Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(CC)CC.[O:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]2[C:16]([NH2:21])=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:9]1.[C:22]([O:26][C:27]([NH:29][C@@H:30]([CH3:34])[C:31](O)=[O:32])=[O:28])([CH3:25])([CH3:24])[CH3:23].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:22]([O:26][C:27](=[O:28])[NH:29][C@H:30]([C:31](=[O:32])[NH:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[NH:14][CH:10]1[CH2:11][CH2:12][CH2:13][O:8][CH2:9]1)[CH3:34])([CH3:23])([CH3:24])[CH3:25]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccccc1NC1CCCOC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccccc1NC1CCCOC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83.3 %

Procedure:
Et3N (1.6 mL, 11.3 mmol) was added to a stirred mixture of N-(tetrahydropyran-3-yl)benzene-1,2-diamine (0.61 g, 3.17 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (0.78 g, 4.14 mmol), HOAt (0.56 g, 4.14 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.79 g, 4.14 mmol) in anhydrous DCM (20 mL) at 0° C. under a nitrogen atmosphere. Stirring was continued for 10 min at 0° C. then the mixture was slowly warmed to RT and stirred at RT for 3 h. The reaction mixture was partitioned between DCM and a saturated solution of NaHCO3. The aqueous phase was further extracted with DCM (×2) and the combined organic layers were washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-4% 2M NH3/MeOH in DCM) affording {(S)-1-[2-(Tetrahydropyran-3-ylamino)phenylcarbamoyl]ethyl}carbamic acid tertbutyl ester as a white solid (0.96 g, 70%). LCMS: RT 3.00 min [M+H]+ 364.1.
Reaction SMILES: [CH2:1]([O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[CH2:12])[CH2:2]C=C>ClCCCl>[O:5]1[CH:6]2[C:7]([CH2:8][CH2:9][CH2:10][CH2:11]2)=[CH:12][CH2:2][CH2:1]1
Reactant: C=CCCOC1CCCCC1=C
Solvent: ClCCCl
Product: C1=C2CCCCC2OCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(but-3-en-1-yloxy)-2-methylidenecyclohexane (5.21 g, 31.3 mmol) in DCE (313 mL) was degassed 3×N2/pump. Zhan-1b (1.15 g, 1.57 mmol) was then added and the reaction was degassed again. The reaction was stirred at rt for 2 hr. The reaction mixture was concentrated and the residue was purified by column chromatography to give the title compound. 1H NMR (500 MHz, CDCl3) δ 5.48 (d, 1H, J=2.7 Hz), 3.90-3.96 (m, 2H), 3.50-3.60 (m, 1H), 2.18-2.34 (m, 2H), 2.02-2.08 (m, 1H), 1.84-1.99 (m, 2H), 1.76-1.83 (m, 1H), 1.66-1.74 (m, 1H), 1.15-1.43 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12](/[CH:13]=[CH:14]/[C:15](OC)=[O:16])[C:11]([CH:19]([CH3:21])[CH3:20])=[N:10][C:9]=2[C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12](/[CH:13]=[CH:14]/[CH2:15][OH:16])[C:11]([CH:19]([CH3:21])[CH3:20])=[N:10][C:9]=2[C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)/C=C/n1c(C(C)C)nc(-c2cccnc2)c1-c1ccc(F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: CC(C)c1nc(-c2cccnc2)c(-c2ccc(F)cc2)n1/C=C/CO
Reaction time: 1 h

Procedure:
Methyl (E)-3-[5-(4-fluorophenyl)-2-(1-methylethyl)-4-(3-pyridinyl)-1H-imidazol-1-yl]-2-propenoate, 1'-oxide (0.18 g) in dichloromethane (3 ml) at 3° under nitrogen was treated with diisobutylaluminium hydride (1.5M in toluene; 0.94 ml). The mixture was stirred at 0° for 1 h and then quenched with water (1 ml) and extracted with ethyl acetate. The extracts were washed with brine, dried and evaporated. The residue was purified by CC eluting with a mixture of ethyl acetate, petroleum ether (bp. 40°-60°) and methanol (10:10:3) to give the title compound (0.05 g), δ(CDCl3) 8.60(m,1H,C-2 proton of pyridine), 8.48(m,1H,C-6 proton of pyridine), 7.81(m,1H, C-3 proton of pyridine), 6.63(d,1H,J15 Hz,NCH=CH), 5.56(dd,1H, J15 and 6 Hz,NCH=CH), 4.18(m,2H,CH2OH), 3.17(septet,1H,J7 Hz, CH(CH3)2), 1.42(d,6H,J7 Hz,CH(CH3)2).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Cl[C:12]1[C:13](=[O:26])[NH:14][C:15]2[C:20]([N:21]=1)=[CH:19][C:18]([C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:16]=2>CN1C(=O)CCC1>[O:26]=[C:13]1[C:12]([N:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)=[N:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=2)[NH:14]1
Reactant: c1ccc2c(c1)CCCN2
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc2[nH]c(=O)c(N3CCCc4ccccc43)nc2c1
Reaction time: 3 h
Yield: 74.3 %

Procedure:
To a solution of 1,2,3,4-tetrahydroquinoline (1.0 g, 7.51 mmol) in NMP (20 ml) was added methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (670 mg, 2.81 mmol) with stifling 3 h at 130° C. in an oil bath. The product was precipitated with water (80 ml), collected by filtration to afford methyl 2-oxo-3-(1,2,3,4-tetrahydroquinolin-1-yl)-1,2-dihydroquinoxaline-6-carboxylate as a yellow solid (700 mg, 28%).
Reaction SMILES: [NH3:1].[CH3:2][C:3]1[CH:17]=[CH:16][C:6]([S:7][C:8]2[CH:15]=[CH:14][C:11]([CH2:12]Br)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.O>CO>[CH3:2][C:3]1[CH:17]=[CH:16][C:6]([S:7][C:8]2[CH:15]=[CH:14][C:11]([CH2:12][NH2:1])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: N
Reactant: Cc1ccc(Sc2ccc(CBr)cc2)cc1
Solvent: O
Solvent: CO
Product: Cc1ccc(Sc2ccc(CN)cc2)cc1
Reaction time: 96 h
Yield: 53 %

Procedure:
To a stirred mixture of 28% aq NH3 (40 ml) and methanol (200 ml) was added dropwise a solution (20 ml) of 4-(4-methylthiophenoxy)benzylbromide (5.00 g, 16.2 mM) in methanol at room temperature, and the mixture was stirred for 4 days at the same temperature. To the mixture was added water (100 ml), and the mixture was concentrated in vacuo. The residue was diluted with chloroform, and the mixture was washed with water and brine, dried with sodium sulfate, and concentrated in vacuo. The residue was chromatographed over alumina to give 4-(4-methylthiophenoxy)benzylamine (2.11 g, 53%) as colorless crystals, m.p. 61.8° C.
Reaction SMILES: O=[C:2]([CH3:19])[CH2:3][N:4]1[CH2:9][CH2:8][C:7]2[C:10]3[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=3[O:12][C:13](=[O:14])[C:6]=2[CH2:5]1.[CH2:20]([NH2:22])[CH3:21].S([O-])([O-])(=O)=O.[Ca+2].C(O)(=O)C>O1CCCC1>[CH2:20]([NH:22][CH:2]([CH3:19])[CH2:3][N:4]1[CH2:9][CH2:8][C:7]2[C:10]3[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=3[O:12][C:13](=[O:14])[C:6]=2[CH2:5]1)[CH3:21]
Reactant: CCN
Reactant: CC(=O)CN1CCc2c(c(=O)oc3ccccc23)C1
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCNC(C)CN1CCc2c(c(=O)oc3ccccc23)C1
Temperature: 40 °C
Yield: 51.6 %

Procedure:
A mixture of 1,2,3,4-tetrahydro-3-(2-oxopropyl)-5H-[1]benzopyrano[3,4-c]pyridin-5-one (18.2 g, 0.071 moles), ethylamine (10 ml, 0.153 moles), anhydrous calcium sulfate (15 g), and glacial acetic acid (1 ml) in tetrahydrofuran (450 ml) is shaken at 40° C. in a pressure vessel. After 18 hours the mixture is cooled and filtered. The filtrate is hydrogenated at 25° C. and 50 psi in the presence of 10% platinum or carbon until hydrogen uptake ceases. The catalyst is removed by filtration, and the filtrate is evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate gave the product (10.5 g), mp 104°-105° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([OH:17])[CH2:14][S:15][CH3:16])[CH2:9]1)=O)(C)(C)C.[H-].[Na+].[Cl:20][C:21]1[CH:22]=[CH:23][C:24](F)=[C:25]([CH3:27])[CH:26]=1.CCO>CN(C=O)C.Cl>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([O:17][C@H:13]([C@H:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)[CH2:14][S:15][CH3:16])=[C:25]([CH3:27])[CH:26]=1
Reactant: CSC[C@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: Cc1cc(Cl)ccc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CSC[C@H](Oc1ccc(Cl)cc1C)[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(S)-3-((R)-1-Hydroxy-2-methylsulfanylethyl)pyrrolidine-1-carboxylic acid t-butyl ester (20 mg, 80 μmol) was dissolved in DMF (367 μL). NaH (3.7 mg, 153 μmol) was added and the mixture was stirred at room temperature for 15 minutes. 5-Chloro-2-fluorotoluene (33.2 mg mg, 230 tμmol) was added and the mixture was stirred at 100° C. for 1 hour. The mixture was cooled to room temperature, concentrated then dissolved in 1.2M HCl in EtOH (2.2 mL, 2.7 mmol) and stirred overnight at room temperature. The product was concentrated and purified by preparative HPLC to yield the title compound as a mono-TFA salt (0.6 mg, purity 85%). MS m/z: [M+H]+ calcd for C14H20ClNOS, 286.10. found 286.0.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([CH2:16][CH3:17])[N:14]=[CH:15][C:3]=12.[CH:18]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19]1.C(N(CC)CC)C>C(O)C>[CH:18]1([NH:23][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]3[N:13]([CH2:16][CH3:17])[N:14]=[CH:15][C:3]=23)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1Cl
Reactant: NC1CCCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc2c(cnn2CC)c1NC1CCCC1
Temperature: 80 °C
Yield: 121.7 %

Procedure:
Intermediate 1 (0.051 g) and cyclopentyl amine (0.019 g) were suspended in ethanol (2 ml) and triethylamine (0.14 ml) was added. The mixture was stirred under nitrogen and heated at 80° C. for 16 h. After cooling to room temperature, ethanol was removed by evaporation under a stream of nitrogen and the residue partitioned between DCM and water. The organic layer was loaded directly onto an SPE cartridge (silica, 5 g) and eluted sequentially with; (i) DCM, (ii) DCM:Et2O (2:1), (iii) DCM:Et2O (1:1), (iv) Et2O, (v) EtOAc and (vi) MeOH. Fractions containing desired material were combined and concentrated in vacuo to afford Intermediate 2 (0.074 g). LCMS showed MH+303; TRET=3.45 min
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:27]=[CH:26][C:11]2[C:12]3[C:13](=[CH:23][NH:24][CH:25]=3)[CH2:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:10]=2[CH:9]=1.Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>CN(C)C=O.O>[CH2:33]([O:32][C:30](=[O:31])[CH2:29][N:24]1[CH:25]=[C:12]2[C:13]([CH2:14][N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:10]3[CH:9]=[C:8]([Cl:7])[CH:27]=[CH:26][C:11]=32)=[CH:23]1)[CH3:34]
Reactant: CCOC(=O)CBr
Reactant: Clc1ccc2c(c1)C(c1ccccc1)=NCc1c[nH]cc1-2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cc2c(c1)-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reaction time: 0.17 h

Procedure:
To a solution of 1.4 g (12.4 mmole) of potassium t-butoxide in 30 ml of dry dimethylformamide was added 2.4 g (8.2 mmole) of 8-chloro-6-phenyl-2H,4H-pyrrolo[3,4-d][2]benzazepine. The mixture was cooled to 0°, and stirred for 10 min. To the mixture was added 1.3 mol (11.7 mmole) of ethyl bromoacetate. The mixture was stirred at 0° for 45 min, diluted with water, and extracted with ether. The ether solution was washed with water, dried with sodium sulfate, and concentrated at reduced pressure to give a yellow oil. Purification by column chromatography (70 g SiO2, 9:1 methylene chloride/ether) gave as the first major component a yellow oil.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].C1(C)C=CC=CC=1.[OH:12][C:13]1[CH:38]=[CH:37][C:16]([NH:17][C:18]2[CH:34]=[C:33]([F:35])[C:32]([F:36])=[CH:31][C:19]=2[C:20]([NH:22][O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:21])=[CH:15][CH:14]=1>O1CCOCC1>[OH:12][C:13]1[CH:38]=[CH:37][C:16]([N:17]2[C:18]3[C:19](=[CH:31][C:32]([F:36])=[C:33]([F:35])[CH:34]=3)[C:20](=[O:21])[N:22]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:1]2=[O:2])=[CH:15][CH:14]=1
Reactant: O=C(Cl)Cl
Reactant: O=C(NOCc1ccccc1)c1cc(F)c(F)cc1Nc1ccc(O)cc1
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: O=c1c2cc(F)c(F)cc2n(-c2ccc(O)cc2)c(=O)n1OCc1ccccc1
Temperature: 25 °C

Procedure:
A 2N solution of phosgene in toluene (2.5 mL, 5 mmol) was added to a solution of crude 2-(4-hydroxyanilino)-N-benzyloxy-4,5-difluoro-benzamide (Example I-1, 0.35 g, 0.95 mmol) in 20 mL of dioxane. The solution was heated at reflux for 2 hours, cooled down to room temperature and poured into ice water, and extracted with ethyl acetate (3×30 mL). Combined extracts were washed with water, brine, and dried over sodium sulfate to give 0.065 g of the title product as a solid.
Reaction SMILES: C(NC(C)C)(C)C.[Li].[CH3:9][C:10]1[CH:11]=[C:12]([NH:21][C:22]2[N:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][N:23]=2)[CH:13]=[C:14]([C:16]2[S:20][CH:19]=[N:18][CH:17]=2)[CH:15]=1.[Li+].CC([N-]C(C)C)C.[CH3:40][C:41]([S:44]([N:46]=[C:47]1[CH2:50][O:49][CH2:48]1)=[O:45])([CH3:43])[CH3:42]>C1COCC1>[CH3:43][C:41]([S:44]([NH:46][C:47]1([C:19]2[S:20][C:16]([C:14]3[CH:13]=[C:12]([NH:21][C:22]4[N:27]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:25]=[CH:24][N:23]=4)[CH:11]=[C:10]([CH3:9])[CH:15]=3)=[CH:17][N:18]=2)[CH2:50][O:49][CH2:48]1)=[O:45])([CH3:40])[CH3:42]
Reactant: CC(C)(C)S(=O)N=C1COC1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncs2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(NS(=O)C(C)(C)C)COC3)s2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
A solution of lithium diisopropylamine (1.8 M, 4.96 mL, 8.92 mmol) in THF (8 mL) was placed under an Argon atmosphere and was cooled to −78° C. A solution of N-[3-methyl-5-(1,3-thiazol-5-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (Intermediate 4, 1200 mg, 3.57 mmol) in THF (8 mL) was cooled to −78° C. and added drop wise to the LDA solution. The reaction mixture was stirred 30 minutes at −78° C. The product of Step 1 (625 mg, 3.57 mmol) in THF (8 mL) was added drop wise and the reaction was allowed to warm to room temperature overnight. The mixture was quenched with brine, diluted with ethyl acetate. The organics were washed with saturated NaHCO3, followed by brine, dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography on silica (20-100% ethyl acetate in hexanes) to afford 2-methyl-N-{3-[5-(3-methyl-5-[[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]oxetan-3-yl]propane-2-sulfinamide (1.10 g, 2.140 mmol, 60.0% yield). MS ESI: [M+H]+ m/z 512.1.
Reaction SMILES: [S:1]1[C:5]2[C:6]([C:10](Cl)=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[CH3:13][Si:14]([CH3:19])([CH3:18])[CH2:15][CH2:16][OH:17].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:13][Si:14]([CH3:19])([CH3:18])[CH2:15][CH2:16][O:17][C:10]([C:6]1[C:5]2[S:1][N:2]=[N:3][C:4]=2[CH:9]=[CH:8][CH:7]=1)=[O:11]
Reactant: O=C(Cl)c1cccc2nnsc12
Reactant: C[Si](C)(C)CCO
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)CCOC(=O)c1cccc2nnsc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.99 g (0.01 mol) of 7-benzothiadiazolecarboxylic acid chloride in 18 ml of toluene are added dropwise over a period of 25 minutes to a solution of 1.9 ml (0.013 mol) of 2-trimethylsilylethanol, 2.4 ml (0.017 mol) of triethylamine and 18 ml of toluene. The reaction mixture is then stirred for 16 hours at room temperature and afterwards poured onto ice/water and extracted twice with ethyl acetate. The extracts are combined, washed with water, dried over magnesium sulfate, filtered and concentrated and the same amount of hexane is added and the batch is filtered through silica gel. Concentration gives 2.0 g (71% of the theoretical yield) of product; m.p. 37°-39° C.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH2:8]O)=[CH:3][CH:2]=1.C(Br)(Br)(Br)[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:17][CH2:8][CH2:7][C:4]1[CH:5]=[CH:6][C:1]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:2][CH:3]=1
Reactant: OCCc1ccc(-c2ccccc2)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCc1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
4-Biphenylethanol (see Kawasaki et al., Tetrahedron: Asymmetry 2001, 12, 585-596) (1.47 g, 7.41 mmol) and CBr4 (1.12 equiv) were dissolved in CH2Cl2 (25 mL), the mixture was cooled to 0° C. and triphenylphosphine (1.1 equiv) was added in small portions. The reaction mixture was warmed at room temperature and stirred for 1 h before the solvent was removed in vacuo. Flash chromatography (0-5% EtOAc-hexanes) yielded 4-(2-bromoethyl)biphenyl (1.59 g, 82%). The title compound was prepared from S7 (55 mg, 0.27 mmol) and 4-(2-bromoethyl)biphenyl (280 mg, 1.07 mmol) by using general procedure D. Flash chromatography (SiO2, 1.5×18 cm, 50-100% EtOAc-hexanes) afforded the title compound (38 mg, 40%) as a white solid: 1H NMR (CDCl3, 500 MHz) δ 8.84 (dd, 1H, J=0.7, 4.7 Hz), 8.29 (d, 1H, J=7.9 Hz), 7.92 (dt, 1H, J=1.7, 7.8 Hz), 7.57 (m, 2H), 7.53 (m, 3H), 7.42 (t, 2H, J=7.7 Hz), 7.33 (m, 3H), 3.60 (t, 2H, J=7.5 Hz), 3.19 (t, 2H, J=7.5 Hz); 13C NMR (CDCl3, 150 MHz) δ 186.2, 165.3, 161.3, 150.9, 142.7, 141.0, 139.6, 139.0, 137.5, 129.0, 128.9, 127.5, 127.3, 127.2, 126.9, 124.2, 41.7, 29.1; HRMS-ESI-TOF m/z 356.1392 ([M+H]+, C22H17N3O2 requires 356.1393).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]2[NH:6][C:7]3[S:8][CH:9]=[CH:10][C:11]=3[C:12]([N:14]3[CH2:19][CH2:18][NH:17][C@@H:16]([CH2:20][CH2:21][CH2:22][O:23][CH3:24])[CH2:15]3)=[N:13][C:4]=2[CH:3]=1.C=O.[C:29](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]2[NH:6][C:7]3[S:8][CH:9]=[CH:10][C:11]=3[C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH3:29])[C@@H:16]([CH2:20][CH2:21][CH2:22][O:23][CH3:24])[CH2:15]3)=[N:13][C:4]=2[CH:3]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COCCC[C@H]1CN(C2=Nc3cc(Cl)ccc3Nc3sccc32)CCN1
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: COCCC[C@H]1CN(C2=Nc3cc(Cl)ccc3Nc3sccc32)CCN1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 76.5 %

Procedure:
Combine (S)-7-chloro-10-[3-(3-methoxy-propyl)-piperazin-1-yl]-4H-3-thia-4,9-diaza-benzo[f]azulene (280.3 mg, 0.72 mmol), formaldehyde (64.0 μL, 0.79 mmol, 37% in water), and dichloromethane (10.0 ml). Stir the mixture at ambient temperature for 5 minutes and then add sodium triacetoxyborohydride (227.9 mg, 1.08 mmol). After stirring for 30 minutes at ambient temperature, quench the reaction with saturated sodium bicarbonate. Remove the organic portion and wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using a gradient of dichloromethane to dichloromethane/methanol (90:10) to give 223.0 mg (77%) of the title compound: mass spectrum (ion spray): m/z=405.1 (M+1).
Reaction SMILES: C[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=[CH:20][CH:19]=3)=[C:10]3[CH2:15][CH2:14][CH:13]([CH2:16][OH:17])[N:11]3[N:12]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.C(OCC)(=O)C>[N:7]1[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=1[C:8]1[C:9]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][CH:19]=2)=[C:10]2[CH2:15][CH2:14][CH:13]([CH2:16][O:17][S:29]([CH3:28])(=[O:31])=[O:30])[N:11]2[N:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cccc(-c2nn3c(c2-c2ccnc4ccccc24)CCC3CO)n1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CS(=O)(=O)OCC1CCc2c(-c3ccnc4ccccc34)c(-c3ccccn3)nn21
Reaction time: 0.5 h

Procedure:
A solution of [2-(6-methyl-pyridin-2-yl)-3-quinolin-4-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-6-yl]-methanol (30 mg, 0.07 mmol) and 4-dimethylaminopyridine (catalytic) in pyridine (0.2 mL) is cooled to 0° C. and treated with methanesulfonyl chloride (8 mL, 0.105 mmol) and stirred for 30 min. The mixture is stirred at room temperature for 30 min, diluted with ethyl acetate (20 mL), washed with water and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to yield the title compound, 30 mg (86%,) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.ClC1C=CC=C(C(OO)=[O:27])C=1.Cl>CC(C)=O>[NH2:1][C:2]1[C:7]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:27]
Reactant: Nc1ncccc1NC(=O)OCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cl
Solvent: CC(C)=O
Product: Nc1c(NC(=O)OCc2ccccc2)ccc[n+]1[O-]
Temperature: 25 °C

Procedure:
To a solution of benzyl (2-aminopyridin-3-yl)carbamate in acetone was added a solution of m-chloro perbenzoic acid in acetone and the suspension was stirred at room temperature. After 2 hours the suspension was cooled to 0° C., HCl (2N in Et2O) was added, and the precipitate filtered. To the precipitate was added saturated aqueous NaHCO3, EtOAc and MeOH and the mixture stirred until dissolution. The solution was evaporated and the residue washed with water until the pH of the filtrate was neutral. The solid was dried under vacuum.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[O:13]([CH:20]1[CH2:23][NH:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>O1CCCC1>[Cl:12][C:9]1[CH:10]=[N:11][C:2]([N:22]2[CH2:21][CH:20]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:23]2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: c1ccc(OC2CNC2)cc1
Reactant: COC(=O)c1cc(Cl)cnc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1cc(Cl)cnc1N1CC(Oc2ccccc2)C1
Temperature: 25 °C
Yield: 74.7 %

Procedure:
To a solution of methyl 2,5-dichloronicotinate (217 mg, 1.05 mmol) in tetrahydrofuran (5 ml), 3-phenoxyazetidine (D48) (149 mg, 1.05 mmol) and triethylamine (117 mg, 1.16 mmol) were added and the mixture was heated at reflux for 18 hours. The resulting mixture was cooled to room temperature, the precipitates were filtered off and the filtrate was concentrated under vacuo. The residue was dissolved in ethyl acetate (5 ml), washed with water (5 ml) and brine (5 ml), dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash chromatography on silica gel eluting with a mixture petroleum ether/ethyl acetate from 30:1 to 20:1. Collected fractions after solvent evaporation afforded the title compound (D75) (250 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:15]=[CH:16]/[C:17]([NH:19][CH2:20][C:21](=O)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=O)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.C([O-])(=O)C.[NH4+:33]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:15]=[CH:16]/[C:17]2[NH:19][CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:33]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1cc(/C=C/C(=O)NCC(=O)c2ccccc2)ccc1-n1cnc(C)c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: COc1cc(/C=C/c2nc(-c3ccccc3)c[nH]2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 35.8 %

Procedure:
A solution of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-(2-oxo-2-phenylethyl)acrylic acid amide (100 mg) and ammonium acetate (410 mg) in acetic acid (5 mL) was heated under reflux for 10 hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. Ethyl acetate and saturated sodium bicarbonate water were added to the residue, 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→ethyl acetate:methanol=5:1) to obtain 34 mg of the title compound. The property values of the compound are as follows.