Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[N:3]1[C:11]([NH2:12])=[C:10]2[C:6]([N:7]=[CH:8][NH:9]2)=[N:5][CH:4]=1.Br[CH2:14][CH2:15][O:16]C(=O)C1C=CC=CC=1.N>CN(C=O)C.CO>[OH:16][CH2:15][CH2:14][N:7]1[CH:8]=[N:9][C:10]2[C:6]1=[N:5][CH:4]=[N:3][C:11]=2[NH2:12]
Reactant: O=C(OCCBr)c1ccccc1
Reactant: Nc1ncnc2nc[nH]c12
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2CCO
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a suspension of 60% NaH in mineral oil (1.70 g, 42.57 mmol) in anhydrous DMF (120 mL) was added adenine (5.23 g, 38.70 mmol) under argon, and the mixture was heated at 60° C. for 1 h. 2-Bromoethylbenzoate (9.2 mL, 58.06 mmol) was added dropwise at 60° C., and the reaction was stirred at this temperature for 16 h. The mixture was then filtered to remove insoluble materiel, the filtrate was evaporated under reduced pressure and co-evaporated three times with toluene. The residue was triturated with EtOAc then filtered to give a white solid, which was immediately resuspended in a saturated ammonia solution in MeOH (400 mL). The reaction mixture was stirred for 14 h at room temperature, and then methanol was removed under reduced pressure. Recrystallization from EtOH afforded compound 2 (5.87 g, 85%): mp 236° C. (Lit. 238-239° C.); 1H NMR (DMSO-d6): 8.13 (s, 1H, H-2), 8.10 (s, 1H, H-8), 7.23 (bs, 2H, NH2), 5.05 (bs, 1H, OH), 4.19 (t, J=5.2 Hz, 2H, CH2O), 3.71 (t, J=5.2 Hz, 2H, CH2N). 13C NMR (DMSO-d6) δ: 155.79, 152.23, 149.44, 141.46, 118.55, 59.17, 45.61. MS (GT, FAB+): 136 (B+1H)+, 180 (M+1H)+, 202 (M+Na)+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][CH2:27][N:26]([C:29](=[O:31])[CH3:30])[CH2:25][CH2:24]3)=[CH:19][N:18]=2)=[O:15])=[CH:9][C:8]=1[Cl:32])(=O)=O.[CH3:35][N:36](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[C:29]([N:26]1[CH2:25][CH2:24][N:23]([C:20]2[CH:21]=[CH:22][C:17]([NH:16][C:14](=[O:15])[CH2:13][C:10]3[CH:11]=[CH:12][C:7]([C:35]#[N:36])=[C:8]([Cl:32])[CH:9]=3)=[N:18][CH:19]=2)[CH2:28][CH2:27]1)(=[O:31])[CH3:30]
Reactant: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(OS(=O)(=O)C(F)(F)F)c(Cl)c3)nc2)CC1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(C#N)c(Cl)c3)nc2)CC1
Temperature: 80 °C
Reaction time: 96 h

Procedure:
A mixture of 4-(2-(5-(4-acetylpiperazin-1-yl)pyridin-2-ylamino)-2-oxoethyl)-2-chlorophenyl trifluoromethanesulfonate 237-2 (65 mg, 0.125 mmol), Zn(CN)2 (30 mg, 0.255 mmol), Pd(PPh3)4 (14 mg, 0.012 mmol) in DMF (0.6 ml) was stirred at 80° C. under argon for 96 hours. After cooled to room temperature, it was filtered through celite, washed with ethyl acetate, and concentrated by evaporation of solvents. The residue was subjected to reverse phase HPLC purification to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(3-chloro-4-cyanophenyl)acetamide as solid 237-3.
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=[O:10])[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.S(=O)(=O)(O)O.[N+:17]([O-])([OH:19])=[O:18]>O>[N+:17]([C:6]1[CH:7]=[C:8]2[C:3]([CH2:2][CH2:1][CH2:11][C:9]2=[O:10])=[CH:4][CH:5]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])O
Reactant: O=C1CCCc2ccccc21
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C1CCCc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
5 g of alpha-tetralone are added to 18.2 ml of sulfuric acid cooled to 0° C., while maintaining the temperature <10° C. A mixture of 1.87 ml of nitric acid at 70% in water and of 3.65 ml of sulfuric acid is added while maintaining the temperature <10° C. The reaction medium is stirred for 30 minutes at a temperature <10° C. and then stirred for one hour at ambient temperature. The reaction medium is poured into ice-cold water (250 ml). The insoluble material is filtered off under vacuum and dried, so as to give 5.2 g of 7-nitro-3,4-dihydronaphthalen-1(2H)-one in the form of a beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([OH:30])=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:31][C@@H:32](O)[CH2:33][CH3:34]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([O:30][C@@H:32]([CH2:33][CH3:34])[CH3:31])=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CC[C@@H](C)O
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2C2CCCC2)cc1Cl
Product: CC[C@@H](C)OC(=O)c1ccc2c(c1)CCC1C2=NN(c2ccc(C#N)c(Cl)c2)C1C1CCCC1
Yield: 68 %

Procedure:
The title compound was prepared from (±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid, Example 15 and (R)-butan-2-ol according to Method E (yellow solid, 155 mg, 0.326 mmol, 68% yield). ES-HRMS m/z calc. for C28H31ClN3O2 (M+H) 476.2099, found 476.2100.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.CN([CH2:17][C:18]1[C:26]2[C:21](=[N:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH2:17][C:18]3[C:26]4[C:21](=[N:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: CN(C)Cc1c[nH]c2ncccc12
Reactant: Brc1ccc(N2CCNCC2)nc1
Solvent: Cc1ccccc1
Product: Brc1ccc(N2CCN(Cc3c[nH]c4ncccc34)CC2)nc1
Temperature: 25 °C
Yield: 97.3 %

Procedure:
A solution of 1-(5-bromopyridin-2-yl)-piperazine (310 mg,1.28 mmol) (prepared in Example 3(b)) and 3-(N,N-dimethylaminomethyl)-1H-pyrrolo[2,3-b]pyridine (215 mg, 1.16 mmol) (prepared in Example 1(a)) in toluene (10 mL) was heated at reflux for 18 h. The heating was discontinued and the solution allowed to cool to room temperature during which time a colourless solid precipitated out of solution. The solid was collected by filtration and dried in vacuo to yield 3-[4-(5-bromopyridin-2-yl)-piperazin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine as a colourless solid (420 mg, 97%). δH (300 mhz CDCl3) 2.58 (4H, m, piperazinyl), 3.51 (4H, m, piperazinyl), 3.75 (2H, s), 6.50 (1H, d, J=9.0), 7.09 (1H, dd, J=5.0 and 7.9), 7.27 (1H, s), 7.49 (1H, dd, J=2.6 and 9.0), 8.10 (1H, d, J=7.8), 8.17 (1H, d, J=2.3), 8.32 (4.5), 9.69 (1H , br s) ESMS 374 (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10](=[O:16])[N:9]([CH3:17])[C:8]=2[CH:7]=[C:6]1[N:18]1[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:19]1.[Br:36]N1C(=O)CCC1=O.S([O-])(O)(=O)=O.[K+]>CN(C)C=O>[Br:36][C:7]1[C:8]2[N:9]([CH3:17])[C:10](=[O:16])[N:11]([CH3:15])[C:12](=[O:14])[C:13]=2[N:5]([CH2:4][C:3]2[CH:32]=[CH:33][CH:34]=[CH:35][C:2]=2[Cl:1])[C:6]=1[N:18]1[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:30])[CH3:28])[CH2:19]1
Reactant: Cn1c(=O)c2c(cc(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n2Cc2ccccc2Cl)n(C)c1=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(c(Br)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n2Cc2ccccc2Cl)n(C)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
To a solution of tert-butyl {(3R)-1-[5-(2-chlorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (1.00 g) in N,N-dimethylformamide (20 ml) was added N-bromosuccinimide (392 mg), and the resulting mixture was stirred overnight at room temperature. The reaction solution was adjusted to pH 2 with a 10% aqueous potassium hydrogensulfate solution and extracted with ethyl acetate (200 ml). The organic layer was washed with a 10% aqueous potassium hydrogensulfate solution and a saturated aqueous sodium chloride solution, dried over sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain the title compound (1.143 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11]([C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[C:22]([CH3:24])[C:21]([CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:20][N:19]=3)[O:15][N:14]=2)[CH:10]=[C:9]([CH3:29])[C:4]=1[O:5][CH2:6][CH2:7][OH:8])[CH3:2].C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl>[CH2:1]([C:3]1[CH:12]=[C:11]([C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[C:22]([CH3:24])[C:21]([CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:20][N:19]=3)[O:15][N:14]=2)[CH:10]=[C:9]([CH3:29])[C:4]=1[O:5][CH2:6][CH2:7][O:8][S:38]([CH3:37])(=[O:40])=[O:39])[CH3:2]
Reactant: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1OCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1OCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 101.9 %

Procedure:
A solution of the compound of Example 47 (900 mg, 2.28 mmol) and triethylamine (322 mg, 3.18 mmol) in DCM (20 mL) is cooled to 0° C. before methanesulfonyl chloride (313 mg, 2.73 mmol) is added. The mixture is stirred at rt for 90 min. The mixture is diluted with DCM and washed with water. The org. extract is dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 1:1 to give methanesulfonic acid 2-{2-ethyl-4-[5-(5-isobutyl-4-methyl-pyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenoxy}-ethyl ester (1.10 g) as a white solid; LC-MS: tR=1.16 min, [M+H]+=474.02.
Reaction SMILES: [ClH:1].[CH2:2]([O:6][C:7]([C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[C:15]([C:18](=[O:31])[CH:19]([NH:27][CH:28]([CH3:30])[CH3:29])C(OCCCC)=O)[CH:14]=[CH:13][C:12]=2[OH:32])=[O:8])[CH2:3][CH2:4][CH3:5]>CO.O1CCCC1>[ClH:1].[CH2:2]([O:6][C:7]([C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[C:15]([CH:18]([OH:31])[CH2:19][NH:27][CH:28]([CH3:30])[CH2:29][C:7]([O:6][CH2:2][CH2:3][CH2:4][CH3:5])=[O:8])[CH:14]=[CH:13][C:12]=2[OH:32])=[O:8])[CH2:3][CH2:4][CH3:5]
Reactant: CCCCOC(=O)c1cc2c(C(=O)C(NC(C)C)C(=O)OCCCC)ccc(O)c2[nH]1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOC(=O)CC(C)NCC(O)c1ccc(O)c2[nH]c(C(=O)OCCCC)cc12
Yield: 97 %

Procedure:
Under the conditions of Example 14(E), 380 mg of 4-(2-n-butoxycarbonyl-1-methylethylaminoacetyl)-7-hydroxyindole-2-carboxylic acid n-butyl ester hydrochloride in 10 ml of methanol and 5 ml of tetrahydrofuran is hydrogenated and worked up, yielding 185 mg of 4-[1-hydroxy-2-(2-n-butoxycarbonyl-1-methylethylamino)ethyl]-7-hydroxyindole-2-carboxylic acid n-butyl ester hydrochloride, decomposition point 75°-84° C.
Reaction SMILES: [C:1]([C:4]1[C:18]([OH:19])=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[N:16])=[C:6]([CH2:20]Cl)[CH:5]=1)(=[O:3])[CH3:2].[CH3:22][OH:23]>Cl([O-])(=O)(=O)=O.[Ag+]>[C:1]([C:4]1[C:18]([OH:19])=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[N:16])=[C:6]([CH2:20][O:23][CH3:22])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(CCl)c(OCCCCCCC#N)cc1O
Reactant: CO
Agent: [Ag+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: COCc1cc(C(C)=O)c(O)cc1OCCCCCCC#N
Temperature: 25 °C

Procedure:
Approximately 3 millimoles of the chloro compound of Example 127 were treated with 0.624 g of silver perchlorate in 50 ml of methanol at 0° C. The reaction mixture was allowed to warm to room temperature over a 2 hour period. The mixture was then partitioned between ethyl acetate and an acidic sodium chloride solution. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative thin layer chromatography over silica gel eluting with 1:1 ethyl acetate/hexane providing 50 mg of the title compound. NMR, MS.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]([O:23][NH2:24])[C:7]([O:9][CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])=[CH:2]1.[C:25]([NH:44][C:45]1[S:46][CH:47]=[C:48]([C:50](=O)[C:51]([OH:53])=[O:52])[N:49]=1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CO>[C:25]([NH:44][C:45]1[S:46][CH:47]=[C:48](/[C:50](=[N:24]/[O:23][CH:6]([C:7]([O:9][CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:8])[C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)/[C:51]([OH:53])=[O:52])[N:49]=1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(O)C(=O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: NOC(C(=O)OC(c1ccccc1)c1ccccc1)c1ccsc1
Solvent: CO
Product: O=C(O)/C(=N\OC(C(=O)OC(c1ccccc1)c1ccccc1)c1ccsc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 1 h
Yield: 69.2 %

Procedure:
Diphenylmethyl 2-(3-thienyl)-2-aminooxyacetate (140 mg) was dissolved in methanol (14 ml), and 2-(2-tritylaminothiazol-4-yl)-2-oxoacetic acid (171 mg) was added. After stirring the mixture for 1 hr. at the room temperature, and further stirring for 30 min. under ice-cooling to obtain a crystal, the crystal thus obtained was filtered off to give (Z)-2-(2-tritylamino-4-thiazolyl)-2-[(diphenylmethyloxycarbonyl)(3-thienyl)methyl]oxyiminoacetic acid (210 mg).
Reaction SMILES: Br[C:2]([CH3:4])=[CH2:3].C([Li])(C)(C)C.[CH2:10]([S:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=[O:17])[C:11]#[CH:12]>C1COCC1.CCCCC>[CH3:4][C:2](=[CH2:3])[CH:16]([C:15]1[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=1[S:13][CH2:10][C:11]#[CH:12])[OH:17]
Reactant: C=C(C)Br
Reactant: C#CCSc1ccccc1C=O
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: C#CCSc1ccccc1C(O)C(=C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 2-bromopropene (4.53 g, 37.4 mmol) in 85 ml of dry THF at -78° C. was added t-butyllithium (44 ml of a 1.7M solution in pentane) dropwise. After 2 hours, 2-(2-propynylthio) benzaldehyde (3.0 g, 17.0 mmol) prepared according to the procedures described in Example 1, Steps A, B, and C in 30 ml of dry THF was added dropwise. The reaction mixture was allowed to warm up to room temperature (RT). The reaction mixture was quenched with 100 ml of a saturated NH4Cl solution, extracted twice with diethyl ether, washed with water and brine, and then dried over K2CO3 to afford the subtitle compound.
Reaction SMILES: C([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[NH:5][CH:4]=1)C.Cl[CH2:14][C:15]1[S:19][C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)=[N:17][C:16]=1[CH3:30].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)C>CN(C=O)C>[CH3:30][C:16]1[N:17]=[C:18]([C:20]2[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=2)[S:19][C:15]=1[CH2:14][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][CH:4]=[CH:3]2
Reactant: CCc1c[nH]c2ccc(O)cc12
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.8 %

Procedure:
A suspension of 3-ethyl-1H-indol-5-ol (235 mg, 1.46 mmol), 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole [425 mg, 1.46 mmol; PCT Int. Appl. (2002), WO 0292590 A1] and cesium carbonate (712 mg, 2.19 mmol) in DMF (3 ml) was stirred for 1.5 h at ambient temperature. Diethyl ether was added and the mixture was washed with 1N HCl and water. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, ethyl acetate/heptane 1:3) to give 522 mg (1.34 mmol, 86%) 5-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-1H-indole.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([C:16]3[N:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]([F:30])([F:29])[F:28])[N:19]=[C:18]([C:31]([OH:34])([CH3:33])[CH3:32])[CH:17]=3)=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[Br:35]N1C(=O)CCC1=O>CC#N>[Br:35][C:17]1[C:18]([C:31]([OH:34])([CH3:32])[CH3:33])=[N:19][N:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([F:30])([F:28])[F:29])[C:16]=1[C:14]1[S:15][C:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=2)=[CH:12][CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(O)c1cc(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)n(-c2ccccc2C(F)(F)F)n1
Solvent: CC#N
Product: CC(C)(O)c1nn(-c2ccccc2C(F)(F)F)c(-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)c1Br
Temperature: 20 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
To a stirred solution of 2-[5-[5-(3-methanesulfonyl-phenyl)-thiophen-2-yl]-1-(2-trifluoromethyl-phenyl)-1H-pyrazol-3-yl]-propan-2-ol (254 mg, 0.5 mmol) in dry MeCN was added N-bromosuccinimide (94 mg, 0.53 mmol) at 20° C. and the reaction mixture was stirred at 20° C. overnight. Evaporation of solvent gave a residue, which was purified by flash chromatography on silica gel eluted with EtOAC-hexane (0-60%) to afford the title compound as a white solid (286 mg, 98%). 1H-NMR (CDCl3): δ 8.05 (m, 1H), 7.85-7.81 (m, 2H), 7.76 (m, 1H), 7.63-7.61 (m, 2H), 7.56 (t, 1H), 7.39 (m, 1H), 7.25 (d, 1H), 6.98 (d, 1H), 3.09 (s, 1H), 3.07 (s, 3H), 1.74 (s, 6H).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH2:17])=[CH:5][CH:4]=1.[CH2:20]([N:27]=[C:28]=[O:29])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>ClCCl>[CH3:1][N:2]([CH3:19])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][C:28]([NH:27][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:29])=[CH:7][CH:8]=1
Reactant: CCCCCCCN=C=O
Reactant: CN(C)c1ccc(NC(=O)c2ccccc2N)cc1
Solvent: ClCCl
Product: CCCCCCCNC(=O)Nc1ccccc1C(=O)Nc1ccc(N(C)C)cc1
Reaction time: 8 h
Yield: 68.7 %

Procedure:
To a solution of N-(4-dimethylaminophenyl)-2-aminobenzamide (1.5 g) in dichloromethane (20 ml), heptyl isocyanate (2.4 g) was added under ice-cooling and the mixture was stirred overnight while returning slowly to room temperature. The solvent was distilled off and crystallization of the residue from chloroform/ethyl acetate afforded N-(4-dimethylaminophenyl)-2-(3-heptylureido)benzamide (1.6 g, 69%).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:23][C@H:22]([CH2:24][O:25][CH3:26])[C@@H:17]([O:18]C(=O)C)[C@H:12]1[O:13]C(=O)C.[CH:27]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:27]1([NH:32][C:2]2[C:3]3[N:4]=[CH:5][N:6]([C:7]=3[N:8]=[CH:9][N:10]=2)[C@@H:11]2[O:23][C@H:22]([CH2:24][O:25][CH3:26])[C@@H:17]([OH:18])[C@H:12]2[OH:13])[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: NC1CCCC1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Product: COC[C@H]1O[C@@H](n2cnc3c(NC4CCCC4)ncnc32)[C@H](O)[C@@H]1O

Procedure:
Method B. The reaction was carried out with 6-chloro-9-(2,3-di-O-acetyl-5-O-methyl-β-D-ribofuranosyl)-purine (60, 589 mg, 1.53 mmol) and cyclopentylamine (2.3 mmol, 227 μl). The mixture was purified by column chromatography (eluens 5% MeOH in CH2Cl2). Yield 476 mg (1.36 mmol, 89%), mp 164–166° C.; Rf 0.51 (eluens 10% MeOH in CH2Cl2). The product was re-crystallized from CH3CN); 1H NMR (DMSO-d6) δ 8.28 (s, 1H, H-8), 8.18 (s, 1H, H-2), 7.70 (d, 1H, J=7.55 Hz, NH), 5.89 (d, 1H, J=4.80 Hz, H-1′), 5.50 (d, 1H, J=5.15 Hz, OH-2′), 5.26 (d, 1H, J=5.15 Hz, OH-3′), 4.56 (q, 1H, J=4.12 Hz, H-2′), 4.13 (q, 1H, J=4.46 Hz, H-3′), 3.99 (q, 1H, J=4.12 Hz, H-4′), 3.57–3.42 (m, 2H, H-5′), 3.28 (s, 3H, OCH 3), 2.01–1.83 (m, 2H, cyclopentyl), 1.73–1.52 (m, 4H, cyclopentyl); MS m/z 350 (M+H)+; Anal. (C16H23N5O4.0.7 CH3CN) C, H, N.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]1(OB(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:3][CH:4]=1
Reactant: OB(O)Oc1ccccc1
Reactant: Brc1ccc(Br)nc1
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: Cc1ccccc1
Product: Brc1ccc(-c2ccccc2)nc1
Temperature: 50 °C
Reaction time: 6 h
Yield: 88.3 %

Procedure:
2,5-dibromopyridine (7.11 g, 30 mmol), toluene (130 mL), phenylboric acid (4.57 g, 37.5 mmol), and tetrakis(triphenylphosphine)palladium(0) (1.73 g, 1.5 mmol) were weighed and placed into a reactor. A reactant was dissolved under a nitrogen stream while stirring at 50° C. To this, a 2 M sodium carbonate aqueous solution (30 mL) was added, and stirring was performed at 80° C. for 6 hours. An organic layer of the obtained reaction solution was collected, and washed with a sodium carbonate aqueous solution and a saturated brine. The organic layer was dried with sodium sulfate, filtered, and then distilled off. This residue was purified using silica gel column chromatography (hexane/toluene) to distill off the solvent, and 5-bromo-2-phenylpyridine (6.21 g, 26.5 mmol) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[S:8][C:9]3[N:10]=[C:11]4[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][N:12]4[C:18](=[O:20])[C:19]=3[C:6]=2[CH2:5][CH2:4][C:3]=1[CH:21]=[O:22].CC(=CC)C.C1C[O:31]CC1.[O-]Cl=O.[Na+]>CC(O)(C)C.O>[Cl:1][C:2]1[C:7]2[S:8][C:9]3[N:10]=[C:11]4[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][N:12]4[C:18](=[O:20])[C:19]=3[C:6]=2[CH2:5][CH2:4][C:3]=1[C:21]([OH:31])=[O:22]
Reactant: O=CC1=C(Cl)c2sc3nc4n(c(=O)c3c2CC1)CCCCC4
Reactant: C1CCOC1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(O)C1=C(Cl)c2sc3nc4n(c(=O)c3c2CC1)CCCCC4
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Compound 4a (335 mg, 1.00 mmol) and 2-methyl-2-butene (1.06 ml, 10.01 mmol) were dissolved into 50 ml THF. A freshly prepared solution of 80% NaClO2 (339 mg, 3.00 mmol) and NaH2PO4.H2O (414 mg, 3.00 mmol) in 55 ml of t-BuOH/H2O 5:1 was added. The reaction mixture was stirred in room temperature for 6 hours. The reaction was quenched with water and extracted CH2Cl2. The organic phase was extracted with sat. NaHSO4. The water phase was then made acidic with HCl and extracted with CH2Cl2. the organic layer was washed with brine and dried over Na2SO2. After filtration the solvent was evaporated ant the product recrystallized from ethanol.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][C:6]1[CH:10]=[CH:9][O:8][CH:7]=1)[CH:2]=[CH2:3].Br[CH2:12][CH2:13][OH:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([N:4]([CH2:5][C:6]1[CH:10]=[CH:9][O:8][CH:7]=1)[CH2:12][CH2:13][OH:14])[CH:2]=[CH2:3]
Reactant: OCCBr
Reactant: C=CCNCc1ccoc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCN(CCO)Cc1ccoc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of 6.597 g (48.09 mmol) of N-allyl-3-furylmethylamine and 18.0 g (144 mmol) of 2-bromoethanol in 100 ml of N,N-dimethylformamide, 33.2 g of potassium carbonate was added, followed by overnight stirring at 90° C. The reaction mixture was poured into water and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 to 1/1) to yield 2-[allyl-(3-furylmethyl)amino]ethanol.