Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:16][NH2:17]>C1COCC1>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][N:3]=[C:2]2[NH:16][NH2:17]
Reactant: NN
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Solvent: C1CCOC1
Product: COc1cc2ncnc(NN)c2cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.3 %

Procedure:
To a suspension of 4-Chloro-6,7-dimethoxy-quinazoline (0.20 g, 0.89 mmol) in anhydrous THF (0.5 ml) was added hydrazine (1M in THF, 2.0 ml, 2.0 mmol). The mixture was stirred at room temperature for 16 hours whereupon a precipitate had formed which was removed by filtration and washed with cold THF to give the desired product (177 mg, 91%) as a sticky off white solid which was sufficiently pure to be used without any further purification. m/z (LC-MS, ESP): 221 [M+H]+, R/T=2.48 mins.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]([CH2:15][CH2:16][C:17]([OH:19])=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.O=S(Cl)[Cl:22]>CO.O>[CH3:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]([CH2:15][CH2:16][C:17]([Cl:22])=[O:19])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2c1-c1ccccc1C2CCC(=O)O
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: CO
Product: Cc1cccc2c1-c1ccccc1C2CCC(=O)Cl
Reaction time: 2 h

Procedure:
3-(4-Methylfluoren-9-yl)propionic acid (3.5 g, 13 9 mmol) was charged with SOCl2 (20 mL, in excess) at room temperature. The reaction mixture was boiled for 2 hr. The reaction was monitored by TLC (silica RP-18, 70% methanol/water). The excess of thionyl chloride was removed under reduced pressure, the residue (an oil) was used for the next step without further purification.
Reaction SMILES: C([O:5][C:6](=[O:42])[C@@H:7]([NH:32][S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[O:35])=[O:34])[CH2:8][NH:9][C:10]([NH:12][C:13]1[C:22](=[O:23])[N:21]2[C:16]([CH:17]=[CH:18][C:19]([O:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]([NH2:31])=[NH:30])=[CH:20]2)=[CH:15][CH:14]=1)=[O:11])(C)(C)C.[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46]>ClCCl>[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46].[C:36]1([S:33]([NH:32][C@@H:7]([CH2:8][NH:9][C:10]([NH:12][C:13]2[C:22](=[O:23])[N:21]3[C:16]([CH:17]=[CH:18][C:19]([O:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]([NH2:31])=[NH:30])=[CH:20]3)=[CH:15][CH:14]=2)=[O:11])[C:6]([OH:42])=[O:5])(=[O:35])=[O:34])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)Nc1ccc2ccc(OCCCNC(=N)N)cn2c1=O)NS(=O)(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N=C(N)NCCCOc1ccc2ccc(NC(=O)NC[C@H](NS(=O)(=O)c3ccccc3)C(=O)O)c(=O)n2c1
Reaction time: 8 h

Procedure:
To a suspension (S)-2-benzenesulfonylamino-3-{3-[7-(3-guanidino-propoxy)-4-oxo-4H-quinolizin-3-yl]-ureido}-propionic acid tert-butyl ester (30 mg, 0.049 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (6 mL). The mixture was stirred overnight, evaporated to dryness and triturated in ether (3X) and hexane (1X). Compound IX was purified by preparative HPLC using 1:1 MeCN:H2O as eluent and characterized by 1H NMR (400 MHz) (CD3OD) d: 8.51 (d, 1H, J=8.5 Hz), 8.45 (s, 1H), 7.98-7.85 (m, 2H), 7.63 (d, 1H, J=9 Hz), 7.49-7.47 (m, 3H), 7.10 (d, 1H, J=9 Hz), 6.98 (d, 1H, J=8.5 Hz), 4.20 (t, 2H, J=5.5 Hz), 4.03-4.01 (m, 1H), 3.65-3.62 (m, 1H), 3.49-3.42 (m, 3H), 2.20-2.14 (m, 2H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:21]=[CH:20][CH:19]=[CH:18][C:11]=2[C:12]([NH:14][CH2:15][C:16]#[CH:17])=[O:13])=[CH:5][CH:4]=1.[N:22]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)=[N+:23]=[N-:24].O.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>S([O-])([O-])(=O)=O.[Cu+2].C(O)(C)(C)C>[F:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][N:22]2[CH:17]=[C:16]([CH2:15][NH:14][C:12](=[O:13])[C:11]3[CH:18]=[CH:19][CH:20]=[N:21][C:10]=3[NH:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:24]=[N:23]2)=[CH:27][CH:28]=1
Reactant: [N-]=[N+]=NCc1ccc(F)cc1
Reactant: C#CCNC(=O)c1cccnc1Nc1ccc(OC)cc1
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(C)(C)O
Solvent: O
Product: COc1ccc(Nc2ncccc2C(=O)NCc2cn(Cc3ccc(F)cc3)nn2)cc1
Temperature: 25 °C
Reaction time: 11 h
Yield: 75.5 %

Procedure:
Compound 8 (194 mg, 1 mmol) and 4-methoxyaniline (9e, 123 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain 2-(4-methoxyphenylamino)-N-(prop-2-ynyl)nicotinamide 10e as pure product. To a solution of 2-(4-methoxyphenylamino)-N-(prop-2-ynyl)nicotinamide (10e, 150 mg, 0.53 mmol) and 1-(azidomethyl)-4-fluorobenzene (12b, 88 mg, 0.58 mmol) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.005 mmol) were added sequentially. The reaction was stirred at room temperature for 11 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 2e (173 mg, 75%); mp: 169-171° C.; 1H NMR (500 MHz, CDCl3) δ 10.26 (s, 1H), 8.23 (dd, J=4.0, 1.5 Hz, 1H), 7.74 (dd, J=8.0, 1.5 Hz, 1H), 7.50 (d, J=9.0 Hz, 1H), 7.29-7.24 (m, 4H), 7.06 (t, J=9.0 Hz, 2H), 6.83 (d, J=9.0 Hz, 2H), 6.59-6.50 (m, 1H), 5.47 (s, 2H), 4.64 (d, J=5.2 Hz, 2H), 3.78 (s, 3H); MS (ESI m/z): 433 [M+H]+. Yield: 75%
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][CH2:6][NH:7][C:8](=[O:35])[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH:29]2[CH2:32][C:31]([CH3:34])([CH3:33])[CH2:30]2)[NH:16][C:17]2[C:26]([CH3:27])=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([F:28])[CH:23]=3)[N:18]=2)=[CH:11][CH:10]=1)C.[OH-].[Na+].Cl>O1CCCC1.CO>[CH3:33][C:31]1([CH3:34])[CH2:32][CH:29]([CH:15]([NH:16][C:17]2[C:26]([CH3:27])=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([F:28])[CH:23]=3)[N:18]=2)[C:12]2[CH:11]=[CH:10][C:9]([C:8]([NH:7][CH2:6][CH2:5][C:4]([OH:36])=[O:3])=[O:35])=[CH:14][CH:13]=2)[CH2:30]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(C(Nc2nc3ccc(F)cc3cc2C)C2CC(C)(C)C2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2cc(F)ccc2nc1NC(c1ccc(C(=O)NCCC(=O)O)cc1)C1CC(C)(C)C1
Yield: 74.4 %

Procedure:
(+/−)-3-{4-[(3,3-Dimethyl-cyclobutyl)-(6-fluoro-3-methyl-quinolin-2-ylamino)-methyl]-benzoylamino}-propionic acid ethyl ester (14.3 mg, 0.029 mmol), made in a similar manner as Intermediate 27 from Intermediate 29, was dissolved in tetrahydrofuran (1.5 mL) and methanol (0.5 mL), and 1.0 M sodium hydroxide (1 mL) was added. This was stirred as a solution at room temperature for 20 min before 1 N HCl was added to bring to pH 5. This was extracted twice with ethyl acetate and the combined organics dried over MgSO4, and concentrated in vacuo. Purification by reversed-phase HPLC gave (+/−)-3-{4-[(3,3-dimethyl-cyclobutyl)-(6-fluoro-3-methyl-quinolin-2-ylamino)-methyl]-benzoylamino}-propionic acid (10 mg). Analytical LCMS: retention time 2.3998 minutes (Waters Atlantic dC18 4.6×50 mm, 5 μm column; 5% acetonitrile/water (0.05% trifluoroacetic acid modifier) linear gradient to 95% acetonitrile/water over 4.0 minutes, hold at 95% acetonitrile/water for 1.0 minute; flow rate 2.0 mL/minute); MS (M+1): 464.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]1[CH:13]([C:14]([O:16]CC)=[O:15])[CH:8]1[CH2:7][CH2:6]2.[OH-].[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]1[CH:13]([C:14]([OH:16])=[O:15])[CH:8]1[CH2:7][CH2:6]2
Reactant: CCOC(=O)C1C2CCc3cc(OC)ccc3C21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1)CCC1C(C(=O)O)C21
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
Ethyl 5-methoxy-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene-1-carboxylate (0.2 g, 0.8 mmol) was dissolved in 2 ml of methanol and the solution of sodium hydroxide (0.2 g, 50 mmol) in 2 ml of water was added to the reaction mixture and stirred at ambient temperature overnight. The extraction of basic reaction mixture into hexane showed that no starting material present. The reaction mixture was acidified with excess of 3M HCl solution (pH=1), and extracted into ethylacetate (3×15 ml). The combined extracts were washed with water and brine, dried over Na2SO4 and concentrated by rotary evaporation to give 0.15 g of mixture of cis/trans acids as white solid.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:15][C@@H:5]2[O:6][C:7](=[O:14])[CH2:8][CH2:9][CH2:10][CH:11]=[CH:12][CH2:13][C@@H:4]2[C@H:3]1/[CH:16]=[CH:17]/[C@@H:18]([OH:31])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1.[OH-:32].[K+].Cl>CC(O)C>[OH:1][C@@H:2]1[CH2:15][C@H:5]([OH:6])[C@H:4]([CH2:13]/[CH:12]=[CH:11]\[CH2:10][CH2:9][CH2:8][C:7]([OH:32])=[O:14])[C@H:3]1/[CH:16]=[CH:17]/[C@@H:18]([OH:31])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=1
Reactant: O=C1CCCC=CC[C@@H]2[C@@H](/C=C/[C@@H](O)COc3cccc(C(F)(F)F)c3)[C@H](O)C[C@@H]2O1
Reactant: [OH-]
Agent: Cl
Agent: O=C1CCC/C=C\C[C@@H]2[C@@H](/C=C/[C@@H](O)COc3cccc(C(F)(F)F)c3)[C@H](O)C[C@@H]2O1
Agent: [K+]
Solvent: CC(C)O
Product: O=C(O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)COc2cccc(C(F)(F)F)c2)[C@H](O)C[C@@H]1O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A solution of (8aR,9R,10R,11aS,Z)-10-hydroxy-9-((R,E)-3-hydroxy-4-(3-(trifluoromethyl)phenoxy) but-1-en-1-yl)-4,5,8,8a,9,10,11,11a-octahydrocyclopenta[b]oxecin-2(3H)-one (3.0 g from Example 8) in 2-propanol (25 mL) was treated with 3N potassium hydroxide aqueous solution (6.8 mL). This mixture was stirred at 50° C. for 2 hr. The reaction mixture was cooled and further adjusted with 3N hydrochloric acid aqueous solution to a pH of 8.5±0.2, and most of the solvent was removed under reduced pressure. The residue was diluted with saturated aqueous solution of sodium bicarbonate (20 mL) and ethyl acetate (20 mL). The mixture was stirred at room temperature for 5 minutes. The organic phase and the aqueous phase were separately collected. The aqueous layer was adjusted to a pH of 3.0±0.2 with 3N hydrochloric acid aqueous solution at room temperature and extracted with ethyl acetate (100 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give 3.3 g of crude Travoprost acid.
Reaction SMILES: Cl[CH:2]=[C:3](Cl)Cl.[CH2:6]([O:10][C:11](=[O:13])[CH3:12])[CH2:7][CH2:8][CH3:9]>>[CH2:6]([O:10][C:11](=[O:13])[C:12]1[C:12](=[CH:3][CH:2]=[CH:2][CH:3]=1)[C:11]([O:10][CH2:6][CH2:7][CH2:8][CH3:9])=[O:13])[CH2:7][CH2:8][CH3:9]
Reactant: ClC=C(Cl)Cl
Reactant: CCCCOC(C)=O
Product: CCCCOC(=O)c1ccccc1C(=O)OCCCC
Reaction time: 48 h

Procedure:
The procedure for preparing the solution is as follows. Carefully crush the 9.7 grams of Ixan-SGA resin with a mortar and pestle to yield a fine powder. Then, gradually add the Ixan powder to the 30 grams butylacetate while constantly stirring the solution to prevent clusters from forming. Complete dissolution is reached only after approximately 48 hours. After complete dissolution, add the 57.9 grams of trichloroethylene and stir the resulting solution constantly for another 24 hours to yield a clear yellow solution. The last two solvents are used as plasticizers. After filtering the Ixan solution through a millipore filtering apparatus with a filter having a 1.2 μm pore size and 47 mm. diameter, add the plasticizers and again stir the solution for another 12 hours.
Reaction SMILES: C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Cl:30][C:31]1[CH:38]=[C:37]([O:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[Cl:46])[CH:36]=[CH:35][C:32]=1[CH2:33][NH2:34].[N:47]1[CH:52]=[C:51]([C:53]([NH:55][C:56]2([C:59](O)=[O:60])[CH2:58][CH2:57]2)=[O:54])[CH:50]=[N:49][CH:48]=1>O1CCCC1.CN(C=O)C>[Cl:30][C:31]1[CH:38]=[C:37]([O:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[Cl:46])[CH:36]=[CH:35][C:32]=1[CH2:33][NH:34][C:59]([C:56]1([NH:55][C:53]([C:51]2[CH:50]=[N:49][CH:48]=[N:47][CH:52]=2)=[O:54])[CH2:58][CH2:57]1)=[O:60]
Reactant: NCc1ccc(Oc2ccccc2Cl)cc1Cl
Reactant: O=C(NC1(C(=O)O)CC1)c1cncnc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NC1(C(=O)NCc2ccc(Oc3ccccc3Cl)cc2Cl)CC1)c1cncnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29 %

Procedure:
85 mg (0.84 mmol) of triethylamine, 130 mg (0.40 mmol) of TBTU and 100 mg (0.37 mmol) of 2-chloro-4-(2-chloro-phenoxy)-benzylamine were added to a solution of 80 mg (0.38 mmol) of 1-[(pyrimidin-5-carbonyl)-amino]-cyclopropanecarboxylic acid (from 1 b) in 30 mL tetrahydrofuran and 5 mL DMF and the mixture was stirred overnight at ambient temperature. Then the mixture was evaporated to dryness and the residue was combined with 2 M potassium carbonate solution. It was extracted with ethyl acetate and the organic phase was washed with water and saturated sodium chloride solution, dried and evaporated down. The crude product thus obtained was purified by reversed-phase chromatography. The fractions were evaporated down to the aqueous phase, made basic with ammonia and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried and evaporated down. The residue was evaporated out with ether and dried.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=1.[N:24]1([CH2:30][CH2:31][NH2:32])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[CH:21]([C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:5]2[C:4]3[C:9](=[CH:10][N:11]=[C:2]([NH:32][CH2:31][CH2:30][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:12]#[N:13])=[CH:16][CH:17]=1)([CH3:23])[CH3:22]
Reactant: NCCN1CCOCC1
Reactant: CC(C)c1ccc(Nc2c(C#N)cnc3cnc(F)cc23)cc1
Product: CC(C)c1ccc(Nc2c(C#N)cnc3cnc(NCCN4CCOCC4)cc23)cc1
Yield: 55 %

Procedure:
Following the procedure described above in Example 34, 6-fluoro-4-[(4-isopropylphenyl)amino]-1,7-naphthyridine-3-carbonitrile was reacted with 2-morpholin-4-yl-ethylamine. The crude product was purified by flash column chromatography (2% methanol in methylene chloride) to give a yellow solid (0.11 g, 55%). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.2 (d, J=6.8 Hz, 6 H) 2.4 (m, 4 H) 2.6 (m, 2 H) 2.9 (qt, 1 H) 3.3 (m, 1 H) 3.4 (m, 1 H) 3.6 (m, 4 H) 6.6 (m, 1 H) 7.0 (s, 1 H) 7.2 (d, J=8.6 Hz, 2 H) 7.3 (m, 2 H) 8.2 (s, 1 H) 8.8 (s, 1 H) 9.5 (s, 1 H).
Reaction SMILES: C([O:3][C:4]([CH:6]1[C:11](=[O:12])[NH:10][C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[S:7]1)=O)C.[BH4-].[Na+].C(O)(=O)C>C(O)C.O>[OH:3][CH2:4][CH:6]1[C:11](=[O:12])[NH:10][C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[S:7]1
Reactant: CCOC(=O)C1Sc2ccccc2NC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: O=C1Nc2ccccc2SC1CO
Temperature: 25 °C
Yield: 50.6 %

Procedure:
To a suspension of 3.0 g of 2-ethoxycarbonyl-2H-1,4-benzothiazin-3(4H)-one in ethanol (50 ml) was added portionwise 0.95 g of sodium borohydride with stirring at room temperature. After stirring for 2 hours, the mixture was diluted with water, made acidic with acetic acid, and extracted with ether. The ether layer was washed with water, dried (MgSO4), and then concentrated under reduced pressure. The residue was washed with hexane to obtain 1.25 g (50.8%) of 2-hydroxymethyl-2H-1,4-benzothiazin-3(4H)-one as crystals. Recrystallization from ethyl acetate gave prisms, m.p. 156°-157° C.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[C:13]([F:15])[C:12]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:19]=2)=[CH:11][C:10]=1[F:31])=[O:5])C.[OH-].[Na+]>CO>[F:31][C:10]1[CH:11]=[C:12]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:19]=2)[C:13]([F:15])=[CH:14][C:9]=1[C@@H:7]1[CH2:8][C@H:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1cc(F)c(NCc2cccc(Oc3ccccc3)c2)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)[C@@H]1C[C@H]1c1cc(F)c(NCc2cccc(Oc3ccccc3)c2)cc1F
Yield: 83.5 %

Procedure:
A solution of enantiomerically enriched-(trans)-ethyl-2-[2,5-difluoro-4-({[3-(phenyloxy)phenyl]methyl}amino)phenyl]cyclopropanecarboxylate (III-2g) (0.127 g, 0.30 mmol) and 0.5 mL of 15% aqueous sodium hydroxide in 5 mL of methanol was heated at reflux for 1.5 hours. Methanol was evaporated and the residue was dissolved in water and acidified with concentrated hydrochloric acid. The precipitated product was extracted with dichloromethane, the organic phase washed with water, dried over anhydrous sodium sulfate, and the solvent evaporated to give 0.099 g (83% yield) of the title compound as a white solid. 1 HNMR (400 MHz, CDCl3) δ 7.33 (t, J=8.2 Hz, 2H), 7.31 (t, J=7.8 Hz, 1H), 7.11 (t, J=7.5 Hz, 1H), 7.07 (d, J=7.5 Hz, 2H), 7.00 (d, J=7.8 Hz, 2H), 6.91 (d, J=8.2 Hz, 1H), 6.57 (dd, J=11.8 Hz, 6.7 Hz, 1H), 6.29 (dd, J=11.5 Hz, 7.3 Hz, 1H), 4.30 (s, 2H), 2.59 (m, 1H), 1.78 (m, 1H), 1.59 (m, 1H), 1.33 (m, 1H). ES-MS m/z 394(M-H)+. [α]25,D=+140° (chloroform, c=0.8). Product was determined to be 88% ee by chiral SFC according to Method 1.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[N:10]#[C:11]Cl.[OH-].[Na+]>>[CH3:4][CH2:3][CH2:2][CH2:1][N:5]([C:11]#[N:10])[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: N#CCl
Reactant: CCCCNCCCC
Agent: [Na+]
Agent: [OH-]
Product: CCCCN(C#N)CCCC

Procedure:
In the manner given in Example 1, dibutylamine is treated with cyanogen chloride and aqueous sodium hydroxide to give dibutylamine-N-carbonitrile.
Reaction SMILES: [ClH:1].[CH2:2]([C:4]1[C:12]2[C:7](=[N:8][C:9]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[N:10][C:11]=2[OH:13])[N:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:5]=1)[CH3:3].C(OC([N:33]1[CH2:38][CH2:37][CH:36]([C:39](O)=[O:40])[CH2:35][CH2:34]1)=O)(C)(C)C.Cl>>[ClH:1].[CH2:2]([C:4]1[C:12]2[C:7](=[N:8][C:9]([CH:14]3[CH2:15][CH2:16][N:17]([C:39]([CH:36]4[CH2:37][CH2:38][NH:33][CH2:34][CH2:35]4)=[O:40])[CH2:18][CH2:19]3)=[N:10][C:11]=2[OH:13])[N:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:5]=1)[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CCc1nn(-c2ccccc2)c2nc(C3CCNCC3)nc(O)c12
Agent: Cl
Product: CCc1nn(-c2ccccc2)c2nc(C3CCN(C(=O)C4CCNCC4)CC3)nc(O)c12

Procedure:
The title compound was prepared according to the procedure as described in Example 87 reacting 3-ethyl-1-phenyl-6-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidin-4-ol hydrochloride and piperidine-1,4-dicarboxylic acid mono-tert-butyl ester followed by de-protection of the adduct with HCl.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.Cl[CH2:18][C:19]1[CH:38]=[CH:37][C:22]([O:23][CH2:24][C:25]2[N:26]=[C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:28][C:29]=2[CH3:30])=[C:21]([O:39][CH3:40])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH3:40][O:39][C:21]1[CH:20]=[C:19]([CH:38]=[CH:37][C:22]=1[O:23][CH2:24][C:25]1[N:26]=[C:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:28][C:29]=1[CH3:30])[CH2:18][O:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1
Reactant: COC(=O)c1cc(O)nn1-c1ccccc1
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)c(OC)c2)nn1-c1ccccc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 93 %

Procedure:
A mixture of methyl 3-hydroxy-1-phenyl-1H-pyrazole-5-carboxylate (3.36 g), 4-(4-chloromethyl-2-methoxyphenoxymethyl)-5-methyl-2-phenyl-1,3-oxazole (5.30 g), potassium carbonate (4.25 g) and N,N-dimethylformamide (50 mL) was stirred at 80° C. for 5 hrs. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained colorless crystals were collected by filtration to give methyl 3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-phenyl-1H-pyrazole-5-carboxylate (7.53 g, yield 93%). The crystals were recrystallized from acetone-isopropyl ether. melting point: 143-144° C.
Reaction SMILES: [OH:1][CH:2]([C:4]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]C)=[O:13])=[C:6]([O:21][CH3:22])[CH:5]=1)[CH3:3].O.[OH-].[Li+]>CO>[OH:1][CH:2]([C:4]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[C:6]([O:21][CH3:22])[CH:5]=1)[CH3:3]
Reactant: COC(=O)CCCOc1cc([N+](=O)[O-])c(C(C)O)cc1OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(C(C)O)c([N+](=O)[O-])cc1OCCCC(=O)O

Procedure:
Methyl 4-[4-(1-hydroxyethyl)-2-methoxy-5-nitrophenoxy]butyrate (5.04 g) from above was stirred with lithium hydroxide monohydrate in methanol using conventional protocols. 4-[4-(1-Hydroxyethyl)-2-methoxy-5-nitrophenoxy]butyric acid was obtained as an amorphous yellow solid (4.0 g, 83%). 1H NMR (CDCl3) δ1.34 (3H, d, J=11 Hz, MeCOH), 2.03 (2H, m, CCH2C), 2.38 (2H, t, J=7.3 Hz, CH2CO), 3.81 (3H, s, OMe), 3.96 (2H, t, J=7.4 Hz, CH2O), 4.13 (2H, brs, OH), 5.38 (1H, q, J=10.8 Hz, CHOH), 7.19 (1H, s, aromatic, and 7.43 (1H, s, aromatic).
Reaction SMILES: [CH:1]1([CH2:6][N:7]2[C:12](=[O:13])[C:11]([CH2:14]OS(C)(=O)=O)=[CH:10][C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=3)=[N:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:29][NH:30][CH3:31]>>[CH:1]1([CH2:6][N:7]2[C:12](=[O:13])[C:11]([CH2:14][N:30]([CH3:31])[CH3:29])=[CH:10][C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=3)=[N:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CNC
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC3CCCC3)n2)cc1F
Product: COc1ccc(-c2cc(CN(C)C)c(=O)n(CC3CCCC3)n2)cc1F
Yield: 63.7 %

Procedure:
Following the procedure of Example 7, 2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and dimethylamine were reacted to yield the title compound as a yellow oil (yield: 63.7%).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([S:13][C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[CH2:33][O:34][CH2:35][C:36]1[CH:41]=[C:40]([F:42])[C:39]([F:43])=[CH:38][C:37]=1[F:44])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:44][C:37]1[CH:38]=[C:39]([F:43])[C:40]([F:42])=[CH:41][C:36]=1[CH2:35][O:34][CH2:33][C@@H:9]1[CH2:10][C@@H:11]([S:13][C:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:12][NH:8]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1COCc1cc(F)c(F)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1cc(F)c(COC[C@@H]2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2)cc1F
Temperature: 25 °C
Yield: 99 %

Procedure:
A solution of 9.37 g (15.11 mmol) (2S,4R)-2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid tert-butyl ester in 30 ml CH2Cl2 was treated at −20° C. with 34 ml TFA and warmed up to room temperature during 5.5 h. The reaction was evaporated and treated with aqueous saturated NaHCO3 solution/EtOAc (3×) to give 7.77 g (quantitative) (2S,4R)-2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidine, MS: 520 (M).