Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]([F:27])([F:26])[C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][CH:18]([C:21](OCC)=[O:22])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1.O.[OH-].[Na+]>C1COCC1>[F:26][C:8]([F:7])([F:27])[C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:20][CH2:19][CH:18]([CH2:21][OH:22])[CH2:17][CH2:16]2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)C1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCC1CCN(c2ccc(C(F)(F)F)cc2)CC1
Reaction time: 0.5 h
Yield: 98 %

Procedure:
Lithium aluminum hydride (1.58 g, 41.64 mmol) was suspended in THF (30 ml), to which absolution of ethyl 1-(4-trifluoromethylphenyl)piperidine-4-carboxylate prepared in Reference Example 30 (3.18 g, 10.41 mmol) in THF (10 ml) was added dropwise therein while cooling in an ice-bath under a nitrogen atmosphere. The mixture was stirred for 30 minutes. Water and 10% sodium hydroxide aqueous solution were added to the reaction mixture, which was filtered through Celite. The filtrate was extracted with ethyl acetate twice. The extract was washed with water and brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford [1-(4-trifluoromethylphenyl)-piperidin-4-yl]methanol (2.64 g, yield 98%) as a pale yellow oil.
Reaction SMILES: Br[CH:2]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[CH:22]=[C:23]([C:31]([CH3:37])([S:33]([CH3:36])(=[O:35])=[O:34])[CH3:32])[CH:24]=[C:25]3[C:30]=2[N:29]=[CH:28][CH:27]=[CH:26]3)[CH:16]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)=O.[Cl:38][C:39]1[CH:40]=[C:41]([C:45](=[S:47])[NH2:46])[CH:42]=[CH:43][CH:44]=1>CN(C=O)C.O.C([O-])(O)=O.[Na+].CCOCC>[Cl:38][C:39]1[CH:40]=[C:41]([C:45]2[S:47][C:2]([C:15]3[CH:16]=[C:17]([C:21]4[CH:22]=[C:23]([C:31]([CH3:37])([S:33]([CH3:36])(=[O:35])=[O:34])[CH3:32])[CH:24]=[C:25]5[C:30]=4[N:29]=[CH:28][CH:27]=[CH:26]5)[CH:18]=[CH:19][CH:20]=3)=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=3)[N:46]=2)[CH:42]=[CH:43][CH:44]=1
Reactant: NC(=S)c1cccc(Cl)c1
Reactant: CC(C)(c1cc(-c2cccc(C(Br)C(=O)c3ccc(S(C)(=O)=O)cc3)c2)c2ncccc2c1)S(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: CC(C)(c1cc(-c2cccc(-c3sc(-c4cccc(Cl)c4)nc3-c3ccc(S(C)(=O)=O)cc3)c2)c2ncccc2c1)S(C)(=O)=O
Temperature: 80 °C

Procedure:
To a solution of the alpha-bromoketone from step 4 (1.0 eq) in DMF (0.1M) was added 3-chlorobenzenecarbothioamide (1.0 eq). The mixture was heated at 40-120° C. for 1-3 h, cooled, diluted with water, saturated NaHCO3 solution and ether. The organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (Hexane:EtOAc) to afforded the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[C:8]([Cl:16])=[CH:9][C:10]([Cl:15])=[C:11]([CH2:13][OH:14])[CH:12]=1.O1CCCC1.[H-].[Na+].[C:24]1([C:30]2[CH:37]=[CH:36][C:33]([CH2:34]Cl)=[CH:32][CH:31]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O>[C:24]1([C:30]2[CH:31]=[CH:32][C:33]([CH2:34][O:14][CH2:13][C:11]3[CH:12]=[C:7]([C:2]4[N:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[C:8]([Cl:16])=[CH:9][C:10]=3[Cl:15])=[CH:36][CH:37]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: OCc1cc(-c2ncccn2)c(Cl)cc1Cl
Reactant: ClCc1ccc(-c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Clc1cc(Cl)c(-c2ncccn2)cc1COCc1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a 250 ml single neck round bottom flask equipped with a reflux cndensor and an argon inlet was added 3.32 gm of the 5-pyrimidyl-2,4-dichlorophenylcarbinol and 70 ml of anhydrous tetrahydrofuran. The system was cooled to 0° C. and after cooling 0.34 gm sodium hydride was added. The system was stirred for an additional 20 minutes and 3.16 gm of 4-phenylbenzylchloride was then added. The system was allowed to come to room temperature and stirred there for 1 hour. Afterwards, the system was heated at reflux for 48 hours. At this time, water was added to the system and the product extracted with methylene chloride. The methylene chloride extract was washed with water and dried over sodium sulfate. The methylene chloride was removed by stripping to give 3.66 m of the 5-pyrimidyl--2,4-dichlorophenylcarbinol 4-phenylbenzylether --Compound 12 in Table I.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[C:9]([OH:15])=[C:8]([CH:16]([CH3:18])[CH3:17])[CH:7]=1.[Li+].[OH-].O.C1COCC1.O>CCCCCCC.C(OCC)(=O)C>[OH:15][C:9]1[C:8]([CH:16]([CH3:18])[CH3:17])=[CH:7][C:6]([CH2:5][CH2:4][C:3]([OH:19])=[O:2])=[CH:11][C:10]=1[CH:12]([CH3:14])[CH3:13]
Reactant: COC(=O)CCc1cc(C(C)C)c(O)c(C(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CC(C)c1cc(CCC(=O)O)cc(C(C)C)c1O
Yield: 67 %

Procedure:
A solution of 2.64 g (10 mmol) of 3-(4-hydroxy-3,5-diisopropylphenyl)propanoic acid methyl ester (cf. U.S. Pat. No. 3,642,868) and 0.84 g (20 mmol) of LiOH, H2O in 80 ml of a 1/1 mixture THF/H2O was stirred at 20° C. for 7 hours. After evaporation of THF under reduced pressure, the aqueous solution was acidified with KHSO4 (1M) and extracted twice with 50 ml EtOAc. The organic layer was decanted, washed with 20 ml brine, dried over MgSO4 and filtered. The residue of evaporation was triturated with heptane to yield a white powder (67%). Melting point: 106-106.5° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)[C:15]=3[O:14]2)(=O)=O)=CC=1.[N-:32]=[N+:33]=[N-:34].[Na+]>>[N:32]([CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[C:15]=2[O:14]1)=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4ccc(C(F)(F)F)cc4)c3O2)cc1
Agent: [Na+]
Product: [N-]=[N+]=NCC1Cc2cccc(-c3ccc(C(F)(F)F)cc3)c2O1

Procedure:
Treatment of (±)-{7-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate (3.3 g, 7.34 mmol) with sodium azide (1.91 g, 29.38 mmol) generally according to the procedure described for Intermediate 98 gave (±)-2-(azidomethyl)-7-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.205 g, 10 wt. %) generally according to the procedure described for Example 1 provided 1.82 g (75%) of (±)-1-{7-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl methanamine as a white solid, hydrochloride salt. mp >250° C.; Anal. calcd. for C16H14F3NOHCl: C, 58.28; H, 4.59; N, 4.25. Found: C, 57.47; H, 4.82; N, 3.65.
Reaction SMILES: [NH2:1][C@H:2]([C:15]([O:17][CH3:18])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1.C([O-])(O)=O.[Na+].[CH:24]1[CH:29]=[CH:28][C:27]([CH2:30][O:31][C:32](Cl)=[O:33])=[CH:26][CH:25]=1>O.C(OCC)(=O)C>[NH:1]([C:32]([O:31][CH2:30][C:27]1[CH:28]=[CH:29][CH:24]=[CH:25][CH:26]=1)=[O:33])[C@H:2]([C:15]([O:17][CH3:18])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:12])[CH3:13])[CH:5]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)c(C(C)(C)C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@H](Cc1ccc(O)c(C(C)(C)C)c1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Tyr(3-tBu)-OMe (1.1 g) in H2O (10 ml), 0.7 g (6.57 mmol) of NaHCO3 and 0.92 ml (6.57 mmol) of Z-Cl were added under cooling with ice and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluting solvent; ethyl acetate:n-hexane=1:2) to give Z-Tyr(3-t-Bu)-OMe in the amount of 1.44 g (85%).
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH:9]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[CH2:11][CH2:10]1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl.C(OCC)(=O)C>[CH3:17][S:18]([O:8][CH:9]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[CH2:11][CH2:10]1)(=[O:20])=[O:19]
Reactant: O=S1(=O)CCC(O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CCS(=O)(=O)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 95.9 %

Procedure:
Triethylamine (7.80 mL, 55.9 mmol) was added to a solution of 4-hydroxytetrahydro-2H-thiopyran 1,1-dioxide (3.5 g, 23.3 mmol) in dichloromethane (35.0 mL). The reaction solution was cooled to 0° C. and methanesulfonyl chloride (3.25 ml, 41.9 mmol) was added. After 10 minutes, the reaction solution was warmed to room temperature and stirred for 3 h. The reaction was quenched via the addition of saturated aqueous ammonium chloride solution (15 mL). The organic layer was separated and washed with saturated aqueous sodium bicarbonate solution (15 mL) and brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford an off-white solid. The solid residue was suspended in ethyl acetate (20 mL) and filtered. The filtered solid was then collected and dried in vacuo affording 1,1-dioxidotetrahydro-2H-thiopyran-4-yl methanesulfonate (5.1 g, 95%) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 2.38-2.56 (m, 4 H) 2.94-3.06 (m, 2 H) 3.10 (s, 3 H) 3.23-3.39 (m, 2 H) 5.03 (tt, J=4.74, 2.49 Hz, 1 H)
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][O:6][C:7]1[C:16]([Cl:17])=[C:15]([Cl:18])[C:10]2[S:11][C:12]([CH3:14])=[CH:13][C:9]=2[CH:8]=1)C>[OH-].[Na+].C(O)C>[Cl:17][C:16]1[C:7]([O:6][CH2:5][C:4]([OH:19])=[O:3])=[CH:8][C:9]2[CH:13]=[C:12]([CH3:14])[S:11][C:10]=2[C:15]=1[Cl:18]
Reactant: CCOC(=O)COc1cc2cc(C)sc2c(Cl)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc2cc(OCC(=O)O)c(Cl)c(Cl)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.3 %

Procedure:
A mixture of 2.6 g of ethyl[ (6,7-dichloro-2-methylbenzo[b]thien-5-yl)oxy]acetate in 20 ml of 20% sodium hydroxide solution and 20 ml of ethanol is warmed on steam bath for 1 hour. The cooled mixture is concentrated in vacuo to remove the ethanol and the aqueous mixture is acidified with conc. hydrochloric acid to pH 2. After stirring at room temperature for 2 hours, the solid collected on a filter, dried and recrystallized from acetone-hexane to give 2.0 g of [(6,7-dichloro-2-methylbenzo[b]thien-5-yl)oxy]acetic acid as white needles, mp 215°-216°.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([Cl:17])=[CH:13][C:14]=2[NH2:16])[C@H:9]([N:18]([CH2:23][C:24]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:8][C@@H:7]1[CH3:38])=[O:5])[CH3:2].ClCCl.N1C=CC=CC=1.Cl[C:49]([O:51][CH3:52])=[O:50]>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([Cl:17])=[CH:13][C:14]=2[NH:16][C:49]([O:51][CH3:52])=[O:50])[C@H:9]([N:18]([CH2:23][C:24]2[CH:25]=[C:26]([C:34]([F:37])([F:35])[F:36])[CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:29]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:8][C@@H:7]1[CH3:38])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2c(N)cc(Cl)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)N1c2c(NC(=O)OC)cc(Cl)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Yield: 87.4 %

Procedure:
To a pre-dried flask under nitrogen atmosphere was added cis-8-amino-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-chloro-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (Example 109) (30 mg, 0.053 mmol), followed by anhydrous dichloromethane (2 mL), pyridine (0.5 mL), and methyl chloroformate (0.016 mL, 0.21 mmol). The reaction was stirred overnight at room temperature before ethyl acetate was added, and the mixture was extracted three times with 1N HCl, followed by brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give the desired product (29 mg, 87%). MS m/z 626 (M++H); 1H NMR (CDCl3) δ 7.82 (bs, 1H), 7.8 (bs, 1H), 7.7 (bs, 1H), 6.68 (bs, 1H), 6.7 (bs, 1H), 3.8 (s, 3H), 3.75 (s, 3H).
Reaction SMILES: N12CCCN=C1CCCCC2.[NH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[S:27][CH:28]=[CH:29][C:30]=2[NH:31][S:32]([CH:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])=[CH:22][CH:21]=1.[CH:38]([S:41](Cl)(=[O:43])=[O:42])([CH3:40])[CH3:39]>ClCCl>[CH3:39][CH:38]([S:41]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[S:27][CH:28]=[CH:29][C:30]=2[NH:31][S:32]([CH:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])=[CH:22][CH:21]=1)(=[O:43])=[O:42])[CH3:40]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CC(C)S(=O)(=O)Nc1ccsc1-c1ccc(-c2ccccc2CN)cc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)S(=O)(=O)NCc1ccccc1-c1ccc(-c2sccc2NS(=O)(=O)C(C)C)cc1

Procedure:
Add 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) drop wise (85 mg, 0.6 mmol) to a suspension of propane-2-sulfonic acid [2-(2′-aminomethyl-biphenyl-4-yl)-thiophen-3-yl]-amide (57 mg, 0.15 mmol) in dichloromethane (2 ml) at 0° C., followed by drop wise addition of isopropylsulfonyl chloride (42 mg, 0.3 mmol) and stir the reaction at room temperature overnight. Remove solvent under reduce pressure. Purify with flash chromatography (Silica gel-hexane/EtOAc). Concentrate the desired fractions to provide propane-2-sulfonic acid (2-{2′-[(propane-2-sulfonylamino)-methyl]-biphenyl-4-yl}-thiophen-3-yl)-amide. MS (m/e): 491.1(M−1), propane-2-sulfonic acid (2-{2′,2′-bis-[(propane-2-sulfonylamino)-methyl]-biphenyl-4-yl}-thiophen-3-yl)-amide. MS (m/e): 510.2(M−1).
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[N:8]=[C:9]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][C:15]=3[CH:16]=2)[S:10][CH:11]=1)([CH3:6])([CH3:5])[CH3:4].[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:32]([O:34][CH3:35])=[O:33])[CH:30]=2)[CH:25]=[CH:24]1.[I-].[K+]>CN(C)C=O>[C:3]([C:7]1[N:8]=[C:9]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([CH2:21][N:23]4[C:31]5[C:26](=[CH:27][CH:28]=[C:29]([C:32]([O:34][CH3:35])=[O:33])[CH:30]=5)[CH:25]=[CH:24]4)=[CH:17][C:15]=3[CH:16]=2)[S:10][CH:11]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: CC(C)(C)c1csc(-c2cc3cc(CCl)ccc3o2)n1
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2ccn(Cc3ccc4oc(-c5nc(C(C)(C)C)cs5)cc4c3)c2c1
Temperature: 25 °C
Yield: 68.8 %

Procedure:
Sodium hydride (84 mg, 60% in mineral oil) was added to a mixture of 4-tert-butyl-2-[5-(chloromethyl)benzofuran-2-yl]thiazole (0.40 g), methyl indole-6-carboxylate (0.28 g) and potassium iodide (0.22 g) in N,N-dimethylformamide (3 ml) and the mixture was stirred at room temperature. After being stirred at room temperature for 5 hours, the mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with a mixture of toluene and ethyl acetate. The fractions containing the objective compounds were combined and concentrated under reduced pressure to give methyl 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}indole-6-carboxylate (0.40 g).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34].[BH4-].[Na+]>C(OCC)(=O)C.CO.CN(C)C=O>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:31][CH:32]([OH:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)C(=O)CBr
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [BH4-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CO
Product: CCCCc1nc(C)n(CC(O)C(C)(C)C)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 16.4 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 10 min, 1-bromo-3,3-dimethylbutan-2-one (0.75 g) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue obtained by silica gel column chromatography was dissolved in methanol (10 mL), sodium borohydride (0.092 g) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated, and the residue was extracted with ethyl acetate and saturated aqueous ammonium chloride solution. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.21 g, 16%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH:10]=[CH2:11])[C:4]=1[CH3:12])#[N:2].[CH3:13][SiH:14]([CH3:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1CCCCC1.C(O)(C)C.O.Cl.Cl.Cl[Pt](Cl)(Cl)Cl>[CH3:13][Si:14]([CH3:21])([CH2:11][CH2:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[C:4]=1[CH3:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C[SiH](C)c1ccccc1
Reactant: C=CCc1cccc(C#N)c1C
Agent: Cl[Pt](Cl)(Cl)Cl
Agent: Cl
Solvent: O
Solvent: CC(C)O
Solvent: C1CCCCC1
Product: Cc1c(C#N)cccc1CCC[Si](C)(C)c1ccccc1
Temperature: 55 °C
Reaction time: 3 h
Yield: 73.1 %

Procedure:
9.0 g of 1-cyano-2-methyl-3-prop-2-enylbenzene are dissolved in 100 ml of absolute cyclohexane, and 7.75 g of dimethylphenylsilane are added at room temperature. 0.1 g of hexachloroplatinic acid hexahydrate, dissolved in 2 ml of absolute isopropanol, is added to this mixture. The reaction mixture is stirred for 3 hours at 55° C. The solvent is removed by distillation in a rotary evaporator. High boiling components are separated off by distillation under reduced pressure (condensate 82°-105° C./0.1 mbar). The residue is purified by column chromatography (silica gel/toluene). 12.2 g of dimethyl-3-(2'-methyl-3'-cyanophenyl)-propylphenylsilane are obtained.
Reaction SMILES: C1(NC(=NC2CCCCC2)O[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)CCCCC1.CN(C=O)C.[NH2:29][C:30]1[C:38]([N+:39]([O-:41])=[O:40])=[CH:37][CH:36]=[CH:35][C:31]=1[C:32]([OH:34])=[O:33]>C(OCC)(=O)C.CCCCCC>[NH2:29][C:30]1[C:38]([N+:39]([O-:41])=[O:40])=[CH:37][CH:36]=[CH:35][C:31]=1[C:32]([O:34][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:33]
Reactant: c1ccc(COC(=NC2CCCCC2)NC2CCCCC2)cc1
Reactant: Nc1c(C(=O)O)cccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Nc1c(C(=O)OCc2ccccc2)cccc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
Benzyl N,N′-dicyclohexylimidocarbamate (0.82 g) was added to a DMF (3 mL) solution of 2-amino-3-nitrobenzoic acid (0.36 g), followed by heating up to 70° C. and stirring for 2 hours. The reaction mixture was cooled to room temperature, then an ethyl acetate/ether (1/1) solution was poured into it, and the insoluble matter was separated by filtration. The filtrate was washed with aqueous sodium hydrogencarbonate solution and water in that order, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to obtain benzyl 2-amino-3-nitrobenzoate (0.42 g). FA: 273.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[NH:12][C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].S(F)(O[CH3:28])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>O.CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[N:12]([CH3:28])[C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=c1[nH]c(=O)n(-c2cccc([N+](=O)[O-])c2)c2ncccc12
Reactant: COS(=O)(=O)F
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)c2cccnc2n(-c2cccc([N+](=O)[O-])c2)c1=O
Reaction time: 0.5 h

Procedure:
To a solution of 1-(m-nitrophenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione and 30 ml of dry dimethlformamide was dimethylformamide 0.6 g of about 50 % sodium hydride, and stirring was performed for 30 minutes. To this was added dropwise 2.3 g of methyl fluorosulfate and the mixture was reacted for one hour at room temperature. Then the mixture was neutralized with 5 % sodium carbonate solution and concentrated under reduced pressure to leave a residue, to which was added water to yield a crude product. This products was recrystallized from acetone to give 2.6 g of 1-(m-nitrophenyl)-3-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione as pale yellow prisms, melting at 234°-235°C.
Reaction SMILES: C([O:4][CH2:5][CH:6]([CH2:20][O:21]C(=O)C)[CH2:7][CH2:8][N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][C:12]([NH2:19])=[N:13][C:14]=2Cl)(=O)C.C([O-])=O.[NH4+]>CO.[Pd]>[NH2:19][C:12]1[N:11]=[C:10]2[C:15]([N:16]=[CH:17][N:9]2[CH2:8][CH2:7][CH:6]([CH2:20][OH:21])[CH2:5][OH:4])=[CH:14][N:13]=1
Reactant: CC(=O)OCC(CCn1cnc2c(Cl)nc(N)nc21)COC(C)=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Nc1ncc2ncn(CCC(CO)CO)c2n1
Reaction time: 20 h

Procedure:
To a suspension of 9-(4-acetoxy-3-acetoxymethylbut-1-yl)-2-amino-6-chloropurine (4.86 g, 13.7 mmol) in methanol (140 ml) containing ammonium formate (400 mM) was added 10% palladium-on-charcoal (0.4 g) and the mixture was heated under reflux for 40 minutes. After cooling the solution was filtered and the solvent removed. The residue was taken up in water and extracted with chloroform (100 ml and 50 ml). The organic layers were combined, dried (magnesium sulphate) and the solvent removed. The residue was dissolved in methanol saturated with ammonia at 0° C. (150 ml) and the solution was stirred for 20 hours. The solvent was removed and the residue suspended in chloroform (20 ml) and filtered. The solid was recrystallised from isopropanol-water and a second recrystallisation was carried out from the mother liquors from ethanol (total 2.71 g, 83%).
Reaction SMILES: COC1C=CC(C[N:10]2[CH2:27][C:14]3([CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[O:13][CH:12]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:11]2=[O:34])=CC=1.O.[ClH:36]>C(#N)C>[ClH:36].[C:28]1([CH:12]2[O:13][C:14]3([CH2:15][CH2:16][NH:17][CH2:18][CH2:19]3)[CH2:27][NH:10][C:11]2=[O:34])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COc1ccc(CN2CC3(CCN(C(=O)OC(C)(C)C)CC3)OC(c3ccccc3)C2=O)cc1
Agent: Cl
Solvent: O
Solvent: CC#N
Product: O=C1NCC2(CCNCC2)OC1c1ccccc1
Reaction time: 2 h
Yield: 100 %

Procedure:
To tert-butyl 10-[(4-methoxyphenyl)methyl]-9-oxo-8-phenyl-7-oxa-3,10-diazaspiro[5.5]undecane-3-carboxylate (215 mg, 0.46 mmol) in acetonitrile (2.5 mL) was added water (2.5 mL) followed by the addition of ceric ammonium nitrate (500 mg, 0.91 mmol). The reaction mixture was stirred for 2 hours. After this time, a further aliquot of ceric ammonium nitrate (250 mg, 0.46 mmol) was added and the reaction mixture was stirred for an additional 45 minutes, it was then diluted with 1M aq. HCl, extracted with ethyl acetate (2×25 mL), dried over MgSO4 and concentrated in vacuo. The residue was dissolved in methanol (1 mL) and HCl (1 mL of 4 M in dioxane, 4.00 mmol) was added. The reaction mixture was stirred for 1 hour, then concentrated in vacuo to give 10-phenyl-11-oxa-3,8-diazaspiro[5.5]undecan-9-one hydrochloride salt (130 mg, 100%). ESI-MS m/z calc. 246.1. found 247.5 (M+1)+; Retention time: 0.46 minutes (3 min run).