Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].F[C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:24])[CH3:23])=[CH:18][C:17]=1[C:25]([F:28])([F:27])[F:26]>C1COCC1>[CH2:1]([O:8][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:24])[CH3:23])=[CH:18][C:17]=1[C:25]([F:26])([F:27])[F:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(F)c(C(F)(F)F)c1
Reactant: OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)c1ccc(OCc2ccccc2)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 72.4 %

Procedure:
A mixture of benzyl alcohol (10.9 mL; 104.98 mmol) and KOtBu (12.96 g; 115.5 mmol) in THF (500 mL) was heated under reflux for 10 minutes. Subsequently, 4′-fluoro-3′-(trifluoromethyl)acetophenone (21.64 g; 105 mmol) was added and the mixture heated under reflux for another 2 hours. After cooling to RT, the mixture was partitioned between EtOAc and a 5% aqueous NaHCO3 solution. The organic layer was separated, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O:hexanes 1:2.5) to afford 1-(4-Benzyloxy-3-trifluoromethyl-phenyl)-ethanone (22.37 g).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH:16]([CH3:18])[CH3:17])[C:3]=1[C:19]([O:21]CC)=[O:20]>C(O)C>[OH:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:13])[F:14])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH:16]([CH3:18])[CH3:17])[C:3]=1[C:19]([OH:21])=[O:20]
Reactant: CCOC(=O)c1c(C(C)C)nc2c(C(F)(F)F)cccc2c1O
Solvent: CCO
Product: CC(C)c1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)O
Yield: 53.9 %

Procedure:
A solution of 14 g of the product of Step D, 75 ml of 36° Be sodium hydroxide and 150 ml of ethanol was refluxed for 6 hours and was then cooled. The ethanol was distilled and 150 ml of ice water were added. The mixture was washed with methylene chloride and was acidified with slow addition of 2N hydrochloric acid at less than 15° C. The mixture was filtered and washed until the wash waters had a pH of 6 to obtain 6.9 g of 4-hydroxy-2-isopropyl-8-trifluoromethyl-quinoline-3-carboxylic acid melting at 204° C which was used as is for the next step.
Reaction SMILES: [H-].[Na+].C[C:4]1([CH3:11])O[C@H:7]([CH2:9]O)[CH2:6][O:5]1.C(Br)C[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].O>C1COCC1>[CH2:6]([O:5][CH2:4][CH2:11][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14])[CH2:7][CH2:9][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14]
Reactant: CC1(C)OC[C@@H](CO)O1
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOCCCCCCCCCCCCCCCCCC
Temperature: 80 °C
Reaction time: 8 h
Yield: 60.7 %

Procedure:
To a stirred suspension of NaH (80%; 0.55 g, 17.4 mmol, 2 equiv) in THF (20 ml) was added dropwise a solution of (R)-glycerol acetonide 1 (1.15 g; 1 equiv) in THF (20 ml). After that octadecyl bromide (5.8 g, 17.4 mmol, 2 equiv) dissolved in THF (25 ml) was added dropwise and the mixture obtained was stirred overnight at 80° C. The reaction mixture was cooled to 0° C. and water was added. The resulting mixture was concentrated and the residue was extracted with water and diethyl ether and the combined extracts were dried (MgSO4). The crude product obtained was further purified by flash column chromatography (10% ethyl acetate-n-hexane) to yield the title compound 1b (2.03 g, 5.28 mmol, 61%).
Reaction SMILES: FC(F)(F)C([NH:5][CH2:6][C:7]1[CH:11]=[CH:10][N:9]([C:12]2[CH:13]=[C:14]([C:18]3[NH:19][C:20]4[C:26]([C:27]([NH2:29])=[O:28])=[CH:25][CH:24]=[CH:23][C:21]=4[N:22]=3)[CH:15]=[CH:16][CH:17]=2)[CH:8]=1)=O.[OH-].[Li+].Cl>O1CCCC1.O>[NH2:5][CH2:6][C:7]1[CH:11]=[CH:10][N:9]([C:12]2[CH:13]=[C:14]([C:18]3[NH:19][C:20]4[C:26]([C:27]([NH2:29])=[O:28])=[CH:25][CH:24]=[CH:23][C:21]=4[N:22]=3)[CH:15]=[CH:16][CH:17]=2)[CH:8]=1
Reactant: NC(=O)c1cccc2nc(-c3cccc(-n4ccc(CNC(=O)C(F)(F)F)c4)c3)[nH]c12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NCc1ccn(-c2cccc(-c3nc4cccc(C(N)=O)c4[nH]3)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.3 g (5.4 mmol) of the compound from Example 29 were dissolved in 100 ml of tetrahydrofuran and mixed with 0.26 g (10.8 mmol) of lithium hydroxide, dissolved in 50 ml of water. The entire mixture was stirred at room temperature for 2 hours. The mixture was subsequently neutralized by addition of dilute hydrochloric acid and the organic solvent was removed under reduced pressure. The precipitate, which slowly crystallized out, was filtered off with suction. This gave 0.61 g of the product.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5]
Reactant: BrCc1ccccc1
Reactant: O=Cc1c(Cl)cc(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1c(Cl)cc(OCc2ccccc2)cc1Cl
Reaction time: 8 h

Procedure:
Treat a mixture of 2,6-dichloro-4-hydroxy-benzaldehyde (250 g, 1.3 mol) and potassium carbonate (361.8 g, 2.62 mol) in 2 L dimethylformamide with benzyl bromide (268.64 g, 1.57 mol). Stir the reaction at room temperature for 1 hour. Filter off solids and pour into 12 L of water. Filter off solid, wash several times with water, air dry and dissolve in ethyl acetate. Dry over magnesium sulfate, filter and concentrate under vacuum to ˜1.5 L. Allow to sit overnight then filter. Wash solid with minimal amount of hexane and vacuum dry. Concentrate the filtrate under vacuum and triturate with hexane to yield a second crop of product which when combined with the first crop equals 245 g white crystals. Repeat to obtain a third crop of 80 g as a light-tan powder (88% overall yield): 1H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 7.43 (m, 5H), 7.28 (s, 2H), 5.25 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:27])=[CH:4][C:5]([F:26])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:21])=[C:15](F)[C:16]=3[C:18]#[CH:19])[C:11](=[O:22])[C:10]([C:23]([OH:25])=[O:24])=[CH:9]2)[CH:7]=1.[CH3:28][NH2:29]>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]([F:27])=[CH:4][C:5]([F:26])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:21])=[C:15]([NH:29][CH3:28])[C:16]=3[C:18]#[CH:19])[C:11](=[O:22])[C:10]([C:23]([OH:25])=[O:24])=[CH:9]2)[CH:7]=1
Reactant: C#Cc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c12
Reactant: CN
Solvent: c1ccncc1
Product: C#Cc1c(NC)c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1-(5-Amino-2,4-difluorophenyl)-8-ethynyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (40 mg) was dissolved in pyridine (0.3 ml), and a 40% methylamine solution (1 ml) was added to this solution, followed by stirring at room temperature for 5 hours. The solvent was distilled off under reduced pressure, and diethyl ether was added to the residue. Solids were collected by filtration to obtain the title compound (30 mg) as a brown powder.
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[CH2:5]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1COCC1.CCN(CC)CC>[CH2:5]([N:12]1[CH2:17][CH2:16][N:15]([CH2:2][C:3]#[N:4])[CH2:14][CH2:13]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: N#CCCl
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#CCN1CCN(Cc2ccccc2)CC1
Reaction time: 10 h

Procedure:
An excess of chloroacetonitrile (7 ml) was added in to a solution of benzylpiperazine (2 g, 10.5 mmol) in THF (100 ml) and Et3N (10 ml). The reaction was stirred for 10 hours before quenched with saturated aqueous NaHCO3 (100 ml). The aqueous phase was extracted with EtOAc (3×100 ml). The combined organic layer was dried over MgSO4 and concentrated to a residue, which was used in the further reactions without any purification.
Reaction SMILES: CC([O-])(C)C.[K+].O.[OH:8][C:9]1([C:15]2[CH:29]=[CH:28][C:18]([CH2:19][NH:20]C(=O)OC(C)(C)C)=[CH:17][CH:16]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>C1COCC1>[NH2:20][CH2:19][C:18]1[CH:17]=[CH:16][C:15]([C:9]2([OH:8])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C2(O)CCCCC2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: NCc1ccc(C2(O)CCCCC2)cc1
Temperature: 25 °C

Procedure:
355 mg (3.16 mmol) KOtBu and 14 μl (0.79 mmol) H2O were added to a solution of 386 mg (0.79 mmol) tert-butyl 4-(1-hydroxycyclohexyl)benzylcarbamate in 3.9 ml THF. Refluxed for 2 h. Cooled to r.t. The reaction was quenched with NH4Cl (sat.) and the pH was adjusted to 10-11 with 2 M NaOH. The mixture was extracted 3 times with EtOAc. The organic phase was dried (MgSO4) and concentrated. Gave 164 mg (quant. yield). Used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[CH2:13]O)=[CH:4][C:3]=1[CH3:15].O1CCCC1.S(Cl)([Cl:23])=O>C1(C)C=CC=CC=1>[Cl:23][CH2:13][C:9]1[CH:10]=[N:11][O:12][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:15])[CH:4]=1
Reactant: Cc1cc(-c2oncc2CO)ccc1Cl
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1cc(-c2oncc2CCl)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.1 %

Procedure:
To a mixture of 5-(4-chloro-3-methylphenyl)-4-isoxazolylmethanol (5.80 g), tetrahydrofuran (20 ml) and toluene (80 ml) was added dropwise thionyl chloride (4.63 g) at 0° C. and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, saturated aqueous sodium hydrogencarbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were filtrated and recrystallized from ethyl acetate-hexane to give 4-chloromethyl-5-(4-chloro-3-methylphenyl) isoxazole (5.47 g, yield 87%) as a colorless prism. melting point: 84–85° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][NH:6][C:7]([C:9]2[C:25]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][C:28]=3[CH3:35])=[C:24]([F:36])[C:12]3[N:13]=[C:14](COCC[Si](C)(C)C)[NH:15][C:11]=3[CH:10]=2)=[O:8])[CH2:3][CH2:2]1.Cl.[OH-].[Na+]>CCO>[CH:1]1([CH2:4][O:5][NH:6][C:7]([C:9]2[C:25]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][C:28]=3[CH3:35])=[C:24]([F:36])[C:12]3[N:13]=[CH:14][NH:15][C:11]=3[CH:10]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: Cc1cc(C#N)ccc1Nc1c(C(=O)NOCC2CC2)cc2[nH]c(COCC[Si](C)(C)C)nc2c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C#N)ccc1Nc1c(C(=O)NOCC2CC2)cc2[nH]cnc2c1F
Temperature: 50 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a slurry of a 1:1 mixture of N1:N3 isomers 6-(4-cyano-2-methyl-phenylamino)-7-fluoro-(2-trimethylsilanyl-ethoxymethyl)-benzoimidazole-5-carboxylic acid cyclopropylmethyoxy-amide 11zz (28 mg, 0.055 mmol) in 0.5 mL EtOH is added 0.5 mL 10% HCl. The reaction mixture is heated to 50° C. with stirring overnight (Whitten et al., J. Org. Chem., 1986, 51, 1891-1894). An additional 0.5 mL 10% HCl is added and the reaction mixture stirred at 70° C. overnight. The reaction mixture is cooled to room temperature and neutralized to pH ˜8 with 1.5 mL 1N NaOH. The reaction mixture is extracted with ethyl acetate, dried (MgSO4) and concentrated under reduced pressure to give 14 mg (60%) of 90% pure product as a mixture of rotatomers: MS APCI (+) m/z 380 (M+1) detected; MS APCI (−) m/z 378 (M−1) detected; 1H NMR (400 MHz, MeOH-d4) δ 8.41 (bs, 1H), 7.75 (m, 1H), 7.50 (s, 1H), 7.38 (d, 1H), 6.51 (m, 1H), 3.72 (d, 0.5H), 3.65 (d, 1.5H), 2.41 (s, 3H), 0.98 (1H, m), 0.58 (d, 1.5H), 0.40 (d, 0.5H), 0.25 (d, 1.5H), 0.19 (d, 0.5H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9](=[N:11][OH:12])[NH2:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.C(N(CC)CC)C.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:9](=[N:11][O:12][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH2:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC(=NO)c1nc(Br)cnc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=NOC(=O)c1ccccc1)c1nc(Br)cnc1N
Reaction time: 1 h
Yield: 69.8 %

Procedure:
3-amino-6-bromo-N′-hydroxypyrazine-2-carboximidamide (770 mg, 3.318 mmol) was suspended in DCM (10 mL) and triethylamine (369.3 mg, 508.7 μL, 3.650 mmol) followed by benzoyl chloride (513.1 mg, 423.7 μL, 3.650 mmol) were added. After 1 hour, the solvent was removed in vacuo and the residue triturated with MeOH. The resultant filtrate was filtered off to furnish the product as an off-white solid (779 mg, 70% Yield).
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][CH2:8][NH:7][C:6]=2[C:5]([NH2:12])=[CH:4][CH:3]=1.[C:13]([O:17][C:18]([NH:20][C@@H:21]([CH3:25])[C:22](O)=[O:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:13]([O:17][C:18](=[O:19])[NH:20][C@H:21]([C:22](=[O:23])[NH:12][C:5]1[C:6]2[NH:7][CH2:8][CH2:9][O:10][C:11]=2[C:2]([F:1])=[CH:3][CH:4]=1)[CH3:25])([CH3:14])([CH3:15])[CH3:16]
Reactant: Nc1ccc(F)c2c1NCCO2
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)c2c1NCCO2
Temperature: 0 °C
Yield: 89.7 %

Procedure:
To an ice-cooled mixture of 8-fluoro-3,4-dihydro-2H-benzo[1,4]oxazin-5-ylamine (243 mg, 1.445 mmol), (S)-2-tert-butoxycarbonylaminopropionic acid (305 mg, 1.61 mmol) and HOAt (200 mg, 1.463 mmol) in DCM (15 mL) was added EDCI HCl (337 mg, 1.76 mmol). The reaction mixture was stirred in the ice bath for 90 min, then diluted with DCM, washed with aqueous Na2CO3 and then water. The organic layer was dried (Na2SO4) and then concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 50-70% EtOAc in cyclohexane) affording the title compound as a pale yellow foam (440 mg, 89%). LCMS (Method B): RT 3.02 min [M+H]+ 340
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30]([NH:32][CH2:33][C:34]1([C:49]([OH:51])=O)[CH2:39][CH2:38][N:37]([C:40]2[C:41]3[CH:48]=[CH:47][NH:46][C:42]=3[N:43]=[CH:44][N:45]=2)[CH2:36][CH2:35]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].[Cl:52][C:53]1[CH:58]=[CH:57][C:56]([C@@H:59]([NH2:61])[CH3:60])=[CH:55][CH:54]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[Cl:52][C:53]1[CH:58]=[CH:57][C:56]([C@@H:59]([NH:61][C:49]([C:34]2([CH2:33][NH:32][C:30](=[O:31])[O:29][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:35][CH2:36][N:37]([C:40]3[C:41]4[CH:48]=[CH:47][NH:46][C:42]=4[N:43]=[CH:44][N:45]=3)[CH2:38][CH2:39]2)=[O:51])[CH3:60])=[CH:55][CH:54]=1
Reactant: C[C@H](N)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NCC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: C[C@H](NC(=O)C1(CNC(=O)OC(C)(C)C)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 83.5 %

Procedure:
HATU (0.251 g, 0.66 mmol) was added in one portion to 4-((tert-butoxycarbonylamino)methyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 12) (0.225 g, 0.6 mmol), (S)-1-(4-chlorophenyl)ethanamine (0.093 g, 0.60 mmol) and DIPEA (0.314 mL, 1.80 mmol) in DMA (10 mL) at 25° C. under nitrogen. The resulting solution was stirred at 60° C. for 4 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using methanol. Residual HATU was removed by passing the methanol solution through a silica-supported carbonate column. The crude product thus obtained was evaporated to dryness to afford (S)-tert-butyl (4-(1-(4-chlorophenyl)ethylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl)methylcarbamate (0.257 g, 83%) as a colourless gum. This material was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[Br:17][C:18]1[S:26][C:25]2[C:24]([C:27]#[N:28])=[CH:23][N:22]=[C:21](Cl)[C:20]=2[CH:19]=1>CN1CCCC1=O>[Br:17][C:18]1[S:26][C:25]2[C:24]([C:27]#[N:28])=[CH:23][N:22]=[C:21]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:20]=2[CH:19]=1
Reactant: COc1ccc(CN)cc1
Reactant: N#Cc1cnc(Cl)c2cc(Br)sc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ccc(CNc2ncc(C#N)c3sc(Br)cc23)cc1
Temperature: 130 °C
Yield: 66.5 %

Procedure:
To a stirred solution of 4-methoxybenzylamine (1.2 equiv., 2.4 mmol) and K2CO3 (2.4 equiv., 4.8 mmol) in 5 mL anhydrous 1-methyl-2-pyrrolidinone was added 15 (1 equiv., 2 mmol). The mixture was heated at 130° C. under N2 for 1.5 h, allowed to cool, and the product precipitated by the addition of H2O (5 mL). The mixture was filtered, washed with water, and dried, yielding 16 (1.33 mmol) as a brown solid. 1H NMR (400 MHz, d6-DMSO) δ: 8.75 (1H, t, broad), 8.56 (1H, s), 8.21 (1H, s), 7.43 (2H, d, J=8.6 Hz), 7.04 (2H, d, J=8.6), 4.84 (2H, d, J=5.8), 3.88 (3H, s).
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][NH:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.C(=O)(O)[O-].[K+].[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C(OC(=O)C)(=O)C>[CH:19](=[C:2]1[C:1](=[O:12])[O:13][C:4]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[N:3]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)CNC(=O)c1ccccc1
Reactant: O=Cc1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: O=C1OC(c2ccccc2)=NC1=Cc1ccccc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 49.5 %

Procedure:
1.8 g of hippuric acid and 0.4 g of potassium bicarbonate are dissolved in 4 ml of acetic anhydride, the solution is heated for a few minutes at 50° C. and then cooled to room temperature and 1.49 g of benzaldehyde are added. After 1 hour at room temperature, 20 ml of distilled water are added at 80° C. The solid which precipitates is filtered off, washed with water and ethanol and then dried to give 1.24 g of the expected product in the form of a yellow solid.
Reaction SMILES: [F:1][C:2]([F:28])=[C:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:4]12[CH3:5])[C:17]1[CH:16]=[CH:15][C:14]([O:21]C2CCCCO2)=[CH:13][C:12]=1[CH:11]=[CH:10]3.C(O)(=O)C(O)=O>CO.O>[F:1][C:2]([F:28])=[C:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:4]12[CH3:5])[C:17]1[CH:16]=[CH:15][C:14]([OH:21])=[CH:13][C:12]=1[CH:11]=[CH:10]3
Reactant: C[C@]12CC[C@@H]3c4ccc(OC5CCCCO5)cc4C=C[C@H]3[C@@H]1CCC2=C(F)F
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: CO
Product: C[C@]12CC[C@@H]3c4ccc(O)cc4C=C[C@H]3[C@@H]1CCC2=C(F)F
Yield: 69.7 %

Procedure:
A suspension of 1.1 g of 17-difluoromethylene-3-tetrahydropyranyloxy-estra-1,3,5(10),6-tetraene in 25 ml of methanol and 2.5 ml of water is refluxed at a bath temperature of 100° C. with 1.1 mg of oxalic acid for 1.5 hours. Then, it is added to water, extracted with dichloromethane, washed with water, sodium bicarbonate solution as well as with saturated sodium chloride solution, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/ethyl acetate. 0.6 g of 17-difluoromethylene-estra -1,3,5(10),6-tetraen-3-ol is obtained as colorless crystals with a melting point of 132-134° C., [α]D22 =-167.9° (c=0.505% in. pyridine).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[Cl:7][C:8]1[C:13]2[CH2:14][NH:15][CH2:16][CH2:17][S:18][C:12]=2[CH:11]=[CH:10][CH:9]=1>O.ClCCl>[Cl:7][C:8]1[C:13]2[CH2:14][NH:15][CH2:16][CH2:17][S:18](=[O:2])[C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: Clc1cccc2c1CNCCS2
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=S1CCNCc2c(Cl)cccc21
Reaction time: 19 h

Procedure:
A solution of sodium periodate (3.09 g) in water (25 ml) was added dropwise with cooling to a stirred solution of 6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine (2.88 g, prepared in a similar manner to that described in the preceding paragraph) in dichloromethane (75 ml). The stirring was continued at room temperature for 19 hours. Solvent was removed from the mixture by evaporation at reduced pressure. Purification of the residue by flash chromatography using dichloromethane/ethanol (95:5) as eluent gave 6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide, which was recrystallised from ethyl acetate. Yield 2.15 g (m.p. 125°-126° C.).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>CN(C=O)C>[CH2:26]([O:11][C:10](=[O:12])[C@H:9]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:9][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:15][CH:14]=1)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](C(=O)OCc1ccccc1)c1ccc(OCc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 17 h
Yield: 184 %

Procedure:
To a solution of (S)-tert-butoxycarbonylamino-(4-hydroxy-phenyl)-acetic acid (32.03 g, 120 mmol) in DMF (300 ml) was added potassium carbonate (35 g, 252 mmol) and benzylbromide (30 ml, 252 mmol). The reaction mixture was stirred at 50° C. under a nitrogen atmosphere for 17 h. The mixture was poured into water (1l) and extracted with EtOAc (3×600 ml). The combined organic extracts were washed with water (3×600 ml), brine (600 ml), dried over magnesium sulfate, filtered and evaporated in vacuo to yield a yellow oil (49.4 g, 92%). LCMS purity 100%, m/z 470 [M++Na]+.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=S)[CH:7]3[CH2:14][CH2:15][CH2:16][CH:6]3[C:5]=2[CH:4]=1)#[N:2].[NH3:17]>>[NH2:17][C:8]1[CH:7]2[CH2:14][CH2:15][CH2:16][CH:6]2[C:5]2[CH:4]=[C:3]([C:1]#[N:2])[CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: N#Cc1ccc2c(c1)C1CCCC1C(=S)N2
Reactant: N
Product: N#Cc1ccc2c(c1)C1CCCC1C(N)=N2
Yield: 81 %

Procedure:
Analogously to Example 4, 8-cyano-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinoline-4-thione (40 mg, 0.18 mmol) is reacted with 7N methanolic ammonia solution (10 ml) to form 30 mg (81%) of product.
Reaction SMILES: CN([CH2:4][C:5]1[C:9]2[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:8]=2[NH:7][CH:6]=1)C.[N+:16]([CH:19]([CH3:21])[CH3:20])([O-:18])=[O:17]>>[CH3:15][O:14][C:11]1[CH:10]=[C:9]2[C:8](=[CH:13][CH:12]=1)[NH:7][CH:6]=[C:5]2[CH2:4][C:19]([CH3:21])([N+:16]([O-:18])=[O:17])[CH3:20]
Reactant: COc1ccc2[nH]cc(CN(C)C)c2c1
Reactant: CC(C)[N+](=O)[O-]
Product: COc1ccc2[nH]cc(CC(C)(C)[N+](=O)[O-])c2c1

Procedure:
This material was prepared by the reaction of 5-methoxygramine (Procedure 69B) and 2-nitropropane substantially as described in Procedure 67C. The product was initially recovered as a dark oil which crystallized from i-Pr2O solution after treatment thereof with activated carbon, yield 31.3 g. (from 33 g. of 5-methoxygramine), m.p. 83°-85°. The identity of the product was confirmed by inspection of its NMR spectrum.