Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[C:23]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)#[N:24].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:16]=[C:17]([C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([C:23]#[N:24])[CH:30]=2)[CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
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: COCCOC
Solvent: O
Product: N#Cc1cccc(-c2cccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)c2)c1
Yield: 49.7 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-cyanobiphenyl-3-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), 3-cyanophenylboronic acid (0.027 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.035 g (49%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-cyanobiphenyl-3-carboxamide compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:16])=[C:4]([N:8]2[C:13](=[O:14])[CH:12]=[CH:11][NH:10][C:9]2=[O:15])[CH:5]=[CH:6][CH:7]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[C:3]([CH3:16])=[C:4]([N:8]2[C:13](=[O:14])[CH:12]=[CH:11][N:10]([C:21]3[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=3)[C:9]2=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Br)cccc1-n1c(=O)cc[nH]c1=O
Reactant: OB(O)c1ccc(F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1c(Br)cccc1-n1c(=O)ccn(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.4 %

Procedure:
A stirred suspension of copper(II) acetate (0.543 g, 2.99 mmol), 3-(3-bromo-2-methylphenyl)pyrimidine-2,4(1H,3H)-dione (0.42 g, 1.49 mmol), (4-fluorophenyl) boronic acid (0.418 g, 2.99 mmol), and activated molecular sieves (750 mg) in dry DCM (25 mL) was treated with pyridine (0.363 mL, 4.48 mmol) and stirred at room temperature overnight. The mixture was diluted with DCM, filtered through CELITE®, and the solids were washed with DCM and THF. The combined filtrates were washed with water, dried and concentrated. The residue was purified by column chromatography on silica gel (40 g), eluting with EtOAc-hexanes (gradient from 20-40%), to give 3-(3-bromo-2-methylphenyl)-1-(4-fluorophenyl)pyrimidine-2,4(1H,3H)-dione as a yellow glassy solid (0.36 g, 43% yield). Mass spectrum m/z 375, 377 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 7.91 (d, J=7.9 Hz, 1H), 7.68 (dd, J=7.9, 1.3 Hz, 1H), 7.60-7.51 (m, 2H), 7.40-7.22 (m, 4H), 5.95 (d, J=7.9 Hz, 1H), 2.21-2.12 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH:18]1([C:22](Cl)=[O:23])[CH2:21][CH2:20][CH2:19]1>>[CH:18]1([C:22]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:23])[CH2:21][CH2:20][CH2:19]1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)C1CCC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)C4CCC4)nc23)CC1
Yield: 50.4 %

Procedure:
Beginning with 0.25 gm (1.08 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.136 gm (1.19 mMol) cyclobutanecarbonyl chloride, 0.17 gm (50.8%) of the title compound were prepared essentially by the procedure described in Example 4.
Reaction SMILES: ClC1C=C[C:5]([O:6]CC(OC(C)(C)C)=O)=C(CN(C)C2CCN(S(C3C=CC=CC=3)(=O)=O)C2)C=1.[Cl:34][C:35]1[CH:45]=[CH:44][C:38]([O:39][CH2:40][C:41]([OH:43])=[O:42])=[C:37]([CH2:46][N:47]2[CH2:52][CH2:51][N:50]([C:53](=[O:62])[CH2:54][C:55]3[CH:60]=[CH:59][C:58](F)=[CH:57][CH:56]=3)[C@@H:49]([CH3:63])[CH2:48]2)[CH:36]=1.ClC1C=CC(OCC(OC(C)(C)C)=O)=C(COS(C)(=O)=O)C=1.COC1C=CC(CC(Cl)=O)=CC=1>>[Cl:34][C:35]1[CH:45]=[CH:44][C:38]([O:39][CH2:40][C:41]([OH:43])=[O:42])=[C:37]([CH2:46][N:47]2[CH2:52][CH2:51][N:50]([C:53](=[O:62])[CH2:54][C:55]3[CH:60]=[CH:59][C:58]([O:6][CH3:5])=[CH:57][CH:56]=3)[C@@H:49]([CH3:63])[CH2:48]2)[CH:36]=1
Reactant: C[C@H]1CN(Cc2cc(Cl)ccc2OCC(=O)O)CCN1C(=O)Cc1ccc(F)cc1
Reactant: CN(Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C)C1CCN(S(=O)(=O)c2ccccc2)C1
Agent: CC(C)(C)OC(=O)COc1ccc(Cl)cc1COS(C)(=O)=O
Agent: COc1ccc(CC(=O)Cl)cc1
Product: COc1ccc(CC(=O)N2CCN(Cc3cc(Cl)ccc3OCC(=O)O)C[C@@H]2C)cc1

Procedure:
The title compound was prepared by the methods of example 89 part (f) and example 89 part (g) using the product of example 89 part (e) and 4-methoxy-benzeneacetyl chloride.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH:20]2[CH2:25][CH2:24][C:23]([CH2:28][CH3:29])([CH2:26][CH3:27])[CH2:22][CH2:21]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.ClCCl.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C>[CH2:28]([C:23]1([CH2:26][CH3:27])[CH2:24][CH2:25][CH:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:21][CH2:22]1)[CH3:29]
Reactant: CCC1(CC)CCC(c2ccccc2N2CCN(C(=O)OC(C)(C)C)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CCC1(CC)CCC(c2ccccc2N2CCNCC2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 108.4 %

Procedure:
A mixture of 4-[2-(4,4-diethylcyclohexyl)phenyl]piperazine-1-carboxylic acid t-butyl ester (1.12 g, 2.80 mmol) produced in Example (38b), trifluoroacetic acid (10 mL, 130 mmol) and dichloromethane (10 mL) was stirred for 10 minutes at an external temperature of 0° C., and the temperature was raised to room temperature followed by stirring for 30 minutes. Potassium carbonate was then gradually added to the reaction mixture to make the mixture basic. Then, ethyl acetate and water were added and extraction was performed with ethyl acetate. The separated organic layer was washed with brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off and then the filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (dichloromethane/methanol) to give 912 mg of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][OH:11])=[CH:8][CH:7]=1)[C:2]#[CH:3].[CH:14]1([C:17](Cl)=[O:18])[CH2:16][CH2:15]1>>[CH2:1]([O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][O:11][C:17]([CH:14]2[CH2:16][CH2:15]2)=[O:18])=[CH:12][CH:13]=1)[C:2]#[CH:3]
Reactant: C#CCOCc1ccc(CO)cc1
Reactant: O=C(Cl)C1CC1
Product: C#CCOCc1ccc(COC(=O)C2CC2)cc1

Procedure:
In an analogous manner to that described in Example 1, from 4-(hydroxymethyl)benzyl alcohol and propargyl bromide there is obtained 4-[(2-propynyloxy)methyl]benzyl alcohol. This alcohol is reacted in an analogous manner to that described in Example 2 with cyclopropane carboxylic acid chloride to give cyclopropane carboxylic acid p-[(2-propynyloxy)methyl]benzyl ester.
Reaction SMILES: [O:1]1[CH2:12][C@@H:2]1[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:13]([NH2:16])[CH:14]=[CH2:15]>>[CH2:13]([NH:16][CH2:12][C@@H:2]([OH:1])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:14]=[CH2:15]
Reactant: C=CCN
Reactant: c1ccc(COC[C@H]2CO2)cc1
Product: C=CCNC[C@@H](O)COCc1ccccc1
Temperature: 50 °C
Reaction time: 20 h
Yield: 100 %

Procedure:
A 22 L reactor was charged with (2R)-benzyl 2-epoxypropyl ether (0.7692 kg, 4.684 mol) T-internal 18-19C. Allylamine (3800 mL, 51 mol) was added at 18-19° C. and resultant mixture was heated to 50° C. After 20 h, the mixture was concentrated, azeotroped with MTBE (4 L×3) to give (R)-1-(allylamino)-3-(benzyloxy)propan-2-ol, 7 (ca. 1037 g, 4.684 mol, 100% yield assumed) as colorless oil.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7]([C:9]3[CH2:13][C:12]4([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]4)[O:11][N:10]=3)=[N:8][C:4]=2[CH:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O>>[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7]([C:9]3[CH2:13][C:12]4([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]4)[O:11][N:10]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: Brc1ccc2[nH]c(C3=NOC4(CCCCC4)C3)nc2c1
Product: Clc1ccccc1-c1ccc2[nH]c(C3=NOC4(CCCCC4)C3)nc2c1

Procedure:
The title compound was prepared from 3-(5-bromo-1H-benzimidazol-2-yl)-1-oxa-2-aza-spiro[4.5]dec-2-ene (as prepared in the previous step) and 2-chloro-benzene-boronic acid according to the procedure described in Example 1, step D. 1H-NMR (400 MHz, d4-MeOH) δ: 7.46-7.76 (m, 3H), 7.29-7.42 (m, 4H), 3.27 (s, 2H), 1.69-1.87 (m, 6H), 1.46-1.62 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=4[O:27][CH3:28])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:30][CH2:31][N:32]([CH3:34])[CH3:33]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:14][CH2:15][CH:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=4[O:27][CH3:28])[CH2:17][CH2:18]3)=[O:12])=[CH:7][N:8]2[CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])=[CH:4][CH:3]=1
Reactant: COc1cccc(OC)c1C1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Reactant: CN(C)CCCl
Product: COc1cccc(OC)c1C1CCN(C(=O)c2cn(CCN(C)C)c3cc(Cl)ccc23)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone (preparation described herein), with (commercially available) (2-chloro-ethyl)-dimethyl-amine gave the title compound.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][C:7]([OH:9])=O.CN(C)CCCN=C=NCC.Cl.[NH2:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[N:28]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[F:39])[C:27]([C:40]([NH:42][C:43]1[CH:48]=[CH:47][C:46]([NH:49][C:50](=[O:56])[O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[CH:45][CH:44]=1)=[O:41])=[CH:26]2>CN(C)C1C=CN=CC=1.CN(C=O)C>[F:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[CH2:32][N:28]1[C:29]2[C:25](=[CH:24][C:23]([NH:22][C:7](=[O:9])[CH2:6][CH:2]3[CH2:3][CH2:4][CH2:5][O:1]3)=[CH:31][CH:30]=2)[CH:26]=[C:27]1[C:40]([NH:42][C:43]1[CH:44]=[CH:45][C:46]([NH:49][C:50](=[O:56])[O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[CH:47][CH:48]=1)=[O:41]
Reactant: CC(C)(C)OC(=O)Nc1ccc(NC(=O)c2cc3cc(N)ccc3n2Cc2ccccc2F)cc1
Reactant: O=C(O)CC1CCCO1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(NC(=O)c2cc3cc(NC(=O)CC4CCCO4)ccc3n2Cc2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
49 mg (0.38 mmol) of tetrahydro-2-furanylacetic acid, 19.3 mg (0.16 mmol) of 4-dimethylaminopyridine and 91 mg (0.47 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide×HCl are added to 3 ml of DMF. 150 mg (0.32 mmol) of tert-butyl 4-({[5-amino-1-(2-fluorobenzyl)-1H-indol-2-yl]carbonyl}amino)phenyl-carbamate from Example XXIX are added. The mixture is stirred at RT for 5 hours. For work-up, the mixture is diluted and extracted with dichloromethane and aqueous hydrochloric acid. The organic phase is washed with sat. sodium bicarbonate solution, dried with sodium sulphate, filtered and concentrated under reduced pressure using a rotary evaporator. The residue is purified by preparative HPLC.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:11][OH:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCCCCC.[OH-].[Na+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].O>[Cl:1][C:2]1[S:3][C:4]([CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:5]([C:7]([F:8])([F:9])[F:10])[N:6]=1
Reactant: BrCc1ccccc1
Reactant: OCc1sc(Cl)nc1C(F)(F)F
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Product: FC(F)(F)c1nc(Cl)sc1COCc1ccccc1
Yield: 81.2 %

Procedure:
A mixture of 4.34 g (0.02 mol) of the compound of Example 4, 14.1 g (0.0825 mol) of benzyl bromide, 0.1 g of Aliquat 336 (tradename of phase transfer catalyst available from the General Mills Co.) 25 ml of hexane, 15 ml of 50% sodium hydroxide, and 15 ml of water was held at reflux for 30 minutes. The hexane layer was separated, dried over MgSO4 and concentrated under reduced pressure. The residue (6.8 g) was Kugelrohr distilled at 2 mm (pot temperature 120°-130° C.) to give 5.0 g (81% yield) of 2-chloro-4-(trifluoromethyl)-5-[(benzyloxy)-methyl]-thiazole nD25 1.5215.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[C:8]=2[N:14]([CH3:20])[C:15](=O)[O:16]CC)=[CH:4][C:3]=1[F:23].CC[O-].[Na+].[Na]>CCO>[NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[NH:13][C:15](=[O:16])[N:14]([CH3:20])[C:8]=23)=[CH:4][C:3]=1[F:23]
Reactant: CCOC(=O)N(C)c1c(Oc2ccc(N)c(F)c2)ccnc1N
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: Cn1c(=O)[nH]c2nccc(Oc3ccc(N)c(F)c3)c21
Temperature: 100 °C

Procedure:
Ethyl 4-(4-amino-3-fluorophenoxy)-2-aminopyridin-3-yl-methyl-carbamate (7a) (320 mg, 1.0 mmol) was suspended in a solution of EtONa in EtOH (4 mL), obtained from dissolving sodium (480 mg, 21 mmol) in ethanol (9 mL). The suspension was heated under microwave irradiation for 1 hour (100° C., 100 W). The mixture was cooled at room temperature and the solvent was evaporated. The residue was dissolved in water and was acidified with AcOH to pH 4. The precipitate formed was recovered by filtration, to afford the title compound.
Reaction SMILES: [OH-].[Na+].CC(O)CC.[OH:8][C:9]1[C:14]([C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])=[CH:13][C:12]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:11][C:10]=1[N:33]1[N+:37]([O-])=[C:36]2[CH:39]=[CH:40][CH:41]=[CH:42][C:35]2=[N:34]1>ClC1C(=O)C2C(C(=O)C=1Cl)=CC=CC=2.CC(=O)CC>[OH:8][C:9]1[C:14]([C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH3:16])=[CH:13][C:12]([C:29]([CH3:30])([CH3:31])[CH3:32])=[CH:11][C:10]=1[N:33]1[N:37]=[C:36]2[CH:39]=[CH:40][CH:41]=[CH:42][C:35]2=[N:34]1
Reactant: CC(C)(C)c1cc(-n2nc3ccccc3[n+]2[O-])c(O)c(C(C)(c2ccccc2)c2ccccc2)c1
Agent: O=C1C(Cl)=C(Cl)C(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCC(C)=O
Solvent: CCC(C)O
Product: CC(C)(C)c1cc(-n2nc3ccccc3n2)c(O)c(C(C)(c2ccccc2)c2ccccc2)c1
Temperature: 82 °C
Yield: 96.7 %

Procedure:
To a 500 mL three-necked flask fitted with a mechanical stirrer, 3 g of sodium hydroxide pellets and 50 mL of 2-butanol are charged and heated to 82° C. To this solution, a slurry of 200 mL of 2-butanone, 15 g of the benzotriazole N-oxide prepared in Example 4, and 0.67 g of 2,3-dichloro-1,4-naphthoquinone is added over 40 minutes. The mixture is refluxed at 88° C. for five hours while distilling off 2-butanone. Additional 2-butanol (50 mL) is added to replace what is lost during distillation of the 2-butanone. After cooling the reaction mixture to ambient temperature, 25 g of water and 30 mL of ethyl acetate are added at which time the pH is reduced to 2 with 30% aqueous sulfuric acid. After splitting off the aqueous layer, the solvent is removed by distillation and the crude solid purified by silica gel chromatography using heptane/ethyl acetate as the eluent. After collecting the desired fractions and crystallization from methanol/toluene, 14 g of the tide compound is obtained after drying as a light yellow solid melting at 172-173° C. The structure is confirmed by 1H nmr and mass spectroscopy.
Reaction SMILES: [OH:1][CH:2]([C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:32])[C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22](=[O:31])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CS(C)=O.C1CCC(N=C=NC2CCCCC2)CC1>>[O:4]([CH2:3][C:2]([C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:32])[C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22](=[O:31])[CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:1])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(CCc1ccccc1)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)COc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CS(C)=O
Product: O=C(COc1ccccc1)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)CCc1ccccc1
Yield: 35.9 %

Procedure:
(2S)-2-(1-Hydroxy-2-phenoxyethyl)-1-[N-(3-phenylpropionyl)-L-prolyl]pyrrolidine (425 mg) was subjected to DMSO-DCC oxidation as in Example 1D) to give 152 mg of the title compound (See Table 6).
Reaction SMILES: [CH2:1]([C@:3]1([OH:29])[C:26]2[CH:25]=[C:24]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:23])[CH:18]=[C:19]([F:22])[C:20]=3[CH:21]=4)[C:9](=[O:27])[C:8]=2[CH2:7][O:6][C:5](=[O:28])[CH2:4]1)[CH3:2].[CH:30](=O)[CH2:31]C>>[CH2:1]([C@:3]1([OH:29])[C:26]2[CH:25]=[C:24]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:23])[CH:18]=[C:19]([F:22])[C:20]=3[C:21]=4[CH2:30][CH3:31])[C:9](=[O:27])[C:8]=2[CH2:7][O:6][C:5](=[O:28])[CH2:4]1)[CH3:2]
Reactant: CCC=O
Reactant: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2cc3c(F)cc(F)cc3nc2-1
Product: CCc1c2c(nc3cc(F)cc(F)c13)-c1cc3c(c(=O)n1C2)COC(=O)C[C@]3(O)CC

Procedure:
The product of Example 100 is treated with propionaldehyde according to a procedure similar to that in Stage 95e to produce the expected solid (m.p. 255° C.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[C:9]12(O)[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>O>[C:9]12([S:8][C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: Sc1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Brc1ccc(SC23CC4CC(CC(C4)C2)C3)cc1
Yield: 91.2 %

Procedure:
3.78 g (20 mmol) of p-bromothiophenol, 3.04 g (20 mmol) of 1-adamantanol and 10 ml of trifluoroacetic acid are stirred at ambient temperature for 8 hours and then poured into water. Sodium bicarbonate is added until the mixture is neutral at which time it is extracted with methylene chloride. The organic phase is dried and evaporated. After recrystallization in isooctane, 5.9 g of the expected product are obtained. Yield--92%. Melting point: 121°-122° C.
Reaction SMILES: COC[N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)[OH:10].C(O)(=O)C.Cl>O>[C:21]1([C:9]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)([C:5]2[NH:4][CH:8]=[CH:7][N:6]=2)[OH:10])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COCn1ccnc1C(O)(c1ccccc1)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: OC(c1ccccc1)(c1ccc(C(F)(F)F)cc1)c1ncc[nH]1

Procedure:
A mixture of 9 g. (0.025 mol) of 1-(methoxymethyl)-α-phenyl-α-(p-trifluoromethyl-phenyl)imidazole-2-methanol, 70 ml. of glacial acetic acid, 7 ml. of concentrated hydrochloric acid and 7 ml. of water was refluxed for 3.5 hours. After cooling, the liquid was distilled off and 2 N sodium hydroxide solution and a small amount of ethanol were added to the residue. The alcohol was distilled off and the aqueous phase was extracted with diethyl ether. The ethereal solution was washed with water and dried over sodium sulphate and the solvent was distilled off. The residue was first crystallised from a mixture of toluene and petroleum ether (boiling range 40°-60° C.) and subsequently from isopropyl alcohol. α-Phenyl-α-(p-trifluoromethylphenyl)imidazole-2-methanol was obtained. Melting point 174°-175.5° C.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Cl:11])=[CH:4][N:3]=1.[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([O:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:3][CH:4]=1
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1cc(Cl)cnc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Cl)cnc1Oc1ccccc1

Procedure:
This compound was prepared according to the general procedure A described above using 2-bromo-5-chloro-3-nitro-pyridine (500 mg, 2.11 mmol), phenol (258 mg, 2.75 mmol), K2CO3 (437 mg, 3.16 mmol) and DMF (2 mL). MS m/z: 250.4 (M+H).
Reaction SMILES: CS(C)=O.[CH3:5][N:6]1[C:11]([NH:12][CH2:13][CH2:14][NH:15][CH2:16][CH3:17])=[CH:10][C:9](=[O:18])[N:8]([CH3:19])[C:7]1=[O:20].[CH3:21][C:22]1[C:27](=[O:28])[C:26]2[C:29]([O:33][CH2:34][CH2:35][CH2:36]Br)=[CH:30][CH:31]=[CH:32][C:25]=2[O:24][CH:23]=1>C(N(CC)CC)C>[CH3:5][N:6]1[C:11]([NH:12][CH2:13][CH2:14][N:15]([CH2:16][CH3:17])[CH2:36][CH2:35][CH2:34][O:33][C:29]2[C:26]3[C:27](=[O:28])[C:22]([CH3:21])=[CH:23][O:24][C:25]=3[CH:32]=[CH:31][CH:30]=2)=[CH:10][C:9](=[O:18])[N:8]([CH3:19])[C:7]1=[O:20]
Reactant: CCNCCNc1cc(=O)n(C)c(=O)n1C
Reactant: Cc1coc2cccc(OCCCBr)c2c1=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCN(CCCOc1cccc2occ(C)c(=O)c12)CCNc1cc(=O)n(C)c(=O)n1C
Reaction time: 6 h

Procedure:
To 5 ml of dimethyl sulfoxide were added 0.52 g of the previously obtained N-[1,3-dimethyl-2,4-dioxopyrimidine-6-yl]-N'-ethylethylenediamine (Compound 13), 0.7 g of 3-(3-methyl-4-oxo-4H-1-benzopyran-5-yl)oxypropyl bromide (Compound 2) and 0.5 ml of triethylamine, and reaction was carried out at 100° C. for 6 hours. The resultant reaction solution was cooled, and the formed white crystals were collected by filtration, washed with water, and then dried, thereby obtaining 0.56 g of 1,3-dimethyl-6-(2-[N-ethyl-N-[3-(3-methyl-4-oxo-4H-1-benzopyran-5-yl)oxypropyl]amino]ethylamino)-2,4(1H,3H)-pyrimidinedione (the non-oxalate of Compound 14).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:29])=[C:6]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[C:20]([C:21](O)=[O:22])=[CH:19][N:18]=[CH:17][CH:16]=3)[C:11]3[CH2:24][C:25]([CH3:28])([CH3:27])[CH2:26][C:10]=3[N:9]=2)[CH:7]=1.C(N1C=CN=C1)([N:32]1C=CN=C1)=O.N>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:29])=[C:6]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[C:20]([C:21]([NH2:32])=[O:22])=[CH:19][N:18]=[CH:17][CH:16]=3)[C:11]3[CH2:24][C:25]([CH3:27])([CH3:28])[CH2:26][C:10]=3[N:9]=2)[CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC1(C)Cc2nc(-c3cc(Cl)ccc3F)nc(Nc3ccncc3C(=O)O)c2C1
Agent: N
Solvent: CN(C)C=O
Product: CC1(C)Cc2nc(-c3cc(Cl)ccc3F)nc(Nc3ccncc3C(N)=O)c2C1
Temperature: 70 °C

Procedure:
A suspension of 4-[2-(5-Chloro-2-fluoro-phenyl)-6,6-dimethyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino]-nicotinic acid (25 mg, 60.56 μmol) and Carbonyldiimidazole (20 mg, 121.11 μmol) in dry DMF (3 mL) was heated at 70° C. for 1 h then cooled to r.t. A stream of NH3 gas was passed through the solution for 30 min., giving clean conversion to the amide product. Evaporation of the solution, followed by HPLC purification gave, after lyophilization, the pure amide 62 as the TFA salt (20 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]([O-:7])=[O:6].[OH:8][CH:9]([CH3:14])[CH2:10][C:11]([O-:13])=[O:12].C[C:16]1(C)S[C@@H]2[C@H](NC([C@H](N)C3C=CC=CC=3)=O)C(=O)N2[C@H:17]1[C:35]([OH:37])=[O:36].C1C([C@@H](O)[C@H](NC(C(Cl)Cl)=O)C[OH:48])=CC=C([N+]([O-])=O)C=1>>[OH:8][CH:9]([CH3:14])[CH2:10][C:11]([O-:13])=[O:12].[OH:1][CH2:2][CH2:3][CH2:4][C:5]([O-:7])=[O:6].[C:35]([O-:37])(=[O:36])[CH:17]([CH3:16])[OH:48]
Reactant: O=C(N[C@H](CO)[C@H](O)c1ccc([N+](=O)[O-])cc1)C(Cl)Cl
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: CC(O)CC(=O)[O-]
Agent: O=C([O-])CCCO
Product: CC(O)C(=O)[O-]
Reaction time: 72 h

Procedure:
3-Hydroxybutyrate-4-hydroxybutyrate-lactate terpolymer was prepared according to the method of example 2 except that the collected cells was anaerobically cultured for 3 days in MR medium further containing 2 g/L of 4-hydroxybutyrate (4-HB), 1 g/L of 3-hydroxybutyrate (3-HB), 100 mg/L of ampicillin and 30 mg/L of chloramphenicol instead of MR medium further containing g/L of 4-HB, 100 mg/L of ampicillin and 30 mg/L of chloramphenicol.