Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][O:3][CH2:4][CH:5](O)[CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C([O-])([O-])=O.[Na+].[Na+].Cl.[CH3:21][N:22]([CH3:32])[C:23](Cl)=[N:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)(Cl)Cl>[CH3:21][N:22]([CH3:32])[C:23]([N:2]([CH3:1])[O:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[N:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CNOCC(O)CN1CCCCC1
Reactant: CN(C)C(Cl)=Nc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CN(C)C(=Nc1ccccc1)N(C)OCCCN1CCCCC1
Yield: 10 %

Procedure:
344 mg (2.0 mmole) 1-methylaminooxy-2-hydroxy-3-(1-piperidinyl)-propane was dissolved in chloroform and 220 mg of Na2CO3 was added, then a solution of 438 mg (2.0 mmole) of N,N-dimethyl-N′-phenyl-chloroformamidine hydrochloride in 3 ml of chloroform was added dropwise. After 8 hours the solid state was filtered and the filtrate was evaporated. This residue was dissolved in ethyl acetate and the product was extracted by addition of HCl solution (pH=1) to water. The aqueous phase was made alkaline then by addition of 2N NaOH solution to pH=11, and extracted with ethyl acetate. The organic phase was evaporated, and the further purification was made by column chromatography to give the title compound as a yellow oil.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22]>C1(C)C=CC=CC=1>[CH2:12]([O:11][C:3](=[O:10])[CH:4]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:13]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C(=O)OCC)c1ccncc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 18.2 %

Procedure:
To a suspension of 3.05 g of 60% sodium hydride (76.0 mmol) in toluene (50 mL) in a 250 mL RB flask was added 12.2 g of diethyl malonate (76.0 mmol) dropwise. The reaction mixture was stirred for 30 min under nitrogen, and a solution of 10.8 g of 4-chloro-3-nitropyridine (prepared according to the procedure of Houston et al. J. Med. Chem. 1985, 28, 467) in toluene (50 mL) was added dropwise and the resulting mixture refluxed for 4 h. The reaction mixture was concentrate, and the residue was partitioned between 100 mL each of dilute hydrochloric acid and diethyl ether. The aqueous phase was extracted twice with 100 mL of ether, and the combined ether phases were dried over magnesium sulfate and concentrated to give a dark oil. This was chromatographed on silica gel eluting With a hexane-30% hexane/EtOAc gradient to give 3.5 g of the title compound as a colorless oil which crystallized on standing. 1H NMR (DMSO-d6): δ 1.15 (t, J=7.1 Hz, 6H), 4.16 (q, J=7.1 Hz, 4H), 5.55 (s, 1H), 7.59 (d, J=5.1 Hz, 1H), 8.89 (d, J=5.1 Hz, 1H), 9.24 (s, 1H); C12H14N2O6: APES−MS m/z 281 (M−H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](Cl)[C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[C:5]1=[O:24])(=O)C.[CH3:25][N:26]([CH2:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)[CH3:27].[OH-].[Na+]>CN(C=O)C.CO>[CH3:27][N:26]([CH2:28][C:29]1[CH:30]=[CH:31][C:32]([NH:33]/[C:13](=[C:6]2\[C:5](=[O:24])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)=[CH:34][CH:35]=1)[CH3:25]
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2ccc([N+](=O)[O-])cc2)c2ccccc21
Reactant: CN(C)Cc1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CN(C)Cc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccc([N+](=O)[O-])cc2)cc1

Procedure:
Prepared analogously to Example 2 from 1-acetyl-3-[1-chloro-1-(4-nitrophenyl)-methylidene)-2-indolinone and 4-dimethylaminomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [NH2:1][C:2]1[CH:33]=[CH:32][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[CH:17]=[N:18][N:19]([CH2:21][CH2:22][N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:20]=4)[S:15][C:8]=23)=[C:4]([F:34])[CH:3]=1.FC1C=C(NC(NC(=O)CC2C=CC=CC=2)=S)C=CC=1OC1C=CN=C2C=C(C3C=CC(S(C)(=O)=O)=CC=3)SC=12.[CH3:75][O:76][C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][C:78]=1[CH2:83][C:84]([N:86]=[C:87]=[S:88])=[O:85]>>[F:34][C:4]1[CH:3]=[C:2]([NH:1][C:87]([NH:86][C:84](=[O:85])[CH2:83][C:78]2[CH:79]=[CH:80][CH:81]=[CH:82][C:77]=2[O:76][CH3:75])=[S:88])[CH:33]=[CH:32][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[CH:17]=[N:18][N:19]([CH2:21][CH2:22][N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])[CH:20]=3)[S:15][C:8]=12
Reactant: COc1ccccc1CC(=O)N=C=S
Reactant: CN(CCn1cc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)cn1)C(=O)OC(C)(C)C
Agent: CS(=O)(=O)c1ccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)c3s2)cc1
Product: COc1ccccc1CC(=O)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4cnn(CCN(C)C(=O)OC(C)(C)C)c4)sc23)c(F)c1
Yield: 90 %

Procedure:
Starting from the amine 182, following the procedure described above for the synthesis of compound 50 (scheme 10, example 55) but replacing 2-phenylacetyl isothiocyanate with 2-(2-methoxyphenyl)acetyl isothiocyanate, title compound 183 was obtained in 90% yield. LRMS (M+1) 691.2 (100%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=2[N:7]([C:15]([CH3:17])=[CH2:16])[C:6]1=[O:18].[NH:19]1[CH2:24][CH2:23][CH:22]([N:25]2[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[NH:27][C:26]2=[O:34])[CH2:21][CH2:20]1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[O:34]=[C:26]1[N:25]([CH:22]2[CH2:21][CH2:20][N:19]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=4[N:7]([C:15]([CH3:17])=[CH2:16])[C:6]3=[O:18])[CH2:24][CH2:23]2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[NH:27]1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: C=C(C)n1c(=O)n(CCCCl)c2ccc(C)cc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: C=C(C)n1c(=O)n(CCCN2CCC(n3c(=O)[nH]c4ccccc43)CC2)c2ccc(C)cc21
Yield: 67 %

Procedure:
A mixture of 5.3 parts of 1-(3-chloropropyl)-1,3-dihydro-5-methyl-3-(1-methylethenyl)-2H-benzimidazol-2-one, 4.3 parts of 1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 6.4 parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone is stirred and refluxed overnight with water-separator. After cooling, water is added and the layers are separated. The 4-methyl-2-pentanone-phase is dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 6 parts (67%) of 1-{3-[4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]propyl}-1,3-dihydro-5-methyl-3-(1-methylethenyl)-2H-benzimidazol-2-one as an oily residue.
Reaction SMILES: CCN(C(C)C)C(C)C.[NH:10]1[CH2:13][CH2:12][CH2:11]1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.[NH2:38][C:39]1[N:40]=[CH:41][C:42]([C:51]2[CH:61]=[CH:60][C:54]([C:55]([N:57]([CH3:59])[CH3:58])=[O:56])=[CH:53][CH:52]=2)=[N:43][C:44]=1[C:45]1[O:46][C:47](=O)[NH:48][N:49]=1>CN(C=O)C>[NH2:38][C:39]1[N:40]=[CH:41][C:42]([C:51]2[CH:52]=[CH:53][C:54]([C:55]([N:57]([CH3:59])[CH3:58])=[O:56])=[CH:60][CH:61]=2)=[N:43][C:44]=1[C:45]1[O:46][C:47]([N:10]2[CH2:13][CH2:12][CH2:11]2)=[N:48][N:49]=1
Reactant: CN(C)C(=O)c1ccc(-c2cnc(N)c(-c3n[nH]c(=O)o3)n2)cc1
Reactant: C1CNC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc(-c2cnc(N)c(-c3nnc(N4CCC4)o3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 15.8 %

Procedure:
DIPEA (38.44 mg, 51.81 μL, 0.2974 mmol), azetidine (8.490 mg, 0.1487 mmol) and bromo(tripyrrolidin-1-yl)phosphonium hexafluorophosphate (76.27 mg, 0.1636 mmol) were added to a solution of 4-(5-amino-6-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-N,N-dimethylbenzamide (50 mg, 0.1487 mmol) in DMF (485.1 μL) and the resulting solution stirred at room temperature for 2 h. The reaction mixture was filtered and purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. Product fractions were concentrated in vacuo and triturated with dichloromethane/diethyl ether to give the product (8.6 mg, 15% yield); 1H NMR (400.0 MHz, DMSO) d 2.96 (s, 3H), 3.00 (s, 6H), 4.25 (t, 4H), 7.52 (dd, 2H), 7.65 (br s, 1H), 8.04-8.06 (m, 2H) and 8.83 (s, 1H) ppm; MS (ES+) 366.21
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][C:4]([CH2:11][NH2:12])([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].[C:18]([O:23][CH:24]([O:26][C:27](OC1CC(=O)NC1=O)=[O:28])[CH3:25])(=[O:22])[CH:19]([CH3:21])[CH3:20]>O.C(#N)C.C(OCC)C>[C:18]([O:23][CH:24]([O:26][C:27]([NH:12][CH2:11][C:4]1([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2][CH2:1][CH2:6][CH2:5]1)=[O:28])[CH3:25])(=[O:22])[CH:19]([CH3:21])[CH3:20]
Reactant: CC(OC(=O)OC1CC(=O)NC1=O)OC(=O)C(C)C
Reactant: NCC1(CC(=O)O)CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CCOCC
Product: CC(OC(=O)NCC1(CC(=O)O)CCCCC1)OC(=O)C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
To a solution of gabapentin (1.7 g, 10 mmol) and sodium bicarbonate (20 mmol) in water (40 mL) was added a solution of compound (10) (2.73 g, 10 mmol) in acetonitrile (20 mL) over 1 min. The reaction was stirred at ambient temperature for 16 h. The reaction mixture was diluted with diethyl ether (100 mL) and washed with 0.1 M aqueous potassium bisulfate (3×100 mL). The organic phase was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford the title compound (12) as a white solid (2.7 g, 96%). The product was recrystallized by dissolution in 1:10 ethyl acetate:heptane (10 mL) at 60° C., followed by slow cooling to 4° C. The white crystalline product was isolated by filtration. Melting point: 63-64° C. 1H NMR (CDCl3, 400 MHz): 1.15 (d, 6H), 1.40-1.55 (m, 10H), 1.45 (d, 3H), 2.32 (s, 2H), 2.49-2.56 (m, 1H), 3.23 (d, 2H), 5.41 (t, 1H), 6.75 (q, 1H). MS (ESI) m/z 330.29 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:10]([NH:11][CH3:12])=[CH:9][CH:8]=[CH:7]C=1C(O)=O.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1.[C:28]([O:31][CH2:32]C)(=[O:30])[CH3:29]>O1CCCC1>[F:1][C:2]1[C:10]([N:11]([CH3:12])[C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][CH:8]=[CH:7][C:29]=1[C:28]([O:31][CH3:32])=[O:30]
Reactant: CNc1cccc(C(=O)O)c1F
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(N(C)C(=O)c2ccccc2)c1F
Yield: 64 %

Procedure:
2-Fluoro3-(methylamino)benzoic acid (1.42 g, 4.94 mmol) was dissolved in tetrahydrofuran (15 ml), and benzoyl chloride (0.83 g, 5.90 mmol) and pyridine (0.47 g, 5.94 mmol) were added thereto. The reaction mixture was allowed to react for 12 hours at room temperature. Ethyl acetate was added to the reaction solution, and the mixture was washed sequentially with water, a 1N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate, and saturated saline, and then dried over anhydrous sodium sulfate. The sodium sulfate was filtered away, and the concentration residue was purified by silica gel column chromatography (developer solvent: ethyl acetate/n-hexane=1/8), as a result of which 1.42 g (yield: 64%) of the indicated compound was obtained.
Reaction SMILES: C(S[CH:5]1[N:8]([C:9](=[C:23]([S:30][C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)[C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[S:11])[C:7](=[O:38])[CH2:6]1)C=C.[Cl:39]Cl>ClCCl.C(Cl)(Cl)(Cl)Cl>[Cl:39][CH:5]1[N:8]([C:9](=[C:23]([S:30][C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)[C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[S:11])[C:7](=[O:38])[CH2:6]1
Reactant: ClCl
Reactant: C=CCSC1CC(=O)N1C(C(=S)OCc1ccc([N+](=O)[O-])cc1)=C(Sc1ccc(C)cc1)C(=O)C(C)(C)C
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(SC(C(=O)C(C)(C)C)=C(C(=S)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)CC2Cl)cc1
Temperature: 25 °C
Yield: 69.5 %

Procedure:
To a solution of 2.28 g of 4-nitrobenzyl 2-(4-allylthioazetidin-2-on-1-yl)-3-(4-methylthiophenoxy)-3-trimethylacetylthiopropenate in dichloromethane at -20° , was added solution of 7.6 mmol of chlorine in carbon tetrachloride. After 30 minutes the mixture was warmed to room temperature, evaporated in vacuo, and the residual oil was chromatographed over silica gel. Elution with hexane-ethyl acetate mixtures afforded 1.48 g of the title compound as a yellow foam (69% of the theoretical yield).
Reaction SMILES: [F-:1].[K+].C1OCCOCCOCCOCCOCCOC1.Cl[C:22]1[N:31]2[CH:32]=[C:33]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[F:41])[N:34]=[C:30]2[C:29]2[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=2[N:23]=1.O>CN(C=O)C>[F:1][C:22]1[N:31]2[CH:32]=[C:33]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[F:41])[N:34]=[C:30]2[C:29]2[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=2[N:23]=1
Reactant: [F-]
Reactant: Fc1ccccc1-c1cn2c(Cl)nc3c(c2n1)CCCC3
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccccc1-c1cn2c(F)nc3c(c2n1)CCCC3
Temperature: 25 °C

Procedure:
To a solution of 700 mg of potassium fluoride and 200 mg 18-crown-6 in 10 mL of DMF was added 5-Chloro-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline (200 mg). This mixture was refluxed for 1.5 h, cooled to room temperature and poured into water. The aqueous solution was extracted with ethyl acetate, the organic layer was separated and dried, and the solvent removed in vacuo to yield 5-Fluoro-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline (Compound 41), m.p. 154-155° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].[Br:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=S)=[CH:14][CH:13]=1.C(N(CC)CC)C>C(#N)C>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[O:10][C:9]3[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=3[N:1]=2)=[CH:14][CH:13]=1
Reactant: S=C=Nc1ccc(Br)cc1
Reactant: N#Cc1ccc(O)c(N)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1ccc2oc(Nc3ccc(Br)cc3)nc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.5 %

Procedure:
To a mixture of 3-amino-4-hydroxybenzonitrile (1.84 g, 0.0137 mol) in acetonitrile (140 mL) was added 4-bromophenyl isothiocyanate (2.93 g, 0.0137 mol) at room temperature. The mixture was stirred for 16 hours at room temperature. Cuprous chloride (1.36 g, 0.0137 mol) and triethylamine (1.9 mL, 0.0137 mol) were added to the reaction mixture. The mixture was stirred for 16 hours at room temperature. The solvent was removed under reduced pressure, and the solid was suspended in methanol. The mixture was filtered through celite pad using methanol. The brownish filtrate was left at 4° for three days. The precipitate was filtered and washed with methanol to yield 2-(4-bromoanilino)-1,3-benzoxazole-5-carbonitrile (2.4 g, 0.0076 mol). RP-HPLC (Delta Pak C18, 5 μm, 300 A, 15 cm; 5%-95% acetonitrile-0.1M ammonium acetate over 10 min, 1 mL/min) Rt 11.1 min. MS: MH: 313
Reaction SMILES: [C@@H:1]1([N:9]2[CH:16]=[N:15][C:13]([NH2:14])=[N:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.[BH4-].[Na+].O>C(O)C>[C@@H:1]1([N:9]2[CH2:16][NH:15][C:13]([NH2:14])=[N:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1
Reactant: Nc1ncn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC1=NC(=O)N([C@H]2C[C@H](O)[C@@H](CO)O2)CN1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.9 %

Procedure:
Method A (Reduction of 2). To a suspension of 2′-deoxy-5-azacytidine (2) (0.045 g, 0.2 mmol) in 96% ethanol (2.9 mL) was added NaBH4 (40 mg, 1.06 mmol), and the mixture was stirred for 10 min at RT. Water (4 mL) was added to the mixture giving a clear solution that was directly used for RP HPLC purification using a gradient of MeCN in 0.1 M triethylammonium bicarbonate buffer. The main fraction after evaporation provided 0.04 g of 9 as a solid. MS ES+231 [M+H+].
Reaction SMILES: [N:1]([O-])=O.[Na+].[ClH:5].[CH2:6]([O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O.Cl>[ClH:5].[C:7]1([CH2:6][O:13][C:14]2[CH:15]=[CH:16][C:17]([NH:18][NH2:1])=[CH:19][CH:20]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(OCc2ccccc2)cc1
Reaction time: 1 h

Procedure:
A solution of sodium nitrite (16.1 g) in water was added dropwise over a period of ca 0.75 h to a cold (salt-ice bath) stirred suspension of 4-benzyloxyaniline hydrochloride (50 g) in concentrated hydrochloric acid (120 ml). The temperature was kept between -6° and -12° during the addition and stirring was continued for 1 h at the same temperature. The mixture was filtered (Hyflo) and the filtrate cooled to ca -18°. The solution of the diazonium salt was then added to a cold (-12°) stirred solution of tin (II) chloride dihydrate (157.9 g) in concentrated hydrochloric acid (400 ml) over a period of ca 0.5 h. During the addition the temperature gradually rose to 0°, and subsequently stirring was continued for 2 h while allowing the reaction mixture to reach room temperature. Filtration of the suspension afforded a solid. This material was washed with anhydrous ether (750 ml) and dried at room temperature for ca 16 h to present the title compound as a powder (34.4 g) m.p. 165°-170°. T.l.c. (E), Rf 0.5.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](Br)[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[Cl:25])[CH:10]=2)=[O:5])[CH3:2].[C:27]([Cu])#[N:28].N#N.Cl>C(Cl)Cl.CN1C(=O)CCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:27]#[N:28])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[Cl:25])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2cc(Oc3ccc(F)cc3Cl)ccc2c1O
Reactant: N#C[Cu]
Agent: Cl
Agent: N#N
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1nc(C#N)c2cc(Oc3ccc(F)cc3Cl)ccc2c1O
Temperature: 130 °C
Reaction time: 3 h
Yield: 77.9 %

Procedure:
A 20-mL scintillation vial was charged with 1-bromo-4-hydroxy-7-(4-fluoro-2-chloro-phenoxy)-isoquinoline-3-carboxylic acid ethyl ester (340 mg, 0.77 mmol), CuCN (138 mg, 1.54 mmol) and NMP (1.8 mL). It was filled with N2 gas and close-capped. The mixture was stirred in a 130° C. oil bath for 3 h. Reaction mixture was diluted with CH2Cl2 (100 mL) and stirred at room temperature for 3 days. To the mixture was added 100 mL of 0.5 N HCl aq. solution. It was stirred vigorously for 3 min. Two phases were separated. Organic layer was washed with brine, dried over MgSO4, filtered and concentrated. Crude product was purified by silica gel chromatography, eluting with 5-50% EtOAc/hexanes to provide the title compound 231 mg (0.60 mmol) in 78% yield. 1H NMR (200 MHz) in CDCl3, δ ppm: 12.42 (s, 1H), 8.45 (d, J=8.8 Hz, 1H), 7.54 (dd, J=9.2, 2.6 Hz, 1H), 7.40-7.10 (m, 4H), 4.58 (q, J=7.0 Hz, 2H), 1.51 (t, J=7.0 Hz, 3H).
Reaction SMILES: Br[C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH2:13][CH3:14])[CH:5]=1)=[CH2:3].[Li]C(C)(C)C.[CH:20]([CH:22]=[CH2:23])=[O:21]>>[CH2:13]([O:12][C:6]1[CH:5]=[C:4]([C:2]([CH:20]([OH:21])[CH:22]=[CH2:23])=[CH2:3])[CH:9]=[CH:8][C:7]=1[O:10][CH3:11])[CH3:14]
Reactant: C=CC=O
Reactant: C=C(Br)c1ccc(OC)c(OCC)c1
Agent: [Li]C(C)(C)C
Product: C=CC(O)C(=C)c1ccc(OC)c(OCC)c1
Yield: 86.2 %

Procedure:
According to the General Procedure C, 1-bromo-1-(3-ethoxy-4-methoxyphenyl)ethene (1.40 g, 5.44 mmol), t-BuLi (8.00 ml, 13.60 mmol) and acrolein (914 mg, 16.32 mmol) are converted to give after workup and chromatography [SiO2, PE/EE gradient from 5:1 to 2:1, Rf(PE/EE=2:1)=0.31] the title compound (1.10 g, 4.69 mmol) as a colorless oil;
Reaction SMILES: CS(O)(=O)=O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2(O)[CH2:18][CH2:17][CH2:16][N:15]3[N:19]=[C:20](/[CH:22]=[CH:23]/[C:24]4[CH:29]=[CH:28][C:27]([N:30]5[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]5)=[C:26]([O:36][CH3:37])[CH:25]=4)[N:21]=[C:14]23)=[CH:9][CH:8]=1.[N-:39]=[N+:40]=[N-:41].[Na+].O.C(=O)(O)[O-].[Na+]>C(O)(C(F)(F)F)=O.C(OCC)(=O)C>[N:39]([C:13]1([C:10]2[CH:11]=[CH:12][C:7]([F:6])=[CH:8][CH:9]=2)[CH2:18][CH2:17][CH2:16][N:15]2[N:19]=[C:20](/[CH:22]=[CH:23]/[C:24]3[CH:29]=[CH:28][C:27]([N:30]4[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]4)=[C:26]([O:36][CH3:37])[CH:25]=3)[N:21]=[C:14]12)=[N+:40]=[N-:41]
Reactant: COc1cc(/C=C/c2nc3n(n2)CCCC3(O)c2ccc(F)cc2)ccc1-n1cnc(C)c1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: COc1cc(/C=C/c2nc3n(n2)CCCC3(N=[N+]=[N-])c2ccc(F)cc2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methanesulfonic acid (0.3 mL) was added to a solution of 8-(4-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-ol synthesized by the method in Examples 70 and 71 (45 mg) and sodium azide (66 mg) in TFA (1 mL), and the reaction solution was stirred at room temperature for 16 hours. The reaction solution was diluted with ethyl acetate. The solution was added to saturated sodium bicarbonate water, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane:ethyl acetate=1:1->ethyl acetate) to obtain 28 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.C(N(CC)CC)C.[CH:19]1(B(O)O)[CH2:21][CH2:20]1>C(Cl)Cl.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[CH:10]=[CH:9][N:8]([CH:19]3[CH2:21][CH2:20]3)[C:6]=2[N:7]=1
Reactant: OB(O)C1CC1
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Clc1nc(Cl)c2ccn(C3CC3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.4 %

Procedure:
A mixture of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (210 mg, 1.12 mmol) in methylene chloride (4.86 mL) was treated with triethylamine (314 μL, 2.26 mmol), copper(II) acetate monohydrate (232 mg, 1.16 mmol) and cyclopropylboronic acid (95.9 mg, 1.12 mmol). The reaction was stirred at room temperature overnight. At this time, the reaction was warmed to 70° C. for 3 h. At this time, the reaction was treated with additional triethylamine (314 μL, 2.26 mmol), copper(II) acetate monohydrate (232 mg, 1.16 mmol) and cyclopropylboronic acid (95.9 mg, 1.12 mmol). The reaction was allowed to stir overnight at room temperature. At this time, the reaction was filtered through a plug of Celite®, washing with a 10% methanol/methylene chloride solution. The filtrate was concentrated in vacuo onto silica gel. Flash chromatography (24 g silica gel column, 2-20% ethyl acetate/hexanes) afforded 2,4-dichloro-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine as an off-white solid (70 mg, 27.5%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.82-1.28 (m, 4H) 3.62 (s, 1H) 6.66 (d, J=3.58 Hz, 1H) 7.73 (d, J=3.39 Hz, 1H). LC-MS calcd. for C9H8Cl2N3 [(M+H)+] 228, obsd. 227.9.