Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:7]([CH2:9][CH2:10][C:11](=O)[CH3:12])[CH:8]=1.[CH2:22]([NH2:34])[CH2:23][C:24]1[CH:33]=[CH:32][C:29]([O:30][CH3:31])=[C:26]([O:27][CH3:28])[CH:25]=1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH3:28][O:27][C:26]1[CH:25]=[C:24]([CH2:23][CH2:22][NH:34][CH:11]([CH3:12])[CH2:10][CH2:9][C:7]2[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:33]=[CH:32][C:29]=1[O:30][CH3:31]
Reactant: COc1ccc(CCN)cc1OC
Reactant: COc1ccc(C#Cc2ccccc2)c(CCC(C)=O)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(C#Cc2ccccc2)c(CCC(C)NCCc2ccc(OC)c(OC)c2)c1
Yield: 90.2 %

Procedure:
4-[5-Methoxy-2-(phenylethynyl)phenyl]-2-butanone (0.5 g, 1.8 mmole), the product of Example 1d, and homoveratryl amine (0.33 g 1.8 mmole) were combined in 10 mL of absolute methanol. With stirring, sodium cyanoborohydride (0.21 g, 3.3 mmole) was added in three portions. During this addition, the pH was adjusted to 6 with glacial acetic acid. After stirring for 5 hr, the reaction mixture was concentrated in vacuo and the resulting residue dissolved in methylene chloride. The methylene chloride solution was washed with 1N sodium hydroxide, water, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 0.72 g of the title compound as a golden oil. The free base was dissolved in absolute methanol (5 mL) and treated with oxalic acid (0.2 g). After stirring for several hours, ether (50 mL) was added and the solution was cooled and filtered to give 1.0 g of the title compound as the oxalate salt.
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]1[N:13]3[C@@H:14]([CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:15][O:16][CH2:17][C:12]3=[N:11][C:4]=1[CH:5]=[N:6]2.ClC1C=C(C=CC=1)C(OO)=[O:34].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[O-:34][N+:6]1[C:7]2[C:2](=[CH:1][CH:10]=[CH:9][CH:8]=2)[C:3]2[N:13]3[C@@H:14]([CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:27])[CH3:26])[CH2:15][O:16][CH2:17][C:12]3=[N:11][C:4]=2[CH:5]=1
Reactant: CC(C)(C)OC(=O)NCCC[C@H]1COCc2nc3cnc4ccccc4c3n21
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC[C@H]1COCc2nc3c[n+]([O-])c4ccccc4c3n21
Reaction time: 2 h
Yield: 99.2 %

Procedure:
tert-Butyl 3-[(11S)-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-11-yl]propylcarbamate (820 mg, 2.15 mmol) was dissolved in 20 mL of CH2Cl2 and treated with 3-chloroperoxybenzoic acid (648 mg, 57-86%). After stirring for 2 h, the reaction mixture was treated with 20 mL of 2% Na2CO3 solution and the layers were separated. The aqueous layer was then extracted with CH2Cl2 (3×20 mL). The combined organic layers were concentrated under reduced pressure to give tert-butyl 3-[(11S)-5-oxido-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-11-yl]propylcarbamate (850 mg) as a crusty, off-white solid.
Reaction SMILES: Cl.[OH:2][CH:3]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1[NH2:5].CO[Na].CO.[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[C:19]([NH:5][C@@H:4]1[C@@H:6]([OH:7])[C@H:8]([OH:9])[C@@H:10]([CH2:12][OH:13])[O:11][CH:3]1[OH:2])(=[O:21])[CH3:20]
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: CC(=O)OC(C)=O
Agent: CO[Na]
Agent: Cl
Solvent: CO
Product: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reaction time: 0.08 h

Procedure:
D-glucosamine hydrochloride (100 g, 0.46 mol) is added to a 0.6M solution of MeONa/MeOH and stirred for 5 minutes. Acetic anhydride (48 ml) is then added, and after 30 minutes a white precipitate appears, which is filtered and washed with cold ethanol. The liquor is recrystallised from absolute ethanol, obtaining 79.3 g of the compound (quantitative).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[Na+].[Na+].Br[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=[O:24])[N:18]=1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:23]([C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:18]=1)=[O:24]
Reactant: O=Cc1cccc(Br)n1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=Cc1cccc(-c2ccccc2)n1
Temperature: 70 °C

Procedure:
Phenylboronic acid (1.46 g, 12 mmol) and Na2CO3 (2.65 g, 25 mmol) were dissolved in 60 mL of degassed 4:1 H2O/MeOH. This solution was added via cannula to a solution of 1.86 g (10 mmol) of 2-bromo-6-formylpyridine and 116 mg (0.10 mmol) of Pd(PPh3)4 in 50 mL of degassed toluene. The biphasic mixture was vigorously stirred and heated at 70° C. under N2 for 4 h. On cooling to RT, the organic phase was separated and the aqueous phase was washed with 3×25 mL of Et2O. The combined organic extracts were washed with 3×25 mL of H2O and 20 mL of brine and dried over Na2SO4. After removing the volatiles in vacuo, the resultant brown oil was chromatographed on silica with hexanes/CH2Cl2. Clean fractions were combined and the volatiles were removed to provide 2-formyl-6-phenylpyridine as a white solid.
Reaction SMILES: Cl.NC[C:4]([O:6][CH2:7][CH3:8])=O.Cl.Cl.[NH2:11][C@H:12]([C:23]([O:25]CC)=O)[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1>>[CH3:4][O:6][C:7]1[C:7]([O:6][CH3:4])=[CH:8][C:12]2[NH:11][C:23](=[O:25])[CH:12]([CH2:13][C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[NH:16][CH:15]=3)[N:11]=[C:14]([C:22]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:13]=2[CH:8]=1
Reactant: CCOC(=O)CN
Reactant: CCOC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: Cl
Product: COc1cc2c(cc1OC)C(c1ccccc1)=NC(Cc1c[nH]c3ccccc13)C(=O)N2
Yield: 10 %

Procedure:
By replacing ethyl glycinate hydrochloride in example XXIIaa by ethyl tryptophanate dihydrochloride and proceeding in the same manner, the abovenamed product is obtained. Yield: 10%. M: 180–185° C. 1H-NMR (DMSO, 200 MHz): d 3.44–3.57 (m, 5H, 1CH2+OCH3), 3.83 (s, 3H, OCH3), 4.35–4.41 (m, 1H, CH), 6.64 (s, 1H Ar), 6.80 (s, 1H Ar), 6.97–7.07 (m, 2H Ar), 7.21–7.63 (m, 7H Ar), 10.37 (s, 1H, NH), 10.83 (s, 1H, NH Indole). Mass: (M+H)+=426.19.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[C:20]2[C:11](=[CH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10]([NH:21][CH2:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])=[N:9][N:8]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>N1C=CC=CC=1>[CH3:28][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][N:6]([C:7]1[C:20]2[C:11](=[CH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10]([NH:21][CH2:22][CH2:23][CH2:24][N:25]([CH3:26])[CH3:27])=[N:9][N:8]=1)[C:29](=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: CN(C)CCCNc1nnc(NCCCN(C)C)c2cc3ccccc3cc12
Solvent: c1ccncc1
Product: CC(=O)N(CCCN(C)C)c1nnc(NCCCN(C)C)c2cc3ccccc3cc12

Procedure:
A solution of 1,4-bis[N-(3-dimethylaminopropyl) amino]-2,3-diaza-anthracene (0.76 g) in pyridine (0.6 ml) and acetic anhydride (94 ml) is left at room temperature for 15 hours. After distillation of the solvent at reduced pressure the residue is dissolved in ethyl acetate (20 ml) and the organic solution is washed with 5% sodium bicarbonate (2×15 ml) and with brine (5 ml). Drying over sodium sulphate and removal of the solvent at reduced pressure gives 0.57 g of 1-[N-(3-dimethylaminopropyl)-N-(acetyl)amino]-4-[N-(3-dimethylaminopropyl)amino]-2,3-diaza-anthracene.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4]([CH:13]=[N:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[CH:3]=1.[C:22]([Si](C)(C)C)#[N:23]>C1C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-]>[CH3:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:10][C:11]=1[CH3:12])[C:6](=[O:8])[N:14]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)[CH:13]2[C:22]#[N:23]
Reactant: C[Si](C)(C)C#N
Reactant: COC(=O)c1cc(C)c(C)cc1C=Nc1cccc(F)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: Cc1cc2c(cc1C)C(C#N)N(c1cccc(F)c1)C2=O
Yield: 78 %

Procedure:
The product of above-mentioned (25-b) (0.45 g, 1.6 mmol), cyanotrimethylsilane (0.40 ml, 3.2 mmol) and aluminum chloride (13 mg) were stirred in anhydrous benzene (5.5 ml) at 25° C. for 20 hrs under an argon atmosphere. The reaction solution was concentrated under reduced pressure, and the residue was washed with petroleum ether to give 0.35 g of 5,6-dimethyl-2-(3-fluorophenyl)-3-cyano-isoindolin-1-one. [IUPAC name: 2-(3-fluorophenyl)-5,6-dimethyl-3-oxo-1-isoindolinecarbonitrile].
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]([C:7]([F:10])=[CH:8][CH:9]=1)[C:5]#[N:6].C(OC([NH:25][C@@H:26]([CH3:30])[C:27](O)=O)=O)(C)(C)C.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.[ClH:48].CN(C)CCCN=C=NCC>C(Cl)Cl.O>[ClH:48].[NH2:25][C@H:26]([C:30]1[N:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:3]2[C:4]([C:5]#[N:6])=[C:7]([F:10])[CH:8]=[CH:9][C:2]=2[N:1]=1)[CH3:27]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N#Cc1c(F)ccc(N)c1Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: O
Product: C[C@H](N)c1nc2ccc(F)c(C#N)c2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3-amino-6-fluoro-2-phenylaminobenzonitrile (960 mg, 4.22 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (879 mg, 4.6 mmol), HOAt (633 mg, 4.6 mmol), 4-methylmorpholine (1.02 mL, 9.29 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (892 mg, 4.6 mmol) in DCM (5 mL) was stirred at RT for 1 h. The reaction mixture was diluted with water and extracted with DCM (×3). The combined organic fractions were washed with brine, then dried (MgSO4) and concentrated in vacuo. A solution of the resulting residue in AcOH (5 mL) was heated at 70° C. for 18 h and then concentrated under reduced pressure. The resulting residue was partitioned between EtOAc and a saturated aqueous solution of NaHCO3. The aqueous phase was extracted with EtOAc (×3) and the combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was dissolved in 4N HCl in dioxane (5 mL) and stirred at RT for 1 h. The volatiles were removed under reduced pressure to afford 2-((S)-1-aminoethyl)-5-fluoro-3-phenyl-3H-benzoimidazole-4-carbonitrile hydrochloride as a brown solid which was used in the following step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7](=[N:16][OH:17])[NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)=[N:4][O:5][N:6]=1.C1N=CN([C:23](N2C=NC=C2)=[O:24])C=1>O1CCCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:7]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=3)[C:23](=[O:24])[O:17][N:16]=2)=[N:4][O:5][N:6]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1nonc1C(=NO)Nc1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1nonc1-c1noc(=O)n1-c1cccc(Cl)c1
Yield: 95.4 %

Procedure:
A solution of 4-amino-N-(3-chlorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide (540 mg, 2.1 mmol) and N,N-carbonyldiimidazole (380 mg, 2.3 mmol) in tetrahydrofuran (10 mL) was heated at 80° C. for 1 h. The reaction mixture was diluted with ethyl acetate (150 mL) and washed with 0.1 N HCl (3×75 mL) and brine (75 mL). The organic layer was dried with sodium sulfate, filtered, and concentrated to give the desired product (560 mg, 94%) as a white solid which was used without further purification. LCMS for C10H7ClN5O3 (M+H)+: m/z=279.9.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][CH:7]([CH2:13][CH2:14][CH3:15])[C:8]([O:10]CC)=[O:9])#[N:2].[OH-].[Li+]>CO.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][CH:7]([CH2:13][CH2:14][CH3:15])[C:8]([OH:10])=[O:9])#[N:2]
Reactant: CCCC(Oc1cccc(C#N)c1)C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCC(Oc1cccc(C#N)c1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 9.00 g (36.5 mmol) of ethyl 2-(3-cyanophenoxy)pentanoate in 10 ml of methanol is treated with a solution of 1.29 g (54.0 mmol) of lithium hydroxide in 10 ml of water and the mixture is stirred at room temperature for 18 hours. The reaction mixture is concentrated in vacuo, extracted with ethyl acetate, and the aqueous phase is acidified and extracted with ethyl acetate. The organic phase is dried over sodium sulfate and evaporated. A colourless solid is obtained; FAB 220
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:28])[NH:10][C@@H:11]([CH3:27])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]3[O:24][C:23]([CH2:25][NH2:26])=[CH:22][C:20]3=2)[CH:15]=[N:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:38](Cl)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[N:41][CH:40]=1>C1COCC1>[CH2:1]([O:8][C:9](=[O:28])[NH:10][C@@H:11]([CH3:27])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]3[O:24][C:23]([CH2:25][NH:26][C:38]([C:39]4[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=4)=[O:45])=[CH:22][C:20]3=2)[CH:15]=[N:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: C[C@@H](Cn1ncc2ccc3oc(CN)cc3c21)NC(=O)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[C@@H](Cn1ncc2ccc3oc(CNC(=O)c4cccnc4)cc3c21)NC(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 39.1 %

Procedure:
To a solution of the product from Step B (0.32 g, 0.847 mmol) in THF (20 mL) was added polymer supported di-isopropyl ethyl amine (3.86 mmol/g, 0.44 g, 1.69 mmol, 2 eq); this suspension was cooled (ice bath) and nicotinoyl chloride (0.15 g, 0.847 mmol) was added. The ice bath was removed and mixture was stirred for one hour, additional nicotinoyl chloride (50 mg) was added and the mixture was stirred at room temperature overnight. Triethylamine was added and after stirring for 10 min saturated aqueous sodium bicarbonate (150 mL) was added. This mixture was extracted with ethyl acetate (2×100 mL). The combined extracts were dried (MgSO4) and evaporated to an oil which was purified by chromatography (silica gel, hexane/ethyl acetate gradient) to give a solid (0.16 g, 39%): LC/MS m/z 484 [M+H]+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[H-].[Na+].[CH3:14][C:15]1[CH:16]=[C:17]([NH:24][C:25]([C:27]2([CH3:30])[CH2:29][O:28]2)=[O:26])[CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22]>C1COCC1>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:30][C:27]([OH:28])([CH3:29])[C:25]([NH:24][C:17]2[CH:18]=[CH:19][C:20]([N+:21]([O-:23])=[O:22])=[C:15]([CH3:14])[CH:16]=2)=[O:26])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: Cc1cc(NC(=O)C2(C)CO2)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(OCC(C)(O)C(=O)Nc2ccc([N+](=O)[O-])c(C)c2)cc1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
A solution of 4-acetamidophenol (2.9 g, 19 mmol) in THF (60 ml) was added dropwise to a stirred suspension of sodium hydride (0.46 g, 19 mmol, 60% dispersion in mineral oil) in THF (60 ml) and the temperature was kept below 5° C. during the addition. The mixture was stirred for 10 min and a solution of 2-methyl-oxirane-2-carboxylic acid (3-methyl-4-nitrophenyl)amide (3.05 g, 13 mmol) in THF (120 ml) was added. The mixture was heated to 60° C. and stirred at this temperature for 7 h, and allowed to cool to the room temperature. The solvent was evaporated and the residue was dissolved to the mixture of water (150 ml) and ethyl acetate (150 ml). The pH was adjusted to 2-3 with 2 M HCl and the phases were separated. The aqueous phase was extracted with ethyl acetate (4×150 ml). The combined organic phase was washed with 1 M Na2CO3 (5×100 ml), dried over Na2SO4 and evaporated. The oily residue was crystallised from the mixture of ethyl acetate-diethyl ether (10:1). The crude product was recrystallised from ethyl acetate. The yield was 2.5 g. 1H NMR (DMSO-d6): 1.42 (3H, s), 1.99 (3H, s), 2.53 (3H, s), 3.93 (1H, d, J=9.6 Hz), 4.16 (1H, d, J=9.6 Hz), 6.20 (1H, bs), 6.84 (2H, d, J=9.0 Hz), 7.44 (2H, d, J=9.0 Hz), 7.88 (1H, dd, J=9.0 Hz and 2.3 Hz), 7.93 (1H, d, J=2.3 Hz), 8.04 (1H, d, J=9.0 Hz), 9.76 (1H, s), 10.15 (1H, bs).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([CH:12]=O)=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)=[C:17]([C:34]([F:37])([F:36])[F:35])[CH:16]=1.[CH3:38][NH2:39].[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([CH2:12][NH:39][CH3:38])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:31])[CH3:32])=[O:28])[CH2:23][CH2:22]2)=[C:17]([C:34]([F:36])([F:35])[F:37])[CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3c(C=O)cnc4ccc(Cl)nc34)cc2C(F)(F)F)CC1
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CNCc1cnc2ccc(Cl)nc2c1Nc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
tert-butyl 4-(4-((6-chloro-3-formyl-1,5-naphthyridin-4-yl)amino)-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate (0.223 g, 0.416 mmol) was dissolved in 20 mL of ethanol, added 0.3 mL of a solution of methylamine in ethanol (concentration 27%), and stirred at room temperature for 24 h. After confirming a disappearance of the raw materials by LC-MS, to the system added sodium borohydride (0.09 g, 2.38 mmol), continued stirring at room temperature for 18 h. The reaction was quenched with a saturated aqueous solution of sodium carbonate, concentrated under reduced pressure to remove ethanol, extracted with 100 mL dichloromethane. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to give 0.193 g of a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.Cl[CH2:12][CH2:13][CH3:14].[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][CH2:13][CH3:14])[C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: CCCCl
Reactant: N#CCc1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Product: CCCC(C#N)c1ccc(Cl)cc1
Temperature: 35 °C

Procedure:
In a four neck one liter flask fitted with a reflux condenser, mechanical stirrer and addition funnel was placed 227.4 gm (1.5 mol) of 4-chlorophenylacetonitrile, 235.6 gm (3.0 mol) of 1-chloropropane and 4.8 gm (0.15 mol) of tetrabutylammonium bromide. 300 gm (3.75 mol) of 50% (w/w) NaOH was added dropwise over 30 minutes. The reaction mixture quickly exothermed to 50° C. and the reaction flask was placed in a cold water bath until the reaction mixture cooled to 35° C. Thereafter, the reaction mixture was heated for an additional 4 hours at 50° C., then the reaction was quenched by adding 1500 ml of water. The mixture was extracted twice with ether and the organic phase was washed with water and then with 200 ml of 10% (w/w) hydrochloric acid. The ether was dried, filtered, concentrated and distilled. The distillate was collected, at 105° C. at 0.5 mm, and two main fractions of 156.3 gm (88% purity) and 88 gm (60% purity) were obtained. The higher purity material was used in the bromomethylation of step B.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:30])[C@@H:14]([OH:29])[CH2:15][C@@H:16]3[C@@:21]4([CH3:27])[CH2:22][CH2:23][C@@H:24]([OH:26])[CH2:25][C@H:20]4[CH2:19][C@@H:18]([OH:28])[C@H:17]3[C@@H:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][C:5](OC)=[O:6].O>C1COCC1>[OH:26][C@@H:24]1[CH2:23][CH2:22][C@@:21]2([CH3:27])[C@H:20]([CH2:19][C@@H:18]([OH:28])[C@@H:17]3[C@@H:16]2[CH2:15][C@H:14]([OH:29])[C@@:13]2([CH3:30])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C@H:2]([CH3:1])[CH2:3][CH2:4][CH2:5][OH:6])[CH2:25]1
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](CCCO)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Yield: 82.9 %

Procedure:
A suspension of LiA1H4 (0.06 g, 3 mols. equiv.) in dry THF (25 ml) was stirred under nitrogen whilst standing in an ice/methanol bath. Methyl cholate (5a) (0.22 g, 0.52 mmol) in dry THF (10 ml) was then added dropwise and the resultant mixture stirred at ambient temperature overnight. Water was then introduced carefully to the mixture until all the excess LiA1H4 ad been destroyed. The resultant mixture was acidified with 2M HCl and extracted into EtOAc (3×). The combined organic extracts were washed with water (2×), dried and evaporated to give a white solid (0.17 g, 83%). Recrystallisation of 0.11 g from ethyl acetate afforded pure 3α,7α,12α,24-tetrahydroxy-5β-cholane (7a)7 (40 mg., 31%): m.p. 226°-227° and 231°-234° C. [Lit.7 226°-227° C.]; 1H nmr (90 MHz; CDCl 3 /DMSO d6) δ 0.64 (3H, s, 18-CH3), 0.85 (3H, s, 19-CH3), 3.0-3.6 (4H, m [exchanges on adding D2O], 3α-,7α-,12α- and 24- OH's), 3.0-3.6 (1H, m, 3β-H), 3.35-3.55 (2H, t[broadened], 24-CH2), 3.6-3.8 (1H, m, 7β-H), 3.8-4.0 (1H, 12β-H); IR (KBr) 3382 (OH's) cm-1.
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C([O-])(=O)C.[Na+].C(O[CH2:20][O:21][CH2:22][CH3:23])C.[CH3:24][N:25]1[C:33]2[N:32]=[CH:31][NH:30][C:29]=2[C:28](=[O:34])[NH:27][C:26]1=[O:35]>CN(C)C=O>[CH2:22]([O:21][CH2:20][N:30]1[C:29]2[C:28](=[O:34])[NH:27][C:26](=[O:35])[N:25]([CH3:24])[C:33]=2[N:32]=[CH:31]1)[CH3:23]
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Reactant: CCOCOCC
Agent: CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCn1cnc2c1c(=O)[nH]c(=O)n2C
Temperature: 90 °C

Procedure:
52.5 g (0.28 mol) of p-toluenesulfonyl chloride were initially introduced into 50 ml of dimethylformamide and 22.6 g (0.29 mol) of sodium acetate were introduced with stirring and ice-cooling. The mixture was subsequently stirred for one hour, treated with 39.1 g of formaldehyde diethyl acetal and again subsequently stirred for one hour. 41.5 g of 3-methylxanthine were then introduced and the reaction mixture was heated at 90° C. for 2 hours. After cooling to 10° C., the precipitated product was filtered off with suction, washed with a little dimethylformamide and washed with demineralized water until chloride-free. The crude product obtained was recrystallized from dimethylformamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:13][CH2:12][CH2:11][C:10]1=[O:14].[C:15](Cl)([N:17]=[C:18]=[O:19])=[O:16].C1(C)C=CC=CC=1>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:10]2[O:14][C:18](=[O:19])[NH:17][C:15](=[O:16])[C:11]=2[CH2:12][CH2:13]1
Reactant: O=C=NC(=O)Cl
Reactant: O=C1CCCC1c1ccc(F)cc1F
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=c1[nH]c(=O)c2c(o1)C(c1ccc(F)cc1F)CC2
Temperature: 120 °C
Yield: 36.4 %

Procedure:
A mixture of 2-(2,4-difluorophenyl)cyclopentanone (1.014 g, 5.17 mmol) and 50% wt. carbonisocyanatidic chloride solution in toluene (1.963 g, 9.30 mmol) was heated at 58° C. for 1 h and at 120° C. for 3 h. The reaction mixture was dissolved in ethyl acetate and washed with an aqueous solution of sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel to give 7-(2,4-difluorophenyl)-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione (499.3 mg, 1.883 mmol, 36.4% yield) as a brown solid. LC-MS (M+H)+=266.2. 1H NMR (500 MHz, CDCl3) δ ppm 8.19-8.64 (1H, m), 7.10 (1H, td, J=8.5, 6.3 Hz), 6.78-6.92 (2H, m), 4.36-4.49 (1H, m), 2.79-2.92 (1H, m), 2.59-2.78 (2H, m), 2.08 (1H, ddd, J=9.3, 6.9, 6.7 Hz).