Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][C:18](=[O:25])[CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[C:15](=[O:26])[N:10]2[C:11]=1[C:12]([O-:14])=[O:13])(=O)C.[Na+].C(OCCCC)(=O)C.C([O-])(=O)C.[K+]>O>[OH:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][C:18](=[O:25])[CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[C:15](=[O:26])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13]
Reactant: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCCCOC(C)=O
Product: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12
Reaction time: 42 h
Yield: 84.7 %

Procedure:
A solution of sodium (6R,7R)-3-acetoxymethyl-7-(thien-2-ylacetamido)ceph-3-em-4-carboxylate (4 g) in demineralised water (80 ml) was treated with a suspension of cells obtained by culture of Rhodosporidium toruloides CBS 14, in a similar manner to that described in Example 1. Deacetylation was shown by t.l.c. to be complete after 42 hours, whereupon the reaction mixture was centrifuged to remove solid matter and the resulting solution was vigorously mixed with butyl acetate (200 ml). The pH of the mixture was adjusted to 2.2 - 2.5 by dropwise addition of concentrated phosphoric acid. The aqueous layer was separated and extracted with further butyl acetate (20 ml), a few drops of Gemex detergent being added to break the emulsion which formed. The butyl acetate fractions were combined and a 12.5% w/v solution of potassium acetate in industrial methylated spirit (≈8 ml) was slowly added thereto, until no further precipitation occurred. The precipitate was isolated by suction filtration, washed with a small volume of acetone and dried under vacuum at room temperature to give the title compound (2.87 g). This was shown by t.l.c. on cellulose-coated plates using an ethyl acetate - n-butanol - sodium acetate solvent system, comparing with an authentic sample and assaying densitometrically, to have a purity of about 75%, indicating an overall yield of 65%.
Reaction SMILES: C[O:2][C:3]([C:5]1([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[CH2:10][CH2:9][N:8]([C:11](=[O:24])[CH2:12][N:13]2[C:17]([CH3:18])=[C:16]([Cl:19])[C:15]([C:20]([F:23])([F:22])[F:21])=[N:14]2)[CH2:7][CH2:6]1)=[O:4].CCO.[OH-].[Na+]>O>[Cl:19][C:16]1[C:15]([C:20]([F:23])([F:22])[F:21])=[N:14][N:13]([CH2:12][C:11]([N:8]2[CH2:7][CH2:6][C:5]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([C:3]([OH:4])=[O:2])[CH2:10][CH2:9]2)=[O:24])[C:17]=1[CH3:18]
Reactant: COC(=O)C1(c2ccc(Cl)cc2)CCN(C(=O)Cn2nc(C(F)(F)F)c(Cl)c2C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCC(C(=O)O)(c2ccc(Cl)cc2)CC1

Procedure:
In a 4 mL vial was added 100 mg of 1-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-4-(4-chloro-phenyl)-piperidine-4-carboxylic acid methyl ester (0.21 mmol, 1.0 equiv) and 400 mL EtOH. A solution of 9.2 mg of NaOH (0.23 mmol, 1.10 equiv) dissolved in 100 μL H2O was added to the reaction solution and the resultant mixture was stirred overnight at room temperature. The crude product was purified by reversed phase HPLC (acetonitrile—H2O with 0.1% TFA as the eluent) to yield 1-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-4-(4-chloro-phenyl)-piperidine-4-carboxylic acid: MS (ES) M+H expected=464.3, found=464.1.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:47]([O:48]CC2C=CC=CC=2)[C@H:46]([O:56][C@@H:57]2[O:86][C@H:85]([CH2:87][O:88][CH3:89])[C@@H:76]([O:77]CC3C=CC=CC=3)[C@H:67]([O:68]CC3C=CC=CC=3)[C@H:58]2[O:59]CC2C=CC=CC=2)[C@@H:45]([CH2:90][O:91]CC2C=CC=CC=2)[O:44][C@@H:10]1[O:11][C@H:12]1[C@H:16]([O:17]CC2C=CC=CC=2)[CH2:15][N:14](C(OCC2C=CC=CC=2)=O)[C@@H:13]1[CH2:35][O:36]CC1C=CC=CC=1)C1C=CC=CC=1.Cl>CO.[OH-].[Pd+2].[OH-].[C]>[CH3:89][O:88][CH2:87][C@H:85]1[O:86][C@@H:57]([O:56][C@@H:46]2[C@@H:45]([CH2:90][OH:91])[O:44][C@H:10]([O:11][C@H:12]3[C@H:16]([OH:17])[CH2:15][NH:14][C@@H:13]3[CH2:35][OH:36])[C@H:9]([OH:8])[C@H:47]2[OH:48])[C@H:58]([OH:59])[C@@H:67]([OH:68])[C@@H:76]1[OH:77]
Reactant: COC[C@H]1O[C@@H](O[C@H]2[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H](O[C@@H]3[C@@H](COCc4ccccc4)N(C(=O)OCc4ccccc4)C[C@H]3OCc3ccccc3)O[C@@H]2COCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: COC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O[C@H]3[C@H](O)CN[C@@H]3CO)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 2 h
Yield: 94.7 %

Procedure:
The compound (150.1 mg, 0.11 mmol) synthesized in Example 8 (8c) was dissolved in methanol (10 mL) containing 1% aqueous hydrochloric acid solution and 20% palladium hydroxide-carbon (100 mg) was added thereto, followed by stirring of the mixture under a hydrogen atmosphere for 2 hours. After the catalyst was removed by celite filtration, 28% ammonia water (0.5 mL) was added thereto and the mixture was stirred for 10 minutes. After the solvent was distilled off under reduced pressure and the aqueous solution (100 mL) was subjected to ion exchange resin (Dowex 50w×8) column, it was eluted with 1% ammonia water (100 mL). The ammonia water containing the desired compound was concentrated under reduced pressure and the residue was purified using silica gel flash column chromatography (ethyl acetate:methanol:water, 5:2:1-1:1:1, V/V) to obtain the desired title compound (49.1 mg, 95%) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([CH2:17][C:18](OC)=[O:19])[C:13](OC)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[BH4-].[Na+]>CCO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C@@H:12]([CH2:13][OH:14])[CH2:17][CH2:18][OH:19])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: COC(=O)C[C@@H](NS(=O)(=O)c1ccc(F)cc1)C(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=S(=O)(N[C@@H](CO)CCO)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled (0° C.) solution of dimethyl (2R)-2-{[(4-fluorophenyl)sulfonyl]-amino}succinate (1 equiv.) from step 1 in EtOH (10 mL/g) was added NaBH4 (5 equiv.) in 3 portions and the reaction was stirred overnight at rt. The reaction was quenched with brine (5 mL/g) and filtered. The solid was suspended in EtOAc (10 mL/g). The mother liquor was concentrated in vacuo and then saturated with NaCl. The EtOAc suspension was then filtered.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:9][CH2:10][OH:11])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.F[C:13]1[CH:22]=[C:21]2[C:16]([CH:17]=[C:18]([NH:27][C:28]3[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=3)[N:19]=[C:20]2[O:23][CH:24]([CH3:26])[CH3:25])=[CH:15][C:14]=1[O:34][CH3:35]>C(O)(=O)C>[CH:24]([O:23][C:20]1[C:21]2[C:16](=[CH:15][C:14]([O:34][CH3:35])=[C:13]([O:11][CH2:10][CH2:9][N:3]3[CH2:8][CH2:7][O:6][CH2:5][CH2:4]3)[CH:22]=2)[CH:17]=[C:18]([NH:27][C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=2)[N:19]=1)([CH3:26])[CH3:25]
Reactant: OCCN1CCOCC1
Reactant: COc1cc2cc(Nc3cc(C)[nH]n3)nc(OC(C)C)c2cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc2cc(Nc3cc(C)[nH]n3)nc(OC(C)C)c2cc1OCCN1CCOCC1
Temperature: 180 °C
Reaction time: 1 h

Procedure:
NaH (155 mg) was added to a solution of 2-Morpholin-4-yl-ethanol (2 ml) and stirred for 1 hour. (7-Fluoro-1-isopropoxy-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine (100 mg) was added to the mixture, and the mixture was heated at 180° C. for 1 hour under microwave irradiation. The reaction mixture was acidified to PH=7 with acetic acid and purified by preparative LC-MS to give [1-Isopropoxy-6-methoxy-7-(2-morpholin-4-yl-ethoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine (28 mg). LC-MS: m/e 442(MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[N:13]=[C:14](S(C)(=O)=O)[N:15]=[CH:16][C:11]=2[CH:10]=1.[OH:25][CH2:26][C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=1)[NH2:30].C(O)(=O)C>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[N:13]=[C:14]([NH:30][C:29]3[CH:31]=[CH:32][CH:33]=[C:27]([CH2:26][OH:25])[CH:28]=3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: Nc1cccc(CO)c1
Reactant: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(S(C)(=O)=O)nc21
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(Nc3cccc(CO)c3)nc21
Temperature: 180 °C

Procedure:
A mixture of 0.155 g (0.40 mmol) of 6-(2,6-dichlorophenyl)-2-methanesulfonyl-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 39 and 0.500 g (4.10 mmol) of 3-(hydroxymethyl)aniline was heated in a 180° C. oil bath for 10 minutes. At ca. 120° C., 2 mL of glacial acetic acid were added to dissolve the gum. Water (20 mL) was added to precipitate a solid. The mixture was filtered. The cake was washed well with water and dried; wt 0.130 g. Purification was effected by silica gel chromatography eluting with chloroform and then with ethyl acetate to obtain the fraction containing the pure product. The ethyl acetate eluent was concentrated to 1 mL volume. The crystals that separated one inducement were filtered and washed with 0.5 mL of ethyl acetate and then 1 mL of ether; wt 0.059 g; mp 215°-217° C.
Reaction SMILES: [CH2:1]([C:8]1([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:13][CH2:12][C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([NH:14][CH3:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:28](B)#N.[Na].C(O)(=O)C>C(#N)C>[CH2:1]([C:8]1([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:13][CH2:12][C:11]([N:14]([CH3:28])[CH3:15])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BC#N
Reactant: CNC1(c2ccccc2)CCC(Cc2ccccc2)(CN(C)C)CC1
Agent: C=O
Agent: [Na]
Solvent: CC#N
Solvent: CC(=O)O
Product: CN(C)CC1(Cc2ccccc2)CCC(c2ccccc2)(N(C)C)CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of the title compound from Example 33 (1.40 g, 4.16 mmol) and formalin (5.8 mL, 37% aqueous solution) in acetonitrile (40 mL) was mixed in portions with sodium cyanoboron hydride (1.03 g, 16.6 mmol) and stirred for 45 min at room temperature. Concentrated acetic acid was then added until a neutral reaction occurred and the mixture stirred for 45 min at room temperature. For work up the solvent was removed in a vacuum, the residue taken up in 2N NaOH (40 mL) and then extracted with ether (3×40 mL). The organic phase was dried over Na2SO4, filtered and concentrated to low volume in a vacuum. The remaining residue was purified by flash chromatography with ethyl acetate (methanol→methanol+2% TEA).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([OH:17])=O)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:21](=[O:26])[NH:22][CH2:23][CH2:24][CH3:25].[NH:27]1[CH2:30][CH2:29][CH2:28]1.CN1CCOCC1.ON1C2C=CC=CC=2N=N1>CN(C=O)C.O>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]3[CH:20]=[CH:19][CH:18]=[C:14]([C:15]([N:27]4[CH2:30][CH2:29][CH2:28]4)=[O:17])[CH:13]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:21]([NH:22][CH2:23][CH2:24][CH3:25])=[O:26]
Reactant: C1CNC1
Reactant: CCCNC(=O)c1nnc2c(-c3cccc(C(=O)O)c3)cccc2c1N
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: CCCNC(=O)c1nnc2c(-c3cccc(C(=O)N4CCC4)c3)cccc2c1N
Temperature: 25 °C
Reaction time: 19 h
Yield: 82 %

Procedure:
To a stirred solution of 3-[4-amino-3-(propylcarbamoyl)cinnolin-8-yl]benzoic acid (67 mg, 0.191 mmol) dissolved in anhydrous DMF (2 mL) at ambient temperature under argon was added azetidine (16.4 mg, 0.287 mmol), N-methylmorpholine (29 mg, 0.287 mmol), 1-hydroxybenzotriazole (44 mg, 0.287 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcabodiimide hydrochloride (55 mg, 0.287 mmol). The mixture was stirred at ambient temperature for 19 hours then diluted with water and extracted with ethyl acetate. The residue from the organic extracts was purified by flash chromatography on silica gel eluting with increasingly polar gradient of ethyl acetate in hexanes to afford the title compound (61 mg, 82% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.54 (br, 1H), 8.03-7.64 (m, 6H), 7.53 (t, J=7.7 Hz, 1H), 4.38 (br, 2H), 4.25 (br, 2H), 3.47 (apparent quartet, J=7.0 Hz, 2H), 2.34 (apparent pentet, J=7.5 Hz, 2H), 1.67 (apparent sextet, J=7.0 Hz, 2H), 1.01 (t, J=7.4 Hz, 3H) MS APCI, m/z=390 (M+H) HPLC 1.70 min.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:4][CH:3]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>C(O)C>[C:22]([NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12]([OH:15])(=[O:13])=[O:14])=[CH:4][CH:3]=1)(=[O:24])[CH3:23].[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(S(=O)(=O)O)c2ccccc12
Solvent: CCO
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(S(=O)(=O)O)c2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.4 %

Procedure:
12 g (0.05 mole) of 1-amino-4-naphthalenesulphonic acid, 7.2 ml of pyridine and 15 ml of acetic anhydride are placed in a flask provided with a stirrer and heater. The mixture is heated until the solution is clear, at which point 10 ml of absolute ethanol is added and the mixture is allowed to cool, first to ambient temperature and then in a refrigerator to 3° C. for 3 hours. The precipitate obtained is collected in a filter and is recrystallized in ethanol to give 11 g (Yield 59.4%) of pyridine N-acetyl-1-aminonaphthalene-4-sulphonate, having a m.p. of 172°-175° C. and whose IR spectrum (KBr) has the following bands: 3,400; 3,220; 1,640; 1,525; 1,370; 1,325; 1,200; 1,030; 850; 675; 635.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.[I:11]I>C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][C:3]=1[I:11]
Reactant: II
Reactant: Nc1ccc(CCO)cc1
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: Nc1ccc(CCO)cc1I
Reaction time: 1.5 h
Yield: 32.6 %

Procedure:
4-Aminophenethyl alcohol (9.60 g, 70 mmol, 1.0 eq) was added to a mixture of iodine (17.78 g, 70 mmol, 1.0 eq) and silver sulfate (21.83 g, 70 mmol, 1.0 eq) in anhydrous ethanol (200 mL) at room temperature. The reaction mixture was stirred under nitrogen for 1.5 hours. After stirring was stopped, the solid was removed by filtration. The filtrate was concentrated, and the residue was dissolved in dichloromethane (200 mL), and then washed with aqueous 5% NaOH solution (2×150 mL) and water (150 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo to give a crude oil which was purified by flash chromatography (SiO2, hexanes-ethyl acetate) to yield 6.0 g of the desired ortho-iodo aniline as orange gel-like solid (32.4% yield).
Reaction SMILES: S[C:2]1[N:3]([CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:6]=1.N([O-])=O.[Na+].[N+]([O-])(O)=O.[OH-].[Na+]>O>[C:18]1([CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]2[C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:6]=[CH:2]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)c1cnc(S)n1C(c1ccccc1)c1ccccn1
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=[N+]([O-])O
Product: COC(=O)c1cncn1C(c1ccccc1)c1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.3 %

Procedure:
A mixture of 123.6 parts of methyl 2-mercapto-1-[phenyl(2-pyridinyl)methyl]-1H-imidazole-5-carboxylate, 0.2 parts of sodium nitrite, 219 parts of nitric acid and 440 parts of water was stirred for 2 hours at room temperature. The reaction mixture was poured into water and the whole was treated with a sodium hydroxide solution (on an ice bath). The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized twice: first from 2-propanone and then from 4-methyl-2-pentanone. The product was filtered off (the filtrates were set aside) and dried in vacuo at 70° C., yielding a first fraction of 37.2 parts (33.3%) of methyl 1-[phenyl(2-pyridinyl)methyl]-1H-imidazole-5-carboxylate; mp. 96.3° C.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[NH:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[C:30]1[CH2:38][CH2:39][OH:40]>>[OH:40][CH2:39][CH2:38][C:30]1[N:29]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][N:13]4[CH2:14][CH2:15][CH:16]([C:19]([OH:22])([CH3:20])[CH3:21])[CH2:17][CH2:18]4)[N:8]3[CH3:11])=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:3]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=1
Reactant: OCCc1nc2ccccc2[nH]1
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-n3c(CCO)nc4ccccc43)nc21

Procedure:
Following General Procedure I for Buchwald coupling, 2-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol and 2-(1H-benzo[d]imidazol-2-yl)ethanol were reacted to give 218. LCMS m/z: 535.3 (MH+)
Reaction SMILES: CON(C)[C:4](=[O:20])[CH:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[CH3:22][Mg]Br>O1CCCC1>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:4](=[O:20])[CH3:22])=[CH:8][CH:9]=1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)C(Cc1ccc(Cl)cc1)c1ccccc1
Solvent: C1CCOC1
Product: CC(=O)C(Cc1ccc(Cl)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of N-methoxy-N-methyl-3-(4-chlorophenyl)-2-phenylpropanamide (Step C, 16 g, 53 mmol, dried by azeotroping with toluene) in anhydrous tetrahydrofuran (200 mL) at 0° C. was added methylmagnesium bromide (3 M in ether, 35 mL, 0.11 mol). After stirring at 0° C. for 2 h, the reaction was quenched with methanol (5 mL) and 2 M hydrochloric acid (50 mL). The volatile materials were removed by concentrating on a rotary evaporator and the residue partitioned between saturated ammonium chloride (200 mL) and ether (200 mL). The organic layer was separated, and the aqueous layer was extracted with ether (2 times 200 mL) The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to dryness to give the title compound, which was used without further purification. 1H NMR (500 MHz, CD3OD): δ 7.45-7.02 (m, 9H), 4.08 (dd, 1H), 3.34 (dd, 1H), 2.90 (dd, 1H), 2.03 (s, 3H).
Reaction SMILES: [C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])(=[O:4])[CH2:2][CH3:3].C(N(CC)CC)C.[Cl:22][CH2:23][CH2:24][CH:25]=[O:26]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:22][CH2:23][CH2:24][C@@H:25]([OH:26])[C@H:2]([CH3:3])[C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])=[O:4]
Reactant: O=CCCCl
Reactant: CCC(=O)n1c(=O)oc2ccccc21
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](C(=O)n1c(=O)oc2ccccc21)[C@H](O)CCCl
Reaction time: 0.5 h

Procedure:
A vigorously stirred solution of 3-propionyl-2-benzoxazolone (19.1 g) in 200 mL of CH2Cl2 at 0° C. was treated with titanium tetrachloride (12.0 mL) followed by slow addition of triethylamine (16.7 mL). After stirring for 30 minutes, the dark red solution was treated with 60 mL of 1.8 M 3-chloropropanal in CH2Cl2 for 30 minutes, then quenched by addition of 200 mL of 2 N HCl. The phases were separated, and the organic phase was filtered through a pad of silica gel. The aqueous phase was extracted with ether, and the extract was used to wash the pad of silica. The combined silica eluate was concentrated under reduced pressure, resulting in crystallization. The white crystals were collected by vacuum filtration and dried to provide 19.9 g of product; mp=116-117° C.
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]2[N:17]=[C:18]([NH:25][C:26]3[CH:30]=[C:29]([CH:31]([CH3:33])[CH3:32])[NH:28][N:27]=3)[C:19]3[CH2:24][CH2:23][CH2:22][C:20]=3[N:21]=2)=[O:10])=[CH:4][CH:3]=1.[CH3:34][S-:35].[Na+]>C(O)C>[CH:31]([C:29]1[NH:28][N:27]=[C:26]([NH:25][C:18]2[C:19]3[CH2:24][CH2:23][CH2:22][C:20]=3[N:21]=[C:16]([N:12]3[CH2:13][CH2:14][CH2:15][C@@H:11]3[C:9]([NH:8][C:5]3[CH:6]=[N:7][C:2]([S:35][CH3:34])=[CH:3][CH:4]=3)=[O:10])[N:17]=2)[CH:30]=1)([CH3:33])[CH3:32]
Reactant: C[S-]
Reactant: CC(C)c1cc(Nc2nc(N3CCC[C@@H]3C(=O)Nc3ccc(F)nc3)nc3c2CCC3)n[nH]1
Agent: [Na+]
Solvent: CCO
Product: CSc1ccc(NC(=O)[C@H]2CCCN2c2nc3c(c(Nc4cc(C(C)C)[nH]n4)n2)CCC3)cn1
Temperature: 100 °C
Yield: 4.7 %

Procedure:
A suspension of (R)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide (200 mg, 0.44 mmol) and sodium thiomethoxide (100 mg, 1.42 mmol) in ethanol (2 mL) was heated at 100° C. in a microwave for 1 h. The solvent was removed under reduced pressure and the residue was diluted with EtOAc (50 mL). The solution was washed with saturated sodium bicarbonate solution (20 mL) followed by brine (20 mL), and dried over anhydrous sodium sulfate. Removal of EtOAc under reduced pressure gave an oily residue that was purified by reverse phase HPLC followed by chiral HPLC to afford 10 mg of (R)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-(methylthio)pyridin-3-yl)pyrrolidine-2-carboxamide. 1HNMR (400 MHz, CDCl3) δ (ppm): 1.18-1.32 (m, 6H), 1.90-2.20 (m, 5H), 2.51 (s, 3H), 2.60-2.77 (m, 3H), 2.84-2.98 (m, 3H), 3.60-3.79 (m, 2H), 4.78 (d, 1H), 6.40 (s, 1H), 6.70 (s, 1H), 7.08 (d, 1H), 7.98 (brs, 1H), 8.20 (s, 1H). The other enantiomer is prepared using the (S) starting material.
Reaction SMILES: Cl.[C:2]1([N:8]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:9](=[O:51])[CH2:10][C@@H:11]2[O:16]C(C)(C)[O:14][C@H:13]([CH2:19][CH2:20][N:21]3[C:25]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)=[C:24]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:23]([C:39]([NH:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[O:40])=[C:22]3[CH:48]([CH3:50])[CH3:49])[CH2:12]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C:25]2[N:21]([CH2:20][CH2:19][CH:13]([OH:14])[CH2:12][CH:11]([OH:16])[CH2:10][C:9]([N:8]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:51])[C:22]([CH:48]([CH3:50])[CH3:49])=[C:23]([C:39]([NH:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[O:40])[C:24]=2[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:27][CH:28]=1
Reactant: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@H](CC(=O)N(c2ccccc2)c2ccccc2)OC(C)(C)O1
Agent: Cl
Solvent: CO
Product: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CCC(O)CC(O)CC(=O)N(c1ccccc1)c1ccccc1

Procedure:
U.S. Pat. No. 5,298,627, also discloses a process for making the hemicalcium salt. In Example 1 of this patent, (4R-cis)-1-[2-[6-[2-(diphenylamino)-2-oxoethyl]-2,2-dimethyl-1,3-dioxan-4-yl]ethyl]-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1H-pyrrole-3-carboxamide is dissolved in methanol and reacted with hydrochloric acid to form [R-(R*,R*)]-5-(4-fluorophenyl)-β,δ-dihydroxy-2-(1-methylethyl)-N,N,4-triphenyl-3-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanamide, which is mixed with methanol and sodium hydroxide. The filtrate is washed with tert-butyl methyl ester and the aqueous layer is acidified using aqueous hydrochloric acid and extracted with tert-butyl methyl ester to form the sodium salt of [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid. The sodium salt is converted to the hemicalcium salt by the addition of calcium acetate in water.