Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9]#[N:10].[Cl:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](Cl)=[O:17]>N1C=CC=CC=1>[Cl:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9]#[N:10])=[O:17]
Reactant: Cc1nn(C)c(N)c1C#N
Reactant: O=C(Cl)CCCCCl
Solvent: c1ccncc1
Product: Cc1nn(C)c(NC(=O)CCCCCl)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-amino-1,3-dimethyl-1H-pyrazole-4-carbonitrile (1.59 g, 11.67 mmol) in anhydrous pyridine (15 mL) was slowly added 5-chlorovaleryl chloride (1.80 mL, 14.0 mmol) at 0° C. After addition, the reaction mixture was allowed to warm up to rt and stir at rt overnight. The reaction mixture was concentrated on a rotavapor and the residue was partitioned between ethyl acetate and brine. The organic phase was washed with brine and concentrated. The residue was separated by flash chromatography (silica gel, 50-80% gradient EtOAc in hexane) to provide Example 96A. Yield: 2.42 g (81%). MS (DCI): m/z 255 (M+H)+.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:21]([OH:38])(=[O:37])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].[OH-].[Zn+2:40].[OH-]>>[C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Zn+2:40].[C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:21]([OH:38])(=[O:37])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: CCCCCCCCCCCCCCCC(=O)O
Agent: [OH-]
Agent: [Zn+2]
Product: CCCCCCCCCCCCCCCCCC(=O)[O-]

Procedure:
Stearic acid and palmitic acid were mixed at a mass ratio of 50:50 to prepare a mixture, and zinc hydroxide was mixed and melted with the resulting mixture to be reacted therewith, and then dried to produce particles in which zinc stearate and palmitic acid were dissolved in each other (particle diameter: 11 μm to 23 μm). A part of the particles thus produced was dissolved in a hydrochloric acid-methanol solution, and the product was heated to 80° C. to methylate the stearic acid and palmitic acid. The methylation product was analyzed by gas chromatography to determine the zinc stearate content and the palmitic acid content and to express them in terms of the equivalent ratio of zinc stearate to zinc palmitate, and the ratio was found to be 48:52 (mass ratio).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:31][CH2:30][NH:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(N(CC)CC)C>O1CCCC1>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:31][CH2:30][N:29]([S:33]([CH3:32])(=[O:35])=[O:34])[CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ncnn2c(C3CCNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.3 %

Procedure:
(5-(2-benzyl-2H-indazol-6-yl)-7-pyrrolidin-3-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (40 mg, 0.098 mmol) was dissolved in tetrahydrofuran (2 mL). Methanesulfonyl chloride (18 mg, 0.127 mmol) was added to the reaction mixture followed by triethylamine (136 uL, 0.977 mmol). The suspension was stirred at rt overnight. The compound was triturated with 1:1 ether-hexanes to yield desired product (14 mg, 29%). 1H NMR (300 MHz, dichloromethane-d2) δ 7.95 (1d, 1 H), 7.80 (1s, 1 H), 7.69-7.97.64 (m, 3 H), 7.27-7.25 (m, 4 H), 7.13 (d, 1 H), 6.54 (s, 1 H) 5.61 (bs, 2 H), 5.61 (bs, 2 H), 5.52 (s, 2H), 4.05-3.90 (m, 2H), 3.60-3.35 (m, 3 H), 2.75 (s, 3 H), 2.45 (m, 1 H), 2.20 (m, 1 H); ES-MS m/z 488.3 [M+H]+, HPLC RT (min) 2.72.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:19][CH2:20][CH:21]=[C:22]([Cl:24])[Cl:23])[CH:5]=[C:6]([Cl:18])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][CH:16]=[CH2:17].S(=O)(=O)(O)[OH:26]>S([O-])([O-])(=O)=O.[Hg+2].O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([O:19][CH2:20][CH:21]=[C:22]([Cl:24])[Cl:23])[CH:5]=[C:6]([Cl:18])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][C:16](=[O:26])[CH3:17]
Reactant: O=S(=O)(O)O
Reactant: C=CCOCCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Hg+2]
Solvent: C1CCOC1
Product: CC(=O)COCCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 60 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
A mixture of 4.12 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(5-(2-propenyloxy)pentyloxy)benzene, 0.36 g of mercury (II) sulfate, 5 ml of 1% aqueous sulfuric acid solution, and 50 ml of tetrahydrofuran was stirred at 60° C. for 1 hour. The reaction mixture was filtered through Celite, and the filtrate was poured into diluted hydrochloric acid, and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with diluted hydrochloric acid and water in this order, dried over magnesium sulfate, and concentrated to give a crude product. This crude product was subjected to silica gel chromatography, which afforded 4.05 g (yield, 94%) of 5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentyloxyacetone, nD25.5 1.5350.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[NH2:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([CH2:19][NH:20][C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[C:23]([O:28][CH3:29])[N:22]=2)[CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([CH2:19][NH:20][C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[C:23]([O:28][CH3:29])[N:22]=2)[CH2:15][CH2:14]1)=[O:8]
Reactant: COc1ccc(Cl)c(NC[C@H]2CC[C@H](N)CC2)n1
Reactant: Cc1ncc(Cl)cc1C(=O)Cl
Product: COc1ccc(Cl)c(NC[C@H]2CC[C@H](NC(=O)c3cc(Cl)cnc3C)CC2)n1

Procedure:
The title compound is prepared from 5-chloro-2-methylnicotinoyl chloride (Intermediate C) and trans-(4-Amino-cyclohexylmethyl)-(3-chloro-6-methoxy-pyridin-2-yl)-amine (Intermediate BB) analogously to Example 2.0; 1H NMR (d6-DMSO, 400 MHz) δ 8.52 (1H, d), 8.39 (1H, d), 7.80 (1H, d), 7.42 (1H, d), 6.45 (1H, t), 5.90 (1H, d), 3.79 (3H, s), 3.69 (1H, my 3.22 (2H, t), 2.48 (3H, a), 1.91 (2H, m), 1.80 (2H, m), 1.60 (1H, m), 1.21 (2H, m), 1.07 (2H, m); LC-MS Rt 2.70 mins, [M+H]+ 423.55; Method LowpH_v002.
Reaction SMILES: [CH2:1]([O:17][C:18]1[CH:28]=[CH:27][C:21]([O:22][CH2:23][C:24](O)=[O:25])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(Cl)(=O)C([Cl:32])=O>CN(C)C=O.C(Cl)Cl>[CH2:1]([O:17][C:18]1[CH:28]=[CH:27][C:21]([O:22][CH2:23][C:24]([Cl:32])=[O:25])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCCCCCCCCCCCCOc1ccc(OCC(=O)O)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCOc1ccc(OCC(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 97.7 %

Procedure:
A mixture of 13.2 g of product from Example 86, 6.4 g of oxalyl chloride, 225 ml of methylene chloride and 5 drops of dimethylformamide is stirred at room temperature for 17 hours. The solvent is concentrated in vacuo, the residue is dissolved in ether, filtered through diatomaceous earth and concentrated in vacuo to give 13.5 g of the desired product.
Reaction SMILES: [CH3:1][Si:2]([CH3:5])([CH3:4])Cl.[CH2:6]([N:8](CC)[CH2:9][CH3:10])[CH3:7].C(NCC)C>CCCCCC>[CH2:6]([N:8]([Si:2]([CH3:5])([CH3:4])[CH3:1])[CH2:9][CH3:10])[CH3:7]
Reactant: C[Si](C)(C)Cl
Reactant: CCN(CC)CC
Solvent: CCNCC
Solvent: CCCCCC
Product: CCN(CC)[Si](C)(C)C
Temperature: 55 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
In a 1 liter four-neck flask equipped with a stirrer, a reflux condenser, a dropping funnel and a thermometer were placed 108.5 g (1.0 mol) of trimethylchlorosilane, 111.1 g (1.1 mol) of triethylamine and 300 ml of hexane. Thereto, 73.0 g (1.0 mol) of diethylamine was added dropwise from the dropping funnel over a 1-hour period. During the addition, the temperature of the reaction system was kept within the range of 20° C. to 60° C. to make the reaction be proceeding. At the conclusion of the addition, the temperature was raised to 50-60° C. and kept there for 2 hours, whereby the reaction was matured. Then, the reaction mixture was filtered through a glass filter to remove the salt yielded as a by-product. The filtrate was allowed to stand for one day at room temperature to precipitate the salt. The salt precipitated was filtered off, and the filtrate was subjected to distillation under ordinary pressure to obtain 136.3 g of diethylaminotrimethylsilane as a fraction having a boiling point of 125-126° C. The yield was 94%, and the chlorine concentration was 146 ppm.
Reaction SMILES: [SH:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:9])[N:3]=1.[OH-].[Na+].CN1C[CH2:16][C:15](=O)[CH2:14]1.ICCC.Cl>O>[CH2:14]([S:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:9])[N:3]=1)[CH2:15][CH3:16]
Reactant: Oc1cc(O)nc(S)n1
Reactant: CN1CCC(=O)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCI
Solvent: O
Product: CCCSc1nc(O)cc(O)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 2-mercaptopyrimidine-4,6-diol (25 g, 173.61 mmol, 1.00 equiv.), sodium hydroxide (15.8 g, 395.00 mmol, 2.27 equiv.), 1-methylpyrrolidin-3-one (50 mL), and 1-iodopropane (30.6 g, 180.00 mmol, 1.05 equiv.) dissolved in water (60 mL) was stirred at ambient temperature for about 48 hours. The pH value of the solution was adjusted to 2-3 by adding hydrochloric acid. The solids were then collected by filtration to give the product as an off-white solid (35 g; (crude)). 1H NMR (300 MHz, DMSO-d6) δ: 11.78 (b, 1H), 10.30 (b, 1H), 5.13 (s, 1H), 3.07 (t, J=7.2 Hz, 2H), 1.58-1.70 (m, 2H), 0.96 (t, J=7.2 Hz, 2H).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12]([O:14]CC)=O)[N:9]([CH2:17][C:18]3[S:19][CH:20]=[CH:21][N:22]=3)[C:6]2=[N:7][CH:8]=1.[NH:25]1[C:29]2=[N:30][CH:31]=[C:32]([NH2:34])[CH:33]=[C:28]2[CH:27]=[CH:26]1.C[Al](C)C>>[NH:25]1[C:29]2=[N:30][CH:31]=[C:32]([NH:34][C:12]([C:10]3[N:9]([CH2:17][C:18]4[S:19][CH:20]=[CH:21][N:22]=4)[C:6]4=[N:7][CH:8]=[C:3]([C:2]([F:24])([F:23])[F:1])[CH:4]=[C:5]4[CH:11]=3)=[O:14])[CH:33]=[C:28]2[CH:27]=[CH:26]1
Reactant: Nc1cnc2[nH]ccc2c1
Reactant: CCOC(=O)c1cc2cc(C(F)(F)F)cnc2n1Cc1nccs1
Agent: C[Al](C)C
Product: O=C(Nc1cnc2[nH]ccc2c1)c1cc2cc(C(F)(F)F)cnc2n1Cc1nccs1
Yield: 62.2 %

Procedure:
Compound 30 was prepared according to a process similar to that described in step 5.1 by reacting 186 mg (0.523 mmol) of ethyl 5-trifluoromethyl-1-[(thiazol-2-yl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylate prepared according to the protocol described in step 7.1 with 84 mg (0.628 mmol) of pyrrolo[2,3-b]pyrid-5-ylamine in the presence of 0.39 mL (0.785 mmol) of a solution of trimethylaluminium (2M/toluene). The product is collected by filtration, to give 144 mg of expected product.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH2:11].C(N(CC)CC)C.Cl[C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>ClCCl>[CH2:24]([O:23][C:21]([C:20](=[O:26])[NH:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)=[O:22])[CH3:25]
Reactant: Nc1ccc2ccccc2c1
Reactant: CCOC(=O)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(=O)Nc1ccc2ccccc2c1
Temperature: 25 °C
Yield: 88.1 %

Procedure:
To a solution of naphthalen-2-amine (2 g, 14.0 mmol) in dichloromethane (30 ml) was added triethylamine (4.24 g, 41.9 mmol, 3 eq). Then, ethyl 2-chloro-2-oxoacetate (1.92 g, 14.1 mmol, 1 eq) was added dropwise to the solution kept at 0-5° C. using an ice-bath. The resulting solution was allowed to warm to room temperature while stirring. The reaction was then quenched by the addition of water (50 ml), the product was extracted with dichloromethane (2×50 ml), and the organic layers were combined. The organic solution was washed with saturated aqueous sodium chloride (50 ml), dried over anhydrous sodium sulfate, filtered, and then concentrated under vacuum to afford ethyl[(naphthalen-2-yl)carbamoyl]formate as a black solid (3 g, 88%). (ES, m/z) [M+H]+ 244; 1H NMR (300 MHz, CDCl3): δ 9.06 (broad s, 1H), 8.32 (d, J=1.8 Hz, 1H), 7.72-7.88 (m, 3H), 7.59 (dd, J=2.1 Hz, 8.7 Hz, 1H), 7.53 (m, 2H), 4.44 (q, J=7.2 Hz, 2H), 1.43 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH3:55][N:56]1[CH2:61][CH2:60][CH:59]([NH2:62])[CH2:58][CH2:57]1>CN(C=O)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:62][CH:59]2[CH2:60][CH2:61][N:56]([CH3:55])[CH2:57][CH2:58]2)=[O:21])=[CH:17][N:16]=1
Reactant: CN1CCC(N)CC1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2CCN(C)CC2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.3 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) in DMF (2 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (114 mg, 0.35 mmol), N,N-diisopropyl ethyl amine (275 μL, 1.6 mmol) and 1-methylpiperidin-4-amine (41 mg, 0.35 mmol). The resulting reaction mixture was stirred overnight at room temperature. Concentration and purification by preparative HPLC on reversed phase eluting with acetonitrile/water [0.1% aq NH3 (25%)]. Then the residue was partitioned with ethyl acetate and water, the organic extract was washed with aqueous sodium hydrogen carbonate (saturated) dried over sodium sulfate and concentrated to afford the title compound (94 mg, 72%) which was obtained as a white solid. MS: m/e=407.5 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:14](N1C=CN=C1)([N:16]1C=CN=C1)=[S:15]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[S:15])[NH2:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(N)=S)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.8 %

Procedure:
To a solution of piperazine-1-carboxylic acid tert-butyl ester (32.2 mmol) in tetrahydrofuran (60 ml) was added thiocarbonyldiimidazole (37.0 mmol). The reaction was stirred at RT for 2 h then heated at 55° C. for 1 h. The reaction was concentrated in vacuo to approximately half the volume and methanolic ammonia added (7N, 107.4 mmol). The reaction was heated at 55° C. for 16 h. The reaction was concentrated in vacuo to approximately half the volume and cooled to 0° C. at which point the product precipitated from solution. The product was collected by filtration to yield the title compound as a white solid (3.3 g). 1H NMR (400 MHz, d6-DMSO) 1.40 (9H, s), 3.32 (4H, s), 3.71 (4H, s), 7.42 (1H,s).
Reaction SMILES: [H-].C(O[Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].[CH3:19][C@:20]12[CH2:37][CH:36]=[C:35]3[C@@H:25]([CH2:26][CH2:27][C@H:28]4[C@:33]3([CH3:34])[CH2:32][CH2:31][C:30](=[O:38])[CH2:29]4)[C@@H:24]1[CH2:23][CH2:22][C:21]2=[O:39]>C1COCC1>[OH:38][C@@H:30]1[CH2:31][CH2:32][C@@:33]2([CH3:34])[C@H:28]([CH2:27][CH2:26][C@@H:25]3[C:35]2=[CH:36][CH2:37][C@@:20]2([CH3:19])[C@H:24]3[CH2:23][CH2:22][C:21]2=[O:39])[CH2:29]1
Reactant: C[C@]12CCC(=O)C[C@H]1CC[C@@H]1C2=CC[C@]2(C)C(=O)CC[C@@H]12
Agent: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@]12CC[C@@H](O)C[C@H]1CC[C@@H]1C2=CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 2 h
Yield: 99.2 %

Procedure:
A THF solution of lithium tri-tert-butoxyaluminum hydride (1.0 M, 84.4 mL, 84.4 mmol) was added to a cold (−40° C.) solution of compound 1.2 (23.0 g, 80.4 mmol) in THF (230 mL) under an inert atmosphere. The resulting reaction mixture was stirred for 2 h. At this point the reaction was determined to be complete, as evidenced by TLC, and the reaction mixture was quenched by adding a mixture of 1N HCl (200 mL) and ethyl acetate (230 mL). The resulting two phase mixture was separated and the aqueous layer was extracted twice with ethyl acetate (2×100 mL). The organic phases were combined and washed sequentially with water (150 mL) and saturated brine solution (100 mL). The organic phase was then dried over Na2SO4 (75 g) and filtered. The filtrate was evaporated under vacuum to afford compound 1.3 (23.0 g) as an off-white solid. The above crude product was used “as is” in the next step without purification.
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].C(O[CH:10]1[NH:14][C:13](=[O:15])[CH2:12][CH2:11]1)C>>[CH2:3]([O:4][CH:10]1[NH:14][C:13](=[O:15])[CH2:12][CH2:11]1)[C:2]([CH3:6])([CH3:5])[CH3:1]
Reactant: CCOC1CCC(=O)N1
Reactant: CC(C)(C)CO
Product: CC(C)(C)COC1CCC(=O)N1
Reaction time: 2 h
Yield: 40.2 %

Procedure:
35 g 2,2-dimethyl propanol (previously melted at 45° C.), 6 g of 5-ethoxy pyrrolidin-2-one and 3 g of Amberlite-15 resin are agitated at 40° C. for 2 hours 15 minutes. After filtering, the 2,2-dimethyl propanol is distilled off under 0.8 mm/Hg at 35° C. The residue is dissolved in hexane and iced for 2 hours. 3.2 g of the expected product is obtained, m.p. 67°-69° C., crystallized from hexane.
Reaction SMILES: [CH2:1]([N:8]1[CH2:31][CH:30]([CH:32]=C)[O:29][C:10]2([CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH3:28])[CH:19]=3)=[O:17])[CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:34]=[O+][O-].[BH4-].[Na+]>C(Cl)Cl.CO>[CH2:1]([N:8]1[CH2:31][CH:30]([CH2:32][OH:34])[O:29][C:10]2([CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:26])[CH3:27])=[C:20]([CH3:28])[CH:19]=3)=[O:17])[CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC1CN(Cc2ccccc2)CC2(CCN(C(=O)c3ccc(OC(C)C)c(C)c3)CC2)O1
Reactant: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(C(=O)N2CCC3(CC2)CN(Cc2ccccc2)CC(CO)O3)ccc1OC(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
To (8-benzyl-10-vinyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)-(4-isopropoxy-3-methyl-phenyl)methanone (135 mg, 0.30 mmol) in DCM (4 mL) and methanol (1 mL) at −78° C. was bubbled ozone until the solution turned faint blue. NaBH4 (91 mg, 2.41 mmol) and methanol (˜2 mL) was added under an atmosphere of nitrogen and the reaction mixture was stirred at −78° C. for 30 minutes, then at 0° C. for 1 hour. The reaction mixture was concentrated in vacuo, quenched with 4N HCl/dioxane, concentrated in vacuo, then diluted with methanol-water (1:1), microfiltered and purified by prep LCMS (1-99% ACN/Water, 5 mM HCl modifier) to give [8-benzyl-10-(hydroxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (50 mg, 34%). ESI-MS m/z calc. 452.6. found 453.5 (M+1)+; Retention time: 1.18 minutes (3 min run).
Reaction SMILES: [C:1]([C:9]#[C:10][C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]1([C:25]2C(=O)[C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[C:27]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:26]=2[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(C1C=CC=CC=1)(=O)C1C=CC=CC=1>CO>[C:11]([C:10]1[C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:27]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:26]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[C:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]=1[C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(C#CC(=O)c1ccccc1)c1ccccc1
Reactant: O=C1C(c2ccccc2)=C(c2ccccc2)C(c2ccccc2)=C1c1ccccc1
Agent: O=C(c1ccccc1)c1ccccc1
Solvent: CO
Product: O=C(c1ccccc1)c1c(C(=O)c2ccccc2)c(-c2ccccc2)c(-c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Temperature: 30 °C
Yield: 43 %

Procedure:
1,2-bis(benzoyl)acetylene (C16H10O2, 234.27, 2 g, 8.54 mmol), tetraphenylcyclopenta-dienone (C29H20O, 384.47, 3.28 g, 8.54 mmol), and 40 g benzophenone were refluxed for 2 hr under an atmosphere of nitrogen. The reaction mixture was cooled to 30° C. and poured into a large volume (250 ml) of methanol. The tan precipitation was washed with methanol (2×10 ml) and refluxed in toluene (25 ml) charcoal (a spoon) to give a white crystal in 43% yield.
Reaction SMILES: [C:1](=[O:12])([O:5][CH2:6][CH:7]1[O:11][CH2:10][CH2:9][CH2:8]1)[O:2][CH2:3]Cl.[I-:13].[Na+]>C(#N)C>[C:1](=[O:12])([O:5][CH2:6][CH:7]1[O:11][CH2:10][CH2:9][CH2:8]1)[O:2][CH2:3][I:13]
Reactant: O=C(OCCl)OCC1CCCO1
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Product: O=C(OCI)OCC1CCCO1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 96 %

Procedure:
Chloromethyl (2,3,4,5-tetrahydrofurfuryl) carbonate (3.4 g) and sodium iodide (10.46 g) were added to acetonitrile (70 ml), and then the mixture was heated with stirring at 60° C. for 90 minutes. After the reaction solution was cooled, the solvent was distilled off under reduced pressure, and the residue was partitioned between ether (70 ml) and a saturated sodium chloride aqueous solution (50 ml). The organic layer was washed with an aqueous 5% sodium thiosulfate solution (50 ml), water (50 ml) and a saturated sodium chloride aqueous solution (50 ml) successively, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain iodomethyl (2,3,4,5-tetrahydrofurfuryl) carbonate (4.8 g) as a pale yellow oily product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[CH:10]=[N:9]2)[CH:5]=[C:4]([Cl:16])[C:3]=1[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[C:18]#[N:19].[C:27](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:13](=[O:14])[N:12]([CH3:27])[C:11](=[O:15])[CH:10]=[N:9]2)[CH:5]=[C:4]([Cl:16])[C:3]=1[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[C:18]#[N:19]
Reactant: O=C([O-])[O-]
Reactant: N#CC(c1ccc(Cl)cc1)c1c(Cl)cc(-n2ncc(=O)[nH]c2=O)cc1Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c(=O)cnn(-c2cc(Cl)c(C(C#N)c3ccc(Cl)cc3)c(Cl)c2)c1=O
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 59.2 %

Procedure:
To a stirred mixture of 4 parts of 2,6-dichloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)-benzeneacetonitrile, 1.4 parts of potassium carbonate and 22.5 parts of N,N-dimethylformamide were added 2.84 parts of iodomethane at room temperature. The reaction mixture was stirred for 1.5 hours at 40° C. After evaporation in vacuo, the residue was taken in water. The precipitated product was filtered off and washed with water. After crystallization from acetonitrile, the product was filtered off, washed with 2,2'-oxybispropane and dried, yielding 2.5 parts (59.2%) of 2,6-dichloro-α-(4-chlorophenyl)-4-(4,5-dihydro-4-methyl-3,5-dioxo-1,2,4-triazin-2(3H)-yl) benzeneacetonitrile; mp. 159.7° C. (intermediate 46).