Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8](I)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:12].[C:13]([O:17][C:18]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]1B(O)O)=[O:19])([CH3:16])([CH3:15])[CH3:14].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:21]2[N:20]([C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[C:28]3[C:23]([CH:22]=2)=[CH:24][CH:25]=[CH:26][CH:27]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:12]
Reactant: O=C1NCc2c(Cl)ccc(I)c21
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2ccccc21
Yield: 43.7 %

Procedure:
In a similar manner to Step 2 of Example 1, 4-chloro-7-iodoisoindolinone (100 mg, 0.341 mmol) was dissolved in acetonitrile (7 mL), and the solution was treated with 1-(tert-butoxycarbonyl)indol-2-boronic acid (178 mg, 0.682 mmol), palladium acetate (6.1 mg, 0.027 mmol), tri(o-tolyl)phosphine (17 mg, 0.055 mmol) and triethylamine (0.475-mL, 3.41 mmol), followed by purification by preparative thin-layer chromatography (chloroform/methanol=30/1) to obtain 4-chloro-7-(1-(tert-butoxycarbonyl)indol-2-yl)isoindolinone (57 mg, yield 44%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12](=O)[C:13]([O:15]C)=O)=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[CH3:18][N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:26]=2)[C:21]([CH2:34][C:35]([NH2:37])=[O:36])=[CH:20]1>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[C:13](=[O:15])[NH:37][C:35](=[O:36])[C:34]=3[C:21]3[C:22]4[C:27](=[CH:26][C:25]([N:28]5[CH2:29][CH2:30][O:31][CH2:32][CH2:33]5)=[CH:24][CH:23]=4)[N:19]([CH3:18])[CH:20]=3)=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1cc(CC(N)=O)c2ccc(N3CCOCC3)cc21
Reactant: COC(=O)C(=O)c1cn(C)c2cc(Br)ccc12
Product: Cn1cc(C2=C(c3cn(C)c4cc(N5CCOCC5)ccc34)C(=O)NC2=O)c2ccc(Br)cc21
Yield: 48.7 %

Procedure:
3-(6-Bromo-1-methyl-1H-indol-3-yl)-4-(1-methyl-6-morpholin-4-yl-1H-indol-3-yl)pyrrole-2,5-dione (139 mg, 49%) was prepared from methyl (6-bromo-1-methyl-1H-indol-3-yl)glyoxylate (190 mg, 0.64 mmol) and (1-methyl-6-morpholin-4-yl-1H-indol-3-yl)acetamide (150 mg, 0.55 mmol).
Reaction SMILES: [C:1]1([C:11]2[C:15]([C:16](O)=[O:17])=[C:14]([CH3:19])[O:13][N:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl:20][C:21]1[C:27]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:26][C:24]([NH2:25])=[C:23]([N+:34]([O-:36])=[O:35])[CH:22]=1.C(Cl)CCl.CN(C=O)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[NH2:25][C:24]1[C:23]([N+:34]([O-:36])=[O:35])=[CH:22][C:21]([Cl:20])=[C:27]([N:28]2[CH2:33][CH2:32][N:31]([C:16]([C:15]3[C:11]([C:1]4[C:10]5[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=5)[CH:4]=[CH:3][CH:2]=4)=[N:12][O:13][C:14]=3[CH3:19])=[O:17])[CH2:30][CH2:29]2)[CH:26]=1
Reactant: Cc1onc(-c2cccc3ccccc23)c1C(=O)O
Reactant: Nc1cc(N2CCNCC2)c(Cl)cc1[N+](=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1onc(-c2cccc3ccccc23)c1C(=O)N1CCN(c2cc(N)c([N+](=O)[O-])cc2Cl)CC1

Procedure:
A mixture of 3-(1-naphthyl)-5-methylisoxazole-4-carboxylic acid (394 mg, 1.558 mmol), 4-chloro-2-nitro-5-(piperazin-1-yl)aniline (400 mg, 1.558 mmol, prepared as described in [El-Abadelah, M. M.; Nazer, M. Z.; El-Abadla, N. S.; Awadallah, A. M. Asian Journal of Chemistry 1999, 11(4), 1463-1468.]), EDC (448 mg, 2.337 mmol), and DMAP (571 mg, 4.67 mmol) in DCM (5 mL)/DMF (3 mL) was stirred overnight.
Reaction SMILES: CC[CH2:3][CH2:4][CH2:5][CH3:6].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[OH:15])=[CH:10][CH:9]=1.[CH3:30]COCC>CS(C)=O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]([O:15][CH2:3][CH:4]=[C:5]([CH3:6])[CH3:30])([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[CH:12][CH:13]=1
Reactant: CCCCCC
Reactant: OC(c1ccc(Cl)cc1)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: CCOCC
Solvent: CS(C)=O
Product: CC(C)=CCOC(c1ccc(Cl)cc1)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
Dry DMSO (20 mL) was added to 14 mmol of hexane-washed KH under Ar with stirring at RT. After H2 evolution ceased, a solution of tris-(p-chlorophenyl) methanol (3.63 g, 10 mmol) in 25 mL dry DMSO was added, giving a deep red anion solution. After 5 min,1-bromo-3-methyl-2-butene (2.0 mL, 19 mmol) was added and stirring continued for 1 h. The crude product was isolated by Et2O extraction and purified by flash chromatography (75 g SiO2, 5% EtOAc-hexanes) giving 3.93 g (91%) of (3-methyl-2-butenyl) tris-(4-chlorophenyl)methyl ether as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:4][C@@H:3]1[C:5](O)=[O:6].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.Cl.Cl.[CH3:37][O:38][C:39](=[O:87])[NH:40][C@H:41]([C:45]([N:47]1[CH2:51][CH2:50][CH2:49][C@H:48]1[C:52]1[NH:53][CH:54]=[C:55]([C:57]2[CH:62]=[CH:61][C:60]([C:63]3[CH:68]=[CH:67][C:66]([NH:69][C:70]([C:72]4[CH:73]=[N:74][C:75]([N:78]5[CH2:83][C@H:82]([CH3:84])[NH:81][CH2:80][C@H:79]5[CH3:85])=[CH:76][CH:77]=4)=[O:71])=[C:65]([CH3:86])[N:64]=3)=[CH:59][CH:58]=2)[N:56]=1)=[O:46])[CH:42]([CH3:44])[CH3:43].C(N(CC)C(C)C)(C)C>CC(N(C)C)=O>[CH3:37][O:38][C:39](=[O:87])[NH:40][C@H:41]([C:45]([N:47]1[CH2:51][CH2:50][CH2:49][C@H:48]1[C:52]1[NH:53][CH:54]=[C:55]([C:57]2[CH:62]=[CH:61][C:60]([C:63]3[CH:68]=[CH:67][C:66]([NH:69][C:70]([C:72]4[CH:73]=[N:74][C:75]([N:78]5[CH2:83][C@H:82]([CH3:84])[N:81]([C:5]([C@H:3]6[CH2:4][C:2]6([CH3:8])[CH3:1])=[O:6])[CH2:80][C@H:79]5[CH3:85])=[CH:76][CH:77]=4)=[O:71])=[C:65]([CH3:86])[N:64]=3)=[CH:59][CH:58]=2)[N:56]=1)=[O:46])[CH:42]([CH3:44])[CH3:43]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(NC(=O)c4ccc(N5C[C@H](C)NC[C@H]5C)nc4)c(C)n3)cc2)c[nH]1)C(C)C
Reactant: CC1(C)C[C@@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(NC(=O)c4ccc(N5C[C@H](C)N(C(=O)[C@H]6CC6(C)C)C[C@H]5C)nc4)c(C)n3)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
A mixture of (s)-(+)-2,2-dimethylcyclopropane carboxylic acid (2.13 mg, 0.019 mmol), and HATU (8.52 mg, 0.022 mmol) was stirred in DMA (1 mL) for 10 min and then [(S)-1-((S)-2-{4-[4-(5-{[6-((2R,5S)-2,5-dimethyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-6-methyl-pyridin-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester 4 HCl (15 mg, 0.018 mmol; Preparation 59) and N,N-diisopropylethylamine (16.3 μL, 0.093 mmol) were added. The reaction mixture was stirred at RT overnight, concentrated by rotary evaporation, dissolved in 1:1 acetic acid:water (1.5 mL) and purified by reverse phase HPLC to provide the tri-TFA salt of the title compound (11 mg). m/z): [M+H]+ calcd for C44H55N9O5 790.43 found 790.4.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3I)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:19][CH:20]([CH3:23])[C:21]#[CH:22]>C(NCC)C.C(Cl)CCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:22]#[C:21][CH:20]([CH3:23])[CH3:19])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C#CC(C)C
Reactant: CN1Cc2c(I)ncn2-c2cccc(Cl)c2C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCCl
Solvent: CCNCC
Product: CC(C)C#Cc1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2

Procedure:
3.73 g (10 mmol) of 7-chloro-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was heated to 100° in a pressure tube for 20 hours with 0.87 g of 3-methyl-1-butyne, 70 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 19 mg of copper(I) iodide in 20 ml of diethylamine and 10 ml of ethylene chloride. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate there was obtained a mixture of product and starting material of about 2:1. In order to remove the starting material, the mixture was heated under reflux the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate there was obtained a mixture of product and starting material of about 2:1. In order to remove the starting material, the mixture was heated under reflux for 5 hours with 0.8 ml of 2-methyl-3-butyn-2-ol, 70 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 15 mg of copper(I) iodide in 15 ml of diethylamine. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate the byproduct can be separated from the desired product. After recrystallization from ether there was obtained 7-chloro-4,5-dihydro-5-methyl-3-(3-methyl-1-butynyl)-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 128°-130°.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH3:8].[OH:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[C:12](=[O:29])[N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[C:14]2=[O:19].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:13]2[C:12](=[O:29])[C:11]3[C:15](=[CH:16][CH:17]=[CH:18][C:10]=3[O:9][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH3:8])[C:14]2=[O:19])=[CH:22][CH:23]=1
Reactant: COCCOCCBr
Reactant: COc1ccc(CN2C(=O)c3cccc(O)c3C2=O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOCCOc1cccc2c1C(=O)N(Cc1ccc(OC)cc1)C2=O
Temperature: 60 °C
Reaction time: 3.5 h
Yield: 72.9 %

Procedure:
1-(2-Bromo-ethoxy)-2-methoxy-ethane (107 mg, 0.58 mmol) was added to a suspension of 4-hydroxy-2-(4-methoxy-benzyl)-isoindole-1,3-dione (150 mg, 0.53 mmol) and potassium carbonate (200 mg, 1.4 mmol) in DMF (2 mL). After 3.5 hours, a catalytic amount of potassium iodide was added. After a further 17 hours, the mixture was warmed to 60° C. After 3 hours, an additional amount of 1-(2-bromo-ethoxy)-2-methoxy-ethane (20 mg, 0.11 mmol) was added and the mixture maintained at 60° C. for a further 20 hours. The mixture was concentrated in vacuo then the residue was taken up in ethyl acetate and washed with potassium carbonate solution and brine. The organic phase was dried (MgSO4) and concentrated to give the title compound as a yellow oil (149 mg, 73%). 1H NMR (methanol-d4) 7.71 (1H, t), 7.43-7.40 (2H, m), 7.31-7.27 (2H, m), 6.87-6.83 (2H, m), 4.71 (2H, s), 4.37-4.34 (2H, m), 3.92-3.89 (2H, m), 3.77-3.74 (5H, m), 3.55-3.53 (2H, m), 3.33 (3H, s). MS: [M+H]+ 386.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH:11]=O)[N:10]=2)[CH:7]=1.[CH:13]1([C:18]2([CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([CH2:35][C:36]([F:39])([F:38])[F:37])[CH:29]=3)[O:23][C:22](=[O:24])[CH2:21][C:20](=[O:25])[CH2:19]2)[CH2:17][CH2:16][CH2:15][CH2:14]1>CO>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH2:11][C:21]3[C:22](=[O:24])[O:23][C:18]([CH:13]4[CH2:14][CH2:15][CH2:16][CH2:17]4)([CH2:26][CH2:27][C:28]4[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([CH2:35][C:36]([F:38])([F:39])[F:37])[CH:29]=4)[CH2:19][C:20]=3[OH:25])[N:10]=2)[CH:7]=1
Reactant: O=Cc1nc2ncc(Cl)cn2n1
Reactant: O=C1CC(=O)OC(CCc2ccc(O)c(CC(F)(F)F)c2)(C2CCCC2)C1
Solvent: CO
Product: O=C1OC(CCc2ccc(O)c(CC(F)(F)F)c2)(C2CCCC2)CC(O)=C1Cc1nc2ncc(Cl)cn2n1
Reaction time: 0.25 h
Yield: 5.1 %

Procedure:
6-chloro-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (0.131 g, 0.72 mmol) was added to a solution of example A(228) 6-cyclopentyl-6-{2-[4-hydroxy-3-(2,2,2-trifluoroethyl)phenyl]ethyl}dihydro-2H-pyran-2,4(3H)-dione (0.230 g, 0.60 mmol) in MeOH (10 mL). The reaction mixture was stirred for 15 mins and then treated with borane-dimethylamine complex (53 mg, 0.9 mmoL). After 15 hours the reaction mixture was quenched with concentrated HCl, and concentrated to a residual oil. Purification by flash column chromatography (EtOAc then 0%-5% MeOH in CH2Cl2) gave the product as a white solid (17 mg). 1H NMR (DMSO): δ 1.30-1.80 (brm, 8H), 2.08-2.18 (brm, 3H), 2.74 (s, 2H), 2.99(m, 2H); 3.15 (m, 2H), 3.47 (m, 3H), 6.81 (m, 2H), 7.00(s, 1H), 8.76 (s, 1H), 8.82 (s, 1H). Anal. Calcd. For C26H26O4N4ClF3: C, 56.68; H, 4.75; N, 10.17. Found: C, 56.50; H, 4.69; N, 10.20.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](/[CH:9]=[CH:10]\[C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=2)[CH:6]=[C:5]([O:23][CH3:24])[C:4]=1[OH:25].C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([CH:45]2[NH:54][C:53](=[O:55])[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[NH:46]2)=[CH:41][C:40]=1[O:56][CH3:57]>CN(C=O)C.C(OCC)(=O)C.CCCCCC>[CH3:24][O:23][C:5]1[CH:6]=[C:7](/[CH:9]=[CH:10]\[C:11]2[CH:12]=[C:13]([O:21][CH3:22])[C:14]([O:19][CH3:20])=[C:15]([O:17][CH3:18])[CH:16]=2)[CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[O:25][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([CH:45]2[NH:54][C:53](=[O:55])[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[NH:46]2)=[CH:41][C:40]=1[O:56][CH3:57]
Reactant: COc1cc(C2NC(=O)c3ccccc3N2)ccc1OCCCCCBr
Reactant: COc1cc(/C=C\c2cc(OC)c(OC)c(OC)c2)cc(OC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C2NC(=O)c3ccccc3N2)ccc1OCCCCCOc1c(OC)cc(/C=C\c2cc(OC)c(OC)c(OC)c2)cc1OC
Temperature: 30 °C
Reaction time: 30 h
Yield: 79.7 %

Procedure:
(Z)-2,6-dimethoxy-4-(3,4,5-trimethoxystyryl)phenol (38b) (346.37.36 mg 1.0 mmol) in DMF (20 mL) was added anhydrous potassium carbonate (690 mg, 5.0 mmol) and 2-[4-(5-Bromo-pentyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one (2d) (419.29 mg, 1.0 mmol). The reaction mixture was stirred at a temperature of 30° C. for 30 h and the reaction was monitored by TLC using ethyl acetate-hexane (6:4) as a solvent system. Then to this ice is added and extracted with ethyl acetate. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate:hexane (6:4) as a solvent system to obtain the pure product (43d) (546 mg, 80% yield).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]3[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=3)=[CH:33][CH:32]=2)[C:19](=[O:29])[C:20]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)=[C:21]([CH3:23])[N:22]=1)[CH2:14][CH2:15][CH3:16]>O>[CH2:13]([C:17]1[N:18]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[C:43]3[NH:3][C:4](=[O:7])[O:5][N:44]=3)=[CH:35][CH:36]=2)[C:19](=[O:29])[C:20]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)=[C:21]([CH3:23])[N:22]=1)[CH2:14][CH2:15][CH3:16]
Reactant: O=C([O-])O
Reactant: CCCCc1nc(C)c(-c2cccs2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCc1nc(C)c(-c2cccs2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
A mixture of hydroxylammonium chloride (0.54 g), sodium hydrogen carbonate (0.76 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[2-butyl-4-methyl-6-oxo-5-(2-thienyl)pyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.38 g) was added, and the mixture was stirred at 90° C. for 16 hr. The mixture was allowed to cool to room temperature. Water was added to the reaction mixture, and the precipitate was collected by filtration. The obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (5 mL), N,N′-carbonyldiimidazole (0.21 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.19 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.38 g, 78%).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:10].[CH3:11][O:12][C:13](=[O:17])[C:14]#[C:15][CH3:16].N12CCCN=C1CCCCC2>O1CCCC1>[CH3:11][O:12][C:13](=[O:17])/[CH:14]=[C:15](/[O:10][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[F:1])\[CH3:16]
Reactant: CC#CC(=O)OC
Reactant: COc1cccc(O)c1F
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)/C=C(\C)Oc1cccc(OC)c1F
Yield: 67.4 %

Procedure:
To a stirred mixture of 2-fluoro-3-methoxy-phenol (3.88 g, 0.027 mol) and methyl-2-butynoate (5.97 g, 0.061 mol) in tetrahydrofuran (30 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (4.64 g, 0.030 mol) slowly. After addition was complete the mixture was stirred at reflux overnight. Upon completion of the reaction the tetrahydrofuran was removed in vacuo and the residue was diluted in diethyl ether and washed first with 1N aqueous hydrochloric acid, then 10% aqueous sodium hydroxide solution, a saturated sodium chloride solution and dried over magnesium sulfate. The mixture was filtered and evaporated and the residue dried under high vacuum which afforded (E)-3-(2-fluoro-3-methoxy-phenoxy)-but-2-enoic acid methyl ester (4.37 g, 63%) as a colorless oil and used without further purification.
Reaction SMILES: Cl.NO.C([N:7](CC)C(C)C)(C)C.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]([NH:26][C:27]([NH:29]C(OCC)=O)=S)=[N:22][CH:23]=[CH:24][CH:25]=2)=[CH:16][CH:15]=1>CO.CCO>[F:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:21]3[N:22]([N:7]=[C:27]([NH2:29])[N:26]=3)[CH:23]=[CH:24][CH:25]=2)=[CH:18][CH:19]=1
Reactant: CCOC(=O)NC(=S)Nc1ncccc1-c1ccc(F)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: CO
Product: Nc1nc2c(-c3ccc(F)cc3)cccn2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of hydroxylamine hydrochloride (370 mg, 5.32 mmol) and N,N-diisopropylethylamine (543 μL, 3.19 mmol) in MeOH (2 mL) and EtOH (2 mL) was added a solution of N-(3-(4-fluoro-phenyl)-pyridin-2-yl)-N′-ethoxycarbonyl-thiourea (340 mg, 1.06 mmol) in MeOH (2 mL) and EtOH (2 mL). The reaction mixture was stirred at room temperature for 1 hour and then at 60° C. for 3 hours. The solvents were evaporated and saturated aqueous NaHCO3 solution was added to the residue. The aqueous phase was extracted with CH2Cl2, the combined organic phases were dried over sodium sulfate, the solvent was evaporated and the residue purified by silica gel chromatography using dichloromethane/methanol (with 10% ammonia) as eluent. The title compound was obtained as a white solid (205 mg, 84%).
Reaction SMILES: [OH:1][C:2]1[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][C:4](=[O:13])[CH:3]=1.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]=O.[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([CH2:31][CH2:32][NH:33][C:34](=[O:36])[CH3:35])=[CH:23]1>>[OH:1][C:2]1[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][C:4](=[O:13])[C:3]=1[CH:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=1)[C:23]1[NH:22][C:30]2[C:25]([C:24]=1[CH2:31][CH2:32][NH:33][C:34](=[O:36])[CH3:35])=[CH:26][CH:27]=[CH:28][CH:29]=2
Reactant: O=C1C=C(O)C(c2ccccc2)C1
Reactant: CC(=O)NCCc1c[nH]c2ccccc12
Reactant: O=Cc1ccccn1
Product: CC(=O)NCCc1c(C(C2=C(O)C(c3ccccc3)CC2=O)c2ccccn2)[nH]c2ccccc12

Procedure:
Using general procedure C, 3-hydroxy-4-phenyl-cyclopent-2-enone (Lit. 17) was reacted with pyridine-2-carbaldehyde and N-[2-(1H-indol-3-yl)-ethyl]-acetamide to give the title compound as a white solid. MS: 466.3 ([M+H]+).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[Cl:6][C:7]1[CH:8]=[C:9]2[C:23](=[CH:24][C:25]=1[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH3:34])=[CH:29][CH:28]=1)[C@:12]1([C@H:17]([OH:18])[C@@H:16]([OH:19])[C@H:15]([OH:20])[C@@H:14]([CH2:21][OH:22])[O:13]1)[CH2:11][CH2:10]2.Cl>C(Cl)Cl.N1C(C)=CC(C)=CC=1C>[C:2](=[O:3])([O:4][CH3:5])[O:22][CH2:21][C@H:14]1[O:13][C@@:12]2([C:23]3[C:9](=[CH:8][C:7]([Cl:6])=[C:25]([CH2:26][C:27]4[CH:28]=[CH:29][C:30]([CH2:33][CH3:34])=[CH:31][CH:32]=4)[CH:24]=3)[CH2:10][CH2:11]2)[C@H:17]([OH:18])[C@@H:16]([OH:19])[C@@H:15]1[OH:20]
Reactant: COC(=O)Cl
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)CC[C@]32O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Agent: Cl
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClCCl
Product: CCc1ccc(Cc2cc3c(cc2Cl)CC[C@]32O[C@H](COC(=O)OC)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: -40 °C
Reaction time: 1.5 h

Procedure:
A solution of methyl chloroformate (114 mg, 1.20 mmol) in CH2Cl2 (0.5 mL) was added dropwise to a solution of (1S,3′R,4′S,5′S,6′R)-5-chloro-6-(4-ethylbenzyl)-6′-(hydroxymethyl)-2,3,3′,4′,5′,6′-hexahydrospiro[indene-1,2′-pyran]-3′,4′,5′-triol (compound AV) (418 mg, 1.00 mmol) in 2,4,6-collidine (5 mL) at −40° C. The whole was stirred at −40° C. for 1 h and at room temperature for 1.5 h. The reaction mixture was poured into ice-cooled 10% HCl and extracted with AcOEt. The organic layer was washed with saturated NaHCO3 and brine, dried over MgSO4, and evaporated. The residue was chromatographed on silica gel to give the acylated product BH (420 mg, 87%). 1H NMR (CD3OD, 300 MHz) δ 7.25 (s, 1H), 7.23 (s, 1H), 7.09 (m, 4H), 4.05 (s, 2H), 3.80 (m, 1H), 3.65 (s, 3H), 3.62-3.34 (m, 5H), 2.91 (dd, J=6.6, 7.8 Hz, 2H), 2.60 (q, J=7.8 Hz, 2H), 2.55 (dt, J=7.5, 13.2 Hz, 1H), 2.10 (dt, J=7.5, 13.2 Hz, 1H), 1.20 (t, J=7.8 Hz, 3H); MS ESI m/e 477 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([N:12]2[CH2:17][CH2:16][N:15]3[C:18]4[CH:24]=[C:23]([S:25]([CH3:28])(=[O:27])=[O:26])[C:22]([C:29]([O:31][CH3:32])=[O:30])=[CH:21][C:19]=4[N:20]=[C:14]3[C@H:13]2[CH:33]([CH3:35])[CH3:34])[N:3]=1.[C:36]([O-])(O)=[O:37].[Na+]>CO>[CH:33]([C@H:13]1[N:12]([C:4]2[N:3]=[C:2]([O:37][CH3:36])[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)[CH2:17][CH2:16][N:15]2[C:18]3[CH:24]=[C:23]([S:25]([CH3:28])(=[O:27])=[O:26])[C:22]([C:29]([O:31][CH3:32])=[O:30])=[CH:21][C:19]=3[N:20]=[C:14]12)([CH3:35])[CH3:34]
Reactant: O=C([O-])O
Reactant: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN(c1ncc(C(F)(F)F)c(Cl)n1)[C@@H]3C(C)C
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN(c1ncc(C(F)(F)F)c(OC)n1)[C@@H]3C(C)C
Temperature: 60 °C
Reaction time: 20 h
Yield: 88 %

Procedure:
To a solution of (R)-methyl 2-(4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (15 mg, 0.028 mmol) in methanol (4 mL) was added NaHCO3 (25 mg, 0.29 mmol). The mixture was stirred at 60° C. for 20 h. The mixture was concentrated under vacuum. Water (5 mL) and EtOAc (5 mL) were added to the mixture. The aqueous phase was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative TLC to afford (R)-methyl 1-isopropyl-2-(4-methoxy-5-(trifluoromethyl)pyrimidin-2-yl)-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (13.0 mg, 87.2% yield) as a white solid.