Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([O:13]C)=[C:9]([O:15]C)[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>Br.C(O)(=O)C>[CH:1]1([CH2:6][C:7]2[CH:8]=[C:9]([OH:15])[C:10]([OH:13])=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(CC2CCCC2)cc1OC
Agent: Br
Solvent: CC(=O)O
Product: Oc1ccc(CC2CCCC2)cc1O
Temperature: 25 °C
Yield: 97.5 %

Procedure:
A solution 4-(cyclopentylmethyl)-1,2-dimethoxybenzene (7.1 g, 0.032 mol) in 43 ml of hydrobromic acid (48% in water) and 4 ml of acetic acid was heated at 120° C. during 24 hours. The reaction mixture was cooled to room temperature and quenched with 50 ml of NH4Cl solution. The aqueous phase extracted with three 100 ml portions of ether. The ethereal phase was washed with 50 ml of brine and dried over MgSO4. Filtration and concentration gave 6.0 g (97%) of a brownish solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.O>CN(C=O)C>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[O:11][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: O=[N+]([O-])c1cccc(O)c1Cl
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cccc(OCCN2CCOCC2)c1Cl
Reaction time: 15 h
Yield: 84.2 %

Procedure:
2-chloro-3-nitrophenol (1 g, 5.8 mmol) was dissolved in DMF (6 mL). K2CO3 (1.6 g, 11.5 mmol) was added and the solution changed from yellow to red. 4-(2-chloroethyl)morpholine hydrochloride (1.07 g, 5.8 mmol) was added and the solution was allowed to stir for 15 h. The reaction was poured into H2O (30 mL) and extracted with EtOAc (3×30 mL). The organics were washed with 1N NaOH (100 mL) and brine (100 mL) and then dried over MgSO4, filtered, and concentrated in vacuo to provide 4-(2-(2-chloro-3-nitrophenoxy)ethyl)morpholine (1.4 g, 87%) as a golden oil.
Reaction SMILES: [Mg].CI.Br[C:5]1[CH:13]=[CH:12][C:8]2[S:9][CH:10]=[CH:11][C:7]=2[CH:6]=1.[CH2:14]1[O:16][CH2:15]1.Cl>C1COCC1>[OH:16][CH2:15][CH2:14][C:5]1[CH:13]=[CH:12][C:8]2[S:9][CH:10]=[CH:11][C:7]=2[CH:6]=1
Reactant: C1CO1
Reactant: Brc1ccc2sccc2c1
Agent: Cl
Agent: [Mg]
Solvent: CI
Solvent: C1CCOC1
Product: OCCc1ccc2sccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.8 %

Procedure:
To a flame dried flask under N2 was added magnesium turnings (6 g, 0.25 mol) and THF (100 ml). The mixture was heated at reflux and a solution of methyl iodide (7.2 ml, d=2.28, 0.116 mol), and 5-bromobenzo[b]thiophene (24.4 g, 0.114 mol) in THF (50 ml) were added dropwise. The mixture was heated at reflux for 5 hours, then cooled to 0°-4° C. and a solution of ethylene oxide (15 g, 0.33 mol) in THF (20 ml) was added dropwise. After the addition, the reaction mixture was allowed to stir at room temperature overnight. The suspension was then cooled and a solution of 3N HCl (75 ml) was added dropwise. The aqueous layer was extracted with ethyl acetate (3X) and the organic layer was backwashed with saturated Na2CO3, dried, filtered and concentrated to dryness. The residue was chromatographed on silica gel and the product was eluted with 30% ethyl acetate/hexane to yield 9.3 g (48%) of product, m.p. 56°-57° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:8].[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1)([O-:11])=[O:10]>N1C=CC=CC=1>[N+:9]([C:12]1[CH:13]=[CH:14][C:15]([S:18]([O:8][N:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]2=[O:1])(=[O:20])=[O:19])=[CH:16][CH:17]=1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: [O-][n+]1ccccc1O
Solvent: c1ccncc1
Product: O=c1ccccn1OS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Yield: 92 %

Procedure:
2-Hydroxypyridine-1-oxide (0.5 g, 4.5 mmol) was reacted with 4-nitrobenzenesulfonyl chloride (3.0 g, 13.5 mmol) in 40 mL of pyridine to afford PZBG-1c in 92% yield (1.23 g, 4.2 mmol). 1H NMR (500 MHz, CDCl3) δ=8.42 (d, J=8.6 Hz, 2H), 8.23 (d, J=9.2 Hz, 2H), 7.65 (dd, J1=7.5 Hz, J2=1.8 Hz, 1H), 7.34 (dt, J1=9.2 Hz, J2=1.7 Hz, 1H), 6.52 (d, J=9.2 Hz, 1H), 6.22 (t, J=7.7 Hz, 1H). 13C NMR (100 MHz, DMSO) δ=156.6, 152.3, 141.6, 139.4, 138.3, 131.8, 125.6, 122.8, 106.4. ESI-MS(+): m/z 297.28 [M+H]+, 319.02 [M+Na]+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[C:16]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>CCO>[C:16]([C:20]1[CH:21]=[CH:22][C:23]([CH2:24][S:15][C:13]2[O:14][C:10]([C:7]3[CH:8]=[CH:9][C:4]4[NH:3][CH:2]=[N:1][C:5]=4[CH:6]=3)=[N:11][N:12]=2)=[CH:26][CH:27]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: Sc1nnc(-c2ccc3nc[nH]c3c2)o1
Solvent: CCO
Product: CC(C)(C)c1ccc(CSc2nnc(-c3ccc4[nH]cnc4c3)o2)cc1

Procedure:
1 (0.33 g, 1.5 mmol), TEA (0.209 mL, 1.5 mmol) and 4-tert-butylbenzylbromide (0.292 mL, 1.5 mmol) were dissolved in 10 mL of EtOH and kept under reflux overnight. The solvent was removed and the remaining oil was purified by flash-chromatography on silica gel, applying a CHCl3/MeOH gradient.
Reaction SMILES: [C@@H:1]12[O:8][C@@H:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[CH:10]=[C:11]([NH:15][C:16]3[C:17]4[N:34]=[CH:33][S:32][C:18]=4[N:19]=[C:20]([C:22]4[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=4)[C:25]([O:27]C)=[O:26])[N:21]=3)[CH:12]=[CH:13][CH:14]=1)[CH2:2]2.[OH-].[Na+]>O1CCOCC1.O>[C@@H:5]12[O:8][C@@H:1]([CH2:7][CH2:6]1)[CH2:2][N:3]([C:9]1[CH:10]=[C:11]([NH:15][C:16]3[C:17]4[N:34]=[CH:33][S:32][C:18]=4[N:19]=[C:20]([C:22]4[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=4)[C:25]([OH:27])=[O:26])[N:21]=3)[CH:12]=[CH:13][CH:14]=1)[CH2:4]2
Reactant: COC(=O)c1cccc(-c2nc(Nc3cccc(N4C[C@H]5CC[C@@H](C4)O5)c3)c3ncsc3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cccc(-c2nc(Nc3cccc(N4C[C@H]5CC[C@@H](C4)O5)c3)c3ncsc3n2)c1
Temperature: 30 °C
Reaction time: 2 h
Yield: 45.7 %

Procedure:
The mixture of methyl 3-(7-(3-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)phenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoate (0.094 g, 0.2 mmol) and NaOH (0.079 g, 2.0 mmol) in dioxane (10 mL) and H2O (5 mL) was stirred at 30° C. for 2 h. It was concentrated, residue diluted with water, washed with ether (2×5 mL) and the aqueous layer was adjusted to pH=4 by the addition of conc. HCl, then the solid formed was filtered and purified by recrystallization (15 mL, MeOH:EtOAc:ether=5:20:100, v/v/v) to afford 3-(7-(3-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)phenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoic acid (0.042 g, 46%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 13.23 (s, 1H), 10.15 (s, 1H), 9.42 (s, 1H), 8.98 (s, 1H), 8.61 (d, 1H, J=7.8 Hz), 8.09 (d, 1H, J=7.8 Hz), 7.68-7.62 (m, 2H), 7.41 (d, 1H, J=8.1 Hz), 7.23 (t, 1H, J=8.4 Hz), 6.65 (d, 1H, J=8.4 Hz), 4.44 (s, 2H), 3.43-3.36 (m, 2H), 2.89 (d, 1H, J=9.3 Hz), 1.86 (s, 4H). LC-MS: 460 [M+H]+, tR=1.64 min. HPLC: 95.36% at 214 nm, 96.48% at 254 nm, tR=5.20 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:3]=1.C([Li])CCC.CN([CH:26]=[O:27])C>>[C:14]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[CH:26]=[O:27])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1cc(Br)ccc1N1CCCCC1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Product: CC(C)(C)c1cc(C=O)ccc1N1CCCCC1
Yield: 105.5 %

Procedure:
In a manner analogous to example 1 d, the process is carried out by a reaction of 9.9 g (34 mmol) of 1-(4-bromo-2-tert-butylphenyl)piperidine with 20 ml (50 mmol) of a 2.5M solution of n-butyllithium and 3.9 ml (50 mmol) of DMF. 8.8 g of 3-tert-butyl-4-piperidin-1-ylbenzaldehyde are obtained in the form of a yellow oil (yield=100%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C@@:14]2([CH3:24])[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][S:26]([N:29]1[CH2:34][CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH2:31][CH2:30]1)(=[O:28])=[O:27]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C@@:14]2([CH3:24])[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:32]4[CH2:33][CH2:34][N:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:30][CH:31]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(C2=CCN(S(C)(=O)=O)CC2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC([C@]2(C)Cc3cc(Cl)ncc3O2)CC1
Product: CC(C)(C)OC(=O)N1CCC([C@]2(C)Cc3cc(C4=CCN(S(C)(=O)=O)CC4)ncc3O2)CC1

Procedure:
The title compound is prepared from (S)-4-(5-chloro-2-methyl-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine following a procedure analogous to that described for Intermediate 6. Mass spectrum (ESI+): m/z=478 [M+H]+.
Reaction SMILES: [C:1]([O-])(=O)C.[Na+].[C:6]([O:9][CH2:10][C:11](=[O:42])[C@:12]1([OH:41])[C@:29]2([CH3:30])[C@H:15]([C@H:16]3[C@:26](F)([C@@H:27]([O:31][C:32](=[O:37])[C:33]([F:36])([F:35])[F:34])[CH2:28]2)[C@:24]2([CH3:25])[C:19](=[CH:20][C:21](=[O:39])[CH2:22][CH2:23]2)[CH2:18][CH2:17]3)[CH2:14][C@H:13]1[CH3:40])(=[O:8])[CH3:7].P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl.COCOC>[C:6]([O:9][CH2:10][C:11](=[O:42])[C@:12]1([OH:41])[C@:29]2([CH3:30])[C@H:15]([C@H:16]3[C@H:26]([C@@H:27]([O:31][C:32](=[O:37])[C:33]([F:36])([F:34])[F:35])[CH2:28]2)[C@:24]2([CH3:25])[C:19](=[CH:20][C:21](=[O:39])[CH2:22][CH2:23]2)[C:18](=[CH2:1])[CH2:17]3)[CH2:14][C@H:13]1[CH3:40])(=[O:8])[CH3:7]
Reactant: CC(=O)[O-]
Reactant: CC(=O)OCC(=O)[C@@]1(O)[C@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@@]3(F)[C@@H](OC(=O)C(F)(F)F)C[C@@]21C
Agent: [Na+]
Solvent: COCOC
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: C=C1C[C@@H]2[C@H]([C@@H](OC(=O)C(F)(F)F)C[C@@]3(C)[C@H]2C[C@@H](C)[C@]3(O)C(=O)COC(C)=O)[C@@]2(C)CCC(=O)C=C12
Temperature: 180 °C
Reaction time: 4 h
Yield: 58.7 %

Procedure:
A suspension of 5 g of sodium acetate in 150 ml of chloroform and 150 ml of methylal is combined with 5 g of 21-acetoxy-9α-fluoro-17α-hydroxy-16α-methyl-11β-trifluoroacetoxy-4-pregnene-3,20-dione and, after adding 19 ml of phosphorus oxychloride dropwise, stirred for 4 hours at a bath temperature of 180° C. The reaction solution is neutralized with a saturated soda solution, the organic phase is separated and washed with water. After drying and concentrating, the crude product is purified on silica gel with a hexane-ethyl acetate gradient (0-50% ethyl acetate), thus isolating 2.9 g of 21-acetoxy-17α-hydroxy-16α-methyl-6-methylene-11β-trifluoroacetoxy-4-pregnene-3,20,-dione, mp 217°-219° C.
Reaction SMILES: [ClH:1].N1C=CC=NC=1C(N)CC.[F:12][C:13]([F:31])([F:30])[C:14]1[N:19]=[CH:18][C:17]([C@@H:20]([NH:23][S@](C(C)(C)C)=O)[CH2:21][CH3:22])=[CH:16][N:15]=1>>[ClH:1].[F:31][C:13]([F:12])([F:30])[C:14]1[N:15]=[CH:16][C:17]([CH:20]([NH2:23])[CH2:21][CH3:22])=[CH:18][N:19]=1
Reactant: CC[C@H](N[S@@](=O)C(C)(C)C)c1cnc(C(F)(F)F)nc1
Agent: CCC(N)c1ncccn1
Agent: Cl
Product: CCC(N)c1cnc(C(F)(F)F)nc1

Procedure:
(S)-1-(2-Trifluoromethyl-pyrimidin-5-yl)-propylamine hydrochloride was obtained in analogy to comp. no. 15a from (S)-2-methyl-propane-2-sulfinic acid ((S)-1-(2-trifluoromethyl-pyrimidin-5-yl)-propyl)-amide (Comp. No. 14k).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([NH:9][C:10]12[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][C:12](C(O)=O)([CH2:13]3)[CH2:11]1)[CH2:17]2)=[O:8].C([N:25](CC)CC)C.C1C=CC(OP(OC2C=CC=CC=2)(N=[N+]=[N-])=O)=CC=1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[NH2:25][C:12]12[CH2:13][CH:14]3[CH2:15][CH:16]([CH2:17][C:10]([NH:9][C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[O:8])([CH2:19]3)[CH2:11]1)[CH2:18]2
Reactant: CCN(CC)CC
Reactant: O=C(NC12CC3CC(C1)CC(C(=O)O)(C3)C2)c1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: Cc1ccccc1
Product: NC12CC3CC(C1)CC(NC(=O)c1ccccn1)(C3)C2
Temperature: 90 °C
Yield: 92.7 %

Procedure:
To a round bottom flask was added 3-[(pyridine-2-carbonyl)-amino]-adamantane-1-carboxylic acid (10.0 g, 33.3 mmol) and toluene (100 mL). To the suspension was added triethylamine (5.6 mL, 40 mmol) and the mixture was stirred for a few minutes until most of the solids were dissolved. To the mixture was then added diphenylphosphonic azide (7.9 mL, 37 mmol) and the reaction was stirred at room temperature for 1 hour. The reaction mixture was transferred to an addition funnel and added dropwise to a 3-neck round bottom flask equipped with a reflux condenser containing toluene (70 mL) heated at 90° C. After the addition, the reaction was stirred at 90° C. for two more hours, then allowed to cool down to room temperature. The reaction mixture was then slowly added to a flask containing 6.0 N aqueous hydrochloric acid (55 mL, 330 mmol) and stirred vigorously for 1 hour. The biphasic mixture was transferred to a separatory funnel and the toluene layer was discarded. The aqueous acidic layer was then slowly treated with solid sodium carbonate until a pH of 10 was obtained. The aqueous layer was transferred to a 500-mL separatory funnel and extracted with methylene chloride (3×100 mL). The combined organic layers were then washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 8.38 g (93%) of the title compound, pyridine-2-carboxylic acid (3-amino-adamantan-1-yl)-amide, as a gummy foam. 1H NMR (300 MHz, CDCl3) δ 8.55-8.50 (m, 1H), 8.16 (d, J=7.9 Hz, 1H), 7.94 (br s, 1H), 7.84 (td, J=7.7, 1.7 Hz, 1H), 7.40 (ddd, J=7.6, 4.7, 1.3 Hz, 1H), 2.31-2.21 (m, 2H), 2.13-1.97 (m, 6H), 1.71-1.51 (m, 6H). ESI-MS m/z: 272 (M+H)+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[O:8][CH:9]=[C:10]([Br:12])[CH:11]=1.[NH:13]1[C:21](=[O:22])[C:19](=O)[C:17](=[O:18])[NH:16][C:14]1=[O:15]>CCOCC>[Br:12][C:10]1[CH:11]=[C:7]([CH:19]2[C:17](=[O:18])[NH:16][C:14](=[O:15])[NH:13][C:21]2=[O:22])[O:8][CH:9]=1
Reactant: Brc1coc(Br)c1
Reactant: O=C1NC(=O)C(=O)C(=O)N1
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=C1NC(=O)C(c2cc(Br)co2)C(=O)N1

Procedure:
n-Butyl lithium is reacted with 2,4-dibromofuran in ether according to the procedure of Sornay et al. [Bull. soc. chim. Fr., p. 998 (1971)]. The resulting organolithium solution is reacted with alloxan at -60° to -65° C. according to Example 5, affording 5-(4-bromo-2-furyl)-2,4,6(1H,3H,5H)pyrimidinetrione.
Reaction SMILES: Cl.[F:2][C:3]1([F:32])[CH2:6][CH:5]([CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][C:13]2([CH2:22][CH2:21][CH:20]([O:23][CH3:24])[CH2:19][CH2:18]2)[C:12]3=[N:25]S(C(C)(C)C)=O)[CH2:4]1>O1CCOCC1.C([O-])(O)=O.[Na+]>[F:2][C:3]1([F:32])[CH2:6][CH:5]([CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:15]([CH2:14][C:13]4([CH2:22][CH2:21][CH:20]([O:23][CH3:24])[CH2:19][CH2:18]4)[C:12]3=[NH:25])=[CH:16][CH:17]=2)[CH2:4]1
Reactant: COC1CCC2(CC1)Cc1ccc(OCC3CC(F)(F)C3)cc1C2=NS(=O)C(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: COC1CCC2(CC1)Cc1ccc(OCC3CC(F)(F)C3)cc1C2=N
Reaction time: 8 h
Yield: 116.4 %

Procedure:
HCl (4 M in 1,4-dioxane, 4.13 mL, 16.5 mmol) was added to a solution of N-(5′-((3,3-difluorocyclobutyl)methoxy)-4-methoxyspiro[cyclohexane-1,2′-indene]-3′(1′H)-ylidene)-2-methylpropane-2-sulfinamide (Intermediate 18, 750 mg, 1.65 mmol) in anhydrous 1,4-dioxane (25 mL). A white precipitate formed immediately and the resulting cloudy mixture was stirred under a nitrogen atmosphere overnight. The mixture was diluted with NaHCO3 (aq.) and extracted with DCM. The organic phase was dried and concentrated, to yield 6′-((3,3-difluorocyclobutyl)methoxy)-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-imine (672 mg, 1.92 mmol). The imine, trimethyl orthoformate (0.557 mL, 5.08 mmol) and 2-propanol (5 mL) was placed into a MW tube and the mixture was heated at 60° C. in an oil bath. 2-oxopropanethioamide (Intermediate 1, 397 mg, 3.85 mmol) in MeOH (15 mL) was added and the resulting mixture was stirred overnight. The mixture was concentrated in vacuo. The product was isolated using column chromatography (0-50% EtOAc in heptane) to give 106 mg (12% yield) of the title compound. MS (ES+) m/z 435 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]#[N:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[Cl-].N>CCO.O.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:10][C:11]#[N:12])[CH:7]=[CH:8][CH:9]=1
Reactant: N#CCc1cccc([N+](=O)[O-])c1
Agent: [Fe]
Agent: N
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: N#CCc1cccc(N)c1
Temperature: 85 °C
Yield: 96.3 %

Procedure:
A mixture of (3-nitro-phenyl)-acetonitrile (2.00 g, 12.35 mmol), iron dust (2.07 g, 37.03 mmol) and ammonia chloride (1.96 g, 37.03 mmol) in EtOH (20 mL) and water (4 mL) was refluxed at 85° C. for 1 h. The reaction mixture was filtered through cellite and rinsed with EtOH. The combined filtrate was concentrated and the residue was purified by silica gel column chromatography (20% ethyl acetate in petroleum ether) to afford the title compound (1.57 g, 11.89 mmol, 96% yield) as a pale-yellow solid. MS (ESI) m/z 133.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@:13]([CH2:15][CH2:16]3)([CH3:14])[C:12](=NNS(C3C=CC(C)=CC=3)(=O)=O)[CH2:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1.C([Li])CCC.[Cl-].[NH4+]>COC(C)(C)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@:13]([CH2:15][CH2:16]3)([CH3:14])[CH:12]=[CH:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@@]2(C)C(=NNS(=O)(=O)c3ccc(C)cc3)CC[C@@H]12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: COC(C)(C)C
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@@]2(C)C=CC[C@@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
2.43 g (5.37 mmol) of 3-methoxy-17-tosylhydrazono-13α-estra-1,3,5(10)-triene is suspended in 20 ml of anhydrous methyl-tert-butylether. 1.61 ml of a 10 M n-butyllithium solution in hexane is slowly added in drops to this suspension. It is stirred for 1 hour at room temperature. While being cooled, 50 ml of saturated ammonium chloride solution is added in drops. After the organic phase is separated, it is extracted with ethyl acetate. The combined organic phases are washed with water and saturated sodium chloride solution and dried (MgSO4). The crude product (2.1 g of brown oil) is chromatographed on silica gel, whereby 0.81 g of 3-methoxy-13α-estra-1,3,5(10),16-tetraene is obtained as a colorless oil; [α]D=−6° (chloroform; c=0.94).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:10]2)=[CH:4][CH:3]=1.C1([O:25][C:26](=O)[NH:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[N:38]([CH3:39])[N:37]=[N:36][N:35]=3)=[CH:30][CH:29]=2)C=CC=CC=1.Cl.C(OCC)C>C(#N)C.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH2:16][CH2:17][NH:18][C:26]([NH:27][C:28]3[CH:29]=[CH:30][C:31]([C:34]4[N:38]([CH3:39])[N:37]=[N:36][N:35]=4)=[CH:32][CH:33]=3)=[O:25])[CH2:10]2)=[CH:4][CH:3]=1
Reactant: NCCCN1CCC[C@@H](Cc2ccc(F)cc2)C1
Reactant: Cn1nnnc1-c1ccc(NC(=O)Oc2ccccc2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CC#N
Product: Cn1nnnc1-c1ccc(NC(=O)NCCCN2CCC[C@@H](Cc3ccc(F)cc3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring solution of 25 mg 3-[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]propylamine (0.1 mmol, 1 eq) in 1 ml of dry acetonitrile was added 32.5 mg [4-(1-methyl-1H-tetrazol-5-yl)-phenyl]-carbamic acid phenyl ester (0.1 mmol, 1.1 eq). This mixture was stirred at room temperature for two hours, then concentrated in-vacuo to a pale yellow oil. This oil was purified via radial chromatography, eluting with a 19:1 mixture of methylene chloride and methanol, to yield a white solid. This solid was dissolved in methylene chloride and treated with 1 M hydrochloric acid in diethyl ether (0.1 ml, 1 eq). This mixture was stirred for 30 minutes, then concentrated in-vacuo to a white solid. This solid was dissolved in a 1:1 mixture of acetonitrile and water, and lyophilized to 26 mg of a white solid as product. NMR (300 MHz, CD3OD) δ 7.72 (d, 2H, J=9 Hz), 7.64 (d, 2H, J=9 Hz), 7.21-7.16 (m, 2H), 7.01 (dd, 2 H, J=8, 17 Hz), 4.17 (s, 3H), 3.59-3.54 (m, 1H), 3.40-3.11 (m, 4H), 2.89-2.81 (m, 1H), 2.73-2.59 (m, 3H), 2.10-1.70 (m, 7H), 1.43-1.34 (m, 1H). MS (ESI+) 452 (M−Cl).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:25])[CH3:24]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:23](=[O:25])[CH3:24])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(Sc2ccc(F)cc2)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc(Sc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 2.19 g portion of this amine was dissolved in 50 ml of dichloromethane, cooled in an ice bath and treated with 1.52 g of triethylamine. The mixture was then treated dropwise with a solution of 1.18 g of acetyl chloride in 20 ml of dichloromethane over 20 minutes. This mixture was stirred at room temperature overnight, then the solution was washed successively with water, saturated aqueous sodium bicarbonate, water and brine, dried over magnesium sulfate, filtered and concentrated to dryness. The residue was recrystallized from methanol-water, giving 2.26 g of the desired product as colorless crystals, mp 140°-141° C.
Reaction SMILES: [CH2:1]([C:4]1([C:10]([O:12][CH3:13])=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[CH:2]=C.I(O)(=O)(=O)=[O:15].[Na].O>O1CCCC1.[Os](=O)(=O)(=O)=O>[CH:2]([CH2:1][C:4]1([C:10]([O:12][CH3:13])=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)=[O:15]
Reactant: [O-][I+3]([O-])([O-])O
Reactant: C=CCC1(C(=O)OC)CCCCC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C1(CC=O)CCCCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 72.7 %

Procedure:
To a solution of methyl 1-allylcyclohexanecarboxylate (340 mg) in tetrahydrofuran (7 mL) were added an aqueous solution of sodium periodic acid (3.4 g, 16.0 mmol) and osmium tetraoxide (100 mg) successively under ice cooling. The solution was stirred at room temperature for 20 hours. Water was added to the reaction solution and insolubles were filtered off. The filtrate was extracted with ethyl acetate, and it was washed in turn with water, sodium thiosulfate and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (250 mg). This product was subjected to the subsequent step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([NH2:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24])[C:17](Cl)=[O:18]>N1C=CC=CC=1>[NH2:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[CH:5][N:6]2[C:17]([C:16]2[CH:20]=[C:21]([O:25][CH3:26])[C:22]([O:23][CH3:24])=[C:14]([O:13][CH3:12])[CH:15]=2)=[O:18])=[C:2]([Cl:1])[N:10]=1
Reactant: Nc1nc(Cl)c2nc[nH]c2n1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Solvent: c1ccncc1
Product: COc1cc(C(=O)n2cnc3c(Cl)nc(N)nc32)cc(OC)c1OC

Procedure:
A solution of 6-chloro-9H-purin-2-ylamine in pyridine was treated with 3,4,5-trimethoxybenzoyl chloride at r.t. for 2 h. Work-up and purification by preparative TLC (EtOAc:hexane 1:1) gave the title compound. HPLC Rt: 5.305 min. 1H-NMR (CDCl3): δ 8.24 (s, 1H), 7.13 (s, 2H), 5.36 (s, 2H), 3.99 (s, 3H), 3.88 (s, 6H).