Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([C:13]2[N:14]=[CH:15][N:16]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:17]=2)([OH:12])[CH:9]([CH3:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:42]1[S:43][CH:44]=[CH:45][CH:46]=1)CCC.O>CN(C=O)C.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>[CH3:10][CH:9]([CH3:11])[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:42]2[S:43][CH:44]=[CH:45][CH:46]=2)[CH:3]=1)([C:13]1[N:14]=[CH:15][N:16]([C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=1)[OH:12]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: CC(C)C(O)(c1cccc(Br)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C(O)(c1cccc(-c2cccs2)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
1-(3-Bromophenyl)-1-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol (1.70 g) and a solution of tri-n-butyl(2-thienyl)tin (1.31 ml) in DMF (10 ml) were deaerated and tetrakis(triphenylphosphine)palladium(0) (110 mg) was added. The mixture was stirred under an argon atmosphere at 80° C. for 4 h. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate, washed twice with water and then with saturated brine, and dried. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chomatography (eluent, hexane:ethyl acetate=6:1→3:1). Recrystallization from ethyl acetate-hexane gave the title compound (1.32 g) as colorless powder crystals.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[CH3:24][N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](O)=[O:35])=[CH:26]1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:34]([C:27]3[C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:25]([CH3:24])[CH:26]=3)=[O:35])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Reactant: Cn1cc(C(=O)O)c2ccccc21
Product: Cn1cc(C(=O)NC[C@@H]2C[C@@H]3C[C@@H]3N2C(=O)c2nc(N)sc2-c2cccc(F)c2)c2ccccc21

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with 1-methyl-1H-indole-3-carboxylic acid. LC-MS (basic): tR=0.81 min; [M+H]+=489.9.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:21])=[C:5]([O:10][C:11]2[C:12]([Cl:20])=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:22][C:23]1[N:24]=[CH:25][N:26](COCC[Si](C)(C)C)[C:27]=1[C:28](O)=[O:29].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Cl:22][C:23]1[N:24]=[CH:25][NH:26][C:27]=1[C:28]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:13]([C:14]#[N:15])[C:12]=2[Cl:20])[C:4]=1[F:21])=[O:29]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1Cl
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1Cl
Yield: 77.9 %

Procedure:
3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-2,5-dichlorobenzonitrile (0.062 g, 0.181 mmol), 4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (0.05 g, 0.181 mmol) and DIPEA (0.063 mL, 0.361 mmol) were combined in THF (2 mL) and treated with HATU (0.076 g, 0.199 mmol) at 25° C. for 6 h with stirring. The reaction mixture was concentrated to dryness, dissolved in DCM, washed with saturated aqueous NaHCO3, dried over MgSO4, filtered and concentrated to dryness. The residue was dissolved in DCM (2.5 mL) and treated with TFA (2.5 mL) at 25° C. for 16 h. The reaction mixture was concentrated to dryness, dissolved in DCM, washed with saturated aqueous NaHCO3, dried over MgSO4, filtered and concentrated to dryness. The resultant solid was recrystallized from boiling EtOH, cooled in an ice bath and filtered to give 4-chloro-N-({4-chloro-3-[(2,5-dichloro-3-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1H-imidazole-5-carboxamide (0.067 g, 0.141 mmol, 78% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.18 (br. s., 1H), 8.27 (s, 1H), 8.02 (d, J=2.06 Hz, 1H), 7.78 (s, 1H), 7.53 (d, J=8.38 Hz, 1H), 7.40 (t, J=7.69 Hz, 1H), 7.25 (d, J=1.65 Hz, 1H), 4.53 (d, 2H). LC-MS (ES−) m/z 471.01, 473.00, 474.99 [M−1]. LC-MS (ES+) m/z 472.91, 474.92, 476.90 [M+H].
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][CH:4]([NH2:14])[C:5]12[O:12][CH2:11][C:8]([CH3:13])([CH2:9][O:10]1)[CH2:7][O:6]2.[S:16]1[CH:20]=[CH:19][N:18]=[C:17]1[CH:21]=O>C1C=CC=CC=1>[CH3:1][CH:2]([CH3:15])[CH2:3][CH:4]([N:14]=[CH:21][C:17]1[S:16][CH:20]=[CH:19][N:18]=1)[C:5]12[O:6][CH2:7][C:8]([CH3:13])([CH2:9][O:10]1)[CH2:11][O:12]2
Reactant: CC(C)CC(N)C12OCC(C)(CO1)CO2
Reactant: O=Cc1nccs1
Solvent: c1ccccc1
Product: CC(C)CC(N=Cc1nccs1)C12OCC(C)(CO1)CO2

Procedure:
A solution of 3-methyl-1-(4-methyl-2,6,7-trioxa-bicyclo[2.2.2]oct-1-yl)-butylamine (1.9 g, 8.8 mmol) and thiazole-2-carboxaldehyde (998 mg, 8.8 mmol) in benzene was refluxed for 3 h using a Dean-Stark trap, during which time water was collected and the remaining residue was evaporated under reduced pressure to get [3-methyl-1-(4-methyl-2,6,7-trioxa-bicyclo[2.2.2]oct-1-yl)-butyl]-thiazol-2-ylmethyleneamine as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH:11]=O)[S:8][C:6]=2[N:7]=1.Cl.[CH3:20][S:21]([N:24]1[CH2:30][CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)(=[O:23])=[O:22]>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:27]3[CH2:28][CH2:29][CH2:30][N:24]([S:21]([CH3:20])(=[O:22])=[O:23])[CH2:25][CH2:26]3)[S:8][C:6]=2[N:7]=1
Reactant: CS(=O)(=O)N1CCCNCC1
Reactant: O=Cc1cc2c(N3CCOCC3)nc(Cl)nc2s1
Agent: Cl
Product: CS(=O)(=O)N1CCCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1

Procedure:
Reaction between 2-chloro-4-morpholin-4-yl-thieno[2,3-d]pyrimidine-6-carbaldehyde and 1-methanesulfonyl-[1,4]diazepane hydrochloride salt using General Procedure C (reductive amination) yielded 2-chloro-6-(4-methanesulfonyl-[1,4]diazepan-1-ylmethyl)-4-morpholin-4-yl-thieno[2,3-d]pyrimidine.
Reaction SMILES: [ClH:1].C(OC([NH:9][CH2:10][C@H:11]([N:16]1[CH2:21][CH2:20][N:19]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:18][CH2:17]1)[C:12]([O:14][CH3:15])=[O:13])=O)(C)(C)C>C(O)(C)C.CO>[ClH:1].[NH2:9][CH2:10][C@H:11]([N:16]1[CH2:21][CH2:20][N:19]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:18][CH2:17]1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)N1CCN(S(C)(=O)=O)CC1
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: COC(=O)[C@H](CN)N1CCN(S(C)(=O)=O)CC1
Temperature: 40 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
15 ml of a solution of hydrochloric acid in isopropanol having a concentration of 5-6N are added dropwise to a solution of 2.7 g (7.4 mmol) of methyl (S)-3-tert-butoxycarbonylamino-2-(4-methanesulphonylpiperazin-1-yl)propanoate in 30 ml of methanol. The reaction medium is stirred at 40° C. for 2 h, concentrated under vacuum then taken up in 20 ml of methanol and 150 ml of diethyl ether. The product precipitates, is filtered, rinsed with diethyl ether then dried under vacuum. 2.3 g (100%) of methyl (S)-3-amino-2-(4-methanesulphonylpiperazin-1-yl)propanoate hydrochloride are obtained in the form of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]([CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17](C(C)=C)[C:16]2=[O:27])=[C:12]2[C:8]([C:9]([CH3:30])=[C:10]([CH3:29])[N:11]2[CH3:28])=[CH:7][CH:6]=1)=[O:4].Cl>CO>[CH3:1][O:2][C:3]([C:5]1[C:13]([CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[NH:17][C:16]2=[O:27])=[C:12]2[C:8]([C:9]([CH3:30])=[C:10]([CH3:29])[N:11]2[CH3:28])=[CH:7][CH:6]=1)=[O:4]
Reactant: C=C(C)n1c(=O)n(Cc2c(C(=O)OC)ccc3c(C)c(C)n(C)c23)c2ccccc21
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccc2c(C)c(C)n(C)c2c1Cn1c(=O)[nH]c2ccccc21
Yield: 93.6 %

Procedure:
7-(3-Isopropenyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1,2,3-trimethyl-1H-indole-6-carboxylic acid methyl ester (100 mg. 0.25 mmol) was dissolved in MeOH (10 mL) and HCl (5 mL) solution at room temperature. The solution was heated to 60 C for 2 hours. The solution was cooled down and was extracted with EtOAc. The combined organic layer was dried with MgSO4 and was filtered. The filtrate was concentrated and the residue was purified by CombiFlash with 10% EtOAc in hexane as the eluent to afford the desirable product 1,2,3-Trimethyl-7-(2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1H-indole-6-carboxylic acid methyl ester (85 mg, 94%) as a colorless oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[OH:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[CH2:2][O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][CH:15]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: NC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 80 °C
Yield: 45 %

Procedure:
To a solution of 2-Chloromethyl-quinoline (1.57 g) and 4-Hydroxy-benzamide (995 mg) in dimethyl formamide (20 mL) was added cesium carbonate (7.3 g) and the reaction mixture heated at 80° C. for 18 h. The reaction mixture was poured into water and extracted with chloroform, dried magnesium sulfate, filtered and concentrated to provided the title compound (909 mg). MS: (M+H m/z=279.3).
Reaction SMILES: [CH3:1][O:2][Si:3]([O:10][CH3:11])([O:8][CH3:9])[C:4]([CH:6]=[CH2:7])=[CH2:5].[C:12]1(=[O:18])[O:17][C:15](=[O:16])[CH:14]=[CH:13]1>>[CH3:1][O:2][Si:3]([O:8][CH3:9])([O:10][CH3:11])[C:4]1[CH2:5][CH:13]2[C:12](=[O:18])[O:17][C:15](=[O:16])[CH:14]2[CH2:7][CH:6]=1
Reactant: C=CC(=C)[Si](OC)(OC)OC
Reactant: O=C1C=CC(=O)O1
Product: CO[Si](OC)(OC)C1=CCC2C(=O)OC(=O)C2C1
Reaction time: 1 h
Yield: 85 %

Procedure:
To 0.36 g (2.1 mmol) of 2-(trimethoxy)silyl-1,3-butadiene [II], were added 0.19 g (1.9 mmol) of maleic acid anhydride [III]at room temperature and stirred for one hour. After the reaction was over, the reaction product was separated on chromotography using silica gel and developing with a mixed solvent of n-hexane-diethyl ether to obtain 0.44 g of 4-(trimethoxy)silyl-1,2,3,6-tetrahydrophthalic acid anhydride [I](yield: 80 %, liquid).
Reaction SMILES: C1(C)C=CC(S([O:10][C@H:11]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]2)(=O)=O)=CC=1.[C:24]1(O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[O:10]([C@@H:11]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:12]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Reactant: Oc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@@H](Oc2ccccc2)C1

Procedure:
Analogously to Method G, 1.01 g of tert-butyl (S)-3-(toluene-4-sulphonyloxy)pyrrolidine-1-carboxylate and 0.418 g of phenol are reacted. The title compound is obtained as a colourless oil. Rf=0.47 (2:1 EtOAc-heptane); Rt=4.88.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.S(=O)(=O)(O)O.[N+:17]([O-])([OH:19])=[O:18]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[C:3]=1[N+:17]([O-:19])=[O:18]
Reactant: Cc1cc(Cl)ccc1C(=O)O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1c(C(=O)O)ccc(Cl)c1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A round bottom flask was charged with 4-chloro-2-methylbenzoic acid (200 mg, 0.001 mol) and sulfuric acid (1 mL, 0.02 mol). Fuming nitric acid (0.05 mL, 0.001 mol) was added at −20° C. and the reaction was stirred for 1 hour at 70° C. and poured into ice cold water, whereupon the mixture of 2- and 4-nitro compounds precipitated out. The precipitate was filtered and dissolved in ethyl acetate (30 mL) and washed with saturated aqueous sodium bicarbonate solution and brine, and dried over sodium sulfate. The solvent was reduced to ¼ volume whereby the undesired isomer precipitated out. The precipitate was filtered and the filtrate was dried to afford a 1:1 mixture of isomers as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1)[OH:4].[C:15](Cl)(Cl)=[O:16].N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:14][O:13][C:7]1[CH:6]=[C:5]([CH:3]2[O:4][C:15](=[O:16])[NH:1][CH2:2]2)[CH:10]=[CH:9][C:8]=1[O:11][CH3:12]
Reactant: COc1ccc(C(O)CN)cc1OC
Reactant: O=C(Cl)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2CNC(=O)O2)cc1OC
Reaction time: 1 h
Yield: 75 %

Procedure:
100 mmol of 2-amino-1-(3,4-dimethoxyphenyl)-ethanol is dissolved in 100 ml. of chloroform. After cooling to 0°, a solution of 100 mmol of phosgene in 100 ml. of chloroform is added dropwise so slowly that the internal temperature does not rise above 5°. After one hour of agitation at 5°-10°, 200 mmol of pyridine in 100 ml. of chloroform is added dropwise to the reaction mixture, and the latter is stirred for 3 hours. After washing the organic phase in semisaturated NaCl solution, the mixture is concentrated by evaporation and recrystallized from methanol, thus obtaining in a 75% yield 5-(3,4-dimethoxyphenyl)-2-oxazolidinone, m.p. 114°-117°.
Reaction SMILES: [O:1]1[CH2:4][C:3]2([CH2:9][CH:8]3[CH:6]([CH:7]3[C:10]([O:12]CC)=[O:11])[CH2:5]2)[CH2:2]1.[OH-].[Na+]>C(O)C.O>[O:1]1[CH2:4][C:3]2([CH2:5][CH:6]3[CH:8]([CH:7]3[C:10]([OH:12])=[O:11])[CH2:9]2)[CH2:2]1
Reactant: CCOC(=O)C1C2CC3(COC3)CC21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C1C2CC3(COC3)CC21
Reaction time: 16 h
Yield: 62.6 %

Procedure:
To a solution of ethyl spiro[bicyclo[3.1.0]hexane-3,3′-oxetane]-6-carboxylate (1.5 g, 7.6 mmol) in ethanol (15 mL) was added sodium hydroxide (917 mg, 22.9 mmol) in water (5 mL). After 16 h, the reaction mixture was concentrated, and the resulting residue was dissolved with water (20 mL). The resulting solution was extracted with ethyl acetate (15 mL). The aqueous layer was acidified with 1 M aqueous HCl solution to pH=3, and the aqueous solution was extracted with dichloromethane (20 mL). The collected organic was dried over anhydrous sodium sulfate, filtered, and concentrated to provide a white solid (0.80 g, 62% yield).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:15]([CH2:16]/[CH:17]=[C:18](\[CH3:25])/[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:14]([O:26][CH3:27])[C:13]([CH3:28])=[C:12]2[C:8]=1[C:9](=[O:29])[O:10][CH2:11]2)(=O)=O.[C-:32]#[N:33].[K+].C(OCC)(=O)C>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:32]([C:7]1[C:15]([CH2:16]/[CH:17]=[C:18](\[CH3:25])/[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:14]([O:26][CH3:27])[C:13]([CH3:28])=[C:12]2[C:8]=1[C:9](=[O:29])[O:10][CH2:11]2)#[N:33]
Reactant: COC(=O)CC/C(C)=C/Cc1c(OC)c(C)c2c(c1OS(=O)(=O)C(F)(F)F)C(=O)OC2
Reactant: [C-]#N
Agent: [Pd]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)CC/C(C)=C/Cc1c(C#N)c2c(c(C)c1OC)COC2=O
Reaction time: 18 h
Yield: 94.1 %

Procedure:
A nitrogen-flushed mixture of 5.8 g (12.4 retool) of methyl (E)-6-(1,3-dihydro-4-trifluoromethylsulfonyloxy -6-methoxy-7-methyl-3-oxoisobenzofuran5-yl)-4-methyl-4-hexenoate, 1.5 g (23.0 mmol) of potassium cyanide, and 1.11 g (0.96 mmol) of tetrakis(triphenylphosphine) palladium in 100 ml of 1,4-dioxane was heated at reflux for 18 hours. Upon cooling, the mixture was partitioned between water and ethyl acetate. The organic phase was washed with water six times, with brine once, and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting solid was stirred with hexane for 18 hours and then filtered off. This solid was further purified by silica gel chromatography using 5:4 hexane:ethyl acetate to give 4.0 g (11.7 mmol) of methyl (E)-6-(1,3-dihydro-4-cyano-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4hexenoate, mp 87°-88° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.[CH3:11][N:12]([CH3:26])[C:13]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][CH:16]3[CH2:15][CH2:14][C:13]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)([N:12]([CH3:26])[CH3:11])[CH2:18][CH2:17]3)=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: Nc1ccc2c(c1)CCC2
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN(C)C1(c2ccccc2)CCC(Nc2ccc3c(c2)CCC3)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5-Aminoindane (266 mg) and 4-dimethylamino-4-phenylcyclohexanone (434 mg) were dissolved in dry 1,2-dichloroethane (10 ml) under argon. Glacial acetic acid (2 mmol) and sodium triacetoxyborohydride (600 mg) were added and the mixture was stirred for 24 hours at RT. For working up, the reaction mixture was concentrated and the residue was adjusted to pH 11 with five molar sodium hydroxide solution. The alkaline phase was diluted with water (10 ml) and extracted with ethyl acetate (4×20 ml). The combined extracts were dried over sodium sulfate and filtered and the filtrate was concentrated. The crude product obtained was chromatographed over silica gel with ethyl acetate/ethanol (1:1). 270 mg of the nonpolar diastereoisomer of N′-indan-5-yl-N,N-dimethyl-1-phenyl-cyclohexane-1,4-diamine were obtained as a white solid (m.p. 162-164° C.).
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][CH:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.C([O:23][C@@H:24]1[C@H:28]([O:29]C(=O)C2C=CC=CC=2)[C@@H:27]([CH2:38][O:39]C(=O)C2C=CC=CC=2)[O:26][C@H:25]1[N:48]1[CH:56]=[N:55][C:54]2[C:49]1=[N:50][C:51]([Cl:58])=[N:52][C:53]=2Cl)(=O)C1C=CC=CC=1.N>>[Cl:58][C:51]1[N:52]=[C:53]([NH:1][N:2]2[CH2:7][CH2:6][CH:5]([S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:4][CH2:3]2)[C:54]2[N:55]=[CH:56][N:48]([C:49]=2[N:50]=1)[C@@H:25]1[O:26][C@H:27]([CH2:38][OH:39])[C@@H:28]([OH:29])[C@H:24]1[OH:23]
Reactant: NN1CCC(Sc2ccccc2)CC1
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: N
Product: OC[C@H]1O[C@@H](n2cnc3c(NN4CCC(Sc5ccccc5)CC4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Yield: 63.4 %

Procedure:
1-Amino-4-phenylthiopiperidine (1.10 g, 6.7 mmol) was reacted with 9-(2',3',5'tri-O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (2.5 g, 4 mmol), followed by debenzoylation of the purified product using methanolic ammonia. This provided the title 2-chloro-N-(4-phenylthio-1-piperidinyl)adenosine (1.25 g, 65%) as a foam, 1H NMR (DMSO-d6) δ3.51-3.60 (1H, m, H-5'a), 3.62-3.68 (1H, m, H-5'b), 3.95 (1H, q, H-4'), 4.14 (1H, q, H-3'), 4.50 (1H, q, H-2'), 5.08 (1H, t, 5'-OH), 5.21, 5.50 (2H, 2d, 2'- and 3'-OH), 5.83 (1H, d, H-1'), 7.24-7.45 (5H, 2m, Ar-H), 8.41 (1H, s, H-8), 9.44 (1H, s, N-H).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]([CH3:11])([CH3:10])[CH2:8][OH:9])=[O:5])[CH3:2].[N+:12]([C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([N+]([O-])=O)[C:16]=1[C:17]#[N:18])([O-:14])=[O:13]>>[C:17]([C:16]1[C:15]([N+:12]([O-:14])=[O:13])=[CH:22][CH:21]=[CH:20][C:19]=1[O:9][CH2:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])([CH3:10])[CH3:11])#[N:18]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CCNC(=O)NC(C)(C)CO
Product: CCNC(=O)NC(C)(C)COc1cccc([N+](=O)[O-])c1C#N
Yield: 65 %

Procedure:
Prepared as in Example 197c from 1-ethyl-3-(1-hydroxy-2-methylpropan-2-yl)urea (Example 209d) and 2,6-dinitrobenzonitrile in 65% yield. MS 307 (MH+).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([Cl:13])[CH:3]=1.[F:14][C:15]1[CH:21]=[C:20]([I:22])[CH:19]=[CH:18][C:16]=1[NH2:17]>CCO.Cl>[Cl:13][C:4]1[CH:3]=[C:2]([NH:17][C:16]2[CH:18]=[CH:19][C:20]([I:22])=[CH:21][C:15]=2[F:14])[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=1
Reactant: Nc1ccc(I)cc1F
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cnc(Cl)cc1Nc1ccc(I)cc1F
Temperature: 90 °C

Procedure:
Ethyl 4,6-dichloronicotinate [prepared according to the literature procedure of J. Chem. Soc. 5163 (1963)] (4.00 g, 18.2 mmol) and 2-fluoro-4-iodoaniline (4.30 g, 18.2 mmol) were dissolved in EtOH (80 mL), to which was added conc. HCl (6 drops). This mixture was heated, in an oil bath at 90° C., for 15 h. The solution was allowed to cool, then refrigerated whereupon the desired product crystallised out of solution as fine needles. The product was isolated by filtration and washed with 10% Et2O/hexanes to give ethyl 6-chloro-4-(2-fluoro-4-iodoanilino)nicotinate as white needles (3.79 g, 50%), m.p. (EtOAc/n-hexane) 162-164° C. 1H NMR [(CD3)2SO, 400 MHz] δ 9.62 (s, 1H), 8.69 (s, 1H), 7.82 (dd, J=9.9, 1.9 Hz, 1H), 7.61-7.66 (m, 1H), 7.33 (t, J=8.5 Hz, 1H), 6.67 (d, J=1.8 Hz, 1H), 4.37 (q, J=7.1 Hz, 2H), 1.35 (t, J=7.1 Hz, 3H). Anal. Calcd for C14H11ClFIN2O2: C, 40.0; H, 2.6; N, 6.7. Found: C, 40.3; H, 2.2; N, 6.7.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].C(=O)(O)[O-].[Na+:18].[Na+].[Na+].[Na+].[Na+].Cl[C:24]1[N:29]=[C:28]([NH:30][C:31]2[CH:32]=[C:33]([C:40]([O-:42])=[O:41])[CH:34]=[C:35]([CH:39]=2)[C:36]([O-:38])=[O:37])[N:27]=[C:26]([NH:43][C:44]2[CH:45]=[C:46]([C:53]([O-:55])=[O:54])[CH:47]=[C:48]([CH:52]=2)[C:49]([O-:51])=[O:50])[N:25]=1>O.[OH-].[Na+]>[Na+:18].[Na+:18].[Na+:18].[Na+:18].[Na+:18].[Na+:18].[N:25]1[C:24]([NH:1][C:2]2[CH:3]=[C:4]([C:11]([O-:13])=[O:12])[CH:5]=[C:6]([CH:10]=2)[C:7]([O-:9])=[O:8])=[N:29][C:28]([NH:30][C:31]2[CH:32]=[C:33]([C:40]([O-:42])=[O:41])[CH:34]=[C:35]([CH:39]=2)[C:36]([O-:38])=[O:37])=[N:27][C:26]=1[NH:43][C:44]1[CH:52]=[C:48]([C:49]([O-:51])=[O:50])[CH:47]=[C:46]([CH:45]=1)[C:53]([O-:55])=[O:54]
Reactant: Nc1cc(C(=O)O)cc(C(=O)O)c1
Reactant: O=C([O-])c1cc(Nc2nc(Cl)nc(Nc3cc(C(=O)[O-])cc(C(=O)[O-])c3)n2)cc(C(=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])c1cc(Nc2nc(Nc3cc(C(=O)[O-])cc(C(=O)[O-])c3)nc(Nc3cc(C(=O)[O-])cc(C(=O)[O-])c3)n2)cc(C(=O)[O-])c1

Procedure:
To a stirred solution of 3.62 g of 5-aminoisophthalic acid and 1.85 g of sodium bicarbonate in 80 ml of water plus 7.8 ml of 5 N sodium hydroxide is added 11.24 g of crude 5,5'-[6-chloro-s-triazine-2,4-diyl)diimino]diisophthalic acid tetrasodium salt (prepared as described in Example 2). The reaction mixture is refluxed for 15 hours, then is filtered. The filtrate is diluted with 100 ml of absolute ethanol to give a precipitate. The precipitate is collected by filtration and is washed with (8:10) aqueous ethanol, 75% aqueous ethanol, ethanol and ether to give 14.2 g of crude product. The product is warmed with 80 ml of water and 0.1 ml of 5 N sodium hydroxide is added to achieve pH 9. The mixture is filtered through diatomaceous earth and the filtrate is diluted with 100 ml of absolute ethanol with formation of a thick paste on stirring. The paste is filtered, stirred in absolute ethanol and filtered again, then is washed with ether and dried by conventional means to give 9.9 g of a colorless powder as the product of the example.