccccc12
Reactant: N
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: NC(Cc1noc2ccccc12)=NO
Reaction time: 0.5 h

Procedure:
In a mixture of chloroform (250 ml) and ethanol (250 ml) was dissolved 1,2-benzisoxazole-3-acetohydroximic chloride (0.5 g) and the mixture was saturated with ammonia by passing through thereto ammonia gas under ice-cooling. The mixture was allowed to stand for 0.5 hour and then the solvent was distilled off under a reduced pressure. To the residue was added chloroform and the insoluble substance was filtered off. The filtrate was distilled to remove the solvent and the residue was recrystallized from ethanol to give the desired compound (0.38 g). m.p. 161° to 163°C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:30]2(O)[CH2:35][CH2:34][C:33]([CH3:37])([CH3:36])[CH2:32][CH2:31]2)=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:29][CH2:28][C:23]2(OCC[O:24]2)[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].FC(F)(F)C(O)=O.O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:30]2[CH2:35][CH2:34][C:33]([CH3:36])([CH3:37])[CH2:32][CH:31]=2)=[CH:8][C:9]=1[N:10]([C:11]([C@H:13]1[CH2:14][CH2:15][C@H:16]([CH3:19])[CH2:17][CH2:18]1)=[O:12])[CH:20]1[CH2:21][CH2:22][C:23](=[O:24])[CH2:28][CH2:29]1)=[O:4]
Reactant: COC(=O)c1sc(C2(O)CCC(C)(C)CC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC2(CC1)OCCO2
Solvent: O
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1sc(C2=CCC(C)(C)CC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC(=O)CC1
Reaction time: 1.5 h

Procedure:
To a solution of 3-[(1,4-dioxa-spiro[4.5]dec-8-yl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-5-(1-hydroxy-4,4-dimethyl-cyclohexyl)-thiophene-2-carbo-xylic acid methyl ester (14.4 g, previous step) in dry toluene (50 mL) at room temperature was added trifluoroacetic acid (50 mL). The reaction mixture was stirred for 90 min. Water (1.28 g, 71.1 mmol) was added to the mixture and stirred for 90 min. The reaction mixture was evaporated to dryness, extracted with EtOAc and washed with saturated NaHCO3 and brine. The organic phase was dried over MgSO4, filtered and evaporated to obtain crude 5-(4,4-dimethyl-cyclohex-1-enyl)-3-[(trans-4-methyl-cyclohexanecarbonyl)-(4-oxo-cyclohexyl)-amino]-thiophene-2-carboxylic acid methyl ester (13.3 g) which was used for the next step without any purification.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[C:14]3[N:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:16]=[N:17][C:13]=3[CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>CN1C(=O)CCC1>[N:28]1([CH2:2][C:3]2[CH:4]=[C:5]([C:9]3[C:14]4[N:15]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)[CH:16]=[N:17][C:13]=4[CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=3)[CH:6]=[CH:7][CH:8]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: FC(F)(F)c1cc(-c2cccc(CCl)c2)c2c(c1)ncn2-c1ccccc1
Reactant: C1COCCN1
Solvent: CN1CCCC1=O
Product: FC(F)(F)c1cc(-c2cccc(CN3CCOCC3)c2)c2c(c1)ncn2-c1ccccc1

Procedure:
This was prepared analogeously to the above product from 7-(3-(chloromethyl)phenyl)-1-phenyl-5-trifluoromethylbenzimidazole (0.97 g, 2.5 mmol) and morpholine (0.74 ml, 7.5 mmol) in NMP (5 ml) to yield 0.81 g (74%), m/z, 382.1 (M+H)+.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:14](O)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:30][C:31]1[S:32][CH:33]=[CH:34][N:35]=1.Cl>C(Cl)Cl.N1C=CC=CC=1.CN(C=O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([O:17][CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:14]([NH:30][C:31]3[S:32][CH:33]=[CH:34][N:35]=3)=[O:15])=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(O)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: Nc1nccs1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1nccs1)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Temperature: 0 °C

Procedure:
2-(4-Cyclopropylsulfonylphenyl)-2-tetrahydropyran-4-yloxy-acetic acid (preparation 4) was dissolved in DCM. To this solution was added DMF and cooled to 0° C., followed by the addition of oxalyl chloride under stirring. To this mixture, a solution of 2-aminothiazole and pyridine in DCM was added drop wise at 0° C. and was stirred further for 4 h. at room temperature. The reaction mixture was poured into IN aqueous HCl under stirring, organic layer was again washed with 1N HCl, followed by 5% brine, dried over anhydrous sodium sulfate, solvent was removed under reduced pressure to get the crude compound which was purified by flash chromatography to get the title product.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][C:6]([CH2:7][NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[CH2:24]([O:26][C@H:27]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:28][C:29]1[CH:39]=[CH:38][C:32]([O:33][CH2:34][C:35](O)=[O:36])=[CH:31][CH:30]=1)[CH3:25].C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[F:1][C:2]([F:22])([F:23])[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:14][CH:15]=2)[C:35](=[O:36])[CH2:34][O:33][C:32]2[CH:31]=[CH:30][C:29]([CH2:28][C@H:27]([O:26][CH2:24][CH3:25])[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:39][CH:38]=2)=[CH:20][CH:21]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OCC
Reactant: FC(F)(F)c1ccc(CNCc2ccc(C(F)(F)F)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1ccc(OCC(=O)N(Cc2ccc(C(F)(F)F)cc2)Cc2ccc(C(F)(F)F)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.4 %

Procedure:
To a solution of N,N-bis[4-(trifluoromethyl)benzyl]amine (0.733 g, 2.20 mmol) and {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.593 g, 2.00 mmol) in methylene chloride (20 mL) were added N,N-diisopropylethylamine (0.80 mL, 4.6 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.674 g, 2.10 mmol) and the reaction mixture was stirred at room temperature for 4 h. The resulting solution was diluted with methylene chloride (130 mL) and the organic phase was washed with 5% HCl (3×75 mL), saturated aqueous NaHCO3 (2×75 mL), and brine (75 mL), dried over Na2SO4, and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 70 g/150 mL) with methanol (0-1% gradient) in methylene chloride as the eluent yielded 0.91 g (74%) of a whitish oil.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][C:11](=[O:13])[CH2:10][C:9](=[O:14])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.S([N:32]=[N+:33]=[N-])(C1C=CC(C)=CC=1)(=O)=O>C(O)C>[N+:32](=[C:10]1[C:9](=[O:14])[CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:12][C:11]1=[O:13])=[N-:33]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: O=C1CC(=O)CC(c2ccccc2)C1
Solvent: CCN(CC)CC
Solvent: CCO
Product: [N-]=[N+]=C1C(=O)CC(c2ccccc2)CC1=O
Yield: 36.9 %

Procedure:
A solution of 20.0 g (0.106mol) of 5-phenyl-cyclohexane-1,3-dione in 75 ml of ethanol was cooled to -10° C. and stirred magnetically under nitrogen. To the mixture was added 10.75 g (0.106 mol) of triethylamine. The tosyl azide (20.95 g 0.106 mol) was added all at once, and the mixture stirred for one hour at 0°-5° C. The solvent was removed under vacuum at a temperature less than 40° C. To the residue was added 200 ml ether, and the mixture extracted with a solution containing 3.1 g potassium hydroxide in 200 ml of water. The etheral solution was dried over anhydrous MgSO4 filtered and the solvent removed to give a yellow solid which was recrystallized from ethanol -hexane to give 8.38 g (32%) of 2-diazo-5-phenyl-cyclohexane-1,3-dione as yellow crystals, mp 122°-124° C.