Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[Br:7][C:8]1[N:9]=[C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][CH:19]([N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)[CH2:18][CH2:17]3)=[N:12][N:11]2[CH:27]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1>C(Cl)(Cl)Cl.ClCCl>[Br:7][C:8]1[N:9]=[C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][CH:19]([N:22]4[CH2:23][CH2:24][CH2:25][CH2:26]4)[CH2:18][CH2:17]3)=[N:12][N:11]2[C:27]=1[CH:32]1[CH:31]=[CH:30][N:29]([C:2]([O:4][CH2:5][CH3:6])=[O:3])[N:28]=[CH:33]1
Reactant: CCOC(=O)Cl
Reactant: Brc1cn2nc(N3CCC(N4CCCC4)CC3)ccc2n1
Reactant: c1ccnnc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)N1C=CC(c2c(Br)nc3ccc(N4CCC(N5CCCC5)CC4)nn23)C=N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
1.3 g (12 mmol) of ethyl chloroformate are added, dropwise in 5 minutes, while cooling in an ice bath, to a mixture of 1.68 g (4.8 mmol) of 2-bromo-6-(4-pyrrolidin-1-ylpiperidin-1-yl)imidazo[1,2-b]pyridazine and 1.92 g (24 mmol) of pyridazine in 25 ml of chloroform. The mixture is stirred at ambient temperature for one hour and is then diluted with dichloromethane, and the solution is washed successively with a solution of sodium bicarbonate and then with a saturated solution of sodium chloride. The organic phase is dried over sodium sulfate and then concentrated under reduced pressure after the addition of silica gel. The evaporation residue is loaded onto a silica gel column and the product is purified by silica gel column chromatography, elution being carried out with a mixture of 0 to 10% of methanol in dichloromethane. 1.93 g of product sufficiently pure for the rest of the synthesis are thus isolated.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].N1CCCCC1>C(O)(=O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[CH:11][C:12]([OH:14])=[O:13]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cccc(O)c1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: O=C(O)C=Cc1cccc(O)c1
Yield: 76 %

Procedure:
A mixture of 3-hydroxybenzaldehyde (1 g, 0.008 mol), malonic acid (1.69 g, 0.016 mol), piperidine (1 to 3 mL) and acetic acid (10–20 mL) were taken in a 100 ml Erlenmeyer flask and irradiated under microwave for 2–8 minutes in parts. The cooled mixture was poured into ice cold water and extracted with ethyl acetate. The organic layer was washed with dil HCl., saturated sodium chloride and then organic layer dried over sodium sulphate. The solvent was evaporated under reduced pressure to obtain crude solid which was recrystallised with methanol, provided a white solid in 76% yield; 193° C. (lit mp 194° C.); 1H NMR (CDCl3) δ 6.73(1H, s, H-3 and H-5), 6.62 (1H, dd, H-7), 5.61(1H, d, J=10.9 Hz trans, H-8), 5.16(1H, d, J=17.6, cis-H-8).; 13C NMR (CDCl3) δ 147.4 (C-2 and C-6), 137.2 (C-1), 135.1 (C-7), 129.5 (C-4), 112.2 (C-8), 103.3 (C-3 and C-5), 56.0 (2 OMe). This experiment clearly indicates that utilization of microwave technique as well as presence of hydroxy at 4-position of phenylaldehydes is important for the preparation of 4-vinylphenols (Example I, II and III).
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][C:4]([C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]#[N:10])=[CH:3][CH:2]=1.[N-:16]=[N+:17]=[N-:18].[Na+].C([Sn](Cl)(CCCC)CCCC)CCC.[OH-].[Na+].[C:36]1([C:42](Cl)([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C1(C)C=CC=CC=1.CCCCCCC.O>[C:36]1([C:42]([N:10]2[C:9]([C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[C:4]3[CH:5]=[CH:6][C:1]([CH3:15])=[CH:2][CH:3]=3)=[N:18][N:17]=[N:16]2)([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(-c2ccccc2C#N)cc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 110 °C
Reaction time: 70 h

Procedure:
2-(p-Tolyl)benzonitrile (9.00 g), sodium azide (3.00 g), toluene (35 ml) and tributyltin chloride (16.4 g) were charged to a 250 ml round-bottomed flask equipped with mechanical stirrer, condenser with N2 inlet and thermometer, in a heating mantle. The mixture was heated to 110° C. and held for 70 hours. The mixture was diluted with 35 ml toluene and cooled to room temperature. 10N Sodium hydroxide (5.5 ml) and triphenylmethylchloride (13.5 g) were added and the mixture stirred 3 hours at room temperature. D.I. water (35 ml) and heptane (70 ml) were added and the resulting slurry cooled in an ice bath 11/2 hours. The mixture was vacuum filtered, washed 2×50 ml water and once with 50 ml (3/2, V/V) heptane/toluene, and dried in vacuo overnight at 40° C. Crude Yield=18.32 g, 82.2%. The crude product was dissolved in methylene chloride (200 ml) and washed 1× 52 ml 0.4N sodium hydroxide. The organic phase was gravity filtered, stripped on a rotary evaporator and the product reslurried with heptane (100 ml), filtered and dried in vacuo at 40° C. overnight. Overall Yield: 15.1 g, 68%. M.P.: 161°-162° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-])=O)=[CH:4][N:3]=1.N12CCCN=C1CCCCC2.O.[C:24](OCC)(=O)[C:25]([O:27][CH2:28][CH3:29])=[O:26]>C(OCC)(=O)C.[Fe]>[CH2:28]([O:27][C:25]([C:24]1[NH:9][C:5]2=[CH:4][N:3]=[C:2]([Br:1])[CH:7]=[C:6]2[CH:8]=1)=[O:26])[CH3:29]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1cc(Br)ncc1[N+](=O)[O-]
Agent: [Fe]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cc2cc(Br)ncc2[nH]1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
Route B: To a solution of 2-bromo-4-methyl-5-nitropyridine (Preparation 24, 5.7 g, 26.3 mmol) in diethyl oxalate (17.9 mL) under argon was added 1,8-diazabicyclo[5,4,0]undec-7-ene (4.5 mL, 30.2 mmol) to give a dark red precipitate. Reaction mixture was stirred at rt for 4.5 h and concentrated in vacuo. Acetic acid (140 mL) was added to the residue under argon and heated to 60° C. Iron (2.94 g, 52.6 mmol) was added in small portions over a period of 1 h. The reaction mixture was heated at 80° C. for 4 h. The reaction mixture was cooled to rt and poured into water (300 mL) which gave a beige precipitate. The precipitate was isolated and washed with water. The solid obtained was dissolved in ethyl acetate (700 ml) and filtered. The filtrate was concentrated in vacuo to give the title compound. m/z (ES+)=269 [M+H]+; RT=3.39 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[O:15][CH:14]([CH2:17][NH2:18])[CH2:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[O:15][CH:14]([CH2:17][NH:18][C:29](=[O:30])[O:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2cccc3c2OC(CN)C3)cc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cccc3c2OC(CNC(=O)OCc2ccccc2)C3)cc1
Yield: 55.8 %

Procedure:
Treatment of (±)-1-[7-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (5.8 g, 24.24 mmol) with diisopropylethylamine (4.69 g, 36.35 mmol) followed by benzyl chloroformate (5.17 g, 30.30 mmol) generally according to the procedure described for Intermediate 12 provided 5.05 g (56%) of (±)-benzyl {[7-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate as a clear oil. Anal. calcd. for C24H23NO3: C, 77.19; H, 6.21; N, 3.75. Found: C, 76.97; H, 5.99; N, 3.68. Chiral HPLC separation of (±)-benzyl {[7-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (Chiralpak OD, methanol:carbon dioxide 1:1) provided two fractions. Fraction 1 (Rt=3.735 min, Chiralpak OD, methanol:carbon dioxide 1:1); Fraction 2 (Rt=4.381 min, Chiralpak OD, methanol:carbon dioxide 1:1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([C@H:18]3[CH2:23][CH2:22][C@H:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][C:3]=1[O:31][CH3:32].[OH:33]N1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C([N:58]([CH2:62][CH3:63])[CH:59]([CH3:61])[CH3:60])(C)C>CN(C)C=O>[C:3]([OH:31])(=[O:33])[CH3:4].[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([C@H:18]3[CH2:23][CH2:22][C@H:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[CH2:20][CH2:19]3)[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:61]([C@H:59]4[CH2:60][CH2:63][CH2:62][NH:58]4)=[O:33])=[C:3]([O:31][CH3:32])[CH:4]=3)[C:16]=12
Reactant: CCN(C(C)C)C(C)C
Reactant: On1nnc2cccnc21
Reactant: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CC(=O)O
Product: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)[C@H]1CCCN1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of trans 3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.200 g, 0.00046 mol) in N,N-dimethylformamide (10 mL) was reacted with 1-hydroxy-7-azabenzotriazole (0.068 g, 0.00050 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.132 g, 0.00069 mol), D-Boc-proline (0.108 g, 0.00050 mol) and N,N-diisopropylethylamine (0.184 g, 0.00142 mol) at ambient temperature for 24 hours. The solvent was removed in vacuo and the residue was partitioned between dichloromethane (10 mL) and a 5% aqueous citric acid solution (20 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2×10 mL). The combined organic phases were washed with saturated aqueous sodium bicarbonate (15 mL) and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was stirred in 20% trifluoroacetic acid in dichloromethane for 6 hours at ambient temperature. The solvent was removed in vacuo and the residue was purified by preparative RP-HPLC (Rainin C18, 8 mm, 300 A, 25 cm; 5% isocratic for five minutes, then 5%-40% acetonitrile-0.1M ammonium acetate over 20 min, 21 ml/min). The acetonitrile was removed in vacuo and the aqueous mixture was lyopholyzed to give trans N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-(2R)tetrahydro-1H-2-pyrrolecarboxamide acetate (0.096 g, 0.00016 mol) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:37][CH2:38][CH:39]([OH:43])[CH2:40][CH2:41][CH3:42].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:26](=[O:28])[O:43][CH:39]([CH2:38][CH3:37])[CH2:40][CH2:41][CH3:42])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: CCCC(O)CC
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(CC)OC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C)c1C
Yield: 55.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 3-hexanol (24 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (39 mg, yield 53%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][C:10]1[N:15]=[C:14]([Cl:16])[N:13]=[C:12]([N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]2[CH3:27])[CH:11]=1>CN(C)C=O>[ClH:16].[CH3:9][C:10]1[N:15]=[C:14]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)[N:13]=[C:12]([N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]2[CH3:27])[CH:11]=1
Reactant: Nc1ccc(F)cc1
Reactant: Cc1cc(N2CCc3ccccc3C2C)nc(Cl)n1
Solvent: CN(C)C=O
Product: Cc1cc(N2CCc3ccccc3C2C)nc(Nc2ccc(F)cc2)n1
Product: Cl
Yield: 70.9 %

Procedure:
After 4-fluoroaniline(0.8 ml, 8.4 mmol) was added to a mixture solution of 6-methyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-chloropyrimidine(1.5 g, 5.5 mmol) and dimethylformamide (10 ml), 1.5 g of the title compound was obtained in accordance with the same procedure as in Step 2 of Example 1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([OH:13])[CH2:7]2)([O-:3])=[O:2].[C:14]([O-])([O-])=O.[K+].[K+]>>[CH3:14][O:13][CH:8]1[CH2:7][C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:9]1
Reactant: O=[N+]([O-])c1ccc2c(c1)CC(O)C2
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: COC1Cc2ccc([N+](=O)[O-])cc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.1 %

Procedure:
5-nitro-indan-2-ol (1.55 g, 8.65 mmol) and K2CO3 (2.8 g, 20 mmol) was charged into a schlenk flask. The flask was evacuated and back filled with N2. DMF (10 mL) was added and stirred at r.t. for 30 min. MeI (excess, 10 mL) was added and the reaction mixture was stirred at 100° C. overnight. The reaction mixture was allowed to cool to room temperature. Water was added and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with water and brine and dried over Na2SO4. Purification of the concentrated crude product by column chromatography (EtOAc:Hexane=1:9) afforded the title product as a pale yellow oil (520 mg, 74% based on recovered starting material).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:15][CH2:14]C=C[CH2:11][CH2:10]1.C[N+]1([O-])[CH2:22][CH2:21][O:20]CC1.S(=O)(O)[O-:25].[Na+]>CC(C)=O.O.[Os](=O)(=O)(=O)=O>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:15][CH2:14][CH:22]([OH:25])[CH:21]([OH:20])[CH2:11][CH2:10]1
Reactant: O=S([O-])O
Reactant: Fc1cccc(C2CCC=CCC2)c1F
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: OC1CCC(c2cccc(F)c2F)CCC1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
See: D. A. Spiegel et al. Tetrahedron 2002, 58, 6545-6554. In a 250 mL round-bottomed flask (t=g) was added (Z)-5-(2,3-difluorophenyl)cyclohept-1-ene (1.249 g, 6.00 mmol) and NMO (1.546 g, 13.19 mmol) in Acetone (9 mL) and Water (0.18 mL) to give a white suspension. Osmium tetroxide (0.301 mL, 0.024 mmol) (2.5 wt % solution in 2-methyl-2-propanol) was added. The mixture was stirred at room temperature. NMO gradually dissolved within 30 minutes to become a yellow solution. 1 h: TLC showed complete conversion to a much polar spot. Sodium bisulfite (200 mg) was added and stirring continued for 30 minutes. Acetone was stripped off and the residue was extracted with EtOAc three times. The combined organic layers were washed with brine, dried and concentrated to a white solid (crude weight: 1.7 g). It was directly carried onto next reaction.
Reaction SMILES: C1(S([CH:10]2[CH:20]([C:21]3[CH:26]=[C:25]([Br:27])[CH:24]=[C:23]([CH3:28])[N:22]=3)[NH:19][C:12]3([CH2:16][CH2:15][N:14]([CH3:17])[C:13]3=[O:18])[CH2:11]2)(=O)=O)C=CC=CC=1.CC(C)([O-])C.[K+].C(O)(=O)C>C1COCC1>[Br:27][C:25]1[CH:24]=[C:23]([CH3:28])[N:22]=[C:21]([C:20]2[CH2:10][CH2:11][C:12]3([CH2:16][CH2:15][N:14]([CH3:17])[C:13]3=[O:18])[N:19]=2)[CH:26]=1
Reactant: Cc1cc(Br)cc(C2NC3(CCN(C)C3=O)CC2S(=O)(=O)c2ccccc2)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1cc(Br)cc(C2=NC3(CC2)CCN(C)C3=O)n1
Reaction time: 1.5 h

Procedure:
To a solution of 7-(benzenesulfonyl)-8-(4-bromo-6-methyl-2-pyridyl)-3-methyl-3,9-diazaspiro[4.4]nonan-4-one (which may be prepared as described in Description 12) in THF (20 mL) at 00° C. was added 1.7 M potassium tert-butoxide in THF (2.69 mL, 4.58 mmol) dropwise over 5 minutes. The reaction mixture was stirred at 00° C. for 1.5 hours. The reaction was quenched by the addition of acetic acid (0.26 mL, 4.58 mmol) and then the mixture was filtered, washed with dichloromethane and the filtrate concentrated at reduced pressure to give a brown gum. The product was purified by silica gel chromatography eluting with 40-100% ethyl acetate in iso-hexane to give racemic 2-(4-bromo-6-methyl-2-pyridyl)-7-methyl-1,7-diazaspiro[4.4]non-1-en-6-one a pale yellow solid (D13) (314 mg);
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10]([CH3:13])([CH3:12])Cl)([CH3:9])([CH3:8])[CH3:7].[CH3:14][C:15]([CH3:21])([CH2:18][C:19]#[CH:20])[CH2:16][OH:17]>CN(C=O)C>[C:6]([Si:10]([O:17][CH2:16][C:15]([CH3:21])([CH3:14])[CH2:18][C:19]#[CH:20])([CH3:13])[CH3:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C#CCC(C)(C)CO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C#CCC(C)(C)CO[Si](C)(C)C(C)(C)C
Temperature: 22 °C
Reaction time: 20 h

Procedure:
Imidazole (58.3 g, 857 mmol) and t-butydimethylchlorosilane (64.6 g, 429 mmol) were added to a stirred solution of 2,2-dimethylpent-4-yn-1-ol (43.7 g, 390 mmol) in DMF (195 mL), then the solution was stirred at 22° C., under N2, for 20 hours. The reaction solution was extracted with ether (3×300 mL), washed with water (100 mL), brine (75 mL), dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel 60 (330 g), eluting with hexane, to give the title product. 1H NMR (400 MHz, CDCl3) δ 3.29 (s, 2H); 2.10 (d, J=2.8 Hz, 2H); 1.91 (t, J=2.6 Hz, 1H); 0.90 (s, 6H); 0.86 (s, 9H); 0.00 (s, 6H) ppm.
Reaction SMILES: C[O-].[Na+].[NH:4]([CH2:11][CH2:12][C:13]#[N:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O[CH:16]([C:22]1[CH:23]=[C:24]([NH:34][CH3:35])[C:25]([CH3:33])=[C:26]([CH:32]=1)[N:27]([CH3:31])[C:28](=[O:30])[CH3:29])CS(C)(=O)=O.CS(C)=O>O>[NH:4]([CH:11]=[C:12]([C:13]#[N:14])[CH2:16][C:22]1[CH:23]=[C:24]([NH:34][CH3:35])[C:25]([CH3:33])=[C:26]([CH:32]=1)[N:27]([CH3:31])[C:28](=[O:30])[CH3:29])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N#CCCNc1ccccc1
Reactant: CNc1cc(C(O)CS(C)(=O)=O)cc(N(C)C(C)=O)c1C
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CNc1cc(CC(C#N)=CNc2ccccc2)cc(N(C)C(C)=O)c1C

Procedure:
A mixture of 27 g. of sodium methylate, 41 g. of β-anilinopropionitrile and 79.5 g. of 5'-[1-hydroxy-2-(methylsulfonyl)ethyl]-N,2'-dimethyl-3'-methylaminoacetanilide in 350 ml. of absolute dimethylsulfoxide was stirred for 1 hour at 50° C., then diluted with 2 liters of water and extracted with 6 liters of ethyl acetate. The ethyl acetate extract was washed with 1 liter of water, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on 2 kg. of silica gel with ethyl acetate/methylene chloride (1:1), there being obtained 5'-(3-anilino-2-cyanoallyl)-N,2'-dimethyl-3'-methylaminoacetanilide as an oil.
Reaction SMILES: [S-]C#N.[K+].[CH:5]1([O:10][CH2:11][C:12]([NH:14][NH2:15])=O)[CH2:9][CH2:8][CH2:7][CH2:6]1.[N:16]([C:19]([C:21]1[CH:37]=[CH:36][C:24]([O:25][C@@H:26]2[CH2:31][CH2:30][C@H:29]([C:32]([O:34][CH3:35])=[O:33])[CH2:28][CH2:27]2)=[CH:23][CH:22]=1)=[O:20])=[C:17]=[S:18]>C(#N)C>[CH:5]1([O:10][CH2:11][C:12]2[S:18][C:17]([NH:16][C:19]([C:21]3[CH:37]=[CH:36][C:24]([O:25][C@@H:26]4[CH2:27][CH2:28][C@H:29]([C:32]([O:34][CH3:35])=[O:33])[CH2:30][CH2:31]4)=[CH:23][CH:22]=3)=[O:20])=[N:15][N:14]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: COC(=O)[C@H]1CC[C@@H](Oc2ccc(C(=O)N=C=S)cc2)CC1
Reactant: NNC(=O)COC1CCCC1
Agent: N#C[S-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)[C@H]1CC[C@@H](Oc2ccc(C(=O)Nc3nnc(COC4CCCC4)s3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.4 g of cis-4-(4-methoxycarbonylcyclohexyloxy)benzoic acid is placed in 10 mL of dichloromethane with stirring, at room temperature, under a nitrogen atmosphere. 0.18 mL of oxalyl chloride (2.16 mmol, 1.5 eq.) and 2 drops of dimethylformamide are successively added. The reaction medium is stirred for 2 hours and concentrated under vacuum. The methyl cis-4-(4-chlorocarbonylphenoxy)cyclohexanecarboxylate formed is dissolved in 15 mL of acetonitrile and placed under nitrogen. The mixture is cooled in an ice bath and 0.210 g of potassium thiocyanate (2.16 mmol, 1.5 eq.) is added. The reaction mixture is stirred at room temperature for 1 hour 30 minutes. 0.455 g of cyclopentyloxyacetic acid hydrazide (2.87 mmol, 2 eq.) dissolved in 5 mL of acetonitrile is then added to the methyl cis-4-(4-isothiocyanatocarbonylphenoxy)cyclohexanecarboxylate obtained and the mixture is refluxed for 2 hours 30 minutes and then left to stand at room temperature for 36 hours. The precipitate formed is filtered off and washed with acetonitrile. 0.450 g of methyl cis-4-[4-(5-cyclopentyloxymethyl[1.3.4]thiadiazol-2-ylcarbamoyl)phenoxy]cyclohexanecarboxylate is obtained.
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]([CH3:36])([CH3:35])[CH2:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:17][C:16]3[CH:18]=[C:19]([C:22]4[O:23][C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[CH3:33])=[N:25][N:26]=4)[CH:20]=[CH:21][C:15]=3[N:14]=2)=[C:8]([CH3:34])[CH:7]=1.[OH-].[Na+].Cl>C1COCC1.CO.O>[CH3:12][C:10]1[CH:11]=[C:6]([CH2:5][C:4]([CH3:36])([CH3:35])[C:3]([OH:37])=[O:2])[CH:7]=[C:8]([CH3:34])[C:9]=1[C:13]1[NH:17][C:16]2[CH:18]=[C:19]([C:22]3[O:23][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[N:25][N:26]=3)[CH:20]=[CH:21][C:15]=2[N:14]=1
Reactant: COC(=O)C(C)(C)Cc1cc(C)c(-c2nc3ccc(-c4nnc(-c5ccccc5C)o4)cc3[nH]2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccccc1-c1nnc(-c2ccc3nc(-c4c(C)cc(CC(C)(C)C(=O)O)cc4C)[nH]c3c2)o1
Reaction time: 4 h

Procedure:
Dissolve 3-{3,5-dimethyl-4-[6-(5-o-tolyl-[1,3,4]oxadiazol-2-yl)-1H-benzoimidazol-2-yl]-phenyl}-2,2-dimethyl-propionic acid methyl ester (286 mg, 0.578 mmol) in THF (2.9 mL)/MeOH (2.9 mL). Add 1 N NaOH (2.9 mL) and stir for 4 h. Add NaOH (102 mg, 2.55 mmol) in water (1 mL). Upon disappearance of the ester by LC/MS, concentrate the reaction. Acidify to pH 1.5 by addition of 1 N HCl (5.4 mL). Collect the solid by filtration and dry at 40° C. in a vacuum oven. Triturate the solid with DCM to afford the title compound as a white solid: (M+H)+ 481.0.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Cl)[N:9]=[C:10]=[O:11])=[CH:4][CH:3]=1.[F:13][C:14]([F:29])([F:28])[C:15]1[CH:16]=[C:17]([NH:21][C:22]2[CH2:26][CH2:25][C:24](=[O:27])[CH:23]=2)[CH:18]=[CH:19][CH:20]=1.O>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:9][C:10](=[O:11])[N:21]([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([F:13])([F:28])[F:29])[CH:16]=3)[C:22]3[CH2:26][CH2:25][C:24](=[O:27])[C:23]2=3)=[CH:4][CH:3]=1
Reactant: O=C1C=C(Nc2cccc(C(F)(F)F)c2)CC1
Reactant: O=C=NC(Cl)c1ccc(Br)cc1
Solvent: O
Solvent: ClCCl
Product: O=C1CCC2=C1C(c1ccc(Br)cc1)NC(=O)N2c1cccc(C(F)(F)F)c1

Procedure:
A solution of 1-bromo-4-(chloro(isocyanato)methyl)benzene (14.7 g, 47.6 mmol) in dichloromethane (100 mL) is added to a solution of 3-(3-(trifluoromethyl)phenylamino)-cyclopent-2-enone (11.0 g, 45.6 mmol) in dichloromethane (100 mL) and the mixture is heated at reflux for 1.5 hours. Water is added, and the phases are extracted twice with dichloromethane. The combined organic layers are concentrated and the residue is purified by flash chromatography on silica (gradient cyclohexane/ethyl acetate 4:1 to ethyl acetate). Yield: 7.5 g; ESI mass spectrum: ESI mass spectrum: [(79Br)-M+H]+=451, [(81Br)-M+H]+=453; Retention time HPLC: 1.15 min (V012_S01).