Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[CH2:7]([O:9][NH2:10])[CH3:8].[C:11]([C:15]1[C:16](=[O:36])[CH2:17][CH:18]([C:22]2[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[C:24]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:23]=2[CH3:35])[CH2:19][C:20]=1[OH:21])(=O)[CH2:12][CH3:13]>C(O)C.C(Cl)Cl>[CH2:7]([O:9][N:10]=[C:11]([C:15]1[C:16](=[O:36])[CH2:17][CH:18]([C:22]2[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[C:24]([NH:30][S:31]([CH3:34])(=[O:32])=[O:33])[C:23]=2[CH3:35])[CH2:19][C:20]=1[OH:21])[CH2:12][CH3:13])[CH3:8]
Reactant: CCC(=O)C1=C(O)CC(c2c(C)cc(C)c(NS(C)(=O)=O)c2C)CC1=O
Reactant: CCON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CCON=C(CC)C1=C(O)CC(c2c(C)cc(C)c(NS(C)(=O)=O)c2C)CC1=O
Reaction time: 18 h

Procedure:
Sodium acetate (0.19 g, 2.29 mmol) and ethoxyamine hydrochloride (0.22 g, 2.29 mmol) were added to a solution of 2-propionyl-3-hydroxy-5-(3-methylsulphonamido-2,4,6-trimethylphenyl)cyclohex-2-en-1-one (0.58 g, 1.53 mmol) in ethanol (25 ml) and methylene chloride (25 ml). Stirring was continued at 20° for 18 hrs. The solvent was removed under reduced pressure and the residue partitioned between chloroform and water. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to yield2-[1-(ethoxyimino)propyl]-hydroxy-5-[3-(methylsulphonamido)-2,4,6-trimethylphenyl]cyclohex-2-en-1-one as a brown oil (0.27 g, 42%). The compound was characterized by proton magnetic resonance spectroscopy. The spectroscopic data are recorded in Table 2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[N:16]=[C:15]([C:25]([N:27]3[CH2:31][CH2:30][S:29][CH2:28]3)=[O:26])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.ClC1C=C(C2N(C3C=NC=CC=3)N=C(C(N3CCS(=O)C3)=[O:52])C=2)C=C(F)C=1.ClC1C=CC=C(C(OO)=O)C=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[N:16]=[C:15]([C:25]([N:27]3[CH2:31][CH2:30][S:29](=[O:52])[CH2:28]3)=[O:26])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:10])([F:11])[F:12])[CH:7]=1
Reactant: O=C(c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2ccc(Cl)nc2)n1)N1CCSC1
Reactant: O=C(c1cc(-c2cc(F)cc(Cl)c2)n(-c2cccnc2)n1)N1CCS(=O)C1
Agent: O=C(OO)c1cccc(Cl)c1
Product: O=C(c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2ccc(Cl)nc2)n1)N1CCS(=O)C1

Procedure:
38 mg (0.07 mmol) of the compound of Example 36 is reacted analogously to the synthesis of the compound of Example 6 with 18 mg (0.07 mmol, 70%) of meta-chloroperbenzoic acid for 72 hours at room temperature. After the crude product is purified by means of preparative HPLC (mobile solvent: acetonitrile/water gradient), 31 mg (79% of theory) of the title compound is obtained.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCN(CC)CC.[Si:27]([O:34][C@@H:35]([CH3:63])[C@@H:36]([NH:51][C:52]1[C:60]2[CH:59]=[CH:58][S:57][C:56]=2[C:55]([C:61]#[N:62])=[CH:54][CH:53]=1)[C:37]([NH:39][NH:40][C:41](=O)[C:42]1[CH:47]=[CH:46][C:45]([C:48]#[N:49])=[CH:44][CH:43]=1)=[O:38])([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>C(Cl)Cl>[Si:27]([O:34][C@@H:35]([CH3:63])[C@@H:36]([NH:51][C:52]1[C:60]2[CH:59]=[CH:58][S:57][C:56]=2[C:55]([C:61]#[N:62])=[CH:54][CH:53]=1)[C:37]1[O:38][C:41]([C:42]2[CH:47]=[CH:46][C:45]([C:48]#[N:49])=[CH:44][CH:43]=2)=[N:40][N:39]=1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](Nc1ccc(C#N)c2sccc12)C(=O)NNC(=O)c1ccc(C#N)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](Nc1ccc(C#N)c2sccc12)c1nnc(-c2ccc(C#N)cc2)o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.3 %

Procedure:
To a solution of triphenylphosphine (275 mg, 1.43 mmol) in DCM (24 mL) was added 12 (363 mg, 1.43 mmol) at 0° C. After 12 was dissolved completely, Et3N (0.40 mL, 2.87 mmol) was added, followed by a solution of N′-((2R,3S)-3-(tert-butyldimethylsilyloxy)-2-(7-cyanobenzo[b]thiophen-4-ylamino)butanoyl)-4-cyanobenzohydrazide (380 mg, 0.71 mmol) in DCM (12 mL). After addition, the reaction mixture was allowed to warm to room temperature and stirred for additional 10 min. The reaction was quenched with saturated sodium thiosulfate (3 mL) and diluted with DCM (100 mL). The organic layer was separated and washed with water, brine and dried over Na2SO4. Removal of the solvent gave a residue, which was purified by flash chromatography to provide the title compound 4-((1R,2S)-2-(tert-butyldimethylsilyloxy)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)propylamino)benzo[b]thiophene-7-carbonitrile (360 mg, 98%). 1H NMR (400 MHz, CDCl3, δ in ppm) 8.22 (d, J=8.4 Hz, 2H), 7.93 (d, J=8.4 Hz, 2H), 7.73 (d, J=5.5 Hz, 1H), 7.68 (d, J=8.2 Hz, 1H), 7.55 (d, J=5.5 Hz, 1H), 6.63 (d, J=8.2 Hz, 1H), 5.89 (d, J=8.6 Hz, 1H), 5.12 (m, 1H), 4.74 (m, 1H), 1.61 (d, J=6.2 Hz, 3H), 1.05 (s, 9H), 0.26 (s, 3H), 0.00 (s, 3H).
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:6]1[N:7]([CH2:19][C:20]2([C:24]([O:26]CC)=[O:25])[CH2:23][CH2:22][CH2:21]2)[C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:18]=1)[CH2:4][CH3:5]>C(O)C>[CH2:3]([C:6]1[N:7]([CH2:19][C:20]2([C:24]([OH:26])=[O:25])[CH2:23][CH2:22][CH2:21]2)[C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:18]=1)[CH2:4][CH3:5]
Reactant: CCCc1nc2cnc3ccccc3c2n1CC1(C(=O)OCC)CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1nc2cnc3ccccc3c2n1CC1(C(=O)O)CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
Aqueous sodium hydroxide (7 mL of 6 M) was added to a solution of ethyl 1-[(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclobutanecarboxylate (7.55 g, 21.5 mmol) in ethanol (60 mL); the reaction was stirred at ambient temperature for one hour and concentrated under reduced pressure. The residue was dissolved in water (40 mL) and adjusted to pH 7 with the addition of 2 M hydrochloric acid. A precipitate formed, was isolated by filtration, and dried in a vacuum oven at 70° C. for two hours to provide 6.76 g of 1-[(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclobutanecarboxylic acid as a tan solid.
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])([CH3:5])[CH3:4].[CH3:13][O:14][CH2:15][CH2:16][O:17][CH2:18]Cl>O1CCCC1>[CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])([CH3:5])[CH3:4]
Reactant: COCCOCCl
Reactant: CC(C)c1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOCOc1ccccc1C(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 80.8 %

Procedure:
In dry tetrahydrofuran (60 mL) was suspended 4.80 g (120 mmol) of 60% sodium hydride, and a dry tetrahydrofuran (80 mL) solution containing 13.6 g (100 mmol) of 2-isopropylphenol was added dropwise to the suspension at 0° C. After stirring at 0° C. for 10 minutes, a dry tetrahydrofuran (80 mL) solution containing 14.9 g (119 mmol) of 2-methoxyethoxymethyl chloride was added dropwise thereto. The reaction mixture was stirred in an ice bath for 2 hours, poured into ice-cold water (250 mL), and extracted with ethyl acetate. The organic layers were combined, washed succeccively with 1 mol/L aqueous sodium hydroxide solution and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (eluted with hexane:ethyl acetate=50:1) to obtain 18.1 g (80.8 mmol, Yield: 80.8%) of 1-isopropyl-2-[(2-methoxyethoxy)methoxy]benzene.
Reaction SMILES: C(OC([CH:6]1[CH:14]2[C:9]3([CH:18]=[CH:17][CH:16]=[CH:15][C:10]3=[N:11][CH2:12][CH2:13]2)[S:8][CH2:7]1)=O)C.[C:19]([O:23][C:24](SC1N=C(C)C=C(C)N=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>C(Cl)(Cl)Cl>[CH2:19]([O:23][C:24]([C:7]1([C:24]([O:23][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:25])[S:8][C:9]23[CH:18]=[CH:17][CH:16]=[CH:15][C:10]2=[N:11][CH2:12][CH2:13][CH:14]3[CH2:6]1)=[O:25])[CH3:20]
Reactant: CCOC(=O)C1CSC23C=CC=CC2=NCCC13
Reactant: Cc1cc(C)nc(SC(=O)OC(C)(C)C)n1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1(C(=O)OC(C)(C)C)CC2CCN=C3C=CC=CC32S1
Yield: 123.3 %

Procedure:
In 20 ml of desiccated chloroform were dissolved 6 g of 1,2,3,4-tetrahydro-benzo[b]thieno[2,3-c]pyridinecarboxylic acid ethyl ester synthesized in Example 1 and 6.63 g of 2-(tertiary-butoxycarbonylthio)-4,6-dimethylpyrimidine, and the solution was refluxed for 30 minutes. After distilling off chloroform under reduced pressure, the residue was dissolved in 300 ml of ethyl acetate and the solution was washed thrice with 50 ml of an aqueous 5% sodium hydrogencarbonate, twice with an aqueous 5% citric acid solution, and then twice with a saturated aqueous sodium chloride solution and thereafter dried with sodium sulfate. Ethyl acetate was distilled off under reduced pressure and the residue was recrystallized from a mixture of chloroform and petroleum ether to provide 6.18 g (yield of 76%) of 2 -tert-butoxycarbonyl-1,2,3,4-tetrahydro-benzo[b]thieno[2,3-c]pyridine-carboxylic acid ethyl ester.
Reaction SMILES: Cl[CH2:2][N:3]1[C:7](=[O:8])[CH:6]([CH2:9][CH2:10][C:11]([CH3:14])([Cl:13])[CH3:12])[N:5]([CH3:15])[S:4]1(=[O:17])=[O:16].[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:20]=1[C:21]([OH:23])=[O:22].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:20]=1[C:21]([O:23][CH2:2][N:3]1[C:7](=[O:8])[CH:6]([CH2:9][CH2:10][C:11]([CH3:14])([Cl:13])[CH3:12])[N:5]([CH3:15])[S:4]1(=[O:17])=[O:16])=[O:22]
Reactant: CN1C(CCC(C)(C)Cl)C(=O)N(CCl)S1(=O)=O
Reactant: O=C(O)c1c(Cl)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1C(CCC(C)(C)Cl)C(=O)N(COC(=O)c2c(Cl)cccc2Cl)S1(=O)=O
Temperature: 0 °C
Yield: 10 %

Procedure:
To a solution of 2-chloromethyl-4-(3-methyl-3-chlorobutyl)-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (0.41 g; 1.35 mmol) in DMF was added at room temperature 2,6-dichlorobenzoic acid (0.283 g; 1.48 mmol) and potassium carbonate (0.246 g, 1.78 mmol), and the resulting solution was allowed to react at room temperature for 40 hours. The mixture was poured into ice/water, extracted with ethyl acetate, and the organic layer was washed with water, brine, and dried. The organic solution was concentrated in vacuo and the residue was purified by silica column chromatography to afford 62 mg (10%) of 2-(2,6-dichlorophenylcarbonyloxymethyl) -4- (3-methyl-3-chlorobutyl)-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula I: Ar=2, 6-Cl2 -phenyl; R1 =H; R2 =(CH2)2C (Cl) (CH3)2 ; R3 =CH3) as a gum.
Reaction SMILES: C([Mg]Br)(C)C.[F:6][C:7]([F:18])([F:17])[O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1Br.[B:19](OC(C)C)([O:24]C(C)C)[O:20]C(C)C.Cl>O1CCCC1.C(OCC)(=O)C>[F:6][C:7]([F:18])([F:17])[O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[B:19]([OH:24])[OH:20]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Fc1ccc(OC(F)(F)F)c(Br)c1
Agent: CC(C)[Mg]Br
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OB(O)c1cc(F)ccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of isopropylmagnesium bromide (2M solution in tetrahydrofuran) (83 ml, 0.166 mol) was added drop-wise to a stirred solution of 2-(trifluoromethoxy)-5-fluoro-1-bromobenzene (Preparation 49, 27.6 g, 0.107 mol) in anhydrous tetrahydrofuran (125 ml) at −10° C. under an atmosphere of nitrogen. The resulting mixture was stirred at room temperature for 2 hours. Triisopropyl borate (26.1 g, 0.139 mol) was then added drop-wise at −10° C. and the resulting mixture was stirred at room temperature for 16 hours. Hydrochloric acid (1N aqueous solution) (100 ml) was added drop-wise at 0° C. and the mixture stirred at room temperature for 30 minutes. Ethyl acetate (150 ml) was added and the layers were separated, the aqueous layer was further extracted with ethyl acetate (2×150 ml). The organic extracts were combined and concentrated in vacuo. The residue was dissolved in potassium hydroxide (10% aqueous solution) (50 ml) and extracted with diethyl ether (2×150 ml). The separated aqueous layer was acidified to pH˜4 by addition of hydrochloric acid (1N aqueous solution) (100 ml) and extracted with ethyl acetate (3×150 ml). The combined organic extracts were dried over anhydrous Na2SO4, filtered and evaporated in vacuo to give an off white solid. Purification by preparative HPLC gave the title compound as an off white solid (5.82 g, 24%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:13][C:14]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:11]#[C:10][CH2:9][CH2:8][C:12]1[O:13][C:14]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][C:15]=2[N:16]=1
Reactant: Ic1ccccn1
Reactant: C#CCCc1nc2cc(C#N)ccc2o1
Product: N#Cc1ccc2oc(CCC#Cc3ccccn3)nc2c1
Yield: 37.2 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-iodopyridine (89 mg, 0.43 mmol) and 2-(but-3-ynyl)benzo[d]oxazole-5-carbonitrile (100 mg, 0.51 mmol) at room temperature. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 45 mg (0.16 mmol, 37%) of 2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole-5-carbonitrile as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH:17]([CH2:20][O:21][CH3:22])[CH2:18][CH3:19])[C:11]=1[N+:23]([O-])=O.[O-]S(S([O-])=O)=O.[Na+].[Na+]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH:17]([CH2:20][O:21][CH3:22])[CH2:18][CH3:19])[C:11]=1[NH2:23]
Reactant: CCC(COC)Nc1nccc(-c2ccc(OC)cc2Cl)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: CCC(COC)Nc1nccc(-c2ccc(OC)cc2Cl)c1N
Yield: 88.2 %

Procedure:
[4-(2-Chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl]-(1-methoxymethyl-propyl)-amine (0.10 g, 0.27 mmol) and Na2S2O4 (0.38 g, 2.21 mmol) were treated substantially as described in Part E of Example 9 to give 0.08 g (87%) 4-(2-chloro-4-methoxy-phenyl)-N2-(1-methoxymethyl-propyl)-pyridine-2,3-diamine: MS (AP) m/z 335.8 [(M+H)+, 100].
Reaction SMILES: [C:1]1([S:7]([CH:10]([F:12])[F:11])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].ClCCl>[F:11][C:10]([F:12])([S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:9])=[O:8])[CH:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[OH:22]
Reactant: O=S(=O)(c1ccccc1)C(F)F
Reactant: O=Cc1ccccc1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)C(F)(F)C(O)c1ccccc1
Reaction time: 0.17 h
Yield: 90.3 %

Procedure:
A mixture of 100 mg (0.52 mmol) of difluoromethyl phenyl sulfone, 1.0 mL of dichloromethane, 1.0 mL of 50% aqueous sodium hydroxide and 20 mg (0.050 mmol) of Aliquat 336 was stirred vigorously for 10 minutes and treated with a solution of 0.16 mL (1.6 mmol) of benzaldehyde in 0.5 mL of dichloromethane. Vigorous stirring was continued for four hours and the resulting mixture was poured into 20 mL of 1N HCL. Extraction of the aqueous mixture with three 10 mL portions of dichloromethane followed by combination, drying (MgSO4), and concentration in vacuo of the organic layers gave a residue which was purified by preparative TLC (two 2 mm silica gel plates eluted with dichloromethane), affording 140 mg (90% yield) of 2,2-difluoro-1-phenyl-2-phenylsulfonylethanol as a solid. Crystallization from toluene provided an analytical sample: mp 77°-79° C.; IR (neat) 3503, 3064, 2922, 1447, 1335, 1312, 1197, 1154, 1113, 1089, 996, 738, 715, 698, 685, 585, 558, cm-1 1H NMR (CDCl3) δ3.54 (broad s, 1H), 5.54 (dd, 1H, JHF =21, 3 Hz), 7.20-8.10 (m, 10H); 19F NMR (CDCl3, relative to CFCl3) -106.4 ppm (dd, 1F, JFF =238 Hz, JHF =3Hz), -121.6 ppm (dd, 1F, JFF =238 Hz, JHF =21 Hz); mass spectrum (70 eV) m/e relative intensity) 298 (8, M+), 156(18), 109(31), 107(100), 79(30), 78(18), 77(56), 51(20). Anal. Calcd. for C14H12F2O3S:C, 56.37; H, 4.06. Found: C, 56.58; H, 4.08.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C:7]([CH3:13])([CH3:12])[CH2:8][C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.[Cl:27][C:28]1[CH:29]=[C:30]([C@@H:34]([NH:36][C:37](=[O:70])/[CH:38]=[CH:39]/[C@:40]23[CH2:66][CH2:65][C:64]([CH:67]([CH3:69])[CH3:68])=[C:41]2[C@@H:42]2[C@@:55]([CH3:58])([CH2:56][CH2:57]3)[C@@:54]3([CH3:59])[C@@H:45]([C@:46]4([CH3:63])[C@@H:51]([CH2:52][CH2:53]3)[C:50]([CH3:61])([CH3:60])[C@@H:49](O)[CH2:48][CH2:47]4)[CH2:44][CH2:43]2)[CH3:35])[CH:31]=[CH:32][CH:33]=1.O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:12][C:7]([CH3:13])([CH2:8][C:9]([O:11][C@H:49]1[CH2:48][CH2:47][C@@:46]2([CH3:63])[C@@H:51]([CH2:52][CH2:53][C@:54]3([CH3:59])[C@@H:45]2[CH2:44][CH2:43][C@H:42]2[C@@:55]3([CH3:58])[CH2:56][CH2:57][C@@:40]3(/[CH:39]=[CH:38]/[C:37]([NH:36][C@H:34]([C:30]4[CH:31]=[CH:32][CH:33]=[C:28]([Cl:27])[CH:29]=4)[CH3:35])=[O:70])[CH2:66][CH2:65][C:64]([CH:67]([CH3:69])[CH3:68])=[C:41]32)[C:50]1([CH3:60])[CH3:61])=[O:10])[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:14]
Reactant: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)N[C@@H](C)c2cccc(Cl)c2)CC1
Reactant: CC(C)(C)OC(=O)C(C)(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)N[C@@H](C)c2cccc(Cl)c2)CC1

Procedure:
To a solution of 4-tert-butoxy-3,3-dimethyl-4-oxobutanoic acid (1.174 g, 5.80 mmol), DMAP (0.709 g, 5.80 mmol) in DCM (20 mL) stirred at rt was added EDCl (1.854 g, 9.67 mmol). The reaction mixture was stirred at rt for 2 h. (E)-N—((S)-1-(3-Chlorophenyl)ethyl)-3-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-hydroxy-1-isopropyl-5a,5b,8,8,11a-pentamethyl-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-3a-yl)acrylamide (1.2 g, 1.934 mmol) was added to the reaction mixture. The resultant mixture was stirred at rt overnight. Water was added and the mixture was partitioned and washed with additional water. The organics were dried over sodium sulfate filtered through a short silica gel column and evaporated in vacuo to give the crude product as yellow foam. This material was used in the next step without further purification.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][C@H:28]1[C:33]([OH:35])=[O:34]>>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:27]2[CH2:32][CH2:31][O:30][CH2:29][C@H:28]2[C:33]([OH:35])=[O:34])=[C:4]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Reactant: O=C(O)[C@@H]1COCCN1
Product: CCOC(=O)C1=C(CN2CCOC[C@H]2C(=O)O)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Yield: 80.2 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1.6 g, 3.37 mmol) was reacted with (S)-morpholine-3-carboxylic acid (0.44 g, 3.37 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (1.42 g, 80%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][CH:2](C)[C:3]([O:5][C@@H:6]1[C@@H:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13](=[O:22])[O:12][CH2:11][C@H:10]([NH:23][C:24]([C:26]2[C:31]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[C:30]([O:40][CH3:41])[CH:29]=[CH:28][N:27]=2)=[O:25])[C:9](=[O:42])[O:8][C@H:7]1[CH3:43])=O.C1C=CC(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CCCCCC.CC(C)=O>[CH2:3]([O:5][C@H:6]1[C@H:7]([CH3:43])[O:8][C:9](=[O:42])[C@@H:10]([NH:23][C:24]([C:26]2[C:31]([O:32][CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[C:30]([O:40][CH3:41])[CH:29]=[CH:28][N:27]=2)=[O:25])[CH2:11][O:12][C:13](=[O:22])[C@@H:14]1[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH:2]=[CH2:1]
Reactant: COc1ccnc(C(=O)N[C@H]2COC(=O)[C@H](Cc3ccccc3)[C@@H](OC(=O)C(C)C)[C@H](C)OC2=O)c1OCc1ccccc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(CCCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)=O
Solvent: CCCCCC
Product: C=CCO[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)c2nccc(OC)c2OCc2ccccc2)COC(=O)[C@@H]1Cc1ccccc1
Yield: 69 %

Procedure:
Compound 7 was prepared in 69% yield using Compound 2 (65.2 g, 122.1 mmol) with dppb (5.20 g, 12.21 mmol), Pd2dba3 (2.79 g, 3.05 mmol) and ethyl methallylcarbonate (20.63 g, 158.73 mmol). Crude product upon chromatography on silica gel eluting with a mixture of hexane-acetone (1:1) afforded a white foam: m.p.=55-57° C., MS: (M+1)+=585, (M−1)+=583. Spectral data were consistent with the assigned structure.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([N+:9]([O-:11])=[O:10])=[C:4](Cl)[N:3]=1.[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([C:14]2[O:13][CH:17]=[CH:16][CH:15]=2)[N:3]=1
Reactant: OB(O)c1ccco1
Reactant: Nc1nc(Cl)c([N+](=O)[O-])c(=O)[nH]1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1nc(-c2ccco2)c([N+](=O)[O-])c(=O)[nH]1
Yield: 44 %

Procedure:
To a stirred solution of 15.7 g (75.3 mmol) 2-amino-6-chloro-5-nitro-3H-pyrimidin-4-one in 300 ml dioxane and 100 ml water at room temperature were added 8.40 g (75.0 mmol) 2-furylboronic acid, 8.70 g (7.53 mmol) tetrakis(triphenylphosphine)palladium(O) and 150 ml (300 mmol) 2M aqueous sodium carbonate solution. The reaction mixture was heated at reflux for 7 h, then concentrated in vacuo. The residue was resuspended in acetone and the insoluble material collected by filtration. This solid material was then dissolved in 1.21 water and acidified to pH 4-5 with 25% hydrochloric acid. The resulting crystals were collected by filtration and washed with water. After drying in vacuo they were additionally washed with dichloromethane to afford 7.33 g (44%) 2-amino-6-furan-2-yl-5-nitro-3H-pyrimidin-4-one as a yellow crystalline solid. ES-MS m/e (%): 221 ([M—H]−, 100).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]2[N:14]3[CH2:18][C:19](C(OCC)=O)=[C:20]([O-:21])[C:13]3=[CH:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K+]>CC(O)=O.O>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]2[N:14]3[CH2:18][CH2:19][C:20](=[O:21])[C:13]3=[CH:12][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1=C([O-])c2cc3cc(OCc4ccccc4)ccc3n2C1
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1CCn2c1cc1cc(OCc3ccccc3)ccc12
Temperature: 25 °C
Yield: 81 %

Procedure:
To a 3-neck, 5L RB flask equipped w/a mechanical stirrer, temperature probe, and a reflux condenser was added potassium 7-(benzyloxy)-2-(ethoxycarbonyl)-3H-pyrrolo[1,2-a]indol-1-olate (206 g, 530 mmol) followed by AcOH:H2O (2:1, v/v, 2.65 L). The mixture was heated to reflux for 40 h and cooled to room temperature. Upon cooling a light brown precipitate formed. The mixtures from all four batches were combined and filtered. The solid was washed with H2O and hexanes. The filtrates were further diluted with water (1 L) and an additional solid precipitated. The 2nd crop was filtered and the solid washed with water and hexanes. Both crops were combined and dried in a vacuum oven (50° C., 2 Ton) to give 7-(benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-one (493 g from all 4 batches, 1.72 mol, 81% yield) as a brown solid. Exact mass calculated for C18H15NO2: 277.1, found: LCMS m/z=278.2, [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 3.20 (t, J=6.4 Hz, 2 H), 4.40 (t, J=6.4 Hz, 2 H), 5.11 (s, 2 H), 6.91 (s, 1 H), 7.13 (dd, J1=9.0, J2=2.3 Hz, 1 H), 7.20 (d, J=2.3 Hz, 1 H), 7.33 (m, 2 H), 7.39 (m, 2 H), 7.47 (m, 2 H).