Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[O:19][C@@H:20]3[O:46][C@H:45]([CH2:47][O:48][C:49](=[O:54])[C:50]([CH3:53])([CH3:52])[CH3:51])[C@@H:37]([O:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])[C@H:29]([O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C@H:21]3[O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[CH:12]=[CH:11]2)=[CH:4][CH:3]=1.[C:55](=O)([O-])[O-].[Cs+].[Cs+].CI>CC(C)=O>[CH3:55][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[O:19][C@@H:20]3[O:46][C@H:45]([CH2:47][O:48][C:49](=[O:54])[C:50]([CH3:53])([CH3:52])[CH3:51])[C@@H:37]([O:38][C:39](=[O:44])[C:40]([CH3:41])([CH3:42])[CH3:43])[C@H:29]([O:30][C:31](=[O:36])[C:32]([CH3:33])([CH3:34])[CH3:35])[C@H:21]3[O:22][C:23](=[O:28])[C:24]([CH3:26])([CH3:27])[CH3:25])[CH:12]=[CH:11]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2cccc3ccn(CCc4ccc(O)cc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc(CCn2ccc3cccc(O[C@@H]4O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]4OC(=O)C(C)(C)C)c32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
A mixture of 1-[2-(4-hydroxyphenyl)ethyl]-7-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-indole (50 mg), cesium carbonate (43 mg) and methyl iodide (0.008 mL) in acetone (2 mL) was stirred at room temperature overnight. The reaction mixture was purified by column chromatography on aminopropylated silica gel (eluent: n-hexane/ethyl acetate=5/1) to give 1-[2-(4-methoxyphenyl)ethyl]-7-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-indole (51 mg). This material was dissolved in methanol (1 mL). To the solution were added water (0.1 mL) and lithium hydroxide monohydrate (13 mg), and the mixture was stirred at room temperature overnight. The reaction mixture was purified by column chromatography on silica gel (eluent: methylene chloride/methanol=8/1) to give the title compound (19 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH2:11])[C:5]([OH:7])=[O:6].CN(C)C=O.[CH3:17][C:18]([CH3:20])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(O)(=O)C>[NH2:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[NH:1][CH:18]([CH3:20])[CH3:17]
Reactant: CC(C)=O
Reactant: Nc1ccc(C(=O)O)cc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(C)Nc1cc(C(=O)O)ccc1N

Procedure:
To a stirred mixture of 3,4-diaminobenzoic acid (15.2 g), in 200 mL of tetrahydrofuran, 30 mL of dimethyl formamide, 7.3 mL of acetone, and 5.7 mL of acetic acid, was added 31.8 9 of sodium triacetoxyborohydride in portions. After 3 hours the mixture was filtered through diatomaceous earth and washed with tetrahydrofuran. The filtrate was concentrated to dryness. Crystallization of the residue with ethyl acetate/hexanes gave 11 grams of 4-amino-3-isopropylamino-benzoic acid.
Reaction SMILES: NC1C=C(Cl)C=CC=1S(N)(=O)=O.C(N=C=S)(C)(C)C.[NH2:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[S:28]([NH:31][C:32]([NH:34][C:35]([CH3:38])([CH3:37])[CH3:36])=S)(=[O:30])=[O:29]>>[C:35]([NH:34][C:32]1[NH:20][C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[S:28](=[O:30])(=[O:29])[N:31]=1)([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)NC(=S)NS(=O)(=O)c1ccc(Cl)cc1N
Agent: CC(C)(C)N=C=S
Agent: Nc1cc(Cl)ccc1S(N)(=O)=O
Product: CC(C)(C)NC1=NS(=O)(=O)c2ccc(Cl)cc2N1
Temperature: 60 °C

Procedure:
The title compound was prepared from 2-amino-4-chlorobenzenesulfonamide and tert-butyl isothiocyanate by a method analogous to the one described in Example 4 except that the mixture was heated at 60° C. for 6 days. The intermediate N-(2-amino-4-chlorobenzenesulfonyl)-N′-tert-butylthiourea and the ring closed product were both purified by column chromatography; m.p. 291-294° C. (light petroleum/ethyl acetate); 1H-NMR (DMSO-d6): δ 1.39 (s, 9H, C(CH3)3), 6.92 (br s, 1H, NH), 7.17 (d, 1H, ArH), 7.28 (dd, 1H, ArH), 7.68 (d, 1H, ArH), 10.25 (br.s, 1H, NH); MS: m/e 287/289 (M+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18])([O-])=O>[Pd].CO>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)c1ccccc1CCCCCc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccccc1CCCCCc1ccccc1N
Temperature: 70 °C
Reaction time: 3 h

Procedure:
36 g (0.11 M) of methyl 2-[5-(2-nitrophenyl)pentyl]benzoate and 4 g of palladium-on-charcoal are added to 400 ml of methanol in a 1000 ml stainless-steel autoclave. The reaction medium is then stirred under hydrogen pressure (10 bar) at 70° C. for 3 hours.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:14]([CH3:15])[CH2:13][N:12]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[N+:22]([O-])=O)[CH2:11][C@H:10]1[NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CO.[Pd]>[NH2:22][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:16]=1[N:12]1[CH2:13][C@H:14]([CH3:15])[C@@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[C@H:10]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:11]1
Reactant: C[C@H]1CN(c2ccncc2[N+](=O)[O-])C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: [Pd]
Solvent: CO
Product: C[C@H]1CN(c2ccncc2N)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reaction time: 3 h

Procedure:
A solution of tert-butyl (3R,4R,5S)-4-(tert-butyldimethylsilyloxy)-5-methyl-1-(3-nitropyridin-4-yl)piperidin-3-ylcarbamate (1.0 equiv.) in MeOH (0.05 M) was degassed with nitrogen for 20 min. 10% Pd/C (0.2 equiv.) was added to the mixture and the solution was stirred under a hydrogen balloon for 3 hours. The reaction was filtered and the filtrate was concentrated under reduced pressure to give tert-butyl (3R,4R,5S)-1-(3-aminopyridin-4-yl)-4-(tert-butyldimethylsilyloxy)-5-methylpiperidin-3-ylcarbamate as the desired product in 94% yield. LC/MS=437.4 (M+H), Rt=1.08 min. 1H-NMR (300 MHz, CDCl3): δ 8.01 (s, 1H), 7.95 (d, J=6.0 Hz, 1H), 6.76 (d, J=6.0 Hz, 1H), 4.44 (br s, 1H), 3.74 (br s, 2H), 3.59-3.55 (m, 1H), 3.25-3.13 (m, 2H), 2.47-2.35 (m, 2H), 1.89 (br s, 2H), 1.44 (s, 9H), 1.04 (d, J=6.0, 3H), 0.92 (s, 9H), 0.13 (d, J=9.0, 6H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)=[O:3].[BH4-].[Na+].[NH3:15]>C(OCC)(=O)C>[NH2:15][CH2:1][CH:2]([OH:3])[C:4]1[CH:5]=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=1
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: N
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: NCC(O)c1ccc([N+](=O)[O-])cc1

Procedure:
4-Nitroacetophenone is brominated in the α-position, the product obtained is redcuced by means of sodium borohydride to the corresponding bromohydrin and this is treated with ammonia. Rac.-α-(aminomethyl)-4-nitrobenzyl alcohol, m.p. 138°-139° (from ethyl acetate) is obtained.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH:3]=[CH2:4].[CH:7]1([SiH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH2:11][CH2:10][CH2:9][CH2:8]1>O.[Ir](Cl)(Cl)Cl.CC1C=CC(C)=CC=1>[F:1][C:2]([F:6])([F:5])[CH2:3][CH2:4][Si:12]([CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11]1)([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]
Reactant: C=CC(F)(F)F
Reactant: CCO[SiH](OCC)C1CCCC1
Agent: Cl[Ir](Cl)Cl
Solvent: Cc1ccc(C)cc1
Solvent: O
Product: CCO[Si](CCC(F)(F)F)(OCC)C1CCCC1
Reaction time: 3 h
Yield: 77 %

Procedure:
In analogy to Example 3, a mixture of 3 g of p-xylene, 5.3 g (0.055 mol) of 3,3,3-trifluoro-1-propene and 9.4 g (0.5 mol) of cyclopentyldiethoxysilane was reacted in the presence of 0.1 mg of iridium(III) chloride hydrate, after a mixing time of 70 minutes, at 83° C. over 180 minutes. Analysis by gas chromatography gave a product yield of 77% of 3,3,3-trifluoropropylcyclopentyldiethoxysilane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:6][C:7]=1[F:8].[NH2:18][C:19]1[C:23]([C:24]#[N:25])=[CH:22][NH:21][N:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:20]3[N:21]=[CH:22][C:23]([C:24]#[N:25])=[C:19]3[N:18]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N#Cc1c[nH]nc1N
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(F)c(Cl)c1
Product: N#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(F)c(Cl)c3)nc12
Yield: 32 %

Procedure:
Reaction of 1-(3-chloro-4-fluoro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (269 mg, 1.0 mmol), prepared from commercially available 3-chloro-4-fluoro-acetophenone according to general procedure A, and 3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as an off-white solid (109 mg, 32%). MS (ISP) 341.0 [(M+H)+]; mp 190° C.
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[CH2:29]([O:28][C:26]([N:11]1[CH2:12][C@H:13]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])(=[O:17])=[O:16])[CH2:14][C@H:10]1[C:8](=[O:9])[NH:7][C:4]1([C:2]#[N:3])[CH2:6][CH2:5]1)=[O:27])[CH3:30]
Reactant: CCOC(=O)Cl
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Agent: Cl
Product: CCOC(=O)N1C[C@H](S(=O)(=O)c2ccccc2Cl)C[C@H]1C(=O)NC1(C#N)CC1

Procedure:
L44. (2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride from experiment K4 was acylated with ethyl chloroformate in analogy to experiment L21 to give (2S,4R)-4-(2-chloro-benzenesulfonyl)-2-(1-cyano-cyclopropylcarbamoyl)-pyrrolidine-1-carboxylic acid ethyl ester as a colorless oil. MS: 426.0 [M+H]+.
Reaction SMILES: Br[C:2]1([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:7](=[O:8])[NH:6][C:5](=[O:9])[NH:4][C:3]1=[O:10].[OH:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.O>CS(C)=O>[CH2:11]([C:2]1([CH:23]2[CH2:24][NH:25][CH2:26][CH2:27][N:22]2[CH2:21][CH2:20][OH:19])[C:7](=[O:8])[NH:6][C:5](=[O:9])[NH:4][C:3]1=[O:10])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: OCCN1CCNCC1
Reactant: CCCCCCCCC1(Br)C(=O)NC(=O)NC1=O
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCCCC1(C2CNCCN2CCO)C(=O)NC(=O)NC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-Bromo-5-octylbarbituric Acid (23.52 g) in 70 ml of dimethylsulfoxide, kept under nitrogen atmosphere and at a temperature of 5-10° C., is dropped N-(2-hydroxyethyl)piperazine (36.2 ml), then the mixture is stirred at room temperature for 2 hours 30 minutes. The reaction mixture is poured into water (1 l) under stirring and cooling with an ice bath. The white solid which separates is recovered by filtration, washed with water and dried under vacuum at 40° C. to give, after crystallization from ethanol (140 ml) 10.91 g of the product as a white solid, m.p. 183-184° C.
Reaction SMILES: [F:1][C@@:2]12[CH2:12][CH2:11][O:10][C:9]3[CH:13]=[CH:14][C:15]([N+:17]([O-:19])=[O:18])=[CH:16][C:8]=3[C@@:7]1([CH3:20])[N:6]=[C:5]([N:21](C(OC(C)(C)C)=O)[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:4]([CH3:37])([CH3:36])[S:3]2(=[O:39])=[O:38].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.O1CC1>C1COCC1>[F:1][C@@:2]12[CH2:12][CH2:11][O:10][C:9]3[CH:13]=[CH:14][C:15]([N+:17]([O-:19])=[O:18])=[CH:16][C:8]=3[C@@:7]1([CH3:20])[N:6]=[C:5]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[C:4]([CH3:37])([CH3:36])[S:3]2(=[O:39])=[O:38]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@]2(C)c3cc([N+](=O)[O-])ccc3OCC[C@@]2(F)S(=O)(=O)C1(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1CO1
Product: CC(C)(C)OC(=O)NC1=N[C@]2(C)c3cc([N+](=O)[O-])ccc3OCC[C@@]2(F)S(=O)(=O)C1(C)C
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 40.2 %

Procedure:
To an oven dried flask was added tert-butyl N-[(4aR,11bR)-4a-fluoro-3,3,11b-trimethyl-10-nitro-4,4-dioxo-5,6-dihydro-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate (See procedure for Intermediate 24, Step 1) (0.260 g, 0.475 mmol) and THF (3.17 mL). The resulting mixture was cooled to −78° C. and LHMDS (1 M in THF; 0.712 mL, 0.712 mmol) was added and the mixture was stirred for 40 minutes and then oxirane (7.91 mL, 9.50 mmol) was added. The dry ice/acetone bath was removed and the mixture was stirred for 30 minutes. The resulting mixture was treated with saturated aqueous ammonium chloride and extracted with EtOAc. The organic layer was concentrated and the crude material was eluted through a silica gel column using 10-50% EtOAc/Heptane. The desired fractions were combined and concentrated down to yield tert-butyl ((4aR,11bR)-4a-fluoro-3,3,11b-trimethyl-10-nitro-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate (0.090 g, 0.191 mmol, 40.2% yield)). ESI MS: 494.1 [M+Na] and a mixture of tert-butyl ((4aR,11bR)-4a-fluoro-3,3,11b-trimethyl-10-nitro-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate and tert-butyl N-[(4aR,11bR)-4a-fluoro-3,3,11b-trimethyl-10-nitro-4,4-dioxo-5,6-dihydro-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate (89 mg, 0.156 mmol, 32.8% yield) ESI MS: 494.1/594.1 [M+Na].
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[N:13]3[CH:14]=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:16]=[C:17]([C:18]4[O:22][CH:21]=[N:20][CH:19]=4)[C:12]3=[N:11][CH:10]=2)=[O:8])[CH2:3]1.[H-].[Na+].FC(F)(F)S(O[CH2:35][CH:36]([F:38])[F:37])(=O)=O.[Cl-].[NH4+]>CN(C=O)C>[F:37][CH:36]([F:38])[CH2:35][O:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[N:13]3[CH:14]=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:16]=[C:17]([C:18]4[O:22][CH:21]=[N:20][CH:19]=4)[C:12]3=[N:11][CH:10]=2)=[O:8])[CH2:3]1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: O=C(c1cnc2c(-c3cnco3)cc(C(F)(F)F)cn12)N1CC[C@H](O)C1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=C(c1cnc2c(-c3cnco3)cc(C(F)(F)F)cn12)N1CC[C@H](OCC(F)F)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
((3S)-3-Hydroxypyrrolidin-1-yl) (8-(1,3-oxazol-5-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)methanone (205 mg) was dissolved in DMF (5 mL), and 60% sodium hydride (26.9 mg) and 2,2-difluoroethyl trifluoromethanesulfonate (91 μL) were added thereto at 0° C. The reaction mixture was stirred at room temperature for 2 hr, saturated aqueous ammonium chloride solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was recrystallized from ethyl acetate/hexane to give the title compound (152 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([C:10]1[CH:14]=[CH:13][S:12][C:11]=1[CH:15]=O)(=[O:9])=[O:8].[CH3:17][O:18][C:19](=[O:32])[CH2:20][N:21]1[C:29]2[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=2)[CH:23]=[C:22]1[CH3:31]>>[CH3:17][O:18][C:19](=[O:32])[CH2:20][N:21]1[C:29]2[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=2)[C:23]([CH2:15][C:11]2[S:12][CH:13]=[CH:14][C:10]=2[S:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)(=[O:8])=[O:9])=[C:22]1[CH3:31]
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Reactant: O=Cc1sccc1S(=O)(=O)c1ccccn1
Product: COC(=O)Cn1c(C)c(Cc2sccc2S(=O)(=O)c2ccccn2)c2cc(F)ccc21

Procedure:
The title compound was prepared by the method of Preparation 1c using 3-(pyridine-2-sulfonyl)thiophene-2-carbaldehyde and (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([Cl:25])[C:15]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[CH2:5][CH:6]1[S:10][C:9](=[O:11])[NH:8][C:7]1=[O:12].[Cl:26][S:27](O)(=[O:29])=[O:28]>>[Cl:25][C:14]1[CH:13]=[C:4]([CH2:5][CH:6]2[S:10][C:9](=[O:11])[NH:8][C:7]2=[O:12])[CH:3]=[C:2]([Cl:1])[C:15]=1[O:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[C:21]([S:27]([Cl:26])(=[O:29])=[O:28])[CH:22]=1
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccc(Oc2c(Cl)cc(CC3SC(=O)NC3=O)cc2Cl)cc1
Product: COc1ccc(Oc2c(Cl)cc(CC3SC(=O)NC3=O)cc2Cl)cc1S(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The title compound of Step D (52 mg, 0.13 mmol) was cooled to 0° C. and chlorosulfonic acid (0.5 mL) was added. The mixture was warmed to room temperature and stirred for about 1.5 hours. The solution was poured into ice (75 g), stirred until the ice had melted, and then extracted with ethyl acetate (3×25 ml). The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to afford the title compound (38.0 mg) as a brownish solid which was used in the next step without purification.
Reaction SMILES: Cl[CH:2]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:9][C:8]=1[CH2:18][O:19][CH3:20])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([N:30]([CH3:38])[CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[O:29])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CN(C)C(=O)C.O>[CH3:20][O:19][CH2:18][C:8]1[O:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:11][C:7]=1[CH:2]([NH:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]([N:30]([CH3:38])[CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:29])=[CH:26][CH:27]=1)[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: COCc1oc(-c2ccccc2)cc1C(Cl)CC(C)C
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COCc1oc(-c2ccccc2)cc1C(CC(C)C)Nc1ccc(C(=O)N(C)CCC(=O)O)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 8.8 %

Procedure:
A mixture of 3-(1-chloro-3-methylbutyl)-2-(methoxymethyl)-5-phenylfuran (439 mg), ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (451 mg), sodium carbonate (191 mg) and sodium iodide (270 mg) in N,N-dimethylacetamide (10 mL) was stirred overnight at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (25% ethyl acetate/hexane to 60% ethyl acetate/hexane). To the residue were added ethanol (2 mL), tetrahydrofuran (2 mL) and 1N lithium hydroxide (1.0 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (63 mg, 9%).
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=1)[C:5](=O)[CH3:6].[C:20]([CH2:22][C:23]([NH2:25])=[O:24])#[N:21]>CN(C)C=O.C(O)C>[C:20]([C:22]1[C:23](=[O:24])[NH:25][C:5]([CH3:6])=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)[CH:3]=1)#[N:21]
Reactant: N#CCC(N)=O
Reactant: COC(=O)Cc1ccc(C(=CN(C)C)C(C)=O)cc1
Solvent: CCO
Solvent: CN(C)C=O
Product: Cc1[nH]c(=O)c(C#N)cc1-c1ccc(CC(=O)O)cc1

Procedure:
11 g 4-dimethylamino-3-(4-methoxycarbonylmethylphenyl)-3-buten-2-one are reacted with cyanacetamide as described in Example 1. The title compound is obtained (m.p. 280°-282°--from dimethylformamide/ethanol).
Reaction SMILES: Cl[C:2]1[CH:19]=[CH:18][C:5]2[C:6](=[O:17])[C:7]3[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1.[F:20][C:21]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:22]=1[NH2:23].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C1(C)C=CC=CC=1>CC([O-])=O.CC([O-])=O.[Pd+2].C(O)(C)(C)C>[F:20][C:21]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:22]=1[NH:23][C:2]1[CH:19]=[CH:18][C:5]2[C:6](=[O:17])[C:7]3[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: COc1ccc2c(c1)C(=O)c1ccc(Cl)cc1CC2
Reactant: Nc1ccc(F)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: COc1ccc2c(c1)C(=O)c1ccc(Nc3ccc(F)cc3F)cc1CC2
Yield: 87 %

Procedure:
In accordance with general method AA, 0.50 g (1.8 mmol) of 2-chloro-7-methoxy-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one (34), 0.25 g (1.9 mmol) of 2,4-difluoroaniline, 0.05 g (0.22 mmol) of Pd(OAc)2, 0.10 g (0.21 mmol) of 2-(dicyclohexylphosphino)-2′-,4′-,6′-triisopropyl-biphenyl, 0.70 g (6.2 mmol) of K—O-tert-butylate, 5 ml of toluene and 1 ml of tert-BuOH are used. Reaction time: 1 h. Purification is carried out via flash chromatography (SiO2, hexane/ethyl acetate 8+2). Yield: 87%; melting point: 123-126° C. (decomposition)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[CH:21][CH:20]=[CH:19]2>>[N+:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[NH:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[CH:21][CH:20]=[CH:19]2)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc2ncnc(Cl)c2c1
Reactant: Nc1ccc2ncccc2c1
Product: O=[N+]([O-])c1ccc2ncnc(Nc3ccc4ncccc4c3)c2c1
Yield: 86 %

Procedure:
Using an analogous procedure to that described in Example 1, 4-chloro-6-nitroquinazoline was reacted with 6-aminoquinoline to give 6-nitro-4-(6-quinolylamino)quinazoline in 86% yield, m.p. >300° C.;
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/Br)=[CH:3][CH:2]=1.[I-].[C:11]1([Zn+])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>[Pd].C(F)(F)(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)F.C(#N)C.C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:4]1(/[CH:7]=[CH:8]/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: [Zn+]c1ccccc1
Reactant: Br/C=C/c1ccccc1
Agent: [Pd]
Agent: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: CC#N
Product: C(=C/c1ccccc1)\c1ccccc1
Reaction time: 24 h

Procedure:
In an illustrative example, a coupling reaction was conducted between (E)-2-bromostyrene (PhCH═CHBr) and phenylzinc iodide (PhZnI) promoted by a fluorous palladium catalyst. The catalyst was prepared from Pd2(dba)3 and the known fluorous phosphine (p-C6F13CH2CH2C6H4)3P. A mixture of the catalyst in FC-72 was contacted in a U-tube with a first organic phase containing (E)-2-bromostyrene in acetonitrile and a second organic phase containing phenylzinc iodide in THF. After one day at ambient temperature, each organic phase was removed and subjected to standard aqueous workup. Unreacted (E)-2-bromostyrene was recovered from the first organic phase while the coupled reaction product, (E)-stilbene (PhCH═CHPh) was isolated from the second organic phase.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([S:10][CH2:11][C:12](O)=[O:13])=[S:9])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].SCCO>[OH-].[Na+]>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([S:10][CH2:11][CH2:12][OH:13])=[S:9])=[CH:6][CH:7]=1
Reactant: Nc1ccc(C(=S)SCC(=O)O)cc1
Agent: O=C([O-])O
Agent: OCCS
Agent: [Na+]
Product: Nc1ccc(C(=S)SCCO)cc1
Reaction time: 1 h

Procedure:
Crude carboxymethyl 4-aminobenzenecarbodithioate (7.48 g, 0.033 mole) was dissolved in 0.5 N (66 ml) sodium hydroxide solution containing 10% by weight of sodium bicarbonate and the solution was filtered to remove traces of insoluble material. 2-Mercaptoethanol (2.9 g, 0.037 mole) was added to the stirred filtrate and the reaction mixture soon became turbid as the product began to separate out. After standing for 1 hour at room temperature, the orange precipitate was filtered off, washed with water, and dried in vacuo at a temperature of below 50°C. The yield of the product, an orange crystalline powder, m.p. 87.5°-89.5° was 6.13 g or 87%.