Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[N:6]=[C:5]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:3]=1[C:4]=23.CCN(CC)CC.[Cl:32][CH2:33][C:34](Cl)=[O:35]>C(Cl)(Cl)Cl>[Cl:32][CH2:33][C:34]([NH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[N:6]=[C:5]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:3]=1[C:4]=23)=[O:35]
Reactant: O=C(Cl)CCl
Reactant: CCN(CC)CCn1nc2c3c(c(N)ccc31)Sc1ccccc1-2
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCN(CC)CCn1nc2c3c(c(NC(=O)CCl)ccc31)Sc1ccccc1-2
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.7 %

Procedure:
A mixture of 10.2 g (0.030 mol) of 5-amino-N,N-diethyl-2H[1]benzothiopyrano[4,3,2-cd]indazole-2-ethanamine and 8.3 ml (0.060 mol) of Et3N in 90 ml of CHCl3 was treated dropwise with a solution of 3.6 ml (0.045 mol) of chloroacetyl chloride in 20 ml of CHCl3 over ten minutes. The reaction mixture was stirred at room temperature for three hours, treated with an additional 1.2 ml (0.015 mol) of chloroacetyl chloride in 50 ml of CHCl3, and concentrated to dryness in vacuo. The residue was triturated three times with cold MeOH to give 8.3 g of product, mp 204°-205° C. dec.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:16]3[CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[CH2:28]=O>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[C:16]3[CH2:21][N:20]([CH3:28])[CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2]
Reactant: C=O
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CNC3)cc1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CN(C)C3)cc1

Procedure:
Method as described for example 26 using 1-ethyl-3-(4-(4-morpholino-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (example 14) and formaldehyde as starting materials.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:12]2[S:13][CH:14]=[C:15]([CH3:16])[C:11]=2[C:10](=[O:17])[N:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[C:8]1=[O:27])=[O:5])[CH3:2].S(Cl)([Cl:31])(=O)=O>ClC(Cl)(Cl)Cl.CCCCCC>[CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:12]2[S:13][C:14]([Cl:31])=[C:15]([CH3:16])[C:11]=2[C:10](=[O:17])[N:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[C:8]1=[O:27])=[O:5])[CH3:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)Cn1c(=O)n(Cc2ccc(Cl)c(Cl)c2)c(=O)c2c(C)csc21
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCC
Product: CCOC(=O)Cn1c(=O)n(Cc2ccc(Cl)c(Cl)c2)c(=O)c2c(C)c(Cl)sc21
Yield: 65 %

Procedure:
A 0.427 g quantity of 1-ethoxycarbonylmethyl-3-(3,4-dichlorobenzyl)-5-methylthieno[2,3-d]pyrimidin-2,4(1H,3H)-dione (compound IV-5) synthesized in Reference Example 6 and 0.162 g of sulfuryl chloride were dissolved in 30 ml of anhydrous tetrachloromethane, and the mixture was allowed to react at 50° to 70° C. for 6 hours. The residue obtained by concentration of the reaction mixture was subjected to silica gel column chromatography using a 2:1 mixture of chroloform and n-hexane as an eluent to afford 0.30 g of 1-ethoxycarbonylmethyl-3-(3,4-dichlorobenzyl)-6-chloro-5-methylthieno[2,3-d]pyrimidin-2,4(1H,3H)-dione having m.p. of 141° to 145° C. in a yield of 65%.
Reaction SMILES: [NH2:1][C:2]1([CH2:15][OH:16])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.C(NC(C)C)(C)C.Cl[C:25](Cl)([O:27]C(=O)OC(Cl)(Cl)Cl)Cl.[NH4+].[OH-]>C1(C)C=CC=CC=1.O>[CH2:8]([N:5]1[CH2:6][CH2:7][C:2]2([NH:1][C:25](=[O:27])[O:16][CH2:15]2)[CH2:3][CH2:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NC1(CO)CCN(Cc2ccccc2)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: Cc1ccccc1
Product: O=C1NC2(CCN(Cc3ccccc3)CC2)CO1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a 1 L 4-neck round bottom flask was added (4-amino-1-benzylpiperidin-4-yl)methanol (21.86 g, 99 mmol) and diisopropyl amine (23.0 g, 249 mmol) in dry toluene (300 ml). The reaction mixture was cooled to 0° C. and a solution of triphosgene (35.57 g, 119 mmol) in toluene (100 ml) was added. The reaction mixture was heated to 60° C. for 1.5 h. After cooling to room temperature, the reaction mixture was diluted with water (200 ml), basified with aqueous NH4OH, and extracted with ethyl acetate (3×200 ml). The organic layers were combined and washed with two 200 ml portions of water and 200 ml of brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The solid was stirred in hexanes for 1.5 hours and filtered again to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13](=[O:20])[C:7]=3[C:8](=O)[NH:9]2)=[CH:4][CH:3]=1.O(Cl)[Cl:22]>>[Cl:22][C:8]1[C:7]2[C:13](=[O:20])[C:14]3[C:19]([C:6]=2[C:5]2[C:10](=[CH:11][C:2]([CH3:1])=[CH:3][CH:4]=2)[N:9]=1)=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: ClOCl
Reactant: Cc1ccc2c3c(c(=O)[nH]c2c1)C(=O)c1ccccc1-3
Product: Cc1ccc2c3c(c(Cl)nc2c1)C(=O)c1ccccc1-3
Yield: 73.4 %

Procedure:
A mixture of 3-methyl-5H-indeno[2,1-c]quinoline-6,7-dion obtained in reference example 5 (700 mg, 2.7 mmol) and phophorous oxychloride (10 ml, 107 mmol) was refluxed with heat for 1.5 hours. The reaction mixture was distilled to dryness. To the residue was added water to obtain a crystal precipitated by filtration. The crystal obtained was washed with water and dissolved in chloroform to filter off undissolved substances. Recrystallization from benzene to give 550 mg (yield 73.4%) of the title compound. m.p.: 208-211° C. 1H-NMR(CDCl3) δ: 8.38(1H, d, J=9 Hz), 8.13(1H, d, J=7 Hz), 7.85(1H, s), 7.80(1H, d, J=6 Hz), 7.64(1H, d-d-d, J=8,8,1 Hz), 7.56-7.50(2H, m), 2.60(3H, s). IR(KBr)cm-1 : 1718, 1623, 1557, 1494, 1460, 1413, 1064, 915, 867, 755, 715.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([CH2:9]Br)=[CH:5][CH:6]=[CH:7][CH:8]=1.[CH3:11][CH:12]1[CH2:16][CH2:15][CH:14]([CH3:17])[C:13]1=[O:18].N1CCCC1.O>C(#N)C>[CH3:11][C:12]12[C:13](=[O:18])[C:14]([CH3:17])([CH2:15][CH2:16]1)[CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2]2
Reactant: BrCc1ccccc1CBr
Reactant: CC1CCC(C)C1=O
Solvent: CC#N
Solvent: C1CCNC1
Solvent: O
Product: CC12CCC(C)(Cc3ccccc3C1)C2=O

Procedure:
α,α'-Dibromoxylene (30.3 g., 0.115 Mole) is dissolved in dry acetonitrile (250 ml.) and then, under nitrogen, the pyrrolidine enamine of 2,5-dimethylcyclopentanone (prepared from 2,5-dimethylcyclopentanone and pyrrolidine via the method of Stork) is added dropwise over one-half hour. The mixture is refluxed 2 days, cooled, water (100 ml.) is added; and the mixture is refluxed 1 hour, cooled, concentrated in vacuo, then extracted with ether (3×75 ml.). The combined extracts are washed with 10% HCl (50 ml.), brine (50 ml.), then dried and evaporated to yield 16 g. of solid, which recrystallized from dichloroethane-hexane gives pure title compound (9.7 g.). The mother liquors are chromatographed on silica gel (100 g.), eluting with ether-hexane (1:4) to give 5.8 g. more title compound, which yields 4.9 g. pure on crystallization from ether-hexane (64% total yield), m.p. 134°-135° C.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][C:16]3[NH:17][CH:18]=[CH:19][C:20](=[O:22])[N:21]=3)=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:25]([F:28])([F:27])[F:26].[CH2:29]=O.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][NH:15][C:16]3[NH:17][CH:18]=[C:19]([CH2:29][N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)[C:20](=[O:22])[N:21]=3)=[CH:11][CH:12]=2)=[CH:4][C:3]=1[C:25]([F:26])([F:28])[F:27]
Reactant: C1CCNC1
Reactant: C=O
Reactant: O=c1cc[nH]c(NCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)n1
Product: O=c1nc(NCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)[nH]cc1CN1CCCC1
Yield: 79.5 %

Procedure:
2-{2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]-ethylamino}-1H-pyrimidin-4-one (0.122 mmol, 1 eq), paraformaldehyde (3.66 mg, 0.112 mmol, 1 eq) and pyrrolidine (10 μl, 0.112 mmol, 1 eq) were refluxed for 90 mins. Solvent was evaporated in vacuo to give 2-{2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]-ethylamino}-5-pyrrolidin-1-ylmethyl-1H-pyrimidin-4-one (0.089 mmol, yield: 73%, UPLC-MS/UV:[M+H]+=493.39; rt: 0.98 min; purity: 85%). 1H NMR (300 MHz; CDCl3) δ/ppm 1.88-1.91 (m, 4H), 2.68-2.76 (m, 4H), 2.90 (t, J=7.51, 2H), 3.60 (s, 2H), 3.61-3.68 (m, 2H), 6.89-6.96 (m, 2H), 7.02 (dd, J=8.93 J=3.12, 1H), 7.21-7.23 (m, 1H), 7.30 (d, J=2.97, 1H), 7.40 (d, J=9.07, 1H), 7.74 (s, 1H)
Reaction SMILES: [C:1]1(C(O[Si](C)(C)C)=C)[CH:6]=CC=C[CH:2]=1.[C:14](Cl)(=[O:19])[CH2:15][C:16](Cl)=[O:17].CC[O:23]CC>>[OH:19][C:14]1[CH:2]=[C:1]([CH3:6])[O:17][C:16](=[O:23])[CH:15]=1
Reactant: C=C(O[Si](C)(C)C)c1ccccc1
Reactant: O=C(Cl)CC(=O)Cl
Reactant: CCOCC
Product: Cc1cc(O)cc(=O)o1
Temperature: 25 °C
Reaction time: 14 h
Yield: 67 %

Procedure:
A solution of 1-phenyl-1-trimethylsiloxyethylene (25.0 g, 130 mmol) in absolute ether (400 mL) was cooled to −78° C., and malonyl dichloride (6.40 mL, 65.0 mmol) was added dropwise to the resulting solution by using a dropping funnel. The mixture was gradually heated to room temperature, stirred at room temperature (5 to 10° C.) for 14 hours, and further stirred at 30° C. for 24 hours. The thus-produced yellow precipitate was filtered and washed with absolute ether to give the target 4-hydroxy-6-methyl-2-pyrone (8.40 g, 67%) as a yellow solid.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]=[C:12](B(O)O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:19]1[CH:20]=[C:21]([C:26]2[N:31]=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:29]=[C:28]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:27]=2)[CH:22]=[C:23](Br)[CH:24]=1.C([O-])([O-])=O.[K+].[K+].[N:50]1[CH:55]=[CH:54][CH:53]=[C:52](B(O)O)[CH:51]=1>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(O)C.C1(C)C=CC=CC=1>[C:32]1([C:30]2[N:29]=[C:28]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:27]=[C:26]([C:21]3[CH:22]=[C:23]([C:13]4[C:14]5[C:5]([C:6]6[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=6[CH:12]=4)=[CH:4][CH:3]=[CH:2][CH:1]=5)[CH:24]=[C:19]([C:52]4[CH:51]=[N:50][CH:55]=[CH:54][CH:53]=4)[CH:20]=3)[N:31]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: OB(O)c1cccnc1
Reactant: Brc1cc(Br)cc(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)c1
Reactant: OB(O)c1cc2ccccc2c2ccccc12
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: c1ccc(-c2nc(-c3ccccc3)nc(-c3cc(-c4cccnc4)cc(-c4cc5ccccc5c5ccccc45)c3)n2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 48 %

Procedure:
In a stream of argon, 0.71 g (3.21 mmol) of 9-phenanthreneboronic acid, 1.50 g (3.21 mmol) of 2-(3,5-dibromophenyl)-4,6-diphenyl-1,3,5-triazine and 37.0 mg (0.0321 mmol) of tetrakis(triphenylphosphine)palladium were suspended in a mixed solvent composed of 120 mL of toluene and 15 mL of ethanol, and the resultant suspension was heated to 60° C. To the suspension, 9.63 mL (9.63 mmol) of an aqueous 1M K2CO3 solution was gradually added dropwise, and the mixture was stirred for 6 hours. Then the mixture was cooled to room temperature, and 0.59 g (4.82 mmol) of 3-pyridineboronic acid and 9.63 mL (9.63 mmol) of an aqueous 1M K2CO3 solution were added. Then the mixture was heated to 60° C. and maintained at that temperature for 18 hours while being stirred. Then the reaction mixture was cooled to room temperature, and was then distilled under a reduced pressure to remove all volatile materials. Methanol was added to the concentrate, and the thus-deposited solid was collected by filtration. The obtained crude product was purified by silica gel chromatography using a hexane/chloroform (1:2) mixed solvent as an eluent to give 0.87 g of the target 4,6-diphenyl-2-[5-(9-phenanthryl)-3-(3-pyridyl)phenyl]-1,3,5-triazine as a white solid (yield: 48%).
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[C:15]#[N:16]>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:11][C:12]1[CH:19]=[CH:18][CH:17]=[C:14]([C:15]#[N:16])[CH:13]=1
Reactant: N#Cc1cccc(N)c1
Reactant: Clc1nc2ccccc2[nH]1
Product: N#Cc1cccc(Nc2nc3ccccc3[nH]2)c1

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 3-aminobenzonitrile by Procedure A. The product was isolated by filtration and preparative LCMS to give the title compound as the free base (white solid, mp 272-274° C.). MS(ES+) m/z 235 ([M+1]+, 100).
Reaction SMILES: [CH:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:16][C:17]1[C:26]([O:27][CH:28]([C:36]([O:38][CH3:39])=[O:37])[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[CH:20][C:21]([CH2:40][NH3+:41])=[CH:22]2.[Cl-].C(N(CC)CC)C>C(Cl)Cl>[CH3:39][O:38][C:36](=[O:37])[CH:28]([O:27][C:26]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH2:40][NH:41][C:11](=[O:12])[C:10]3[CH:14]=[CH:15][C:7]([CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:8][CH:9]=3)[CH:22]=2)[C:17]=1[Br:16])[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(Cl)c1ccc(C2CCCCC2)cc1
Reactant: COC(=O)C(Cc1ccccc1)Oc1ccc2cc(C[NH3+])ccc2c1Br
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(Cc1ccccc1)Oc1ccc2cc(CNC(=O)c3ccc(C4CCCCC4)cc3)ccc2c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
4-Cyclohexyl-benzoyl chloride (0.67 mmol) was added under nitrogen to a suspension of 5-bromo-6-(1-methoxycarbonyl-2-phenyl-ethoxy)-naphthalen-2-ylmethyl-ammonium; chloride (0.30 g, 0.67 mmol), prepared in step 3 of Example 53, in 20 mL of methylene chloride at room temperature. Triethylamine (0.186 mL, 1.33 mmol) was then added to the mixture. After the addition the reaction was stirred at room temperature for 18 h (overnight). The reaction was diluted with methylene chloride, extracted one time with 1N HCl and two times with 5% NaHCO3. The organic layer was separated, dried (MgSO4) and the solvent removed under reduced pressure to give 2-{1-bromo-6-[(4-cyclohexyl-benzoylamino)-methyl]-naphthalen-2-yloxyl}-3-phenyl-propionic acid methyl ester (0.3362 g, 84%) as an off-white solid, mp 160-161° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[C:12]([OH:15])[CH:13]=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2].[CH:16]([N:19]1[CH2:24][CH2:23][CH:22](O)[CH2:21][CH2:20]1)([CH3:18])[CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[C:12]([O:15][CH:22]3[CH2:23][CH2:24][N:19]([CH:16]([CH3:18])[CH3:17])[CH2:20][CH2:21]3)[CH:13]=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2ccc(O)cc2s1
Reactant: CC(C)N1CCC(O)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2ccc(OC3CCN(C(C)C)CC3)cc2s1

Procedure:
To 6-hydroxy-benzo[b]thiophene-2-carboxylic acid ethyl ester (0.300 g, 1.35 mmol, prepared as described above, but using ethyl instead of methyl thioglycolate), dissolved in 13.5 mL of THF, was added successively at 10° C. 1-isopropyl-piperidin-4-ol (0.387 g, 2 eq.), triphenylphosphine (0.708 g, 2 eq.) and DIAD (0.530 mL, 2 eq.), and the mixture then kept at this temperature for another 2 h. Pouring onto crashed ice, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of all solvents, followed by flash chromatography (SiO2, MeOH/AcOEt=1/9), delivered 0.360 g of the title compound as off-white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([N:12]=[N+]=[N-])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1.C(OCC)C>[N+:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH2:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C[C@H](N=[N+]=[N-])c1cccc([N+](=O)[O-])c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: O
Product: C[C@H](N)c1cccc([N+](=O)[O-])c1
Temperature: 80 °C
Yield: 61.7 %

Procedure:
To a solution of (S)-1-(3-nitrophenyl)-1-azidoethane (1.55 mmol) in benzene (8 mL) was added water (1.0 mL) and triphenylphosphine (3.18 mmol). The resulting mixture was heated to 80° C. for 19 h. This mixture was cooled, diluted with diethyl ether (50 mL) and washed with 50 mL of 2N aqueous HCl. The aqueous phase was made basic by adding 50 mL of 5N aqueous NaOH then extracted with diethyl ether (3×50 mL). These ether extracts were combined, washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified on silica gel in 3%(2M NH3 in MeOH)/CH2Cl2 to yield 78.4 mg of pure title compound and 159 mg of the title compound that is approximately 80% pure by NMR. 1H NMR (500 MHz, CDCl3): δ 8.23 (m, 1H); 8.06 (m, 1H); 7.70 (d, J=8.1 Hz, 1H); 7.48 (t, J=8.1 Hz, 1H); 4.25 (q, J=6.9 Hz, 1H); 1.40 (d, J=6.9 Hz, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:15][N:16]=[CH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26]C)=[O:25])=[CH:20][CH:19]=2)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].C(O)C.Cl>O.CS(C)=O>[C:1]([C:5]1[CH:6]=[C:7]([NH:15][N:16]=[CH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[CH:20][CH:19]=2)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc(C=NNc2cc(C(C)(C)C)cc(C(C)(C)C)c2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)c1cc(NN=Cc2ccc(C(=O)O)cc2)cc(C(C)(C)C)c1
Temperature: 0 °C
Yield: 56.7 %

Procedure:
2.2g of the ester obtained in Example 5 were refluxed with 3g of potassium hydroxide for 1 hour in 70ml of a 3:3:1 mixture of ethanol, dimethyl sulfoxide and water. The reaction mixture was poured into 140ml of ice water and adjusted to pH 2 with hydrochloric acid, whereupon the precipitate was filtered off in vacuo. After recrystallization from methanol, there were obtained 1.2g of the above compound, m.p. 208°-213° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8]([NH:11][C@@H:12]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13]2)(=[O:10])=[O:9])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:19][C:20]1([CH3:44])[CH2:29][CH2:28][C:27]2[N:26]=[CH:25][N:24]=[C:23]([N:30]3[CH2:36][C:35]4[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][C:34]=4[O:33][CH2:32][CH2:31]3)[C:22]=2[CH2:21]1>>[NH2:1][C:2]1[C:7]([S:8]([NH:11][C@@H:12]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13]2)(=[O:10])=[O:9])=[CH:6][C:5]([C:38]2[CH:39]=[CH:40][C:34]3[O:33][CH2:32][CH2:31][N:30]([C:23]4[C:22]5[CH2:21][C:20]([CH3:19])([CH3:44])[CH2:29][CH2:28][C:27]=5[N:26]=[CH:25][N:24]=4)[CH2:36][C:35]=3[CH:37]=2)=[CH:4][N:3]=1
Reactant: CN1CC[C@@H](NS(=O)(=O)c2cc(Br)cnc2N)C1
Reactant: CC1(C)CCc2ncnc(N3CCOc4ccc(B(O)O)cc4C3)c2C1
Product: CN1CC[C@@H](NS(=O)(=O)c2cc(-c3ccc4c(c3)CN(c3ncnc5c3CC(C)(C)CC5)CCO4)cnc2N)C1

Procedure:
Prepared according to the method of example 5 by using 2-amino-5-bromo-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-3-sulfonamide (reagent preparation 25) and [4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (reagent preparation 23) in step 1. 1H NMR (400 MHz, Methanol-d4): 8.45 (s, 1H), 8.34 (s, 1H), 8.17 (s, 1H), 7.50 (s, 1H), 7.42 (d, 1H), 7.04 (d, 1H), 4.71 (s, 2H), 4.33 (m, 2H), 3.96 (m, 2H), 3.84 (m, 1H), 2.94 (m, 1H), 2.83 to 2.69 (m, 4H), 2.61 (m, 1H), 2.47 (s, 2H), 2.45 (s, 3H), 1.74 to 1.65 (m, 3H), 0.91 (s, 6H); MS (EI) for C29H37N7O3S: 564 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2=O.Cl.[CH2:14]([O:21][NH2:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])(=O)C.[Na+]>C(O)C.O>[CH2:14]([O:21][N:22]=[C:7]1[C:6]2[C:10](=[C:2]([CH3:1])[CH:3]=[CH:4][CH:5]=2)[NH:9][C:8]1=[O:11])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NOCc1ccccc1
Reactant: Cc1cccc2c1NC(=O)C2=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cccc2c1NC(=O)C2=NOCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.6 %

Procedure:
To a suspension of 4.91 g of 7-methylisatin in 100 ml of ethanol was added a solution of 5.59 g of O-benzylhydroxylamine hydrochloride and 3.29 g of sodium acetate in 40 ml of water at room temperature. The mixture was stirred at room temperature for 3 hours and concentrated. The concentrate was diluted with chloroform and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated. Recrystallization of the crude product from benzene yielded 5.40 g (68%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:27]2[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:26])[N:11]([C@H:21]2[CH2:24][C@H:23]([OH:25])[CH2:22]2)[C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17].[N+](=[CH:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[N-]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[C:33]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]2[C:10](=[O:26])[N:11]([C@H:21]3[CH2:22][C@H:23]([O:25][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:24]3)[C:12]3[N:13]([N:18]=[CH:19][N:20]=3)[C:14]=2[CH2:15][CH2:16][CH3:17])=[C:2]([F:1])[CH:3]=1)#[N:34]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2C[C@H](O)C2)c2ncnn12
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2C[C@H](OCC(=O)OCC)C2)c2ncnn12
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
A mixture of 3′-fluoro-4′-{[4-(trans-3-hydroxycyclobutyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.29 g), rhodium(II) acetate (dimer) (0.0028 g) and toluene (3 mL) was heated to 80° C. under an argon atmosphere, a solution of ethyl diazoacetate (0.16 g) in toluene (3 mL) was added dropwise, and the mixture was stirred at 80° C. for 10 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.95 g, 27%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([CH:15]=O)=[C:10]([Cl:17])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C([N:22](C(C)C)CC)(C)C.Cl.NO.ClC(Cl)(Cl)C#N>C1COCC1.O>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]#[N:22])=[C:10]([Cl:17])[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C=O)c(Cl)n1
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Agent: NO
Solvent: C1CCOC1
Solvent: O
Solvent: N#CC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)Nc1cc(Cl)c(C#N)c(Cl)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of compound tert-butyl(4,6-dichloro-5-formylpyridin-2-yl)carbamate (3.0 g, 10.3 mmol) in THF (30.0 mL) was added diisopropylethylamine (2.76 mL, 15.4 mmol) followed by hydroxylamine hydrochloride (0.78 g, 11.3 mmol) at 0° C. and was stirred at room temperature for 3 h. After confirming the completion of starting material by TLC, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to get crude product. To the crude product was added trichloroacetonitrile (30.0 mL) and was heated at 85° C. for 2 h. After confirming the completion of starting material by TLC, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography (hexanes:ethyl acetate=9:1) to afford product. 1H NMR (ppm, 400 MHz, DMSO-d6): δ 11.08 (s, 1H), 8.02 (s, 1H), 1.46 (s, 9H), MS ES calc'd. for C11K11C12N3O2 [M+H]+ 288. Found 288.