Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]=1)[C:8]([OH:10])=O)[CH3:3].[NH2:22][C:23]1[CH:27]=[CH:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:24]=1>>[CH3:3][CH:2]([O:4][C:5]1[CH:6]=[C:7]([C:8]([NH:22][C:23]2[CH:27]=[CH:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:24]=2)=[O:10])[CH:11]=[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]=1)[CH3:1]
Reactant: CC(C)(C)OC(=O)n1ccc(N)n1
Reactant: CC(C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Product: CC(C)Oc1cc(OCc2ccccc2)cc(C(=O)Nc2ccn(C(=O)OC(C)(C)C)n2)c1

Procedure:
The preparations of 3-[(1-methylethyl)oxy]-5-[(phenylmethyl)oxy]benzoic acid and 1,1-dimethylethyl 3-amino-1H-pyrazole-1-carboxylate were described earlier.
Reaction SMILES: C(OC(N1CCC(NC(C2SC=CC=2NC2C=CN=C3NC=CC=23)=O)C1)=O)(C)(C)C.[C:31]1([C@@H:37]([CH2:39][OH:40])[NH2:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[NH:41]1[C:45]2=[N:46][CH:47]=[CH:48][C:49]([NH:50][C:51]3[C:52]4[CH:62]=[CH:61][CH:60]=[CH:59][C:53]=4[S:54][C:55]=3[C:56](O)=[O:57])=[C:44]2[CH:43]=[CH:42]1>>[OH:40][CH2:39][C@@H:37]([NH:38][C:56]([C:55]1[S:54][C:53]2[CH:59]=[CH:60][CH:61]=[CH:62][C:52]=2[C:51]=1[NH:50][C:49]1[CH:48]=[CH:47][N:46]=[C:45]2[NH:41][CH:42]=[CH:43][C:44]=12)=[O:57])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: N[C@H](CO)c1ccccc1
Reactant: O=C(O)c1sc2ccccc2c1Nc1ccnc2[nH]ccc12
Agent: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Product: O=C(N[C@H](CO)c1ccccc1)c1sc2ccccc2c1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using (S)-2-phenylglycinol instead of 1-BOC-3-aminopyrrolidine and 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-benzo[b]thiophene-2-carboxylic acid instead of 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid. LCMS (ESI) 429 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.63 (1H, br. s.) 9.24 (1H, br. s.) 8.57 (1H, d, J=7.96 Hz) 8.09 (1H, d, J=8.10 Hz) 7.84 (1H, d, J=5.66 Hz) 7.59 (1H, d, J=7.96 Hz) 7.52 (1H, td, J=7.60, 1.15 Hz) 7.40 (1H, dd, J=15.13, 0.88 Hz) 7.28 (1H, dd, J=2.95, 1.44 Hz) 7.10-7.18 (1H, m) 7.06 (2H, t, J=7.32 Hz) 6.99-7.03 (2H, m) 6.50 (1H, br. s.) 6.04 (1H, d, J=5.66 Hz) 4.92-5.00 (1H, m) 4.90 (1H, t, J=5.30 Hz) 3.48 (2H, td, J=11.20, 5.71 Hz)
Reaction SMILES: [CH:1]1([C@H:4]2[C@H:8]([OH:9])[CH2:7][C:6](=[O:10])[N:5]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3][CH2:2]1.[C:18]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])([CH3:20])[CH3:19].N1C=CN=C1>CN(C=O)C>[Si:22]([O:9][C@@H:8]1[CH2:7][C:6](=[O:10])[N:5]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@H:4]1[CH:1]1[CH2:2][CH2:3]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1C(=O)C[C@@H](O)[C@@H]1C1CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C(=O)C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1C1CC1
Yield: 90.2 %

Procedure:
(2S,3R)-tert-Butyl 2-cyclopropyl-3-hydroxy-5-oxopyrrolidine-1-carboxylate (16) (1.34 g, 5.55 mmol) was placed in a flame-dried flask under nitrogen. DMF (12 mL) was added and the mixture stirred until dissolved. tert-butylchlorodimethylsilane (1.06 g, 7.02 mmol) and imidazole (0.558 g, 8.19 mmol) were added and the reaction stirred for 16 hr at rt. DMF was removed in vacuo and EtOAc (100 mL) was added and the organics were washed with sat. NaHCO3 (100 mL), brine (100 mL), dried with sodium sulfate, and concentrated in vacuo. The resulting crude product was purified via column chromatography using EtOAc/hexane gradients to yield (2S,3R)-tert-butyl 3-(tert-butyldimethylsilyloxy)-2-cyclopropyl-5-oxopyrrolidine-1-carboxylate (17) (1.78 g, 90%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[CH:12][CH:13]=1)[N:7]=[C:8]([S:10][CH3:11])[N:9]=2.[C:14]1(OC)C=CC=CC=1.[F:22][C:23]([F:30])([F:29])[S:24]([O:27]C)(=[O:26])=[O:25]>C(OCC)(=O)C>[F:22][C:23]([F:30])([F:29])[S:24]([O-:27])(=[O:26])=[O:25].[CH3:14][N:9]1[C:5]2=[CH:4][CH:3]=[C:2]([CH3:1])[CH:13]=[CH:12][C:6]2=[NH+:7][CH:8]1[S:10][CH3:11]
Reactant: CSc1nc2ccc(C)ccc-2n1
Reactant: COc1ccccc1
Reactant: COS(=O)(=O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CSC1[NH+]=C2C=CC(C)=CC=C2N1C
Product: O=S(=O)([O-])C(F)(F)F

Procedure:
6-Methyl-2-methylthiocycloheptimidazole (27 g) was added to 100 ml of anisole and stirred under ice cooling. Then, 28 g of methyl trifluoromethanesulfonate was added dropwise thereto, and stirred under ice cooling. The mixture was further stirred at room temperature for one hour, 200 ml of ethyl acetate was added, and deposited crystals were collected by filtration and dried.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:9][C:10]1[C:11]([N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20]2)=[N:12][C:13]([Cl:18])=[N:14][C:15]=1[CH2:16][CH3:17]>CN(C)C=O>[ClH:18].[CH3:9][C:10]1[C:11]([N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20]2)=[N:12][C:13]([N:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH3:1])=[N:14][C:15]=1[CH2:16][CH3:17]
Reactant: CCc1nc(Cl)nc(N2CCc3ccccc3C2)c1C
Reactant: CNc1ccccc1
Solvent: CN(C)C=O
Product: CCc1nc(N(C)c2ccccc2)nc(N2CCc3ccccc3C2)c1C
Product: Cl
Yield: 52.8 %

Procedure:
After N-methylaniline(0.40 ml, 3.6 mmol) was added to a mixture solution of 5-methyl-6-ethyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-2-chloropyrimidine(0.7 g, 2.4 mmol) and dimethylformamide(5 ml), 0.50 g of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 1.
Reaction SMILES: C(C1C(O[SiH](C)C)=CC(CBr)=CC=1[N:17]1[N:21]=[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]2=[N:18]1)(C)(C)C.CN1C(C)(C)CC(O)CC1(C)C.[H-].[Na+]>CN(C)C=O>[NH:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=[N:17]1
Reactant: C[SiH](C)Oc1cc(CBr)cc(-n2nc3ccccc3n2)c1C(C)(C)C
Agent: CN1C(C)(C)CC(O)CC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc2[nH]nnc2c1
Temperature: 6 °C

Procedure:
This compound was synthesized strictly under dry and inert reaction conditions. The compound 2-(2′-tert-butyl-di-metylsilyloxy-5′-bromomethylphenyl)benzotriazole (2.1 gms, 0.00501 M) was taken in one 25 mL capacity RB and dissolved in 8 mL dry dimethylformamide (DMF) under Argon atmosphere with stirring. In another two-necked RB, 1,2,2,6,6-pentamethyl-4-piperidinol (1.0356 gm, 0.00601 M) and sodium hydride (0.3 gms, 0.01252 M) were taken and dissolved in 6 mL dry DMF with stirring under Argon atmosphere. This reaction mixture was agitated for almost 60 min and then cooled to 4-8° C. To this reaction mixture the contents of the first RB was added gradually over a period of 30-60 min. This reaction mixture was further agitated for 2-4 hrs followed by refluxing the same for a period of 2-4 hrs. The contents of the RB were cooled to room temperature and further agitated for 4-6 hrs at room temperature. The solvent in the RB was evaporated under reduced pressure and the solid mass in the RB was dissolved in 15 mL water and repeatedly extracted with dichloromethane (4×10 mL). Dichloromethane was then evaporated under vacuum at 38° C. over a rotavapor to give pale yellow colored crystalline product 2-[2′-tert-butyldimetylsilyloxy-5′-methyleneoxy((1″, 2″, 2″, 6″, 6″-pentamethyl-4″-piperidinyl) phenyl)benzotriazole. The TLC showed very little amount of unreacted starting material. The crude yield was 2.22 gms (87%). The product was purified by recrystalization technique using an appropriate organic solvent to get (83%) yield of sure product.
Reaction SMILES: Cl.[O:2]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][CH:18]([NH2:21])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[O:2]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][CH:18]([NH:21][C:22](=[O:24])[CH3:23])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NC1CCN(c2ccc(Oc3ccccc3)cc2)CC1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Product: CC(=O)NC1CCN(c2ccc(Oc3ccccc3)cc2)CC1
Yield: 80 %

Procedure:
The title compound (75 mg, 80%) was prepared from the compound from Example 12, step 2 (100 mg, 0.3 mmol) and acetic anhydride by the procedure described in Example 24 Example 14: MS (ESI) m/z 311 (M+H); 1H NMR (400 MHz, CDCl3) δ 1.58 (m, 2H), 2.08 (m, 2H), 2.84 (dd, J=2.8, 12 Hz, 2H), 3.54 (dd, J=2.8, 12.8 Hz, 2H), 3.93 (m, 1H), 5.35 (d, J=7.2 Hz, 1H), 6.91-6.97 (m, 6H), 7.03 (m, 1H), 7.27-7.31 (m, 2H).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:22]=1[CH2:23][NH2:24]>>[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:22]=1[CH2:23][NH:24][C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Reactant: Cc1cccc(Cl)c1CN
Product: Cc1cccc(Cl)c1CNc1nccc(-n2cnc3ccccc32)n1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with 2-chloro-6-methylbenzylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (EI): m/e 350.3 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.66 (s, 1H); 8.40 (br s, 1H); 8.21 (s, 1H); 7.87 (d, J=7.6 Hz, 1H); 7.40 (m, 2H); 7.30 (d, J=8.0 Hz, 1H); 7.17 (m, 2H); 6.85 (d, J=5.5 Hz, 1H); 5.56 (br s, 1H); 4.90 (d, J=5.0 Hz, 2H); 2.51 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19]1([NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH2:25].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14](=[O:16])[NH:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[NH2:26])=[CH:17][CH:18]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccccc1N
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)Nc2ccccc2N)cc1
Yield: 55.7 %

Procedure:
To a suspension of 4-((t-butoxycarbonylamino)methyl)benzoic acid (6.08 g, 24.2 mmol) in DMF was added o-phenylene diamine (2.9 g, 29 mmol), EDCI (9.3 g, 48.4 mmol) and HOBt (3.8 g, 24.2 mmol). TEA (11.8 mL, 84.8 mmol) was added drop wise with constant stirring to the above reaction mixture, which was stirred at room temperature overnight. Subsequently, the reaction mixture was evaporated to half its volume; the resulting solution was dissolved in ethyl acetate, washed successively with saturated NaHCO3 (3×50 mL) and brine solution (3×50 mL). The organic layer was dried over Na2SO4 and concentrated to give the pure compound (4.6 g, 56% yield).
Reaction SMILES: [CH3:1][I:2].[NH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1>CCOCC>[I-:2].[NH2:3][N+:4]1([CH3:1])[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1
Reactant: NN1CCOCC1
Reactant: CI
Solvent: CCOCC
Product: C[N+]1(N)CCOCC1
Product: [I-]
Yield: 96 %

Procedure:
A 12.78-g (0.09 mole) sample of methyl iodide was added dropwise to a solution of 8.6 g (0.084 mole) of N-aminomorpholine in 50 ml ether. The precipitate that formed was collected on a filter, washed with ether and dried in air to give 19.73 g (96% yield) of N-amino-N-methylmorpholinium iodide as colorless crystals, mp 150°-155°(d).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[CH2:34]([CH2:36][NH2:37])[OH:35]>C1COCC1.CCOC(C)=O>[OH:35][CH2:34][CH2:36][NH:37][S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:10]2[N:9]=[C:8]([C:6]3[CH:5]=[C:4]([C:24]4[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:28][CH:29]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:13]=[CH:12][CH:11]=2)[CH:15]=1)(=[O:22])=[O:21]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Reactant: NCCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)NCCO)c3)n2)n1
Yield: 43 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example 1.2) (0.275 g, 0.5 mmol) by treatment with excess ethanolamine in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 1 N HCl, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with n-heptane/EtOAc followed by trituration with n-heptane/diethyl ether to give the title compound (0.110 g, 43%) as a white solid. MS (ISP) 513.9 [(M+H)+]; mp 110° C. (dec.).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26].C1CCN2C(=NCCC2)CC1.[CH2:39]([O:46][C:47](Cl)=[O:48])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CO>[CH2:39]([O:46][C:47]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[O:48])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCCCCCCCCCCCCCCCCCCCCCCC(=O)O
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)CCCCCCCCCCCCCCCCCCCCCCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To D6 (0.500 g, 1.30 mmol) and DBU (794 mg, 5.21 mmol) in refluxing methanol (100 ml) was added neat benzylchloroformate and the reaction refluxed for 3 hours until complete conversion of D6 to either the protected amino acid D19 or its methyl ester was observed. The solvent was removed and the residues taken up into dioxane (60 ml) and water (2 ml) and lithium hydroxide (1 g) added. The reaction was then refluxed for 2 hours until hydrolysis of the methyl ester derivative to D19 was complete. The solvent was removed, the residues suspended in 1M HCl (100 ml) and extracted with hot ethyl acetate (300 ml). The hot ethyl acetate was dried (MgSO4) and the solvent volume reduced to 40 ml. The solution/suspension was left at −10° C. for 1 hour, allowed to warm to room temperature and the resulting white precipitates filtered off and dried under vacuum to yield the title compound (585 mg, 87%). M.Pt 102-104° C. C32H55NO4 requires 517.4. Found ES−: MCI−, 552.6. δH (d6DMSO), 1.32 (38H, s, (CH2)19(CH2)2N), 1.52 (2H, p, CH2CH2CO2H), 1.65 (2H, p, CH2CH2NH), 2.35 (2H, t, CH2CO2H), 3.18 (2H, t, CH2N), 5.14 (2H, s, CH2Ph), 7.35 (5H, m, Ph).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([O:20][CH3:21])[CH:19]=1)[NH2:16]>ClCCl>[Cl:1][C:2]1[C:7]([C:8]([NH:16][C:15]2[CH:17]=[C:18]([O:20][CH3:21])[CH:19]=[C:13]([F:12])[CH:14]=2)=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1
Reactant: O=C(Cl)c1c(Cl)ncnc1Cl
Reactant: COc1cc(N)cc(F)c1
Solvent: ClCCl
Product: COc1cc(F)cc(NC(=O)c2c(Cl)ncnc2Cl)c1
Reaction time: 0.5 h
Yield: 51 %

Procedure:
4,6-Dichloropyrimidine-5-carbonyl chloride (590 mg, 2.79 mmol, prepared according to E. V. Tarasov et al. Synlett 2000, 5, 625-626) was dissolved in dichloromethane (3 ml) and TEA (389 μl, 2.79 mmol) was added. To this solution, 3-fluoro-5-methoxyaniline (394 mg, 2.79 mmol) dissolved in 3 ml dichloromethane was added dropwise and the mixture was stirred for 30 min. The reaction mixture was then diluted with dichloromethane, washed with 4% sodium bicarbonate solution, dried over magnesium sulphate, filtered and evaporated. The crude (800 mg, 56% purity, 51% yield) was used in the next synthetic step without further purification.
Reaction SMILES: [OH:1][C@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[Br:19][CH:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:21](Cl)=[O:22].N1C=CC=CC=1.O>C(Cl)Cl>[CH3:7][O:6][C:4](=[O:5])[CH2:3][C@H:2]([O:1][C:21](=[O:22])[CH:20]([Br:19])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCC[C@@H](O)CC(=O)OC
Reactant: CCCCCCC(Br)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCC[C@H](CC(=O)OC)OC(=O)C(Br)CCCCCC
Reaction time: 0.17 h
Yield: 87.4 %

Procedure:
To a rapidly-stirred slurry of 5.18 g (20.0 mmol) methyl (R)-3-hydroxytetradecanoate and 5.03 g (20.8 mmol) 2-bromooctanoyl chloride in 100 mL hexanes at 0° C. in a flame-dried flask under N2 was added 1.67 mL (20.6 mmol) pyridine all at once. After stirring for 10 minutes the cloudy white mixture was poured into a separatory funnel containing a mixture of 200 mL tap H2O/100 mL ether. This mixture was shaken and the layers separated. The aqueous layer was extracted with 2×100 mL ethr. The combined ether layers were washed with 200 mL brine, and 3×200 mL H2O. The ether was dried over MgSO4 and removed by rotary evaporation, giving 8.95 g crude product. This yellow oil was dissolved in 30 mL CH2Cl2 and suction filtered through a 1" pad of silica gel 60 in a 60 mL coarse sintered glass funnel, washing with 150 mL CH2Cl2. Rotary evaporation gave 8.10 g (87%) (R)-3-[(2-bromo-1-oxooctyl)oxy]tetradecanoic acid methyl ester as a yellow oil. The oil was found to be suitable for use in the cyclization reaction producing the lactone of Example 5. Analytically pure samples could be prepared by subjecting the oil to radial chromatography, eluting with CH2Cl2.
Reaction SMILES: B(F)(F)F.[Br:5][C:6]1[C:14]2[S:13][C:12]([NH2:15])=[N:11][C:10]=2[CH:9]=[C:8](N)[CH:7]=1.N(OC(C)(C)C)=O.[I:24]I>C1COCC1.CCOCC>[Br:5][C:6]1[C:14]2[S:13][C:12]([NH2:15])=[N:11][C:10]=2[CH:9]=[C:8]([I:24])[CH:7]=1
Reactant: II
Reactant: Nc1cc(Br)c2sc(N)nc2c1
Agent: CC(C)(C)ON=O
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: CCOCC
Product: Nc1nc2cc(I)cc(Br)c2s1
Temperature: -2.5 °C
Reaction time: 0.67 h

Procedure:
To THF (6 L) at −78° C. under N2 was added BF3-etherate (50% assay, 708 mL, 2.81 mol) followed by a slow addition of a solution of iv (275 g, 1.02 mol) in THF (500 mL) over 20 min. Tert-butyl nitrite (548 L, 4.61 mol) was then added to the solution at −78° C. and the mixture was stirred at the same temperature for 40 min and then warmed to −5-0° C. Et2O was added (at −5-0° C.) and the mixture stirred for 20 min. The solid was filtered and taken in acetone at 0° C. followed by sequential addition of KI (510 g, 3.07 mol) and iodine (519 g, 2.04 mol) and the mixture stirred at 0° C. for 30 min. The reaction was quenched with saturated solution of sodium metabisulfite and extracted with EtOAc (3×5 L). The combined organics were dried (Na2SO4), filtered and concentrated in vacuo at 45° C. The residue was purified over basic alumina (30-35% EtOAc-hexane) to obtain v (235 g, 65%). 1H NMR (DMSO-d6, 400 MHz): δ 7.50 (d, J=1.20 Hz, 1H), 7.63 (d, J=1.20 Hz, 1H) and 7.91 (br s, 2H). MS: 354.90 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:9]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=1)(=[O:11])=[O:10].Cl[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1>>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][N:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[S:9]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:25][CH:26]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(CCl)cc1
Reactant: Nc1ccccc1
Product: COc1ccc(CN(c2ccccc2)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1

Procedure:
Prepared as in example 5-10 from aniline, methyl 4-(chlorosulfonyl)benzoate (Example 5-10c) and 1-(chloromethyl)-4-methoxybenzene. MS (M−H, 396.1); 1H NMR (400 MHz, DMSO-d6): δ, ppm: 3.66 (s, 3H), 4.73 (s, 2H), 6.78 (d, J=8.4 Hz, 2H), 7.00 (d, J=7.6 Hz, 2H), 7.12 (d, J=8.0 Hz, 2H), 7.24 (d, J=8.0 Hz, 2H), 8.11 (d, J=8.4 Hz, 2H), 13.49 (s, 1H).
Reaction SMILES: C(Cl)(=O)C.[OH:5][C@H:6]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@@H:8]([CH2:9][CH2:10][C@@H:11]3[C@@H:22]2[C:21](=[O:27])[CH2:20][C@@:19]2([CH3:28])[C@H:12]3[CH2:13][CH2:14][C@@H:15]2[C:16](=[O:18])[CH3:17])[CH2:7]1.[Br:29]Br.O>CO>[Br:29][CH2:17][C:16](=[O:18])[C@@H:15]1[C@:19]2([CH3:28])[C@H:12]([C@H:11]3[C@H:22]([C:21](=[O:27])[CH2:20]2)[C@:23]2([CH3:26])[C@H:8]([CH2:7][C@@H:6]([OH:5])[CH2:25][CH2:24]2)[CH2:9][CH2:10]3)[CH2:13][CH2:14]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: BrBr
Solvent: CC(=O)Cl
Solvent: CO
Solvent: O
Product: C[C@]12CC[C@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CBr)[C@@]3(C)CC(=O)[C@@H]12

Procedure:
Acetyl chloride (9.71 ml) was added to a stirred solution of (3β,5α)-3-hydroxypregnane-11,20-dione (97.1 g) [prepared as described by Cameron et al., J. Chem. Soc., 1955, 2807] in methanol (2.4 l) and a solution of bromine (18.5 ml) in methanol (1 l) was then added over 30 min at room temperature. The reaction mixture was poured into water (30 l) and the precipitated solid was filtered off, washed with water and dissolved in dichloromethane. After drying the solution over sodium sulfate, the solvent was removed under reduced pressure to give crude (3β,5α)-21-bromo-3-hydroxypregnane-11,20-dione (120 g). δ (CDCl3) 0.61 (s,3H), 1.02 (s,3H), 3.00-3.20 (m,1H), 3.49-3.62 (m,2H) and 3.85 (s,2H). Potassium acetate (240 g), potassium iodide (6 g) and glacial acetic acid (250 ml) were added to a solution of (3β,5α)-21-bromo-3-hydroxypregnane-11,20-dione (120 g) in acetone (4.8 l) and the mixture was heated under reflux for 3 h. The reaction mixture was poured into water (50 l) and the precipitated solid was filtered off, washed with water and dissolved in dichloromethane. After drying the solution over sodium sulfate, the solvent was removed under reduced pressure. The residue was chromatographed over silica gel and the purified product was crystallised from diethyl ether to give (3β,5α)-21-(acetyloxy)-3-hydroxypregnane-11,20-dione (26 g) m.p. 163°-165° C.; [α]D +103.3° (c 0.97). 4-Toluenesulfonyl chloride (52 g) was added to a solution of (3β,5α)-21-(acetyloxy)-3-hydroxypregnane-11,20-dione (26 g) in pyridine (260 ml) and the solution was stirred for 4 h at room temperature. The reaction mixture was poured into water (2.6 l) and the precipitated solid was filtered off, washed with water and dissolved in dichloromethane. After drying the solution over sodium sulfate, the solvent was removed under reduced pressure. Crystallisation of the residue from methanol gave (3β,5α)-21-(acetyloxy)-3-{[(4-methylphenyl)sulfonyl]oxy}pregnane-11,20-dione (35 g). m.p. 155°-156° C.; [α]D +62.4° (c 1.11).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([OH:13])=O)[CH:9]=2)[NH:4][N:3]=1.[CH:14]1([CH:17]([C:19]2[S:20][CH:21]=[CH:22][N:23]=2)[NH2:18])[CH2:16][CH2:15]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>O.CN(C=O)C>[CH:14]1([CH:17]([C:19]2[S:20][CH:21]=[CH:22][N:23]=2)[NH:18][C:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[I:1])=[O:13])[CH2:16][CH2:15]1
Reactant: NC(c1nccs1)C1CC1
Reactant: O=C(O)c1ccc2[nH]nc(I)c2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NC(c1nccs1)C1CC1)c1ccc2[nH]nc(I)c2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 52.2 %

Procedure:
The title compound was synthesized according to General Method A utilizing 3-iodo-1H-indazole-5-carboxylic acid (255 mg, 0.88 mmol), cyclopropyl(thiazol-2-yl)methanamine (150 mg, 0.97 mmol), TBTU (310 mg, 0.97 mmol), DIPEA (0.31 mL, 1.8 mmol), and DMF (8 mL). The reaction was stirred at 0° C. for 1 h. The crude reaction was subsequently diluted with H2O. A filtration and washing (H2O) of the precipitate provided the desired product as a beige solid (195 mg, 52%). The product used without further purification. 1H NMR (400 MHz, CD3OD) δ ppm 8.16 (br. s., 1H), 7.99 (m., 1H), 7.77 (br. s., 1H), 7.46-7.67 (m, 2H), 1.45-1.68 (m, 1H), 0.46-0.90 (m, 4H); MS ESI 425.0 [M+H]+, calcd for [C15H13IN4OS+H]+ 425.0.