Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[H-].[Na+].CN(C)C=O.[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:26])=[O:25])[CH:9]=[CH:10][C:3]=12
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Brc1ccnc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)(c1ccccc1)n1ccc2c(Br)ccnc21
Temperature: 25 °C
Yield: 140.2 %

Procedure:
4-Bromo-1H-pyrrolo[2,3-b]pyridine (2 g, 10.15 mmol) and sodium hydride (0.406 g, 10.15 mmol) were added to N,N-dimethylformamide (30 mL) with stirring and under nitrogen. After 15 minutes the reaction was cooled in an ice bath and benzenesulfonyl chloride (1.295 mL, 10.15 mmol) was added. The reaction mixture was stirred in the ice bath for 30 min and then allowed to warm up to room temperature. Water (30 mL) was added and the precipitate collected by filtration to afford the title compound as an orange solid (4.8 g).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:8]1.Br[C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[CH2:29][N:28]([S:33]([C:36]1[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=1)(=[O:35])=[O:34])[CH2:27][CH2:26]2>>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][N:17]([C:23]2[CH:24]=[C:25]4[C:30](=[CH:31][CH:32]=2)[CH2:29][N:28]([S:33]([C:36]2[CH:37]=[CH:38][C:39]([CH3:42])=[CH:40][CH:41]=2)(=[O:34])=[O:35])[CH2:27][CH2:26]4)[CH2:16][CH2:15]3)[CH2:8]1
Reactant: Cc1ccc(S(=O)(=O)N2CCc3cc(Br)ccc3C2)cc1
Reactant: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCNC3)C1
Product: Cc1ccc(S(=O)(=O)N2CCc3cc(N4CCc5cc(N6CC[C@H](N7CCC[C@@H]7C)C6)ccc5C4)ccc3C2)cc1

Procedure:
The title compound was synthesized in substantially the same way as Example 1 by condensation of 6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-1,2,3,4-tetrahydro-isoquinoline with 6-bromo-2-(toluene-4-sulfonyl)-1,2,3,4-tetrahydro-isoquinoline.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:13])=[CH:4][C:5]([F:12])=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:7]=1.[Cl:14][CH2:15][S:16](Cl)(=[O:18])=[O:17].O>N1C=CC=CC=1>[Cl:13][C:3]1[C:2]([NH:1][S:16]([CH2:15][Cl:14])(=[O:18])=[O:17])=[CH:7][C:6]([NH:8][C:9](=[O:11])[CH3:10])=[C:5]([F:12])[CH:4]=1
Reactant: O=S(=O)(Cl)CCl
Reactant: CC(=O)Nc1cc(N)c(Cl)cc1F
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a stirred solution of the title compound of Step B (8.10 g, 40 mmol) in pyridine (50 mL) was added chloromethylsulfonyl chloride (3.84 mL, 40.45 mmol) over 30 minutes at 0° C. After stirring at room temperature for 14 h, chloromethylsulfonyl chloride (0.38 mL, 4.05 mmol) was added to complete the reaction. Water was added so that the product precipitated. After filtration and washing with water and petroleum ether, the title compound of Step C was isolated as a bright powder (11.17 g, 89%) melting at 208-210° C. 1H NMR (Me2SO-d6) δ 10.2-10.1 (s, 1H), 9.9 (s, 1H), 8.1 (d, 1H), 7.6-7.5 (d, 1H), 5.0-4.9 (s, 2H), 2.1 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:63])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:53]([C:56]1[S:60][C:59]([NH2:61])=[N:58][C:57]=1[CH3:62])(=[O:55])=[O:54])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[C:64](Cl)(=[O:68])[CH:65]([CH3:67])[CH3:66]>>[CH3:1][O:2][C:3](=[O:63])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:38]=[CH:39][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:41][CH:42]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:53]([C:56]1[S:60][C:59]([NH:61][C:64](=[O:68])[CH:65]([CH3:67])[CH3:66])=[N:58][C:57]=1[CH3:62])(=[O:55])=[O:54])=[O:22])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(N)nc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: CC(C)C(=O)Cl
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(NC(=O)C(C)C)nc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-2-({(S)-7-(2-amino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (30 mg) was reacted with isobutyryl chloride according to General Procedure F to give (S)-3-(4′-cyano-biphenyl-4-yl)-2-({(S)-7-[2-(isobutyryl-amino)-4-methyl-thiazole-5-sulfonyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester. This ester, upon hydrolysis according to General Procedure B, gave the title compound. LCMS (m/z): 980.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])=[O:7])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C)C=O>[NH2:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([O:12][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:11])=[O:7])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20]
Reactant: Nc1ccc(C(=O)c2ccccc2C(=O)O)cc1[N+](=O)[O-]
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ccc(C(=O)c2ccccc2C(=O)OCc2ccccc2)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 16 h
Yield: 80.5 %

Procedure:
To a mixture of 2-(4-amino-3-nitrobenzoyl)benzoic acid (50 g, 175 mmol) and potassium carbonate (50 g, 350 mmol) in N,N-dimethylformamide (200 ml), was added benzyl bromide (22.8 ml, 192 mmol). The mixture was stirred at 60° C. for 16 hours, and then partitioned between ethyl acetate (500 mL) and water. The organic portion was washed with 0.2N sodium hydroxide, water, brine, dried over sodium sulfate, filtered and concentrated in-vacuo. The resultant residue was re-crystallized from chloroform and hexanes (1:1) to afford benzyl 2-(4-amino-3-nitrobenzoyl)benzoate (53 g, 81%) as a yellow solid. 1H NMR (400 MHz, d6-DMSO): 8.11 (br s, 1H), 8.06-8.01 (m, 2H), 7.79-7.75 (m, 1H), 7.72-7.65 (m, 2H), 7.46 (d, 1H), 7.28-7.19 (m, 5H), 7.02 (d, 1H), 5.12 (s, 2H); MS (EI) for C21H16N2O5: 377 (MH+)
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12](=[N:16][OH:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:18]([N:22]=[C:23]=[O:24])[CH2:19][CH2:20][CH3:21].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:18]([NH:22][C:23]([O:17][N:16]=[C:12]1[C:13](=[O:15])[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:24])[CH2:19][CH2:20][CH3:21]
Reactant: O=C1C(=NO)c2ccccc2-c2ccccc21
Reactant: CCCCN=C=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCNC(=O)ON=C1C(=O)c2ccccc2-c2ccccc21
Yield: 99.3 %

Procedure:
22.3 g (0.1 mole) of 9,10-phenanthrene-dione-9-oxime are reacted with 12 ml (0.11 mole) of n-butyl isocyanate in 100 ml of chloroform in the presence of 0.2 ml of triethyl amine for an hour. The reaction mixture is heated to boiling for half an hour and evaporated in vacuo. Thus 32 g of 9,10-phenanthrene-dione-9-(n-butyl-aminocarbonyl)-oxime are obtained in the form of a yellowish brown oil, yield 99%.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][CH2:12][NH2:13])=[CH:6][CH:5]=1.[C:14](Cl)(=[O:16])[CH3:15].C(N(CC)CC)C>C(Cl)Cl>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][CH2:12][NH:13][C:14](=[O:16])[CH3:15])=[CH:6][CH:5]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc(SCCN)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(SCCNC(C)=O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of compound 1-HCl (0.44 g) in CH2Cl2 (15 mL) cooled to ˜0° C. was added acetyl chloride (1.0 mL) and triethylamine (1.0 mL). The reaction mixture was stirred for 1 hour at 0° C. and washed with 1N HCl, sat. NaHCO3. The solvents were removed by evaporation under reduced pressure to give product 10 as solid (pure by TLC and NMR). Yield: 0.5 g.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Cl[CH2:9][CH2:10][O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][CH:13]=1>CN(C)C=O>[C:16]([C:15]1[CH:19]=[CH:20][C:12]([O:11][CH2:10][CH2:9][N:3]2[CH:7]=[CH:6][N:5]=[CH:4]2)=[CH:13][CH:14]=1)(=[O:17])[NH2:18]
Reactant: c1c[nH]cn1
Reactant: NC(=O)c1ccc(OCCCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(OCCn2ccnc2)cc1
Temperature: 100 °C
Yield: 50.8 %

Procedure:
Sodium hydride (14.4 g, 50% suspension in mineral oil) was added cautiously to a stirred and cooled solution of imidazole (20.4 g) in dry N,N-dimethylformamide (100 ml). After the initial vigorous reaction had subsided the mixture was heated to 100° C. for 10 minutes and then stirred at room temperature for a further 1 hour. A solution of 4-(2-chloroethoxy)benzamide (60.0 g) in the minimum volume of N,N-dimethylformamide was added and the mixture was heated at 100° C. for 5.5 hours. The solvent was evaporated and the residue was poured into water. The mixture was extracted several times with chloroform and the combined chloroform extracts were dried (MgSO4) and evaporated to give a mixture of oil and solid. The mixture was triturated with ether and the solid was collected and crystallised from a mixture of methanol and ethyl acetate to give 1-[2-(4-carbamoyl phenoxy)ethyl]imidazole (35.2 g), m.p. 148°-149° C. Found: C, 62.25; H, 5.61; N, 18.54. C12H13N3O2 requires C, 62.32; H, 5.67; N, 18.17%.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([C:11]1[CH:16]=[N:15][C:14](Br)=[C:13]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[N:12]=1)=[O:10].[CH:25]1([CH2:30][OH:31])[CH2:29][CH2:28][CH2:27][CH2:26]1>>[OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([C:11]1[CH:16]=[N:15][C:14]([O:31][CH2:30][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[C:13]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[N:12]=1)=[O:10]
Reactant: OCC1CCCC1
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(Br)c(-c2ccc(Cl)cc2)n1
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(OCC2CCCC2)c(-c2ccc(Cl)cc2)n1

Procedure:
The title compound was prepared in analogy to example 26 starting from 5-bromo-6-(4-chloro-phenyl)-pyrazine-2-carboxylic acid ((1R,2R)-2-hydroxy-cyclohexyl)-amide and replacing ethylenglycolmonomethylether by cyclopentylmethanol. MS (ISP) (M+H+)=430.1.
Reaction SMILES: C(OC([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21]CC=C)=[O:20])=[C:14]([CH2:17]O)[CH:15]([CH3:16])[C@H:11]12)[CH3:9])=O)C=C.[NH2:27][S:28]([NH:31][CH2:32][C:33]1[N:34]2[CH:40]=[N:39][CH:38]=[C:35]2[S:36][CH:37]=1)(=[O:30])=[O:29]>>[OH:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O-:21])=[O:20])=[C:14]([CH2:17][N:39]3[CH:38]=[C:35]4[S:36][CH:37]=[C:33]([CH2:32][NH:31][S:28]([NH2:27])(=[O:29])=[O:30])[N+:34]4=[CH:40]3)[CH:15]([CH3:16])[C@H:11]12)[CH3:9]
Reactant: NS(=O)(=O)NCc1csc2cncn12
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)C(C)[C@H]12
Product: CC1C(Cn2cc3scc(CNS(N)(=O)=O)[n+]3c2)=C(C(=O)[O-])N2C(=O)[C@H]([C@@H](C)O)[C@@H]12
Yield: 12.9 %

Procedure:
The same procedure as in Example 1 was repeated except that 88 mg of allyl (5R,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl]-2-hydroxymethyl-1-methyl-1-carbapen-2-em-3-carboxylate and 87 mg of 3-(aminosulfonyl)aminomethylimidazo[5,1-b]thiazole were used, thereby obtaining 14.2 mg of the title compound.
Reaction SMILES: [CH2:1]([N:5]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:6][CH2:7][C:8]([CH3:11])([NH2:10])[CH3:9])[CH2:2][CH2:3][CH3:4].[C:16](ON1C(=O)CCC1=O)([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>C1COCC1>[CH2:1]([N:5]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:6][CH2:7][C:8]([NH:10][C:16](=[O:17])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:11])[CH3:9])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CCCCN(CCCC)CCC(C)(C)N
Solvent: C1CCOC1
Product: CCCCN(CCCC)CCC(C)(C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 76.3 %

Procedure:
Crude N1,N1-dibutyl-3-methylbutane-1,3-diamine (10.18 g, 47.4 mmol) was dissolved into THF (237 mL, 0.2 M). To this solution was added CbzOSu (11.8 g, 1 equiv, 47.4 mmol) in one portion. The reaction was left to stir at room temperature for 17 h. The solvent was removed and the residue was taken up in a mixture of ethyl acetate (600 mL) and water (200 mL). The layers were separated and the organic layer washed with water (2×300 mL) and brine (100 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated to a pale yellow oil. The crude oil was purified on an ISCO purification system with gradient elution from 60-80% ethyl acetate in hexanes. The desired fractions were collected and concentrated to give a colorless oil (12.6 g, 76.3%). LRMS (ESI+) for C21H36N2O2 (348.3); Found: 349 (MH+).
Reaction SMILES: [O:1]([CH:8]([CH2:12][CH3:13])[C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+]([O-])(O)=O.[O:18]([CH2:22][CH2:23][NH2:24])[N+:19]([O-:21])=[O:20].C(OC(C)C)(C)C>>[O:18]([CH2:22][CH2:23][NH:24][C:9](=[O:11])[CH:8]([O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:12][CH3:13])[N+:19]([O-:21])=[O:20]
Reactant: NCCO[N+](=O)[O-]
Reactant: CCC(Oc1ccccc1)C(=O)O
Solvent: O=[N+]([O-])O
Solvent: CC(C)OC(C)C
Product: CCC(Oc1ccccc1)C(=O)NCCO[N+](=O)[O-]
Yield: 57.8 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.64 g of 2-phenoxybutyric acid and 0.60 g of 2-nitroxyethylamine nitrate, 0.55 g of the title compound was obtained as colorless acicular prisms (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]3[CH:11]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:12]([C:14]([N:16]([O:18][CH3:19])[CH3:17])=[O:15])=[N:13][N:7]3[C:6]=2[CH:26]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:37]1(C)[CH:42]=CC=C[CH:38]=1.C(Br)C=C>C1COCC1>[CH2:42]([C:11]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:8]2[CH2:9][O:10][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:26][C:6]=3[N:7]2[N:13]=[C:12]1[C:14]([N:16]([O:18][CH3:19])[CH3:17])=[O:15])[CH:37]=[CH2:38]
Reactant: CON(C)C(=O)C1=NN2c3cc(Cl)ccc3OCC2C1c1ccccc1
Reactant: Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCC1(c2ccccc2)C(C(=O)N(C)OC)=NN2c3cc(Cl)ccc3OCC21
Temperature: -78 °C
Reaction time: 0.03 h

Procedure:
8-Chloro-N-methoxy-N-methyl-3-phenyl-3a,4-dihydro-3H-pyrazolo[5,1-c][1,4]benzoxazine-2-carboxamide (4-1; a racemic mixture, 0.43 g, 1.1 mmol) was dissolved in anhydrous THF (10 mL) and cooled to −78° C. in an acetone/dry ice bath under an N2 atmosphere. The resulting solution was treated with LHMDS (1.39 mL of a 1M toluene solution, 1.39 mmol) and stirred 2 minutes to produce a deep red color. Allyl bromide (0.20 mL, 2.2 mmol) was added neat and the solution was allowed to stir 10 minutes at −78° C. and then removed from the ice bath. Upon reaching ambient temperature, the reaction was judged complete by TLC and quenched by at addition of sat. aqueous NH4Cl (10 mL). The mixture was extracted with Et2O (3×10 mL), dried over MgSO4, filtered and concentrated. The crude residue was purified using flash column chromatography (ISCO Redisep 40 g SiO2 column, 0-40% EtOAc/hexanes gradient) to provide pure 3-allyl-8-chloro-N-methoxy-N-methyl-3-phenyl-3a,4-dihydro-3H-pyrazolo[5,1-c][1,4]benzoxazine-2-carboxamide (4-2; a racemic mixture): 1H NMR (300 MHz, CDCl3) δ 7.42-7.15 (m, 6H), 6.77 (m, 2H), 5.83 (m, 1H), 5.27 (dd, J=16.9, 1.1 Hz, 1H), 5.21 (d, J=10.0 Hz, 1H), 4.10 (dd, J=10.3, 3.7 Hz, 1H), 3.90 (s, 3H), 3.63 (dd, J=11.0, 3.6 Hz, 1H), 3.35 (dd, J=13.4, 6.0 Hz, 1H), 3.32 (s, 3H), 2.96 (m, 2H); MS (M+H+, C22H22ClN3O3) 412.3 found 412.9 required.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([CH3:22])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH:24]1([C:30]2[O:31][C:32]([CH3:48])=[C:33]([CH2:35][CH2:36]OS(C3C=CC(C)=CC=3)(=O)=O)[N:34]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([C:30]2[O:31][C:32]([CH3:48])=[C:33]([CH2:35][CH2:36][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C:5]([CH3:22])([O:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[CH3:21])[C:4]([OH:3])=[O:23])=[CH:12][CH:11]=3)[N:34]=2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3CCCCC3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1C
Product: Cc1ccccc1OC(C)(Cc1ccc(OCCc2nc(C3CCCCC3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared using the representative Standard Procedure (E) from 3-(4-Hydroxy-phenyl)-2-methyl-2-o-tolyloxy-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethyl ester. 1H NMR (400 MHz, CDCl3): δ 7.14-7.11 (m, 3H), 7.06 (t, 1H, J=7.82 Hz), 6.91 (t, 1H, J=7.82 Hz), 6.79 (d, 1H, J=8.60 Hz), 6.75 (d, 2H, J=8.60 Hz), 4.11 (t, 2H, J=6.26 Hz), 3.24 (d, 1H, J=14.08 Hz), 3.18 (d, 1H, J=14.08 Hz), 2.95 (t, 2H, J=6.26 Hz), 2.90-2.87 (m, 1H), 2.29 (s, 3H), 2.17 (s, 3H), 2.02-1.99 (m, 2H), 1.81-1.78 (m, 2H), 1.71-1.68 (m, 1H), 1.58-1.52 (m, 2H), 1.47 (s, 3H), 1.38-1.21 (m, 5H). MS [ES+] m/z exact mass calcd for C29H36NO5 478.2593, found 478.2611.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1.[Cl:10][C:11]1[N:12]=[C:13](Cl)[C:14]2[C:19]([I:20])=[CH:18][N:17]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:15]=2[N:16]=1>C1COCC1>[Cl:10][C:11]1[N:12]=[C:13]([O:9][CH:6]2[CH2:7][CH2:8][O:3][CH2:4][CH2:5]2)[C:14]2[C:19]([I:20])=[CH:18][N:17]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:15]=2[N:16]=1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)nc(Cl)nc21
Reactant: OC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cc(I)c2c(OC3CCOCC3)nc(Cl)nc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a suspension of sodium hydride (1 equiv) in dry THF (0.42 M) under nitrogen atmosphere was added tetrahydro-2H-pyran-4-ol (1 equiv) at 0° C. The reaction mixture was stirred at room temperature for 30 min before a solution of 2,4-dichloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (0.67 equiv) in dry THF (0.75 M) was added at 0° C. The mixture was stirred at 0° C. for 1 h. The reaction was monitored by thin layer chromatography. Upon completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel flash column chromatography (5% ethyl acetate in petroleum ether) to afford the title compound as a yellowish oil (84% yield). MS (ESI) m/z 510.1 [M+1]+.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.O[C:7]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1>>[Cl:3][C:7]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cc(-c2ccccc2)c2ccccc2n1
Product: Clc1cc(-c2ccccc2)c2ccccc2n1
Temperature: 25 °C

Procedure:
Phosphorus oxychloride (37.4 mL, 402 mmol) was added to 2-hydroxy-4-phenylquinoline and the mixture was heated to reflux for 4 hours. Upon cooling to room temperature, the mixture was added slowly to stirring ice water yielding a white precipitate. The mixture was extracted with methylene chloride, and the organic phases were combined, dried with magnesium sulfate, filtered and concentrated to yield 2-chloro-4-phenylquinoline.
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:6])[CH2:4][CH3:5].I[C:8]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[C:13]2[C:9]=1/[C:10](=[CH:21]/[C:22]1[NH:26][CH:25]=[N:24][C:23]=1[CH3:27])/[C:11](=[O:20])[NH:12]2>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.CN(C=O)C.CCN(CC)CC>[OH:6][CH:3]([CH2:4][CH3:5])[C:2]#[C:1][C:8]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[C:13]2[C:9]=1/[C:10](=[CH:21]/[C:22]1[NH:26][CH:25]=[N:24][C:23]=1[CH3:27])/[C:11](=[O:20])[NH:12]2
Reactant: C#CC(O)CC
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(O)C#Cc1c([N+](=O)[O-])ccc2c1/C(=C/c1[nH]cnc1C)C(=O)N2

Procedure:
Using Method C above, 1-pentyn-3-ol (52.6 mg, 0.63 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-5-nitro-2H-indol-2-one (100 mg, 0.25 mmol) (Starting Material 4 supra) using (Ph3P)2PdCl2 (17.5 mg) and CuI (4.8 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 6 h to give rac-(Z)-1,3-dihydro-4-(3-hydroxy-1-pentynyl)-3-[(4-methyl-1H-imidazol-5-yl)methylene]-5-nitro-2H-indol-2-one. (Yield 12 mg, 14%).
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:25][C:26]1[O:30][C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]3[S:38][CH:39]=[CH:40][CH:41]=3)[CH:32]=2)=[N:28][C:27]=1[CH2:42][CH2:43]OS(C1C=CC(C)=CC=1)(=O)=O>>[CH3:23][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][C:5]([CH3:14])([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:43][CH2:42][C:27]2[N:28]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]4[S:38][CH:39]=[CH:40][CH:41]=4)[CH:32]=3)[O:30][C:26]=2[CH3:25])=[CH:9][CH:8]=1)[C:4]([OH:3])=[O:24]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1OC
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccc(-c4cccs4)c3)oc2C)cc1
Product: COc1ccccc1OC(C)(Cc1ccc(OCCc2nc(-c3cccc(-c4cccs4)c3)oc2C)cc1)C(=O)O

Procedure:
: The title compound was prepared using the representative Standard Procedure (E) from 3-(4-Hydroxy-phenyl)-2-(2-methoxy-phenoxy)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-[5-methyl-2-(3-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethyl ester. 1H NMR (400 MHz, CDCl3): δ 8.05 (d, 2H, J=7.82 Hz), 7.86 (d, 2H, J=8.21 Hz), 7.68 (d, 2H, J=7.82 Hz), 7.45 (t, 1H, J=7.65 Hz), 7.41–7.40 (m, 1H), 7.31–7.30 (m, 1H), 7.19(d, 1H, J=8.40 Hz), 7.10–7.04 (m, 2H), 6.88–6.79 (m, 2H), 6.61 (dd, 1H, J=8.40 Hz, 1.65 Hz), 4.22 (t, 2H, J=5.87 Hz), 3.82 (s, 3H), 3.30 (d, 1H, J=14.08 Hz), 3.10–3.03 (m, 3H), 2.43 (s, 3H), 1.30 (s, 3H). MS [ES+] m/z exact mass calcd for C33H32NO6S 570.1950, found 570.1958.