Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([SnH:5]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[CH2:14]([N:21]1[CH2:26][CH2:25][CH2:24][C:23]([C:28]#[C:29][CH2:30][OH:31])([OH:27])[CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N1CCCC(C([Sn](CCCC)(CCCC)CCCC)=CCO)(O)C1)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:14]([N:21]1[CH2:26][CH2:25][CH2:24][C:23]([CH:28]=[C:29]([Sn:5]([CH2:6][CH2:7][CH2:8][CH3:9])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:1][CH2:2][CH2:3][CH3:4])[CH2:30][OH:31])([OH:27])[CH2:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: OCC#CC1(O)CCCN(Cc2ccccc2)C1
Reactant: CCCC[SnH](CCCC)CCCC
Agent: CCCC[Sn](CCCC)(CCCC)C(=CCO)C1(O)CCCN(Cc2ccccc2)C1
Solvent: Cc1ccccc1
Product: CCCC[Sn](CCCC)(CCCC)C(=CC1(O)CCCN(Cc2ccccc2)C1)CO
Temperature: -5 °C
Reaction time: 2 h

Procedure:
Tributyltin hydride (7.8 ml, 29 mmol) was added dropwise to a degassed solution of 1-benzyl-3-(3-hydroxy-1-propyn-1-yl)piperidin-3-ol (Desc. 1; 5.91 g, 24.1 mmol) and tetrakis(trisphenylphosphine)palladium(0) (0.52 g, 0.45 mmol) in toluene (100 ml) at -5° C. The reaction mixture was stirred at -5° C. for 2 hours, allowed to warm up and concentrated in vacuo to afford an approximately 2.5:1 mixture of the title compound and isomeric 1-benzyl-3-(3-hydroxy-1-tributylstannyl-1-propen-1-yl)piperidin-3-ol. The mixture was purified by flash chromatography, eluting with ethyl acetate/hexane (1:2), to give the title compound (8.82 g, 68%; δH (250 MHz, CDCl3) 0.88 (15 H, m), 1.24-1.53 (14H, m), 1.78 (2H, m), 1.98 (1H, m), 2.11 (1H, d, J 11.1Hz), 2.69-2.80 (2H, m), 3.51 (1H, d, J. 13.2Hz, NCHACHBPh), 3.57 (1H, d, J 13.2Hz, NCHACHBPh), 4.44 (2H, br s, CH2OH), 5.38 (1H, br s, CH=C), 7.26-7.34 (5H, m ArH).
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:6][N:7]([C:24]1[N:25]=[N:26][N:27]([CH3:29])[N:28]=1)[C@H:8]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[CH:15]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:17]([CH3:19])=[CH:18][C:9]1=2.[C:39](Cl)([Cl:41])=[O:40].C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>C1(C)C=CC=CC=1>[F:38][C:2]([F:37])([F:1])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:32]=1)[CH2:6][N:7]([C:24]1[N:25]=[N:26][N:27]([CH3:29])[N:28]=1)[C@H:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:39]([Cl:41])=[O:40])[C:10]2[CH:15]=[C:16]([C:20]([F:21])([F:22])[F:23])[C:17]([CH3:19])=[CH:18][C:9]1=2
Reactant: Cc1cc2c(cc1C(F)(F)F)NCCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reactant: O=C(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc2c(cc1C(F)(F)F)N(C(=O)Cl)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amine (Example 3, Step 18) (0.91 mmol) in toluene (5 mL), add phosgene (0.91 mmol) as a 1.93 M solution in toluene. Next, add diisopropylethylamine (0.96 mmol) dropwise at room temperature. After stirring at room temperature for 1 h, dilute the reaction with ethyl acetate (10 mL) and wash with water (5 mL). Dry the organic phase over sodium sulfate, filter, and remove solvent under a stream of nitrogen. Chromatograph the product over silica gel, eluting with ethyl acetate/hexane (5-25%), to afford the title compound as a colorless foam. MS (ES+): 615 (M+H).
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([OH:13])(=O)[C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1.[Cl-].[Cl-].[Cl-].[Al+3]>ClCCCl.O>[F:14][C:15]1[CH:16]=[C:17]([F:21])[CH:18]=[CH:19][C:20]=1[C:5]([C:6]1[CH:7]=[CH:8][N:9]=[CH:10][CH:11]=1)=[O:13]
Reactant: O=C(O)c1ccncc1
Reactant: Fc1cccc(F)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O
Solvent: O=S(Cl)Cl
Product: O=C(c1ccncc1)c1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40.9 %

Procedure:
219 ml (3.00 mole) of thionyl chloride were added to a solution of 246.2 g (2.00 mole) of isonicotinic acid in 500 ml of 1,2-dichloroethane and the mixture was refluxed for 4 hours. The excess thionyl chloride and the solvent were removed by evaporation at reduced pressure and 392 ml (4.00 mole) of 1,3-difluorobenzene and then, portionwise, 533 g (4.00 mole) of aluminium trichloride were added over the solid residue. Once the exothermal reaction has ended, the mixture was refluxed for 5 hours. it was cooled and poured over a mixture of 3 kg of ice and 1 kg of water, was stirred for 0.5 hours and the phases were separated. The aqueous phase was washed with 1L of methylene chloride, was than basified with 2L of 40% NaOH and extracted with Ch2Cl2 (2 x 1L). The combined organic extracts were dried (MgSO4) and evaporated at reduced pressure to give 179.4 g (41% yield) of the title compound in the form of an ochre coloured oil.
Reaction SMILES: C([Li])CCC.CCCCCC.C([Mg]Br)CCC.Br[C:19]1[C:20]([CH3:29])=[N:21][C:22]([O:27][CH3:28])=[C:23]([CH2:25][CH3:26])[CH:24]=1.[C:30](=O)([O:33]C)[O:31][CH3:32]>C1(C)C=CC=CC=1.O1CCCC1>[CH3:32][O:31][C:30](=[O:33])[C:19]1[CH:24]=[C:23]([CH2:25][CH3:26])[C:22]([O:27][CH3:28])=[N:21][C:20]=1[CH3:29]
Reactant: COC(=O)OC
Reactant: CCc1cc(Br)c(C)nc1OC
Agent: CCCC[Mg]Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCc1cc(C(=O)OC)c(C)nc1OC
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 122.9 %

Procedure:
An oven dried round-bottom flask is charged with toluene (35 mL) and cooled to −15° C. in a dry ice/acetone bath. A solution of butyl lithium in hexane (1.6M, 11.22 mL, 18.0 mmol) is added in one portion. To this mixture is added a solution of butylmagnesium bromide in tetrahydrofuran (2 M, 4.5 mL, 9.0 mmol) drop-wise over 1.25 hr to give a suspension. The reaction is stirred at −10° C. for 1 hr after which a solution of 3-bromo-5-ethyl-6-methoxy-2-methylpyridine (5 g, 21.7 mmol) in anhydrous toluene (10 mL) is added drop-wise over 1.25 hr. The resulting suspension is stirred at −10° C. for 30 min. The bath is cooled to −30° C. and allowed to warm slowly to 0° C. over 12 hr. The reaction is allowed to stir at −10° C. for 5 hr before diluting with anhydrous tetrahydrofuran (15 mL) to give a cloudy cream solution. This solution is added drop-wise over 1.5 hr to a cold solution of dimethyl carbonate (9.14 mL, 108 mmol) in anhydrous toluene (10 mL) stirring under a nitrogen atmosphere at −20° C. The resulting mixture is allowed to warm slowly to 0° C. After 5.5 hr, the reaction is quenched with saturated aqueous ammonium chloride (20 mL) and then partitioned between water and ethyl acetate. The ethyl acetate layer is washed with a further portion of water, and the combined aqueous washes are extracted with seven portions of ethyl acetate and two portions of dichloromethane. The combined organic extract is dried over magnesium sulfate, filtered and evaporated to give crude 5-ethyl-6-methoxy-2-methyl-nicotinic acid methyl ester (5.58 g) as an orange oil. This material is used without further purification. MS: m/e=210 (M+H); 1H NMR (CDCl3, δ, ppm): 7.94 (1H, s), 4.02 (3H, s), 3.90 (3H, s), 2.77 (3H, s), 2.59 (2H, q), 1.23 (3H, t).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]2[CH:15]=[C:14]([C:16](=O)[NH2:17])[CH:13]=[CH:12][N:11]=2)[CH:5]=1)(=O)[NH2:2].S(Cl)(Cl)=O>N1C=CC=CC=1.C(Cl)Cl>[C:16]([C:14]1[CH:13]=[CH:12][N:11]=[C:10]([C:6]2[CH:5]=[C:4]([C:1]#[N:2])[CH:9]=[CH:8][N:7]=2)[CH:15]=1)#[N:17]
Reactant: NC(=O)c1ccnc(-c2cc(C(N)=O)ccn2)c1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: N#Cc1ccnc(-c2cc(C#N)ccn2)c1
Reaction time: 16 h

Procedure:
A suspension of 4.73 g (0.0195 mol) of 4,4'-dicarbamoyl-2,2'-bipyridine [J. Am. Chem. Soc. 80, 2745 (1958)] and 5.67 g (0.0476 mol) of thionyl chloride in 30 ml of pyridine is stirred for 16 hours at 100°. After cooling, the reaction mixture is diluted with 100 ml of methylene chloride, filtered and concentrated to dryness by evaporation. The residue is then chromatographed with methylene chloride over silica gel. In this manner, 4,4'-dicyano-2,2'-bipyridine is obtained in the form of white crystals having a melting point of 238°-240°.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)=[CH:22][CH:21]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=3[F:19])[N:11]=2)=[CH:4][CH:3]=1.[C:36]([C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1)([CH3:39])([CH3:38])[CH3:37]>>[C:36]([C:40]1[CH:45]=[CH:44][C:43]([C:2]2[CH:35]=[CH:34][C:5]([CH2:6][C:7]3[N:8]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[S:30](=[O:31])(=[O:32])[NH:29][C:28](=[O:33])[CH2:27]5)=[CH:22][CH:21]=4)[CH:9]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=4[F:19])[N:11]=3)=[CH:4][CH:3]=2)=[CH:42][CH:41]=1)([CH3:39])([CH3:38])[CH3:37]
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(F)cc4F)nc3Cc3ccc(Br)cc3)cc2)S(=O)(=O)N1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Product: CC(C)(C)c1ccc(-c2ccc(Cc3nc(-c4ccc(F)cc4F)cn3-c3ccc(N4CC(=O)NS4(=O)=O)cc3)cc2)cc1

Procedure:
5-{-4-[2-(4-Bromo-benzyl)-4-(2,4-difluoro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (prepared according to general procedures A, B and C subsequently) (56 mg, 0.1 mmol) was treated as described in general procedure G using 4-tert-butylphenylboronic acid (36 mg, 0.2 mmol) to give 5-{-4-[2-(4′-tert-butyl-biphenyl-4-ylmethyl)-4-(2,4-difluoro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[NH2:5].[CH3:13][C:14](=O)[CH2:15][CH2:16][C:17](=O)[CH3:18]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([N:5]2[C:17]([CH3:18])=[CH:16][CH:15]=[C:14]2[CH3:13])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Reactant: CC(=O)CCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(C)n1-c1cc(Br)cc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 98.4 %

Procedure:
A solution of 3-bromo-5-(trifluoromethyl)aniline (14.00 g, 58 mmol), hexane-2,5-dione (7.05 mL, 60 mmol) and p-toluenesulfonic acid monohydrate (220 mg, 1.2 mmol) in toluene (250 mL) was heated under Dean-Stark conditions. After 1 h, the reaction mixture was concentrated. The residue was purified by column chromatography to give 1-[3-bromo-5-(trifluoromethyl)phenyl]-2,5-dimethyl-1H-pyrrole (18.15 g, 98%) as orange oil. LCMS: (FA) ES+ 318.1.
Reaction SMILES: C([NH:20][CH:21]([CH2:40][O:41][CH2:42][CH2:43][CH2:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[O:32][C:33]3[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=3[N:35]=2)=[CH:27][CH:26]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(Cl)[Cl:53]>CO>[ClH:53].[O:32]1[C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=[C:31]1[C:28]1[CH:29]=[CH:30][C:25]([CH2:24][O:23][CH2:22][CH:21]([NH2:20])[CH2:40][O:41][CH2:42][CH2:43][CH2:44][CH2:45][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)=[CH:26][CH:27]=1
Reactant: ClCCl
Reactant: c1ccc(CCCCOCC(COCc2ccc(-c3nc4ccccc4o3)cc2)NC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Product: Cl
Product: NC(COCCCCc1ccccc1)COCc1ccc(-c2nc3ccccc3o2)cc1
Reaction time: 1.5 h

Procedure:
N-trityl-1-[4-(benzoxazol-2-yl)benzyloxy]-3-(4-phenylbutoxy)-2-propanamine (0.3 g; 0.45 mmol) is dissolved in CH2Cl2 (3 ml) and MeOH (3 ml) and acidified to pH3 with acidic methanol. The reaction is stirred 1.5 hours, concentrated and purified by column chromatography with 8% MeOH/CH2Cl2. The product is isolated, dissolved in MeOH and acidified with acidic methanol. The solution is concentrated to yield 1-[4-(benzoxazol-2-yl)benzyloxy]-3-(4-phenylbutoxy)-2-propanamine hydrochloride (m.p. 125°-126° C.).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[NH:5].[Cl:11][C:12]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:13]=1[CH:14]=[C:15]([C:18]#[N:19])[C:16]#[N:17]>>[NH2:19][CH2:18][C:15]1[C:16]([NH2:17])=[N:5][C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[F:1])=[N:6][C:14]=1[C:13]1[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:12]=1[Cl:11]
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Reactant: N=C(N)c1ccccc1F
Product: NCc1c(N)nc(-c2ccccc2F)nc1-c1ccc(Cl)cc1Cl

Procedure:
The title compound, MS: m/e=363.0 (M+H+), was prepared from 2-fluorobenzamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:29])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:25]=[N:24][C:23]4[C:18]3=[N:19][CH:20]=[N:21][C:22]=4[C:26](O)=[O:27])=[CH:13][CH:12]=2)=[CH:4][C:3]=1[C:30]([F:33])([F:32])[F:31].CN.[CH3:36][N:37](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1>CN(C)C=O>[CH3:36][NH:37][C:26]([C:22]1[N:21]=[CH:20][N:19]=[C:18]2[C:23]=1[N:24]=[CH:25][N:17]2[C:14]1[CH:13]=[CH:12][C:11]([NH:10][C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:30]([F:32])([F:31])[F:33])[CH:4]=2)=[O:29])=[CH:16][CH:15]=1)=[O:27]
Reactant: O=C(Nc1ccc(-n2cnc3c(C(=O)O)ncnc32)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Product: CNC(=O)c1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.8 %

Procedure:
In 3 mL of dimethylformamide, 30 mg (0.063 mmol) of 9-{4-[3-(4-chloro-3-(trifluoromethyl)phenyl)ureido]phenyl}-9H-purine-6-carboxylic acid was dissolved, and 10 μL of 40% methylamine, 17 mg (0.13 mmol) of HATU and HOAt (0.13 mmol) were added thereto and the mixture solution was stirred at room temperature overnight. The reaction solution was partitioned between ethyl acetate and water and the organic layer was washed with water and a saturated sodium chloride solution in the order named, and then concentrated under reduced pressure. The coarse product was recrystallized from ethyl acetate to obtain 16 mg (52%) of a target product as a white solid.
Reaction SMILES: [O:1]=[C:2]1[N:8]2[CH2:9][C@@H:4]([CH2:5][CH2:6][C@H:7]2[C:10]([NH:12][N:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[O:11])[N:3]1[O:26][S:27]([OH:30])(=[O:29])=[O:28].FC(F)(F)C(O)=O>C(Cl)Cl>[O:1]=[C:2]1[N:8]2[CH2:9][C@@H:4]([CH2:5][CH2:6][C@H:7]2[C:10]([NH:12][N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:11])[N:3]1[O:26][S:27]([OH:30])(=[O:28])=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCN(NC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OS(=O)(=O)O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NN1CCNCC1)[C@@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)O
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-({[(2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)piperazine-1-carboxylate 208 (0.12 g, 0.27 mmol) in DCM (12.5 mL) was added trifluoroacetic acid (1.0 mL, 12.96 mmol) dropwise at 0° C. The reaction mixture was stirred for 1 h, then evaporated. Ether was added to the residue and the resulting white precipitate was collected by centrifugation. The solid was triturated with acetonitrile (2×) and the white solid was collected by centrifugation. This white solid was purified by HPLC on a prep-X Bridge-19×250 mm column and freeze-dried to give (2S,5R)-7-oxo-N-(piperazin-1-yl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide Compound 100 (Table 2) (0.11 g, 88%) as a white solid.
Reaction SMILES: [NH2-].[Na+].[CH2:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CO>O1CCCC1>[CH2:3]([NH:10][C:23]1[CH:24]=[C:19]([O:18][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:20]=[CH:21][C:22]=1[CH3:25])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NCc1ccccc1
Reactant: Cc1ccc(OCc2ccccc2)c(Br)c1
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(OCc2ccccc2)cc1NCc1ccccc1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 72.3 %

Procedure:
100.0 g (2.56 mol) of sodium amide was added to 700 g (6.53 mol) of benzylamine under an argon atmosphere, and the mixture was stirred for 10 minutes at 60° C. A solution of 222.20 g (0.801 mol) of 1-benzyloxy-2-bromo-4-methylbenzene was dissolved in 400 ml of tetrahydrofuran was added dropwise to the above mixture over 50 minutes. The mixture was stirred for 50 minutes while maintaining the temperature at 60° C. Methanol was added under cooling with ice, and the mixture was poured into ice water. The reaction mixture was extracted with ethyl acetate-water, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent was purified by column chromatography (silica gel, 10:1 mixture of n-hexane and ethyl acetate). The crude product thus obtained was recrystallized from n-hexane to obtain 175.80 g (yield: 72.3%) of the title compound as colorless needles.
Reaction SMILES: [C@@H:1]1([N:10]2[C:19]3[C:13](=[C:14]([N+:16]([O-])=[CH:17][N:18]=3)[NH2:15])[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[OH-].[Na+].CO.C(=S)=[S:26]>>[CH:11]1[N:10]([C@@H:1]2[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]2[OH:3])[C:19]2[C:13](=[C:14]([NH2:15])[NH:16][C:17]([N:18]=2)=[S:26])[N:12]=1
Reactant: S=C=S
Reactant: Nc1c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2nc[n+]1[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1[nH]c(=S)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 92 %

Procedure:
8.0 g of adenosine 1-oxide (26.67 mmol) was refluxed in 75 ml of a 5N sodium hydroxide aqueous solution for 15 minutes. The resulting liquid was neutralized to a pH of 5.0 with Amberlite IRC-50 (H+-type) and concentrated to a small volume to prepare 1-β-D-ribofuranosyl-5-aminoimidazole-4-carboxamide oxime. To this was added 200 ml of an aqueous solution containing 175 ml of methanol, the resulting solution being found to have a pH of 9. 50 ml of carbon disulfide was added to the solution, and the mixture was allowed to react in an autoclave at 120° C for 5 hours under autogenous pressure (about 10 Kg/cm2). The orange colored substance formed was removed and concentrated to dryness. The residue was dissolved in 63 ml of 2.5N aqueous ammonia, and any impurities were filtered out. A mixture of n-butanol and acetic acid (125 ml: 63 ml) was added to the filtrate to crystallize the product to obtain 5.42 g of 2-thioadenosine having a melting point of 199° C (with decomposition) in a 92% yield.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[Si:28](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]>C1(C)C=CC=CC=1.CN(C=O)C>[Si:28]([O:27][CH2:26][CH2:25][CH2:24][CH2:23][NH:22][C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([Cl:8])[C:18]=1[N+:19]([O-:21])=[O:20])([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1NCCCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCCCNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Triethylamine (83 mL, 0.60 mol) was added to a solution of 4-(2-chloro-3-nitroquinolin-4-ylamino)butan-1-ol (44.34 g, 149.9 mmol). A solution of tert-butyldimethylsilyl chloride (100 g of a 50% w/w solution in toluene, 0.33 mol) in DMF (60 mL) was slowly added, and the reaction was then stirred at room temperature of five hours. Additional tert-butyldimethylsilyl chloride (50 g of a 50% w/w solution in toluene) was added, and the reaction was stirred at room temperature for three days. Additional tert-butyldimethylsilyl chloride (100 g of a 50% w/w solution in toluene, 0.33 mol) was added, and the reaction was stirred at room temperature for three hours. Finally, additional triethylamine (83 mL, 0.60 mol) and tert-butyldimethylsilyl chloride (100 g of a 50% w/w solution in toluene, 0.33 mol) were added, and the reaction was stirred at room temperature for 1.5 hours. The reaction mixture was filtered to remove a solid, and the filtrate was concentrated under reduced pressure. The residue was dissolved in chloroform (250 mL), and the resulting solution was washed sequentially with 5% w/w aqueous ammonium chloride (3×150 mL), saturated aqueous sodium bicarbonate (2×150 mL), and brine (150 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was further dried under vacuum and passed through a layer of silica gel (eluting with dichloromethane) to provide 56.04 g of N-[4-(tert-butyldimethylsilanyloxy)butyl]-2-chloro-3-nitroquinolin-4-amine as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6](I)[C:5]([NH2:9])=[CH:4][CH:3]=1.CCO.C([O-])([O-])=O.[Na+].[Na+].[CH3:19][C:20]1([CH3:29])[CH2:25][CH2:24][C:23](B(O)O)=[CH:22][CH2:21]1>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[N:7]=[C:6]([C:23]2[CH2:24][CH2:25][C:20]([CH3:29])([CH3:19])[CH2:21][CH:22]=2)[C:5]([NH2:9])=[CH:4][CH:3]=1
Reactant: CC1(C)CC=C(B(O)O)CC1
Reactant: Nc1ccc(Br)nc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC1(C)CC=C(c2nc(Br)ccc2N)CC1
Temperature: 80 °C
Yield: 71 %

Procedure:
A solution of 6-bromo-2-iodo-pyridin-3-ylamine (as prepared in the previous step, 1.00 g, 3.35 mmol) in toluene (27 mL) and EtOH (13.5 mL) was treated with 2.0 M aq Na2CO3 (13.4 mL, 26.8 mmol) and 4,4-dimethyl-cyclohex-1-enylboronic acid (567 mg, 3.68 mmol). The mixture was degassed via sonication, placed under Ar, treated with Pd(PPh3)4 (271 mg, 0.234 mmol), and heated to 80° C. for 5 h. The cooled mixture was diluted with EtOAc (100 mL) and washed with water (2×50 mL). The combined aqueous layers were extracted with EtOAc (1×100 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. Silica gel chromatography of the residue on a Varian MegaBond Elut 50-g column with 10% EtOAc-hexane afforded 668 mg (71%) of 6-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-pyridin-3-ylamine as a tan solid. 1H-NMR (CDCl3; 400 MHz): δ 7.06 (d, 1H, J=8.3 Hz), 6.85 (d, 1H, J=8.3 Hz), 5.95 (m, 1H), 3.86 (br s, 2H), 2.43-2.39 (m, 2H), 1.99-1.97 (m, 2H), 1.51 (t, 2H, J=6.4 Hz), 0.99 (s, 6H).