Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C@H:6]([CH2:13][CH3:14])[N:5]([CH:15]([CH3:17])[CH3:16])[C:4]=2[N:3]=1.[C:18]1(C)C=CC(S(OC)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:18])[C:7](=[O:12])[C@H:6]([CH2:13][CH3:14])[N:5]([CH:15]([CH3:16])[CH3:17])[C:4]=2[N:3]=1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: CC[C@H]1C(=O)Nc2cnc(Cl)nc2N1C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC[C@H]1C(=O)N(C)c2cnc(Cl)nc2N1C(C)C
Reaction time: 12 h
Yield: 81 %

Procedure:
The crude compound (7S)-2-chloro-8-isopropyl-7-ethyl-5,7-dihydropteridin-6-one 43c (7.17 g, 28.21 mmol), methyl p-toluenesulfonate (5.77 g, 31.03 mmol) and potassium carbonate (11.70 g, 84.60 mmol) were dissolved in 40 mL of acetone. The reaction solution was stirred for 12 hours and the precipite was filtered. The filter cake was washed with dichloromethane (100 mL). The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with elution system B to obtain (7S)-2-chloro-8-isopropyl-7-ethyl-5-methyl-7H-pteridin-6-one 43d (6.14 g, yield: 81.0%) as a white solid.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH:10]([CH3:12])[CH3:11])[C:6]2[CH:13]=[CH:14][CH:15]=[CH:16][C:5]=2[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])=[N:3]1.N[C@@H]1C(=O)N(C)C2C=CC=CC=2C(C2C=CC=CC=2)=N1.[Cl:44][C:45]1[CH:46]=[C:47]([CH:56]=[CH:57][C:58]=1[Cl:59])[CH2:48][C@H:49]([CH2:53][CH:54]=[CH2:55])[C:50](O)=[O:51]>>[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:4]1[C:5]2[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=2[N:7]([CH:10]([CH3:12])[CH3:11])[C:8](=[O:9])[CH:2]([NH:1][C:50](=[O:51])[C@H:49]([CH2:48][C:47]2[CH:56]=[CH:57][C:58]([Cl:59])=[C:45]([Cl:44])[CH:46]=2)[CH2:53][CH:54]=[CH2:55])[N:3]=1
Reactant: CC(C)N1C(=O)C(N)N=C(c2ccccc2F)c2ccccc21
Reactant: C=CC[C@@H](Cc1ccc(Cl)c(Cl)c1)C(=O)O
Agent: CN1C(=O)[C@@H](N)N=C(c2ccccc2)c2ccccc21
Product: C=CC[C@@H](Cc1ccc(Cl)c(Cl)c1)C(=O)NC1N=C(c2ccccc2F)c2ccccc2N(C(C)C)C1=O

Procedure:
Prepared from 3-amino-5-(2-fluoro-phenyl)-1-isopropyl-2-oxo-1,3-dihydro-2H-benzo[e][1,4]diazepine [available in an analogous fashion to (S)-3amino-1-methyl-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one (i.e. J. Org. Chem. 1987, 52, 3232)] and (2S)-2-(3,4dichlorobenzyl)-pent-4-enoic acid using the procedure of Step 1E shown in Scheme 1.
Reaction SMILES: [C:1]([C:4]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[C:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[C:7]([CH3:26])[NH:6][C:5]=1OCOCC[Cl:32])(=[O:3])[CH3:2].[I-].[Na+].Cl.[C:36]1([C:42]2([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(OCC)C>[ClH:32].[C:1]([C:4]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[C:8]([C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])=[C:7]([CH3:26])[NH:6][C:5]=1[CH2:22][O:21][CH2:19][CH2:8][N:45]1[CH2:44][CH2:43][C:42]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:47][CH2:46]1)(=[O:3])[CH3:2]
Reactant: CC(=O)C1=C(OCOCCCl)NC(C)=C(C(=O)OC(C)(C)C)C1c1cccc([N+](=O)[O-])c1
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(=O)C1=C(COCCN2CCC(c3ccccc3)(c3ccccc3)CC2)NC(C)=C(C(=O)OC(C)(C)C)C1c1cccc([N+](=O)[O-])c1

Procedure:
8.5 g (19 mmol) 3-acetyl-5-tert-butoxycarbonyl-2-(2-chloro-1-ethoxy)methoxy-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-pyridine are reacted first with 5.6 g (38 mmol) sodium iodide, as described for starting compound B, and then with 10.3 g (36 mmol) 4,4-diphenylpiperidine hydrochloride. Working up is carried out as described for starting compound B. The crude product is chromatographed with toluene/acetone=9/1. The product thus obtained is taken up in 50 ml diethyl ether. The title compound is precipitated by addition of ethereal hydrochloric acid. Yield: 11 g (84%). M.p. 175°-177° C. (diethyl ether).
Reaction SMILES: [CH3:1][C:2](=[CH:8][CH:9]([CH3:20])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=1)[CH:3]=[CH:4][C:5](O)=[O:6].O.[OH:22][N:23]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.NO.CCN(CC)CC>CN(C=O)C>[OH:22][NH:23][C:5](=[O:6])[CH:4]=[CH:3][C:2]([CH3:1])=[CH:8][CH:9]([CH3:20])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=1
Reactant: On1nnc2ccccc21
Reactant: CC(C=CC(=O)O)=CC(C)Cc1ccc(N(C)C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C=CC(=O)NO)=CC(C)Cc1ccc(N(C)C)cc1
Reaction time: 1 h
Yield: 40.6 %

Procedure:
To a stirred solution of carboxylic acid 37 (70 mg, 0.256 mmol) at rt in anhydrous DMF (2 mL) was added 1-hydroxybenzotriazole hydrate (41.5 mg, 0.307 mmol) followed by 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride(65 mg, 0.340 mmol). After 1 h, hydroxylamine hydrochloride (89 mg, 1.28 mmol) and Et3N (0.27 mL, 1.92 mmol) was added, and stirring was continued at rt overnight. The solvent was removed in vacuo, and the residue was diluted with ethyl acetate (30 mL), and washed with water and saturated NaHCO3 solution (5 mL). After drying and concentration, the crude product was purified by flash silica gel chromatography (2-10% methanol in chloroform) to give the title compound 38 (30 mg, 41% yield) as a yellow oil: 1H NMR (300 MHz, CDCl3:CD3OD=5:1) δ 7.10 (d, J=14.4 Hz, 1H), 6.88 (d, J=8.7 Hz, 2H), 6.58 (d, J=8.7 Hz, 2H), 5.59 (d, J=9.3 Hz, 1H), 5.55 (br. d, J=14.4 Hz, 1H), 2.78 (s, 6H), 2.63 (m, 1H), 2.40 (d, J=6.9 Hz, 2H), 1.48 (s, 3H), 0.89 (d, J=6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3: CD3OD=5:1) δ 11.8, 19.7, 35.3, 40.8, 42.0, 14.3, 20.0, 35.5, 40.8, 42.2, 113.1, 113.7, 128.7, 129.5, 131.1, 145.9, 146.3, 148.9, 165.5.
Reaction SMILES: CC([N:5]([CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH:16]2[C:20]3=[C:21]([Cl:29])[CH:22]=[N:23][C:24]4[CH:25]=[CH:26][C:27](=[O:28])[N:18]([C:19]=43)[CH2:17]2)[CH2:11][CH2:10]1)C(=O)[O-])(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:5][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH:16]2[C:20]3=[C:21]([Cl:29])[CH:22]=[N:23][C:24]4[CH:25]=[CH:26][C:27](=[O:28])[N:18]([C:19]=43)[CH2:17]2)[CH2:11][CH2:10]1
Reactant: CC(C)(C)N(C(=O)[O-])C1CCN(CC2Cn3c(=O)ccc4ncc(Cl)c2c43)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCN(CC2Cn3c(=O)ccc4ncc(Cl)c2c43)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
A suspension of 1,1-dimethylethyl{1-[(3-chloro-7-oxo-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-4-yl)methyl]-4-piperidinyl}carbamate (1.475 g, 4.63 mmol) in dichloromethane (15 ml) was treated with trifluoroacetic acid (12 ml) and stirred at room temperature for 1 h. The reaction mixture was evaporated and then treated with aqueous sodium bicarbonate solution and a 4:1 dichloromethane:methanol solution. The aqueous phase was extracted about 15 times with a 4:1 dichloromethane:methanol solution and then the combined organic phases were dried and the solvent was removed. The residue was subjected to column chromatography on silica gel using a dichloromethane, methanol and aqueous ammonia gradient to provide the desired compound (0.94 g, 84%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:15][C:14]=2[CH2:32][CH3:33])[N:3]=1.[C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[CH2:42][C:43]([O:45][CH3:46])=[O:44])#[CH:35].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>[Cu]I.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.CN(C=O)C>[CH2:32]([C:14]1[CH:15]=[C:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[CH:17]=[CH:18][C:13]=1[NH:12][C:4]1[N:3]=[C:2]([C:35]#[C:34][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[CH2:42][C:43]([O:45][CH3:46])=[O:44])[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=1)[CH3:33]
Reactant: C#Cc1ccccc1CC(=O)OC
Reactant: CCc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc(C(F)(F)F)c(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc(C(F)(F)F)c(C#Cc2ccccc2CC(=O)OC)n1
Temperature: 120 °C
Yield: 85.5 %

Procedure:
A mixture of tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-ethylphenyl)piperidine-1-carboxylate (I41) (283 mg, 0.584 mmol), methyl 2-(2-ethynylphenyl)acetate (I4) (122 mg, 0.700 mmol), copper(I) iodide (17 mg, 15 mol %), triphenylphosphine (23 mg, 15 mol %), bis(triphenylphosphine)palladium(II) chloride (41 mg, 10 mol %), triethylamine (0.33 mL, 2.3 mmol) and DMF (3 mL) was degassed with a nitrogen then heated under microwave irradiation (120° C./15 min). The cooled mixture was poured into water (30 mL) and extracted with ethyl acetate (3×25 mL). The combined organic extracts were washed with brine (2×50 mL), dried over sodium sulfate and evaporated. Chromatography (12 g silica cartridge, 0-80% ethyl acetate/petroleum benzine 40-60° C.) gave the title compound (I42) (311 mg, 86% yield) as a brown oil; 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 7.73-7.65 (m, 2H), 7.46-7.28 (m), 7.15-7.08 (m), 4.25 (s, 2H), 3.95 (s, J=9.6 Hz, 2H), 3.70 (s, 3H), 2.80 (t, J=12.1 Hz, 2H), 2.70-2.59 (m, 3H), 1.84 (d, J=12.9 Hz, 2H), 1.65 (td, J=12.8, 4.1 Hz, 2H), 1.49 (s, 9H), 1.25 (t, J=7.6 Hz, 3H). LCMS: rt 7.01 min; m/z 623.1 [M+H]+, 567.1 [M-tBu+2H]+, 523.1 [M-Boc+2H]+; m/z 621.2 [M−H]−.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:11])[S:9][CH:10]=1)=[O:5])C.Cl>[OH-].[Na+]>[Br:11][C:8]1[S:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=1
Reactant: CCOC(=O)c1csc(Br)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1csc(Br)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
To a 100 mL 24/40 round bottom flask was charged 3.25 g (13.8 mmol) of 2-bromo-4-thiazolecarboxylic acid ethyl ester (Helv. Chim. Acta, 1942, 25, 1073) dissolved in 20 mL of 1N sodium hydroxide. The reaction was stirred at room temperature for 3 h, cooled down in an ice bath and acidified to pH 2 with SN hydrochloric acid. The white precipitate was filtered, washed with 20 mL cold water, and dried in a vacuum oven to give 2.7 g (94%) of 2-bromo-4-thiazolecarboxylic acid. m.p. 227-229° C., Rf =0.16 (20% methanol/chloroform). 1H NMR (300 MHz, DMSO-d6) δ 8.43 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][NH:12][C:13]2[N:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8]C.[F:21][C:22]([F:33])([F:32])[O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][N:12]([C:13]2[N:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][N:14]=2)[CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[C:24]([O:23][C:22]([F:21])([F:32])[F:33])[CH:25]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CCc1cnc(NCCc2ccc(OC)c(Cl)c2)nc1
Reactant: FC(F)(F)Oc1cccc(CBr)c1
Product: CCc1cnc(N(CCc2ccc(O)c(Cl)c2)Cc2cccc(OC(F)(F)F)c2)nc1

Procedure:
Similarly prepared from N-[2-(3-chloro-4-methoxyphenyl)ethyl]-5-ethylpyrimidin-2-amine and 3-trifluoromethoxy benzyl bromide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:18]([O:20][CH2:21][C:22](O)=O)[CH3:19].[OH-].[Na+]>O>[CH2:18]([O:20][CH2:21][C:22]1[N:12]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH3:19]
Reactant: CCOCC(=O)O
Reactant: CC(C)CCNc1c(N)cnc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOCc1nc2cnc3ccccc3c2n1CCC(C)C
Temperature: 155 °C

Procedure:
3-Amino-4-(3-methylbutylamino)quinoline (7 g, 0.03 mole; Example 106) was combined with ethoxyacetic acid (8 mL, 0.08 mole) and heated at 150-160° C. for about 2 hours. The reaction mixture was cooled to room temperature, diluted with water (100 mL), made basic with sodium hydroxide and then extracted with ethyl acetate. The extract was dried over magnesium sulfate then evaporated to provide the crude product as a crystalline solid. The solid was recrystallized from hexane to provide the desired product as a solid, m.p. 64-65° C. Analysis: Calculated: %C, 72.7; %H, 7.8; %N, 14.1; Found: %C, 72.5; %H, 7.7; %N, 14.1.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH2:8]C(OCC)=O)=[O:7].[OH-].[K+].[N:16]([O-])=[O:17].[Na+].S(=O)(=O)(O)O>O.CCOCC>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:7])/[CH:8]=[N:16]/[OH:17]
Reactant: CCOC(=O)CC(=O)c1ccco1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: O=C(/C=N/O)c1ccco1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 61.4 %

Procedure:
A solution of ethyl 2-(fur-2-oyl)acetate (5.38 g, 29.5 mmol) and potassium hydroxide (2.70 mL, 2.7 g, 48.1 mmol) in water (70 mL) was stirred overnight at rt. sodium nitrite (2.038 g, 29.5 mmol) in water (10 mL) was added and cooled down to 0° C. A solution of 6N sulfuric acid in water (14 mL) was added drop wise and stirred for 15 min (precipitate was formed). Ether was added and the water layer was extracted twice with ether. The combined organic layers were washed with water, dried and evaporated. Crystallization with CH2Cl2 gave (E)-2-(furan-2-yl)-2-oxoacetaldehyde oxime 54 (2.52 g, 61.3%). NMR (400 MHz, CDCl3) 6.59 (q, J=3.5 and 1.5 Hz, 1H), 7.55 (dd, J=3.5 and 0.8 Hz, 1H), 7.72 (m, 1H), 7.96 (s, 1H), 8.27 (br s, 1H).
Reaction SMILES: Cl[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].[Cl:10][SiH:11]([Cl:13])[Cl:12]>[Cl-].C([P+](CCCC)(CCCC)CCCC)CCC>[Cl:10][Si:11]([Cl:13])([Cl:12])[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3]
Reactant: Cl[SiH](Cl)Cl
Reactant: CC(Cl)c1ccccc1
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Product: CC(c1ccccc1)[Si](Cl)(Cl)Cl
Yield: 35.4 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.20 g (0.68 mmol) of tetrabutylphosphonium chloride, 0.96 g (6.83 mmol) of 1-chloroethylbenzene, and 2.71 g (20.00 mmol) of trichlorosilane were reacted at 150° C. for 6 hrs. The resulting mixture was distilled to give 0.58 g 1-trichlorosilylethylbenzene (yield; 35%).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[NH:3]1.C([Li:15])CCC>>[Li:15][N:3]1[C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][CH2:7][C:2]1([CH3:10])[CH3:1]
Reactant: CC1(C)CCCC(C)(C)N1
Reactant: [Li]CCCC
Product: [Li]N1C(C)(C)CCCC1(C)C
Temperature: -70 °C

Procedure:
After cooling 35 ml of tetradydrofuran to -70° C., 2.1 g (15 mmol) of 2,2,6,6-tetramethylpiperidine and 15 mmol of n-butyl lithium were successively added thereto to obtain a lithium tetramethylpiperidide solution. Separately, 2.04 g (15 mmol) of 1-[(2-t-butyldimethylsilyloxyethoxy)methyl]-6-phenylthiouracil was dissolved in 20 ml of tetrahydrofuran and added dropwise to the said lithium tetramethylpiperidide solution to react for an hour at -70° C. Then, a solution of 3.81 g (15 mmol) of iodine in 20 ml of tetrahydrofuran was further added to the reaction solution while maintaining the reaction temperature at -70° C. to react for an hour. After the completion of the reaction, the reaction solution was added to 0.8 ml of acetic acid, allowed to warm to room temperature and distributed between a chloroform layer and a saturated aqueous solution of sodium bicarbonate. The chloroform layer was concentrated to dryness. The residue was crystallized from petroleum ether to obtain 1.835 g of 1-[(2-t-butyldimethylsilyloxyethoxy)methyl]-5-iodo-6-phenylthiouracil (Yield: 62.8%).
Reaction SMILES: C([O:3][C:4](=[O:40])/[CH:5]=[CH:6]/[CH:7]=[CH:8]/[CH2:9][CH2:10][CH:11]([C@@H:13]1[C@:30]2([CH3:31])[C@H:16]([C@H:17]3[C@H:27]([CH2:28][C@@H:29]2[O:32]C(=O)C)[C@:25]2([CH3:26])[C@@H:20]([CH2:21][C@H:22]([O:36]C(=O)C)[CH2:23][CH2:24]2)[CH2:19][CH2:18]3)[CH2:15][CH2:14]1)[CH3:12])C.[OH-].[Na+].C>O>[OH:36][C@@H:22]1[CH2:23][CH2:24][C@@:25]2([CH3:26])[C@H:20]([CH2:19][CH2:18][C@@H:17]3[C@@H:27]2[CH2:28][C@H:29]([OH:32])[C@@:30]2([CH3:31])[C@H:16]3[CH2:15][CH2:14][C@@H:13]2[CH:11]([CH2:10]/[CH:9]=[CH:8]/[CH:7]=[CH:6]/[CH2:5][C:4]([OH:40])=[O:3])[CH3:12])[CH2:21]1
Reactant: CCOC(=O)/C=C/C=C/CCC(C)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)[C@H]3C[C@H](OC(C)=O)[C@]12C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C/C=C/C=C/CC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Yield: 69.1 %

Procedure:
A mixture of 7.25 g of 7-(3α,12α-diacetoxy-5β-pregnane-20-yl)-trans,trans-2,4-heptadienoic acid ethyl ester and 57 ml of 5N aqueous sodium hydroxide solution was stirred and refluxed for 1.5 hr. At the end of this time, 500 ml of water was added and the mixture heated to reflux. The cloudy solution was cooled, charcoal added and the mixture was filtered through a bed of diatomaceous earth. The filtrate was cooled to 0° and made acidic (pH3) by the dropwise addition of concentrated aqueous hydrochloric acid. The precipitate was filtered and air dried overnight under house vacuum. Crystallization from methyl ethyl ketone afforded 4 g of 7-(3α,12α-dihydroxy-5β-pregnane-20-yl)-trans,trans-3,5-heptadienoic acid, mp 208°-211°.
Reaction SMILES: [CH:1]1([CH:7]([NH:24][C:25]2[CH:33]=[CH:32][C:28]([C:29]([OH:31])=O)=[CH:27][CH:26]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=3)[O:10][C:9]=2[CH3:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:34][NH:35][CH2:36][CH2:37][C:38]([O:40]CC)=[O:39].Cl.C(N=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:24][C:25]2[CH:33]=[CH:32][C:28]([C:29]([N:35]([CH3:34])[CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:31])=[CH:27][CH:26]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=3)[O:10][C:9]=2[CH3:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cn2)cc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Reactant: CCOC(=O)CCNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccc(C(F)(F)F)cn2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.3 %

Procedure:
A solution of 4-({cyclohexyl[2-methyl-5-(5-{trifluoromethyl}pyridin-2-yl)furan-3-yl]methyl}amino)benzoic acid (229 mg), ethyl 3-(methylamino)propanoate (79 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (115 mg), hydroxybenzotriazole monohydrate (92 mg) and triethylamine (84 μL) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure. 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 (161 mg, 80%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1([CH:16]([C:18]1[CH:23]=[C:22]([F:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=1)[OH:17])[CH2:13][CH2:14][CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1([C:16](=[O:17])[C:18]1[CH:23]=[C:22]([F:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=1)[CH2:13][CH2:14][CH3:15])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCC1(C(O)c2cc(F)c(Cl)c(Cl)c2)CCCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Product: CCCC1(C(=O)c2cc(F)c(Cl)c(Cl)c2)CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67.6 %

Procedure:
To a stirred solution of 2-[(3,4-dichloro-5-fluoro-phenyl)-hydroxy-methyl]-2-propyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.533 g, 1.31 mmol) in DCM (20 mL) at 0° C. under nitrogen was added DMP (0.557 g, 1.55 mmol) in a single portion. The reaction mixture was warmed to ambient temperature and stirred for 90 minutes. A second portion of DMP (0.110 g, 0.26 mmol) was added, and the reaction mixture was stirred for 30 minutes, then diluted with DCM, washed with 1 N NaOH, brine (20 mL), dried (MgSO4), filtered and concentrated in vacuo to a clear colourless oil (0.55 g). Purification by chromatography (silica, 5-20% EtOAc in hexanes) gave 2-(3,4-dichloro-5-fluoro-benzoyl)-2-propyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.358 g, 0.886 mmol, 68%) as a clear colourless gum.
Reaction SMILES: [C:1]([OH:12])(=O)[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.[NH2:13][CH:14]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:15][OH:16]>>[OH:16][CH2:15][CH:14]([NH:13][C:1]([C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1)=[O:12])[CH2:17][CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)CC(N)CO
Reactant: O=C(O)c1ccc2c(c1)OCO2
Product: CC(C)CC(CO)NC(=O)c1ccc2c(c1)OCO2

Procedure:
N-(1-hydroxy-4-methylpentan-2-yl)benzo[d][1,3]dioxole-5-carboxamide was prepared in a similar manner to example 4 from piperonylic acid and 2-amino-4-methyl-pentan-1-ol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([N:24]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][C:32]=4[O:39][CH3:40])[C:25]4[S:29][N:28]=[CH:27][N:26]=4)(=[O:23])=[O:22])=[CH:18][CH:19]=3)[N:14]([CH3:41])[CH:13]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[N:42]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[CH3:40][O:39][C:32]1[CH:33]=[C:34]([O:37][CH3:38])[CH:35]=[CH:36][C:31]=1[CH2:30][N:24]([C:25]1[S:29][N:28]=[CH:27][N:26]=1)[S:21]([C:17]1[CH:16]=[C:15]2[C:20]([C:12]([C:4]3[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=[C:2]([C:45]4[CH:46]=[CH:47][N:42]=[CH:43][CH:44]=4)[CH:3]=3)=[CH:13][N:14]2[CH3:41])=[CH:19][CH:18]=1)(=[O:23])=[O:22]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4cc(Br)cc(C(F)(F)F)c4)cn(C)c3c2)c(OC)c1
Reactant: OB(O)c1ccncc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4cc(-c5ccncc5)cc(C(F)(F)F)c4)cn(C)c3c2)c(OC)c1

Procedure:
A microwave vial was charged with 3-(3-bromo-5-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (0.050 g, 0.075 mmol), pyridin-4-ylboronic acid (0.018 g, 0.150 mmol), potassium phosphate (0.056 g, 0.262 mmol), and Pd(AmPhos)2Cl2 (5.30 mg, 7.49 μmol). The vial was flushed with Ar, then dioxane (0.375 ml) and water (0.125 ml) were added in sequence. The vial was sealed and microwaved at 100° C. for 30 minutes. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried with sodium sulfate, filtered and concentrated. The material was purified via column chromatography (silica gel, gradient elution 0 to 100% EtOAc/Heptane) to afford N-(2,4-dimethoxybenzyl)-1-methyl-3-(3-(pyridin-4-yl)-5-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide as a yellow solid. m/z (ESI) 666.2 (M+H)+.