Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:10]3([CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH2:9]2)=[CH:4][CH:3]=1.[N:23]#CBr.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:10]3([CH2:15][CH2:14][N:13]([C:16]#[N:23])[CH2:12][CH2:11]3)[CH2:9]2)=[CH:6][CH:7]=1
Reactant: N#CBr
Reactant: CN1CCC2(CC1)CN(c1ccc(Cl)cc1)c1ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: N#CN1CCC2(CC1)CN(c1ccc(Cl)cc1)c1ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 0.95 g of 1-(4-chlorophenyl)-1'-methylspiro[indoline-3,4'-piperidine] (Example 2), 0.42 g of cyanogen bromide and 1 g of potassium carbonate in 25 ml of dichloromethane is stirred at ambient temperature for two hours. The reaction mixture is filtered and the filtrate concentrated to dryness leaving an oily residue which is crystallized from an acetone-hexane mixture leaving colorless crystals, mp 178.5°-180° C. of 1-(4-chlorophenyl)-1'-cyanospiro[indoline-3,4'-piperidine].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.C1(C)C=CC=CC=1.C([O-])(=O)C.[NH4+].[C:23]([CH2:25]C(O)=O)#[N:24]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[CH:25][C:23]#[N:24]
Reactant: N#CCC(=O)O
Reactant: COc1cccc(C=O)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COc1cccc(C=CC#N)c1

Procedure:
3-Methoxybenzaldehyde (20.8 g, 0.15 mol) was treated with toluene (dry, 140 mL), pyridine (dry, 60 mL), ammonium acetate (0.59 g) and cyanoacetic acid (11.9 g, 0.14 mol) and then heated under reflux with a Dean-Stark trap for 71 h according to the procedure of Montgomery et. al (J. Med. Chem. 1993, 36, 55). The reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed with 10% aq. HCl, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel, eluting with 2-5% EtOAc in hexanes to give 3-methoxycinnamonitrile, 14.65 g (60%). This material was dissolved in EtOH (75 mL) and conc. HCl (15 mL) and hydrogenated with 10% Pd/C (2.0 g) at 70 psi on a Parr shaker for 67 h. The reaction mixture was filtered over Celite. The filtrate was extracted with EtOAc, and the EtOAc layer was concentrated under vacuum to give the hydrochloride salt of 3-(3-methoxyphenyl)propylamine as a waxy white solid, 17.3 g (93%). HPLC—(Method B)—tr=1.28 min. [M+H]+=166.30. 1H-NMR (300 MHz, CDCl3/CD3OD): δ=7.14-7.19 (m, 1H), 6.70-6.77 (m, 3H), 4.51-4.58 (m, 2H), 3.75 (s, 3H, OMe), 2.85-2.91 (m, 2H), 2.63-2.68 (m, 2H), 1.95-2.01 (m, 2H).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Br:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1>C(Cl)Cl>[Br:6][C:7]1[S:8][C:9]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:10][CH:11]=1
Reactant: Brc1cccs1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: O=S(=O)(Cl)c1ccc(Br)s1
Yield: 75 %

Procedure:
Chlorosulfonic acid was added dropwise over 20 min. to a cold solution (-78° C.) of 2-bromothiophene (16.3 g, 100 mmol) in methylene chloride (50 ml) was added After addition of chlorosulfonic acid was complete, the cold bath was removed. The reaction mixture was allowed to attain room temperature slowly (2 h), was added dropwise onto the crushed ice (1000 g) and was extracted with methylene chloride (4×100 ml). The combined organic layers was dried over MgSO4, filtered and the solvent was removed under reduced pressure to give a crude product. This was purified by column chromatography using hexane as eluent to give 5-bromothiophene-2-sulfonyl chloride (22 g, 75% yield).
Reaction SMILES: [CH:1]1([N:5]([C@H:18]2[CH2:22][CH2:21][CH2:20][C@@H:19]2[NH:23]C(=O)OC(C)(C)C)[C:6](=[O:17])[C:7]2[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:8]=2[O:15][CH3:16])[CH2:4][CH2:3][CH2:2]1.[ClH:31].O1CCOCC1>CO>[ClH:31].[NH2:23][C@H:19]1[CH2:20][CH2:21][CH2:22][C@@H:18]1[N:5]([CH:1]1[CH2:4][CH2:3][CH2:2]1)[C:6](=[O:17])[C:7]1[C:8]([O:15][CH3:16])=[CH:9][CH:10]=[CH:11][C:12]=1[O:13][CH3:14]
Reactant: COc1cccc(OC)c1C(=O)N(C1CCC1)[C@H]1CCC[C@@H]1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COc1cccc(OC)c1C(=O)N(C1CCC1)[C@H]1CCC[C@@H]1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl N-[(1S,2S)-2-(N-cyclobutyl2,6-dimethoxybenzamido)cyclopentyl]carbamate (1.34 g, 3.20 mmol) in methanol (11 ml) was added HCl in 1,4-dioxane (4 M, 8.00 ml, 32.0 mmol). The reaction was stirred at room temperature for 17 hours (overnight) and then was concentrated in vacuo, azeotropically distilled with toluene to afford the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6](Cl)[N:5]=[C:4]([CH3:10])[C:3]=1[CH3:11].OS(O)(=O)=O>C(O)C.[Zn]>[CH3:10][C:4]1[C:3]([CH3:11])=[CH:2][C:7]([CH3:8])=[CH:6][N:5]=1
Reactant: Cc1nc(Cl)c(C)c(Cl)c1C
Agent: O=S(=O)(O)O
Agent: [Zn]
Solvent: CCO
Product: Cc1cnc(C)c(C)c1

Procedure:
3,8 g (20 mmoles) of 4.6-dichloro-2,3,5-trimethylpyridine are dissolved in a small amount of ethanol and treated with 5 g of zinc powder. After addition of 10 ml of 2 N H2SO4, the mixture is refluxed for 1 hour. After cooling and filtering the solution is treated with NaOH to adjust a pH of 6. The precipitated zinc salts are removed by filtration and the filtrate is extracted three times with petrol ether. After drying and evaporation 2.0 g (83%) of 2,3,5-trimethylpyridine are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5][NH2:6].[Cl:12][C:13]1[N:14]=[C:15](Cl)[C:16]2[C:21]([CH3:22])=[CH:20][S:19][C:17]=2[N:18]=1>>[Cl:12][C:13]1[N:14]=[C:15]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:2]([Cl:1])[CH:3]=2)[C:16]2[C:21]([CH3:22])=[CH:20][S:19][C:17]=2[N:18]=1
Reactant: COc1ccc(CN)cc1Cl
Reactant: Cc1csc2nc(Cl)nc(Cl)c12
Product: COc1ccc(CNc2nc(Cl)nc3scc(C)c23)cc1Cl

Procedure:
Following the procedure of Example 1, the reaction of 3-chloro-4-methoxybenzylamine with 2,4-dichloro-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-5-methyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine
Reaction SMILES: C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[N+:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[S:41]([NH:44][CH2:45][CH2:46][N:47]1[CH:56]=[CH:55][C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[C:48]1=[O:57])(=[O:43])=[O:42])([O-:34])=[O:33].[CH2:58]([N:60]1[C:66](=[O:67])[C:65]([CH3:69])([CH3:68])[C:64](=[O:70])[N:63]([CH3:71])[C:62]2[CH:72]=[C:73]([CH2:76][CH2:77][CH2:78]O)[CH:74]=[CH:75][C:61]1=2)[CH3:59]>O.C1(C)C=CC=CC=1>[CH2:58]([N:60]1[C:66](=[O:67])[C:65]([CH3:69])([CH3:68])[C:64](=[O:70])[N:63]([CH3:71])[C:62]2[CH:72]=[C:73]([CH2:76][CH2:77][CH2:78][N:44]([CH2:45][CH2:46][N:47]3[CH:56]=[CH:55][C:54]4[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=4)[C:48]3=[O:57])[S:41]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=3[N+:32]([O-:34])=[O:33])(=[O:42])=[O:43])[CH:74]=[CH:75][C:61]1=2)[CH3:59]
Reactant: O=c1c2ccccc2ccn1CCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CCCO)ccc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CCCN(CCn3ccc4ccccc4c3=O)S(=O)(=O)c3ccccc3[N+](=O)[O-])ccc21
Reaction time: 8 h
Yield: 26.5 %

Procedure:
Tributyl phosphine (1.2 ml) and 1,1′-(azodicarbonyl)dipiperidine (1.17 g) were added to a toluene solution (100 ml) of 2-nitro-N-[2-(1-oxo-1H-isoquinolin-2-yl)-ethyl]-benzenesulfonamide (1.39 g), and 1-ethyl-7-(3-hydroxy-propyl)-3,3,5-trimethyl-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione (0.94 g). The mixture was stirred overnight. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was washed with water and saturated saline, dried with magnecium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1→1:0). The purified product was condensed under reduced pressure to produce the title compound (0.54 g) as a white amorphous.
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][NH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][N:13]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[NH2:22][CH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[CH2:1]([C:5]1[C:9]([CH2:10][NH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH:22][CH:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:18])=[CH:14][N:13]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1noc(C)c1CNc1ccc(C(=O)O)cn1
Reactant: NC1CCOCC1
Product: CCCCc1noc(C)c1CNc1ccc(C(=O)NC2CCOCC2)cn1
Yield: 86 %

Procedure:
As described for example 19b, 6-[(3-butyl-5-methyl-isoxazol-4-ylmethyl)-amino]-nicotinic acid (70 mg, 0.24 mmol) instead of 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid, was converted, using 4-aminotetrahydropyran instead of rac-2,2,2-trifluoro-1-(methyl)ethylamine, to the title compound (77 mg, 86%) which was obtained as an off white foam after purification by chromatography (silica, heptane:ethyl acetate=1:0 to 2:1). MS: m/e=373.3 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:14](OC(C)(C)C)=O)[CH2:10][CH2:9]2)[N:4]=[CH:3]1.C(O)(C(F)(F)F)=O.[Br:28][C:29]1C(Cl)=[C:31]([N+:36]([O-:38])=[O:37])[C:32]([NH2:35])=[N:33][CH:34]=1>C(Cl)Cl>[Br:28][C:29]1[C:14]([N:11]2[CH2:10][CH2:9][N:8]([CH2:7][C:5]3[N:4]=[CH:3][N:2]([CH3:1])[CH:6]=3)[CH2:13][CH2:12]2)=[C:31]([N+:36]([O-:38])=[O:37])[C:32]([NH2:35])=[N:33][CH:34]=1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Reactant: Cn1cnc(CN2CCN(C(=O)OC(C)(C)C)CC2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cnc(CN2CCN(c3c(Br)cnc(N)c3[N+](=O)[O-])CC2)c1
Reaction time: 1 h
Yield: 51.1 %

Procedure:
tert-Butyl 4-((1-methyl-1H-imidazol-4-yl)methyl)piperazine-1-carboxylate (0.130 g, 0.46 mmol, 1.1 eq) was dissolved in DCM (1.45 mL) and the mixture cooled in a ice-water bath before the dropwise addition of TFA (1.45 mL). Stirring was continued at this temperature for 1 h. The solvents were removed in vacuo, the resulting crude material was azeotroped with toluene and dried. The resulting 1-((1-methyl-1H-imidazol-4-yl)methyl)piperazine (supposedly 0.083 g, 0.46 mmol, 1 eq) was suspended in iPrOH (1.4 mL) and DIPEA (0.35 mL). To this solution, 5-bromo-4-chloro-3-nitropyridin-2-amine (0.100 g, 0.42 mmol, 1 eq) was added and the mixture heated and stirred for 17 h at 65° C. The mixture was filtered, washed with iPrOH (3×3 mL), Et2O (2×3 mL) and dried to give the title compound as a bright yellow powder (0.085 g, 47%); 1H-NMR (500 MHz, DMSO-d6): δ 2.50-2.58 (br s, 4H, piperazine N(CH2)2), 3.03 (m, 4H, piperazine N(CH2)2), 3.39 (s, 2H, NCH2), 3.60 (s, 3H, imidazole Me), 6.95 (s) and 6.97 (s), (3H, NH2 and 6-H), 7.46 (s, 1H), 8.14 (s, 1H, pyridine 6-H); LC (Method B)-MS (ESI, m/z): Rt=1.25 min—396/398 [(M+H+), Br isotopic pattern, 100%].
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH:7][CH2:8][C@:9]12[CH2:47][CH2:46][C@@H:45]([C:48]([CH3:50])=[CH2:49])[C@@H:10]1[C@@H:11]1[C@@:24]([CH3:27])([CH2:25][CH2:26]2)[C@@:23]2([CH3:28])[C@@H:14]([C@:15]3([CH3:44])[C@@H:20]([CH2:21][CH2:22]2)[C:19]([CH3:30])([CH3:29])[C:18]([C:31]2[CH:43]=[CH:42][C:34]([C:35]([O:37]C(C)(C)C)=[O:36])=[CH:33][CH:32]=2)=[CH:17][CH2:16]3)[CH2:13][CH2:12]1)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([NH:4][CH2:5][CH2:6][NH:7][CH2:8][C@:9]12[CH2:47][CH2:46][C@@H:45]([C:48]([CH3:50])=[CH2:49])[C@@H:10]1[C@@H:11]1[C@@:24]([CH3:27])([CH2:25][CH2:26]2)[C@@:23]2([CH3:28])[C@@H:14]([C@:15]3([CH3:44])[C@@H:20]([CH2:21][CH2:22]2)[C:19]([CH3:30])([CH3:29])[C:18]([C:31]2[CH:43]=[CH:42][C:34]([C:35]([OH:37])=[O:36])=[CH:33][CH:32]=2)=[CH:17][CH2:16]3)[CH2:13][CH2:12]1)(=[O:3])[CH3:2]
Reactant: C=C(C)[C@@H]1CC[C@]2(CNCCNC(C)=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(CNCCNC(C)=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 38.9 %

Procedure:
To a solution of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-acetamidoethylamino)methyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (114 mg, 0.167 mmol) in DCM (1 ml) was added TFA (0.4 ml, 5.19 mmol). The mixture was stirred at rt for 3.5 h then was concentrated under reduced pressure. The residue was dissolved in dioxane and MeOH and was purified by pre. HPLC. The fractions containing the expected product were combined and concentrated under reduced pressure to afford the title compound as an off-white solid (40.7 mg, 0.065 mmol, 38.8% yield). LCMS: m/e 629.5 (M+H)+, 2.17 min (method 6). 1H NMR (500 MHz, Acetic) δ ppm 8.03 (d, J=8.24 Hz, 2H),7.30 (d, J=8.24 Hz, 2H), 5.37 (d, J=4.58 Hz, 1H), 4.79 (s, 1H), 4.68 (s, 1H), 3.61-3.70 (m, 2H), 3.40-3.53 (m, 2H), 3.37 (d, J=13.12 Hz, 1H), 2.98 (d, J=12.82 Hz, 1H), 2.49-2.57 (m, 1H), 2.09 (s, 3H), 1.75 (s, 3H), 1.19 (s, 3H), 1.14-2.24 (m, 22H), 1.10 (s, 3H), 1.07 (s, 3H), 1.02 (s, 3H), 1.00 (s, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([N:12]1[C:16]([CH2:17][CH2:18][CH3:19])=[CH:15][CH:14]=[C:13]1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH2:27])[CH:22]=1)[CH2:9][CH2:10][CH3:11].[O-:28][C:29]#[N:30].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.CO>[CH2:8]([N:12]1[C:16]([CH2:17][CH2:18][CH3:19])=[CH:15][CH:14]=[C:13]1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][C:29]([NH2:30])=[O:28])[CH:22]=1)[CH2:9][CH2:10][CH3:11]
Reactant: N#C[O-]
Reactant: CCCCn1c(CCC)ccc1Cc1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CCCCn1c(CCC)ccc1Cc1cccc(NC(N)=O)c1
Yield: 90.5 %

Procedure:
A solution of 11.4 ml (148 mmol) of trifluoroacetic acid in 100 ml of methylene chloride was added dropwise to a mixture of 20 g (74 mmol) of 1-butyl-2-(3'-aminobenzyl)-5-propylpyrrole dissolved in 80 ml of methylene chloride, 20 ml of methanol, and 9.6 g (148 mmol) of sodium cyanate, at room temperature and under stirring. The reaction mixture was stirred for an hour further, poured into 500 ml of saturated sodium carbonate solution and extracted with 200 ml of methylene chloride and 200 ml of ethyl acetate. The combined extracts were washed with water, dried and evaporated under reduced pressure. The residue was purified by column chromatography on 500 g of silica gel, using methylene chloride-methanol (95:5) as eluant, to produce 21 g (91%) of the title compound, 1-butyl-2-(3'-ureidobenzyl)-5-propylpyrrole, which was recrystallized from acetone-hexane.
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li].[Cl:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([Cl:16])[CH:15]=1.IC>O1CCCC1.CCCCCC>[Cl:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([Cl:16])[C:15]=1[CH3:1]
Reactant: CC(C)NC(C)C
Reactant: Clc1cncc(Cl)c1
Agent: [Li]
Solvent: CI
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1c(Cl)cncc1Cl
Temperature: -10 °C
Yield: 68 %

Procedure:
Diisopropylamine (70 mL, 500 mmol) is dissolved in dry tetrahydrofuran (500 mL), the solution is cooled to −10° C. and buthyl lithium (2.5 N in hexane, 210 mL, 525 mmol) is added dropwise under stirring. After 30 minutes the solution is cooled to −20° C. and 3,5-dichloropyridine (66.6 g, 450 mmol) in tetrahydrofuran (200 mL) is added dropwise. The solution is stirred at −10° C. for 30 minutes, then cooled to −70° C. and iodomethane (50 mL, 1.6 mol) in tetrahydrofuran (100 mL) is added dropwise. The reaction mixture is allowed to warm to room temperature, quenched with water (100 mL) and extracted with diethyl ether (3×100 mL); the combined organic layers are dried over sodium sulphate (5 g) and evaporated to dryness. The crude product is crystallized twice from aqueous ethanol, then from hexane to afford 3,5-dichloro-4-methylpyridine (49.9 g, 306 mmol, 68% yield) as a white solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([CH2:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:5][N:4]=1.[CH3:13][N:14]([CH:16](OC)OC)[CH3:15]>>[CH3:13][N:14]([CH3:16])[CH:15]=[C:9]([C:7]1[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=1)[C:10](=[O:12])[CH3:11]
Reactant: COC(OC)N(C)C
Reactant: CSc1nccc(CC(C)=O)n1
Product: CSc1nccc(C(=CN(C)C)C(C)=O)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 49.3 %

Procedure:
1-(2-Methylsulfanyl-pyrimidin-4-yl)-propan-2-one (17) (1.93 g, 10.59 mmol) was taken up in DMF-DMA (20 mL, 149 mmol) and the resulting reaction was warmed to 80° C. and stirred for 2 hours. The solvent was evaporated and the crude residue partitioned between DCM and water. The organic layer was washed with brine, dried with sodium sulfate, and concentrated. The crude residue was purified by flash column chromatography with a gradient of 1-12% MeOH in DCM to give the desired product as a brown/orange oil (1.24 g, 49%). MS (ES+): m/z=238.2/239.3 (100/30) [MH+]. HPLC: tR=0.78 minute over 3 minutes. Purity: 100% [HPLC (LC/MS) at 220 nm].
Reaction SMILES: [H-].[Li+].CCCS.C[O:8][C:9]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:10]=1[C@@:11]1([CH3:30])[C@H:20]([CH2:21][S:22]2)[C@:19]2([CH3:27])[C@H:14]([C:15]([CH3:29])([CH3:28])[CH2:16][CH2:17][CH2:18]2)[CH2:13][CH2:12]1>CN(P(N(C)C)(N(C)C)=O)C>[CH3:30][C@@:11]12[CH2:12][CH2:13][C@@H:14]3[C@:19]([CH3:27])([CH2:18][CH2:17][CH2:16][C:15]3([CH3:29])[CH3:28])[C@H:20]1[CH2:21][S:22][C:23]1[C:10]2=[C:9]([OH:8])[CH:26]=[CH:25][CH:24]=1
Reactant: COc1cccc2c1[C@]1(C)CC[C@H]3C(C)(C)CCC[C@]3(C)[C@H]1CS2
Agent: CCCS
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC1(C)CCC[C@]2(C)[C@H]3CSc4cccc(O)c4[C@]3(C)CC[C@@H]12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
In a reaction vessel HMPA (5 mL) was placed and purged with nitrogen for 1 h. To the vessel LiH (0.137 g, 17.4 mmol) and n-propylthiol (1.65 mL, 18.3 mmol) were added and the mixture was stirred at room temperature for 30 min. A solution of (1R,10R,11S,16S)-3-methoxy-1,11,15,15-tetramethyl-8-thiatetracyclo[8.8.0.02, 7.011,16]octadeca-2,4,6-triene (Compound No. 52) (0.10 g, 0.29 mmol) in HMPA (5 mL) was added to the reaction mixture and heated at 130° C. for 1 h. The reaction was cooled to room temperature, quenched with water (50 mL) and extracted with EtOAc (3×200 mL). The organic layers were combined, dried (Na2SO4) and concentrated. Purification by column chromatography on silica gel (Hexanes/EtOAc, 10:1) gave (1R,10R,11S,16S)-1,11,15,15-tetramethyl-8-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-trien-3-ol (Compound No. 55) (0.09 g, 94%) as a white solid. 1H NMR (CDCl3): δ 6.81 (t, 1H), 6.63 (d, 1H), 6.28 (d, 1H), 4.70 (s, 1H), 3.38 (m, 1H), 2.82 (q, 2H), 1.90-1.40 (m, 9H), 1.38 (s, 3H), 1.36-0.98 (m, 2H), 0.95 (s, 3H), 0.88 (m, 3H), 0.85 (s, 3H).
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:20]([CH3:22])([CH2:21][C@@H:2]12)[C@@H:19]1[C@H:8]([C@H:9]2[C@:16]([CH3:24])([CH2:17][C:18]1=[O:23])[C:12]([C:13](=[O:15])[CH3:14])=[CH:11][CH2:10]2)[CH2:7][CH2:6]3.S(=O)(=O)(O)O.C(=O)(O)[O-].[K+].[CH2:35]([OH:37])[CH3:36]>>[CH2:35]([O:37][C@H:2]1[CH2:21][C@@:20]2([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[C:18](=[O:23])[CH2:17][C@@:16]2([CH3:24])[C@H:9]3[CH2:10][CH:11]=[C:12]2[C:13](=[O:15])[CH3:14])[CH2:4][C@@H:3]1[OH:1])[CH3:36]
Reactant: CC(=O)C1=CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: CCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2C(=O)C[C@]2(C)C(C(C)=O)=CC[C@@H]32)C[C@@H]1O
Temperature: 25 °C

Procedure:
2α, 3α-Epoxy-5α-pregn-16-ene-11,20-dione (3 g.) was dissolved with warming in dry ethanol (80 ml.). The solution was stirred and allowed to cool to room temperature. Concentrated sulphuric acid (0.7 ml.) was added and the solution was stirred at room temperature for 30 minutes. Potassium bicarbonate solution (10%, 35 ml.) was added and the mixture poured into ice-cold water (1 liter) and extracted with chlorform (2 × 200 ml.). The extract was dried over sodium sulphate and evaporated to a colourless oil (2.73 g.) which was purified by preparative TLC in ethyl acetate/petrol 1/1, the plates being run 3 times and the main UV-absorbing, band separated and recrystallised from ethyl acetate/ petrol to give title compound (950 mg.) as fine white crystals, m.p. 89-91° [α]D ± 77° c 0.3).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.[C:9]1([SH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C[O-].[Na+]>[Cu].CO>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][N:3]=1
Reactant: Nc1ccc(I)cn1
Reactant: Sc1ccccc1
Agent: [Cu]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Nc1ccc(Sc2ccccc2)cn1
Yield: 64.3 %

Procedure:
11 G. (0.05 moles) of 2-amino 5-iodo pyridine, 7.2 ml. (0.07 moles) of thiophenol, 3.8 g. (0.07 moles) of sodium methoxide, 1.0 g of copper powder and 100 ml. of methanol are heated 150° C. for 12 hours in a glass lined bomb. The reaction mixture is concentrated to dryness, extracted with chloroform and the chloroform extracts concentrated to dryness in vacuo affording 15 g. of a crude product which is chromatographed on 600 g. of silica gel, eluting with methylene chloride and ethyl acetate-methylene chloride 50% mixture affording 6.5 g of 2-amino 5-phenylthio pyridine, m.p. 127° to 129° C.
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]#[CH:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:20](=[N:22][OH:23])[CH3:21].Cl[O-].[Na+]>C(Cl)(Cl)Cl>[C:1]([O:9][CH2:10][C:11]1[O:23][N:22]=[C:20]([CH3:21])[CH:12]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC=NO
Reactant: C#CCOC(=O)c1ccccc1
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cc(COC(=O)c2ccccc2)on1
Temperature: 0 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
A solution of prop-2-yn-1-yl benzoate (26.0 g, 162 mmol) in chloroform (598 mL) was treated with triethylamine (11.3 mL, 81.2 mmol) and acetaldoxime (14.4 g, 244 mmol). The reaction mixture was cooled to 0° C., treated with sodium hypochlorite (551 mL, 487 mmol) (commercial grade ˜5% aqueous), and stirred overnight at room temperature. The layers were separated and the aqueous layer was extracted with dichloromethane (2×200 mL). The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to give the crude product. Purification by flash column chromatography (100% hexanes to 30% ethyl acetate/hexanes) gave the desired product (20.1 g, 57%). LCMS calculated for C12H12NO3 (M+H)+: m/z=218.1. found: 218.1.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]1([S:25]([N:28](S(C2C=CC=CC=2)(=O)=O)[C:29]2[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][C:30]=2[I:36])(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1.C(OCC)(=O)C.Cl>[Br:35][C:32]1[CH:33]=[CH:34][C:29]([NH:28][S:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:27])=[O:26])=[C:30]([I:36])[CH:31]=1
Reactant: O=S(=O)(c1ccccc1)N(c1ccc(Br)cc1I)S(=O)(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=S(=O)(Nc1ccc(Br)cc1I)c1ccccc1
Reaction time: 18 h
Yield: 90.2 %

Procedure:
A solution of tetrabutylammonium fluoride (1 M in THF, 11 mL) in 30 mL of THF was treated with N,N-bisbenzenesulfonyl-(4-bromo-2-iodoaniline) (5.78 g, 10 mmol) in several portions. After 18 hours, the mixture was diluted with of 40 mL of ethyl acetate and 40 mL of 1 N HCl. The phases were separated and the aqueous layer was extracted with two 40 mL portions of ethyl acetate. The combined organic layers were washed with two 20 mL portions of 1 N HCl, two 20 mL portions of saturated aqueous sodium bicarbonate solution, 20 mL of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 3.95 g (90% yield) of the title compound as a solid, which was used without further purification.