Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21](C(OCC)C)[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].O1CCCC1.Cl.[OH-].[Na+]>COC(C)(C)C>[C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][NH:21][CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CCOC(C)n1cc(-c2ncnc3c2ccn3COC(=O)C(C)(C)C)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)OCn1ccc2c(-c3cn[nH]c3)ncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
Method A. To a 1 L round bottom flask equipped with a stir bar and nitrogen inlet was charged {4-[1-(1-ethoxyethyl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate (18, theoretical amount 41.6 g, 0.112 mol) made as described above and tetrahydrofuran (THF, 610 mL, 7.5 mol) at room temperature, and the resulting mixture was treated with an 2.0 N aqueous solution of hydrochloric acid (140 mL, 0.28 mol, 2.5 equiv) at room temperature. The resulting reaction mixture was subsequently stirred at room temperature for overnight. When the reaction was deemed complete, the reaction mixture was cooled to 0-5° C. before pH was adjusted to 9-10 with a 3 M aqueous sodium hydroxide (NaOH) solution (95 mL). The mixture was then extracted with ethyl acetate (2×300 mL) and the combined organic extracts were washed with 20% aqueous brine solution (250 mL), dried over magnesium sulfate (MgSO4), and concentrated under reduced pressure to afford the crude product as off-white to light yellow solids. The crude product was treated with methyl t-butylether (MTBE, 200 mL) and the slurry was warm to reflux for 30 minutes before being cooled to room temperature. The solids were collected by filtration and washed with MTBE (2×40 mL), dried under reduced pressure to afford [4-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate (19, 30.5 g, 33.52 g theoretical, 91% for two steps) as white to off-white solids. For 19: 1H NMR (DMSO-d6, 300 MHz) δ ppm 13.40 (br s, 1H), 8.75 (s, 1H), 8.66 (s, 1H), 8.32 (s, 1H), 7.68 (d, 1H, J=3.8 Hz), 7.11 (d, 1H, J=3.8 Hz), 6.21 (s, 2H), 1.06 (s, 9H); C15H17N5O2 (MW, 299.33), LCMS (EI) m/e 300 (M++H).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]#[C:7][C:8]([OH:10])=O.ClC(OCC(C)C)=O.CN1CCOCC1.[NH2:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[N:33]=[CH:32][C:31]([C:37]#[N:38])=[C:30]2[NH:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([Br:46])[CH:41]=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[Br:46][C:42]1[CH:41]=[C:40]([NH:39][C:30]2[C:29]3[C:34](=[CH:35][CH:36]=[C:27]([NH:26][C:8](=[O:10])[C:7]#[C:6][CH2:5][O:4][CH2:3][O:2][CH3:1])[CH:28]=3)[N:33]=[CH:32][C:31]=2[C:37]#[N:38])[CH:45]=[CH:44][CH:43]=1
Reactant: COCOCC#CC(=O)O
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COCOCC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 48.1 %

Procedure:
To a solution of 0.51 g (3.54 mmol) of 4-(methoxymethoxy)-but-2-ynoic acid and 0.46 g (3.4 mmol) of isobutyl chloroformate in 12 ml of tetrahydrofuran was added at 0° C. with stirring 0.36 g (3.54 mmol) of N-methylmorpholine. After 15 min, 1.0 g (2.95 mmol) of 6-amino-4-[(3-bromophenyl)amino]-quinoline-3-carbonitrile was added. After stirring 3 hr at room temperature, the mixture was poured into a saturated solution of sodium bicarbonate. The mixture was extracted with ethyl acetate and the organic layer was dries over magnesium sulfate. The solvent was remove and the residue was purified by chromatography on silica gel eluting with chloroform-ethyl acetate mixtures to give 0.66 g of 4-methoxymethoxy-but-2-ynoic acid[4-(3-bromophenylamino)-3-cyano-quinolin-6-yl]-amide as a yellow powder: ma of 6-amino-4-[(3-bromophenyl)amino]-quinoline-3-carbonitrile: mass spectrum (electrospray, m/e,): M+H 465.1, 467.0.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:11]([CH3:13])=[O:12].[CH:14]([C:17]1[N:18]=[C:19]([C:22](NC2C(C)=C(OC)C=CC=2C(=O)C)=[O:23])[S:20][CH:21]=1)([CH3:16])[CH3:15]>>[CH:14]([C:17]1[N:18]=[C:19]([C:22]([NH:1][C:2]2[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=2[C:11](=[O:12])[CH3:13])=[O:23])[S:20][CH:21]=1)([CH3:16])[CH3:15]
Reactant: COc1ccc(C(C)=O)c(N)c1Cl
Reactant: COc1ccc(C(C)=O)c(NC(=O)c2nc(C(C)C)cs2)c1C
Product: COc1ccc(C(C)=O)c(NC(=O)c2nc(C(C)C)cs2)c1Cl

Procedure:
The title product 51 was prepared (79%) from (2-amino-3-chloro-4-methoxyphenyl)-(methyl)ketone (50) following the procedure reported for 2′-[[(4-isopropylthiazole-2-yl)(oxo)methyl]amino]-4′-methoxy-3′-methylacetophenone (35): m/z=353 (M+H)+.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[OH:9].CC1C=CC2C=CC3C=CC(C)=NC=3C=2N=1.[OH2:27].CO>C(OCC)(=O)C.Cl[Cu]>[CH3:10][C:1]1[CH:6]=[C:5]([CH:4]=[C:3]([CH3:8])[C:2]=1[OH:9])[CH:7]=[O:27]
Reactant: Cc1cc(C)c(O)c(C)c1
Reactant: O
Agent: Cl[Cu]
Agent: Cc1ccc2ccc3ccc(C)nc3c2n1
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(C=O)cc(C)c1O
Temperature: 25 °C
Reaction time: 9 h
Yield: 6278.4 %

Procedure:
A mixture of 13.622 g(100 mmol) of mesitol, 285 mg (1.26 mmol) of neocuproine hydrate, 503 mg (5.0 mmol) of CuCl and 120 mL of methanol was stirred at ambient temperature for 9 hours under an oxygen blanket. The reaction mixture was then diluted with ethyl acetate and filtered. The methanol was stripped off and the residue diluted with additional ethyl acetate. The solution was washed twice with a 1% solution of ethylenediaminetetraacetic acid trisodium salt (EDTA-Na3.2H2O), water and brine, dried over MgSO4 and concentrated. There was obtained 13.92 g of an orange-gold solid which was shown by 1H NMR and GC to contain 11.88 g (79.2% yield) of 3,5-dimethyl-4-hydroxybenzaldehyde (DMHB).
Reaction SMILES: O.[C:2]1([CH3:19])[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.C([O:25][C:26](=[O:33])[C@H:27]([CH2:29][C:30](=[O:32])[NH2:31])[NH2:28])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:2]1([CH3:19])[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([NH:28][C@H:27]([C:26]([OH:33])=[O:25])[CH2:29][C:30](=[O:32])[NH2:31])=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@@H](N)CC(N)=O
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](CC(N)=O)C(=O)O)cc1

Procedure:
N-(Toluene4-sulfonyl)-L-proline hydrate was coupled to L-asparagine tert-butyl ester hydrochloride using the procedure described in Method 3. The title compound was prepared, via cleavage of the tert-butyl ester using trifluoroacetic acid in CH2Cl2, to provide a solid, mp=178-180° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=2)[NH2:19])[CH:5]=[CH:4][N:3]=1.[O:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[S:28](Cl)(=[O:30])=[O:29]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:19][S:28]([C:24]3[O:23][CH:27]=[CH:26][CH:25]=3)(=[O:30])=[O:29])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1ccco1
Reactant: CC(C)c1nc(-c2cccc(N)c2)c(-c2ccnc(Cl)n2)s1
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3ccco3)c2)c(-c2ccnc(Cl)n2)s1
Yield: 48.9 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]aniline (3 g, 9.1 mmol) and furan-2-sulfonyl chloride (1.81 g, 10.9 mmol) the title compound was obtained (2.0 g, 48.9% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.74-10.87 (br, 1H), 8.53 (d, J=5.3 Hz, 1H), 7.91-7.93 (m, 1H), 7.33-7.38 (m, 1H), 7.21-7.28 (m, 3H), 7.10-7.13 (m, 1H), 6.98 (d, J=5.3 Hz, 1H), 6.57-6.60 (m, 1H), 3.23-3.35 (m, 1H), 1.36 (d, J=6.8 Hz, 6H). MS (ES+): 661 [M+H]+.
Reaction SMILES: [CH2:1]([OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:18]([CH2:20][C:21](O)=[O:22])#[N:19].C1(N=C=NC2CCCCC2)CCCCC1.CCCCCC>ClCCl.C(OCC)(=O)C.CN(C)C1C=CN=CC=1>[C:18]([CH2:20][C:21]([O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:22])#[N:19]
Reactant: CCCCCCCCCCCCCCCCO
Reactant: N#CCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCOC(=O)CC#N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The esterification reaction of hexadecanol was carried out under an inert atmosphere (Argon). To a solution of cyanoacetic acid (7.4853 g) and of hexadecanol (10.6674 g) in 50 ml of anhydrous dichloromethane and 5 ml of ethyl acetate, 50 ml of anhydrous dichloromethane containing 9.9864 g of dicyclohexylcarbodiimide (DCC) and 50 mg of 4-(dimethylamino)pyridine (DMAP) were added. The reaction mixture was stirred for 24 hours at room temperature. Then 50 ml of anhydrous hexane were added. The formed solid residue was separated by filtration under vacuum and washed with n-hexane (70 ml). The filtrate was concentrated under reduced pressure until obtaining an amorphous yellow solid, subsequently purified by flash chromatography (ligroin/ethyl acetate 9/1 v/v), yielding 14 g of a white solid.
Reaction SMILES: C(N(CC)CC)C.[ClH:8].Cl.Cl.[NH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH2:17][CH2:16]1.[CH2:29]([N:32]=[C:33]=[O:34])[CH:30]=[CH2:31]>C(Cl)Cl>[ClH:28].[ClH:8].[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:18]2[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][CH2:12][NH:11][C:33]([NH:32][CH2:29][CH:30]=[CH2:31])=[O:34])[CH2:16][CH2:17]2)=[CH:27][CH:26]=1
Reactant: C=CCN=C=O
Reactant: NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCNC(=O)NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Yield: 49.6 %

Procedure:
A solution of triethylamine (2.0 g; 20 mmole) in methylene chloride was added dropwise to a mixture of 1-(3-amino-propyl)-4-(4-chlorobenzyl)piperazine trihydrochloride (7.54 g; 20 mmole) and allyl isocyanate (1.66 g; 20 mmole) in methylene chloride. After the addition was completed the mixture was washed with water and the solvent removed. The resulting orange oil was purified on a silica gel column (methylene chloride/methanol; 9:1), precipitated with ethereal hydrochloric acid, and recrystallized from ethanol/water to provide the title compound (2.1 g; 25% yield) as colorless crystals, m.p. 232°-234° C.
Reaction SMILES: [CH2:1]([CH:7]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:8][C:9]1[S:13][C:12]([C:14](O)=[O:15])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(Cl)(=O)C([Cl:28])=O>C(Cl)Cl>[CH2:1]([CH:7]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:8][C:9]1[S:13][C:12]([C:14]([Cl:28])=[O:15])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCCC(CCCCCC)Cc1ccc(C(=O)O)s1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CCCCCCCCC(CCCCCC)Cc1ccc(C(=O)Cl)s1
Temperature: 0 °C
Reaction time: 64 h
Yield: 88.4 %

Procedure:
5-(2-Hexyldecyl)-2-thiophenecarboxylic acid (1.00 g, 2.84 mmol., 1.00 equiv.) and CH2Cl2 (5 mL) were added to a 10 mL schlenk flask. The solution was cooled to 0° C. Oxalyl chloride (0.60 mL, 6.5 mmol, 2.3 equiv.) was then added. The ice/water bath was left in place and the solution was stirred for 64 hours while warming to room temperature. The reaction mixture was concentrated to a clear brown liquid (931 mg, 88% yield). 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J=3.9 Hz, 1H), 6.87 (d, J=3.8 Hz, 1H), 2.81 (d, J=6.7, 2H), 1.68 (b, 1H), 1.34-1.19 (m, 24H), 0.93-0.85 (m, 6H).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]([C@@H:6]1[C@@:10]2([CH3:28])[CH2:11][CH2:12][C@@H:13]3[C@@:18]4([CH3:27])[CH2:19][CH2:20][C@H:21]([O:23][C:24]([CH3:26])=[O:25])[CH2:22][C:17]4=[CH:16][CH2:15][C@H:14]3[C@@H:9]2[CH2:8][CH2:7]1)=[O:5]>C(O)C.C(Cl)Cl>[C:24]([O:23][CH:21]1[CH2:20][CH2:19][C@@:18]2([CH3:27])[C:17](=[CH:16][CH2:15][C@@H:14]3[C@@H:13]2[CH2:12][CH2:11][C@@:10]2([CH3:28])[C@H:9]3[CH2:8][CH2:7][C@@H:6]2[CH:4]([OH:5])[CH3:3])[CH2:22]1)(=[O:25])[CH3:26]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H](C(C)=O)[C@@]4(C)CC[C@@H]32)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CC(=O)OC1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H](C(C)O)[C@@]4(C)CC[C@@H]32)C1
Temperature: 4 °C
Reaction time: 8 h

Procedure:
Sodium borohydride (21 gm) was added to a solution of pregnenolone acetate (100 g, 0.28 mol) in absolute ethanol (1 L) and methylene chloride (0.4 L) at -10° C. After stirring overnight at 4° C., another amount of sodium borohydride (10.5 gm) was added and the reaction stirred at room temperature overnight. The reaction mixture was quenched by pouring into 5% sodium phosphate monobasic (2 L) and extracted with methylene chloride. The organic extracts were dried over anhydrous magnesium sulfate and filtered through a pad of anhydrous sodium sulfate. The solvent was removed by rotoevaporation to give the title compound.
Reaction SMILES: Cl[CH:2]([CH:4]=[CH:5][SiH3:6])Cl.[CH2:7]([OH:15])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N([CH2:21][CH3:22])CC)C>>[CH2:7]([O:15][CH:2]([CH:4]=[CH:5][SiH3:6])[O:15][CH2:7][CH2:8][C:22]1[CH:21]=[CH:11][CH:10]=[CH:9][CH:14]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCN(CC)CC
Reactant: [SiH3]C=CC(Cl)Cl
Reactant: OCCc1ccccc1
Product: [SiH3]C=CC(OCCc1ccccc1)OCCc1ccccc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 0.9 %

Procedure:
Dichloromethylvinylsilane (80 g, 0.567 moles) was added to a stirred solution of phenethyl alcohol (140 g, 114 moles), triethylamine (TEA, 121 g, 1.2 moles) and Isopar C (700 mL) over one hour during which time the reaction mixture was heated to 70° C. After an additional one hour, the reaction was cooled to room temperature, filtered, concentrated in vacuo and then stripped under high vacuum distilled (110° C./4 mm Hg) to give product (1.66 g, 94%).
Reaction SMILES: [OH-].[K+].CN1CCCC1=O.[OH:10][C:11]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:12]=1[CH2:13]Br.C(O)(=O)C.[SH:26][CH2:27][CH:28]([CH2:30][OH:31])[OH:29]>O>[OH:29][CH:28]([CH2:30][OH:31])[CH2:27][S:26][CH2:13][C:12]1[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:11]=1[OH:10]
Reactant: O=[N+]([O-])c1ccc(O)c(CBr)c1
Reactant: OCC(O)CS
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc(O)c(CSCC(O)CO)c1

Procedure:
13.2 g of potassium hydroxide pellets (85 %) are heated to 45° C. in 27 g of thioglycerol. 10 ml of N-methylpyrrolidone are added followed portionwise over 30 minutes by 0.1 mole (23.2 g) of 2-hydroxy-5-nitrobenzyl bromide. The temperature of 67°-70° C. which is obtained is maintained for 30 minutes after the end of addition. The reaction mixture is diluted with 300 g of iced water. After neutralizing with acetic acid, the expected product precipitates. After filtering off, followed by drying at 45° C. under vacuum the product obtained is recrystallized from isopropyl acetate. It melts at 130° C.
Reaction SMILES: [CH3:1][CH:2]([C:16]([OH:18])=[O:17])[C:3]1[CH:4]=[CH:5][C:6]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[C:7]([F:9])[CH:8]=1.CO.S(=O)(=O)(O)O>C(OCC)(=O)C.O>[CH3:1][C@H:2]([C:16]([OH:18])=[O:17])[C:3]1[CH:4]=[CH:5][C:6]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[C:7]([F:9])[CH:8]=1
Reactant: CC(C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: C[C@H](C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Reaction time: 5 h

Procedure:
A sample of 6.2 g (25 mmol) of R,S flurbiprofen was combined with 40 g of methanol and stirred until dissolved. The solution was treated with 3.14 g (21 mmol) of cis (1R,2S)-1-aminoindan-2-ol, seeded with a small amount of (1R,2S)-1-aminoindan-2-ol (S)-flurbiprofen diastereomer, and allowed to crystallize over a period of 17 hours at ambient temperature. The mixture was then cooled and held at 4° C. for 5 hours. The solids were isolated by filtration, washed with 35 mL methanol, and dried to afford 3.8 g (38M % yield) of white crystals. The acid was released by dissolving the solid in 200 mL of an ethyl acetate-water (50/50; v/v) mixture and treating the solution with 3 g of 5N aqueous sulfuric acid. After mixing, the aqueous phase was decanted and the organic phase washed twice with 100 mL of water. The organic phase was then evaporated under vacuum. The weight of the solid residue was 2.1 g. The rotation [α]D of this solid was -18.8 (c=1, ethanol) corresponding to (S)-flurbiprofen of 44.6% enantiomeric excess.
Reaction SMILES: [N:1]1([CH:10]=[O:11])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2N=N1.[F:12][C:13]([F:23])([F:22])[O:14]C1C=CC(N)=CC=1>O1CCCC1>[F:12][C:13]([F:23])([F:22])[O:14][C:8]1[CH:7]=[CH:6][C:5]([NH:1][CH:10]=[O:11])=[CH:4][CH:9]=1
Reactant: O=Cn1nnc2ccccc21
Reactant: Nc1ccc(OC(F)(F)F)cc1
Solvent: C1CCOC1
Product: O=CNc1ccc(OC(F)(F)F)cc1
Temperature: 60 °C
Reaction time: 22.5 h
Yield: 97.3 %

Procedure:
1H-1,2,3-benzotriazole-1-carbaldehyde (299 mg, 2.032 mmol, Sigma-Aldrich) was added to a solution of 4-[(trifluoromethyl)oxy]aniline (0.227 mL, 1.694 mmol) in tetrahydrofuran (THF) (6 mL). The solution was heated to 60° C. and stirred for 22.5 hours. 1H-1,2,3-benzotriazole-1-carbaldehyde (199 mg, 1.355 mmol) was added and the reaction mixture stirred for a further 20 hours before concentrating in vacuo. The resulting solid was dissolved in DCM (30 ml), washed with 2M HCl (15 ml), the organic layer was passed through a hydrophobic frit and reduced in vacuo. The crude material was purified by silica chromatography (Biotage SP4, eluting iso-hexane (5 column volumes) followed by a gradient from 0-20% EtOAc in iso-hexane (over 15 column volumes)) to yield the title compound as a white solid (0.338 g).
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:16]([NH:18][NH2:19])=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1>C(O)C>[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[N:19][NH:18][C:16]([C:8]2[NH:9][C:10]3[C:15]([C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:17])=[CH:23][CH:22]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: NNC(=O)c1[nH]c2ccccc2c1-c1ccccc1
Solvent: CCO
Product: O=C(NN=Cc1ccc(Br)cc1)c1[nH]c2ccccc2c1-c1ccccc1
Temperature: 25 °C

Procedure:
A solution of Example 1C (1.76 g, 7.0 mmol) and 4-bromobenzaldehyde (1.36 g, 7.35 mmol) in ethanol (120 mL) was refluxed for 18 hours, cooled to room temperature, and filtered. The resulting solid was washed with ethanol and dried under vacuum to provide
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][NH2:18].[OH-:19].[Na+]>CCOCC.O>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([NH:12][CH2:13][CH2:14][N:15]([S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:16][CH2:17][NH:18][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:8])=[O:19])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCNCCN
Reactant: [OH-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: Cc1ccc(S(=O)(=O)NCCN(CCNS(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
A solution of p-toluenesulfonyl chloride (191 g) in ether (500 ml) was added drop by drop to a solution of diethylene triamine (38 ml) and sodium hydroxide (40 g) in water (250 ml). The mixture was stirred for one hour at room temperature. A white precipitate was formed and was collected by filtration, washed with water, and then recrystalized using methanol. (Acetonitrile could also be used). The melting point of the recrystalized precipitate was 174° to 175° C. The yield was 90%, and should always be above 70%.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([NH2:12])[C:10]=2[CH:11]=1.[Cl:13][C:14]([Cl:19])([Cl:18])[C:15](Cl)=[O:16]>C(N(CC)CC)C>[Cl:13][C:14]([Cl:19])([Cl:18])[C:15]([NH:12][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:11]=[C:2]([CH3:1])[N:3]=[N:4]2)=[O:16]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Cc1cc2c(N)cccc2nn1
Solvent: CCN(CC)CC
Product: Cc1cc2c(NC(=O)C(Cl)(Cl)Cl)cccc2nn1

Procedure:
The title compound was prepared using 3-methylcinnolin-5-amine (commercially available, Maybridge), triethylamine, trichloroacetyl chloride and the procedure described in Example 1A.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[N:12]1([C:18]2[N:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>>[N:19]1[CH:20]=[CH:21][CH:22]=[N:23][C:18]=1[N:12]1[CH2:17][CH2:16][N:15]([CH2:2][C:3]2[S:4][C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][N:6]=3)[CH2:14][CH2:13]1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: ClCc1nc2cccnc2s1
Solvent: CCN(C(C)C)C(C)C
Product: c1cnc(N2CCN(Cc3nc4cccnc4s3)CC2)nc1

Procedure:
The product from Example 38A (50 mg, 0.81 mmol), 2-(1-piperazinyl)pyrimidine (160 mg, 0.98 mmol), and DIEA (280 μL, 1.6 mmol were processed as described in Example 38B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.65 (m, 4H) 3.80 (m, 4H) 4.04 (s, 2H) 6.63 (t, J=4.92 Hz, 1H) 7.56 (dd, J=8.14, 4.75 Hz, 1H) 8.34 (m, 2H) 8.43 (d, J=4.75 Hz, 1H) 8.59 (dd, J=4.75, 1.70 Hz, 1H); (ESI) m/z 313 (M+H)+.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[OH:14][C@H:15]1[CH2:19][N:18]([C:20]2[N:21]=[C:22]([NH:29][C:30]3[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[NH:32][N:31]=3)[C:23]3[CH2:28][CH2:27][CH2:26][C:24]=3[N:25]=2)[C@H:17]([C:38](OC)=[O:39])[CH2:16]1>C1COCC1>[F:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:38]([C@@H:17]2[CH2:16][C@@H:15]([OH:14])[CH2:19][N:18]2[C:20]2[N:21]=[C:22]([NH:29][C:30]3[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[NH:32][N:31]=3)[C:23]3[CH2:28][CH2:27][CH2:26][C:24]=3[N:25]=2)=[O:39])=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)nc1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1c1nc2c(c(Nc3cc(C(C)C)[nH]n3)n1)CCC2
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)c1cc(Nc2nc(N3C[C@H](O)C[C@H]3C(=O)Nc3ccc(F)nc3)nc3c2CCC3)n[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 13.6 %

Procedure:
To a solution of 6-fluoropyridin-3-amine (4.64 mg, 4.14 mmol) in dry THF (5 mL) was added 2 M solution of isopropylmagnesium chloride (1.98 mL, 3.96 mmol) in THF dropwise under nitrogen at 0° C. The resultant mixture was stirred at 0° C. for 20 min. To this solution was added a solution of (2S,4R)-methyl 4-hydroxy-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylate (400 mg, 1.04 mmol) in THF (2 mL) dropwise at 0° C. and the reaction mixture was allowed to stir at 25° C. for 4 h. The reaction was quenched with saturated ammonium chloride solution (10 mL) and diluted with water (25 mL). The product was extracted with EtOAc (2×50 mL). The combined organic layer was washed with water (2×100 mL) followed by brine (100 mL) and dried over anhydrous sodium sulfate. Removal of EtOAc under reduced pressure gave an oily residue which was purified by reverse phase HPLC to afford 66 mg of (2S,4R)—N-(6-fluoropyridin-3-yl)-4-hydroxy-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide. 1H NMR (400 MHz, CDCl3, freebase) δ (ppm): 0.99-1.30 (m, 6H), 2.10-2.30 (m, 4H), 2.65-2.74 (m, 2H), 2.78-2.98 (m, 4H), 3.78-3.05 (m, 1H), 3.91-3.99 (m, 1H), 4.70-4.78 (m, 1H), 4.92-4.98 (m, 1H), 6.34 (s, 1H), 6.77 (s, 1H), 6.82 (dd, 1H), 7.93 (s, 1H), 8.08-8.18 (m, 1H). The other diasteromers are prepared using appropriate chiral starting materials.