Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].C(=O)([O-])[O-].[K+].[K+].Br[C:21]1[CH:25]=[CH:24][O:23][C:22]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]>C(O)C.C1(C)C=CC=CC=1>[S:1]([C:5]1[CH:10]=[CH:9][C:8]([C:21]2[CH:25]=[CH:24][O:23][C:22]=2[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2]
Reactant: CCOC(=O)c1occc1Br
Reactant: NS(=O)(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1occc1-c1ccc(S(N)(=O)=O)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 55.6 %

Procedure:
(4-sulfamoylphenyl)boronic acid (1.76. gm, 8.77 mmol) and Potassium carbonate (2.52 gm, 18.26 mmol) were added to a stirred suspension of ethyl 3-bromofuran-2-carboxylate (Prepared according to the procedure reported in the literature EP1489077A1, 2004, 1.6 gm, 7.30 mmol) in a mixture of 80 ml of ethanol and 20 ml of toluene (80 ml:20 ml) under nitrogen atmosphere at room temperature (25° C.) in a tube. A nitrogen gas was purged to the suspension for 15 minute at room temperature (about 25° C.). To the reaction mixture was then added Tetrakis(triphenyl phosphine)Palladium(0) (0.422 gm, 0.365 mmol) at 25° C. and tube was sealed. The reaction mixture was then stirred at 100° C. for 18 hours. The progress of the reaction was monitored by TLC. The reaction mixture was then filtered and washed with ethyl acetate (2×100 ml). The combined organic layer was then concentrated under reduced pressure to obtain a crude product as semi-solid (11.2 gm), which was then purified by column chromatography over silica gel (100-200 mesh) using 50% ethyl acetate in hexanes as an eluent to obtain the title compound (1.2 g, 55.60%)
Reaction SMILES: Br[CH:2](Br)[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:8][C:9]([C:13]#[N:14])=[N:10]2)=[CH:5][CH:4]=1.[O:22]1CCOCC1>O.CCOC(C)=O.[N+]([O-])([O-])=O.[Ag+]>[CH:2]([C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:8][C:9]([C:13]#[N:14])=[N:10]2)=[CH:5][CH:4]=1)=[O:22]
Reactant: C1COCCO1
Reactant: N#Cc1cc(-c2ccccc2)c2ccc(C(Br)Br)cc2n1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cc(-c2ccccc2)c2ccc(C=O)cc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7-(dibromomethyl)-4-phenylquinoline-2-carbonitrile (2.02 g, 4.81 mmol) in 1,4-dioxane (75 mL) was added a solution of silver nitrate (3.27 g, 19.24 mmol) in 30 mL of water, and the reaction mixture stirred 1 h at reflux. After cooling to rt, the mixture was diluted with EtOAc and filtered. The solid was washed with EtOAc and the organic phases combined. The filtrate was washed twice with water and the combined aqueous layers were back-extracted twice with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The crude residue obtained was purified by column chromatography (eluting with acetone-CH2Cl2-toluene, 10:40:50) to yield the title compound. 1H NMR (400 MHz, acetone-d6): δ 10.39 (s, 1H), 8.80 (s, 1H), 8.21 (s, 2H), 8.07 (s, 1H), 7.66 (m, 5H).
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][C:22]([F:25])([F:24])[F:23])[CH2:11][NH:10]2)=[O:8])[CH2:5][CH2:4]1)#[N:2].[CH2:26]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([N:37]2[CH2:40][CH2:39][CH:38]2[C:41]([O-])=[O:42])[CH2:33][CH2:32]1)=[O:30])[CH3:27].[Li+]>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][C:22]([F:25])([F:23])[F:24])[CH2:11][N:10]2[C:41]([CH:38]2[CH2:39][CH2:40][N:37]2[CH:34]2[CH2:33][CH2:32][N:31]([C:29]([O:28][CH2:26][CH3:27])=[O:30])[CH2:36][CH2:35]2)=[O:42])=[O:8])[CH2:4][CH2:5]1)#[N:2]
Reactant: CCOC(=O)N1CCC(N2CCC2C(=O)[O-])CC1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](Sc3ccccc3OC(F)(F)F)CN2)CC1
Agent: [Li+]
Product: CCOC(=O)N1CCC(N2CCC2C(=O)N2C[C@H](Sc3ccccc3OC(F)(F)F)C[C@H]2C(=O)NC2(C#N)CC2)CC1

Procedure:
The reaction of (2S,4R)-N-(1-cyanocyclopropyl)-4-(2-(trifluoromethoxy)phenylthio)pyrrolidine-2-carboxamide 12D and lithium 1-(1-(ethoxycarbonyl)piperidin-4-yl)azetidine-2-carboxylate 20J carried out according to the general procedure L yielded ethyl 4-(2-((2S,4R)-2-(1-cyanocyclopropylcarbamoyl)-4-(2-(trifluoromethoxy)phenylthio)pyrrolidine-1-carbonyl)azetidin-1-yl)piperidine-1-carboxylate 1:1 epimers as a white solid (70%). MS ISP (m/e): 610.3 (100) [(M+H)]+.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[CH2:13]([C@@H:15]1[O:17][CH2:16]1)Cl>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.C(O)(C)C>[CH2:13]([C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:4]([NH:5][C:1](=[O:11])[C:2]=12)=[O:6])[C@H:15]1[O:17][CH2:16]1
Reactant: ClC[C@H]1CO1
Reactant: O=C1NC(=O)c2ccccc21
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [K]
Solvent: CC(C)O
Product: O=C1NC(=O)c2c(C[C@@H]3CO3)cccc21
Reaction time: 46 h
Yield: 83.1 %

Procedure:
Into a reaction vessel were put potassium phthalimide (50.0 g, 0.27 mol), benzyltrimethylammonium chloride 5.00 g, 0.027 mol) and isopropanol (500 ml), and the mixture was cooled to 10° C. Thereto was added (R)-epichlorohydrin (74.9 g, 0.81 mol) and the mixture was stirred for 46 hours while being cooled. The solvent was removed and to the residue was added ethyl acetate (250 ml). The mixture was washed with water (250 ml), and then ethyl acetate was removed to give crude (R)-glycidylphthalimide (optical purity: 97% e.e.). The crude product was crystallized from ethyl acetate-hexane to give the object (R)-glycidylphthalimide (45.6 g, yield: 83%, optical purity: 98% e.e.) as white crystals. mp 100-102° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].S1C(C[CH:19]2[C:24](=[O:25])[O:23][C:22]([CH3:27])([CH3:26])[O:21][C:20]2=[O:28])=CC2C=CC=CC1=2.S1C(CC(C(O)=O)C(O)=O)=CC2C=CC=CC1=2>>[CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][CH:19]2[C:24](=[O:25])[O:23][C:22]([CH3:27])([CH3:26])[O:21][C:20]2=[O:28])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(C=O)cc1
Reactant: CC1(C)OC(=O)C(Cc2cc3ccccc3s2)C(=O)O1
Agent: O=C(O)C(Cc1cc2ccccc2s1)C(=O)O
Product: CC1(C)OC(=O)C(Cc2ccc(S(C)(=O)=O)cc2)C(=O)O1

Procedure:
The title compound was prepared using 4-(methylsulfonyl)benzaldehyde in place of benzo[b]thiophene-2-carbaldehyde using the procedure described for the preparation of 5-(benzo[b]thiophen-2-ylmethyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (Intermediate 39: step a).
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([C:18]#[N:19])[C:16]=1[OH:17])[CH:12]=O.N1CCCCC1>C(O)(=O)C>[OH:8][C:9]1[CH:10]=[C:11]([CH:12]=[C:7]2[C:5](=[O:6])[NH:4][C:2](=[S:3])[NH:1]2)[CH:14]=[C:15]([C:18]#[N:19])[C:16]=1[OH:17]
Reactant: N#Cc1cc(C=O)cc(O)c1O
Reactant: O=C1CNC(=S)N1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: N#Cc1cc(C=C2NC(=S)NC2=O)cc(O)c1O
Temperature: 100 °C

Procedure:
A solution containing 0.58 g of thiohydantoin, 0.82 g of 3,4-dihydroxy-5-cyanobenzaldehyde and 0.1 ml of piperidine in 10 ml of acetic acid was heated for 4 h at 100° C. The product was filtered and washed with ether. Yield 0.51 g, mp 210°-213° C.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH3:10][C:4]1[CH:3]=[C:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: Cc1cc(Br)ccc1C#N
Reactant: OB(O)c1ccccc1
Product: Cc1cc(-c2ccccc2)ccc1C#N

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 2 using 4-bromo-2-methylbenzonitrile instead of tert-butyl N-(4-bromobenzyl) carbamate and phenylboronic acid instead of 3-benzyloxyphenylboronic acid.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:7]=[C:8]([CH2:12][CH2:13][O:14][C:15]2[CH:28]=[CH:27][C:18]([CH:19]=[C:20]3[S:24][C:23](=[O:25])[NH:22][C:21]3=[O:26])=[CH:17][CH:16]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:4])=[O:3].C(O)(=O)C>C(OCC)(=O)C.[Pd]>[CH3:1][S:2]([O:5][C:6]1[CH:7]=[C:8]([CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:19][CH:20]3[S:24][C:23](=[O:25])[NH:22][C:21]3=[O:26])=[CH:27][CH:28]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Oc1cccc(CCOc2ccc(C=C3SC(=O)NC3=O)cc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CS(=O)(=O)Oc1cccc(CCOc2ccc(CC3SC(=O)NC3=O)cc2)c1
Yield: 3.3 %

Procedure:
2 g (84 mmole) 5-(4-[2-(3-methanesulfonyloxyphenyl)ethoxy]benzylidene)thiazolidine-2,4-dione was hydrogenated in 200 ml ethyl acetate and 10 ml acetic acid in the presence of Pd/C (10%) at atmospheric pressure over night. The catalyst was filtered off and the solvent was evaporated in vacuo. The residue was crystallized in ethanol to give 1.18 g (yield 59%) of the desired product.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=O.[Cl:12][C:13]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][CH2:36][S:37][CH2:38][CH2:39][CH2:40][OH:41])=[CH:29][C:14]=1[C:15]([NH:17][CH2:18][C:19]12[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]3)[CH2:20]1)[CH2:26]2)=[O:16].[OH-:42].[Ca+2].[OH-:44]>ClCCl>[Cl:12][C:13]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][CH2:36][S:37]([CH2:38][CH2:39][CH2:40][OH:41])(=[O:44])=[O:42])=[CH:29][C:14]=1[C:15]([NH:17][CH2:18][C:19]12[CH2:20][CH:21]3[CH2:27][CH:25]([CH2:24][CH:23]([CH2:22]3)[CH2:28]1)[CH2:26]2)=[O:16]
Reactant: [OH-]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(OCCCSCCCO)ccc1Cl
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Solvent: ClCCl
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(OCCCS(=O)(=O)CCCO)ccc1Cl
Reaction time: 0.5 h
Yield: 28 %

Procedure:
3-Chloroperoxybenzoic acid (0.14 g, 70%) was added to a solution of 2-chloro-5-[3-(3-hydroxypropylthio)propoxy]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (Example 10, 0.1 g) in dichloromethane (10 ml). After 1 hour calcium hydroxide (0.1 g) was added and stirring continued for a further 30 min. The reaction mixture was dried (MgSO4), filtered through celite and concentrated. The residue was triturated with ethanol to leave the title compound as a white solid (0.030 g).
Reaction SMILES: [N:1]1([CH2:10][C:11]([OH:13])=O)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:29]3[CH2:28][CH2:27][CH2:26][NH:25][C:24]=3[CH:23]=[N:22]2)=[CH:17][CH:16]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(=O)(O)[O-].[Na+]>[F:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[C:29]3[CH2:28][CH2:27][CH2:26][N:25]([C:11](=[O:13])[CH2:10][N:1]4[C:5]5=[N:6][CH:7]=[CH:8][CH:9]=[C:4]5[CH:3]=[CH:2]4)[C:24]=3[CH:23]=[N:22]2)=[CH:19][CH:20]=1
Reactant: O=C(O)Cn1ccc2cccnc21
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Cn1ccc2cccnc21)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.2 %

Procedure:
A mixture of 2-pyrrolo[2,3-b]pyridin-1-ylacetic acid (51.2 mg, 0.24 mmol), 1-(4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[4,3-b]pyridine (50.3 mg, 0.29 mmol), triethyl amine (200 μL, 1.4 mmol), and HATU (110.7 mg, 0.29 mmol) in DMF (1 mL) was stirred at room temperature for 2 hours. The reaction mixture was then diluted with 10 mL of aqueous saturated sodium bicarbonate, and extracted with EtOAc (2×15 mL). The combined organic layers were then washed with water (2×20 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (SiO2, 70% ethyl acetate in hexanes) to afford the desired product (25.9 mg, 0.07 mmol, 28%). 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 0.8H), 8.30 (dd, J=4.8, 1.6 Hz, 1H), 7.94 (dd, J=7.2, 1.6 Hz, 1H), 7.81 (s, 0.2H), 7.45 (m, 2H), 7.36 (d, J=3.6 Hz, 0.8H), 7.31 (d, J=3.6 Hz, 0.2H), 7.18 (m, 2H), 7.09 (dd, J=7.6, 4.8 Hz, 1H), 6.58 (d, J=3.6 Hz, 1H), 5.44 (s, 0.2H), 5.32 (s, 0.8H), 3.91 (m, 2H), 2.84 (m, 2H), 2.07 (m, 2H); MS: (ES) m/z calculated for C21H18FN5O [M+H]+ 376.1, found 376.1.
Reaction SMILES: [CH3:1][C:2](=[CH2:42])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18](=[O:41])[C:19]1[CH:24]=[C:23]([O:25][C:26](=[O:39])[C:27]2[CH:32]=[CH:31][C:30](/[CH:33]=[CH:34]/[C:35]([O:37][CH3:38])=[O:36])=[CH:29][CH:28]=2)[CH:22]=[CH:21][C:20]=1[OH:40])=[O:4].[CH2:43]([C:46]1[CH:54]=[CH:53][C:49]([C:50](O)=[O:51])=[CH:48][CH:47]=1)[CH2:44][CH3:45].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[CH3:42][C:2](=[CH2:1])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18](=[O:41])[C:19]1[CH:24]=[C:23]([O:25][C:26](=[O:39])[C:27]2[CH:28]=[CH:29][C:30](/[CH:33]=[CH:34]/[C:35]([O:37][CH3:38])=[O:36])=[CH:31][CH:32]=2)[CH:22]=[CH:21][C:20]=1[O:40][C:50](=[O:51])[C:49]1[CH:53]=[CH:54][C:46]([CH2:43][CH2:44][CH3:45])=[CH:47][CH:48]=1)=[O:4]
Reactant: C=C(C)C(=O)OCCCCCCCCCCCOC(=O)c1cc(OC(=O)c2ccc(/C=C/C(=O)OC)cc2)ccc1O
Reactant: CCCc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C=C(C)C(=O)OCCCCCCCCCCCOC(=O)c1cc(OC(=O)c2ccc(/C=C/C(=O)OC)cc2)ccc1OC(=O)c1ccc(CCC)cc1
Yield: 79.2 %

Procedure:
1.0 g (1.72 mmol) (E)-2-hydroxy-5-[4-(2-methoxycarbonylvinyl)benzoyloxy]benzoic acid 11-(2-methylacryloyloxy)undecyl ester, 0.37 g (2.24 mmol) 4-propylbenzoic acid and 58 mg (0.47 mmol) 4-dimethylaminopyridine were dissolved in 20 ml of dichloromethane. A suspension of 0.43g (2.24 mmol) N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and 10 ml dichloromethane were added dropwise in the course of 45 minutes. After 65 hour at room temperature the reaction mixture was partitioned between dichloromethane and water; the organic phase was washed repeatedly with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation. Chromatography of the residue on 120 g silica gel using cyclohexane:ethyl acetate 4:1 and subsequent crystallisation form 50 ml isopropyl alcohol yielded 0.99 g (79%) (E)-5-[4-(2-methoxycarbonylvinyl)benzoyloxy]-2-(4-propylbenzoyloxy)benzoic acid 11-(2-methylacryloyloxy)undecyl ester as white powder, m.p. (C/N) 86.8° C., cl.p (N/I) 102.8° C.
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([C:24](=[O:37])[N:25]([CH2:29][CH2:30][C:31]2[O:35][N:34]=[C:33]([NH2:36])[N:32]=2)[CH:26]([CH3:28])[CH3:27])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>ClCCl>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[NH2:36][C:33]1[N:32]=[C:31]([CH2:30][CH2:29][N:25]([CH:26]([CH3:28])[CH3:27])[C:24](=[O:37])[C:19]2[CH:18]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]3[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=3)[CH:22]=[C:21]([Cl:23])[CH:20]=2)[O:35][N:34]=1
Reactant: CC(C)N(CCc1nc(N)no1)C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N(CCc1nc(N)no1)C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1

Procedure:
A solution of [2-(3-{[2-(3-amino[1,2,4]oxadiazol-5-yl)-ethyl]-isopropyl-carbamoyl}-5-chloro-phenoxy)-ethyl]-pyridin-4-yl-carbamic acid tert-butyl ester (0.064 g) in dichloromethane (1 ml) and trifluoroacetic acid (1 ml) was stored at room temperature for 5 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc to give the title compound as a pale yellow foam (0.043 g).
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[OH:16][C:17]([CH:19]([C:26]([F:29])([F:28])[F:27])[CH2:20][NH:21][C:22]([NH:24][CH3:25])=[O:23])=O>CN(C=O)C>[CH3:25][N:24]1[C:17](=[O:16])[CH:19]([C:26]([F:29])([F:28])[F:27])[CH2:20][NH:21][C:22]1=[O:23]
Reactant: CNC(=O)NCC(C(=O)O)C(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CN1C(=O)NCC(C(F)(F)F)C1=O
Reaction time: 1 h
Yield: 93.8 %

Procedure:
A solution of DCC (428 mg; 2.1 mmoles) in DMF (1 ml) was added dropwise to a solution of 1-(2-hydroxycarbonyl-3,3,3-trifluoropropyl)-3-methylurea (428 mg; 2.0 mmoles) obtained above in DMF (2 ml). The mixture was stirred for 1 hour, and the precipitated solid was filtered off and washed with ethyl acetate. The solvents were evaporated under reduced pressure from the combined filtrates. The residue was purified by a column chromatography on silica gel (ethyl acetate:chloroform=1:1) to give 368 mg (yield: 94%) of 3-methyl-5-trifluoromethyl-5,6-dihydrouracil (OF-2).
Reaction SMILES: ClC1N=[C:9]2[C:5](N=CN2C2CC(N3C=C(CC)N=N3)C(O)C2O)=[C:4](NCC(C2C=CC=CC=2)C2C=CC=CC=2)[N:3]=1.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[C:47]1([CH:53]([C:88]2[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=2)[CH2:54][NH:55][C:56]2[N:64]=[C:63]([NH:65][CH2:66][CH2:67][N:68]3[CH2:73][CH2:72][CH2:71][CH2:70][CH2:69]3)[N:62]=[C:61]3[C:57]=2[N:58]=[CH:59][N:60]3[C@@H:74]2[CH2:78][C@H:77]([N:79]3C=C(CO)[CH:81]=[N:80]3)[C@@H:76]([OH:86])[C@H:75]2[OH:87])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[C:47]1([CH:53]([C:88]2[CH:89]=[CH:90][CH:91]=[CH:92][CH:93]=2)[CH2:54][NH:55][C:56]2[N:64]=[C:63]([NH:65][CH2:66][CH2:67][N:68]3[CH2:69][CH2:70][CH2:71][CH2:72][CH2:73]3)[N:62]=[C:61]3[C:57]=2[N:58]=[CH:59][N:60]3[C@@H:74]2[CH2:78][C@H:77]([N:79]3[N:3]=[C:4]([CH2:5][CH3:9])[CH:81]=[N:80]3)[C@@H:76]([OH:86])[C@H:75]2[OH:87])[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: OCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NCCN5CCCCC5)nc43)[C@H](O)[C@@H]2O)c1
Reactant: CCc1cn(C2CC(n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(Cl)nc43)C(O)C2O)nn1
Solvent: O=C(O)C(F)(F)F
Product: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NCCN5CCCCC5)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
This compound is prepared from 3-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(4-ethyl-[1,2,3]triazol-1-yl)-cyclopentane-1,2-diol (Intermediate BA9) using a procedure analogous to that of (1R,2S,3R,5S)-3-[6-(2,2-diphenyl-ethylamino)-2-(2-piperidin-1-yl-ethylamino)-purin-9-yl]-5-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentane-1,2-diol trifluoroacetate (Example 46). MS (ES+) m/e 637.42 (MH+).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([SH:30])[CH:25]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:23][C:24]1[CH:25]=[C:26]([S:30][C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: Cc1cccc(S)c1
Reactant: CC(C)[C@@H](NS(=O)(=O)c1ccc(F)cc1)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(Sc2ccc(S(=O)(=O)N[C@@H](C(=O)OC(C)(C)C)C(C)C)cc2)c1
Temperature: 70 °C

Procedure:
To a solution of N-[(4-fluorophenyl)-sulfonyl]-D-valine, 1,1-dimethylethyl ester, from Example 1b (3.0 g, 9.06 mmol) in 35 mL DMF was added m-thiocresol (3.23 mL, 27.2 mmol) and powdered K2CO3 (3.76 g, 27.2 mmol). The mixture was heated to 70° C. for 20 hours. After cooling to room temperature, the solution is washed with H2O (4×100 mL), and sat'd NaCl (2×100 mL), and dried over Mg2SO4. After concentration in vacuo, the residue was purified by flash chromatography (10:90 EtOAc/hexane) to afford N-[[4-[(3-methylphenyl)thio]phenyl]sulfonyl]-D-valine, 1,1-dimethylethyl ester, as a white solid (3.95 g, quantitative yield): MS MH+ calc'd for C22H29NO4S2 : 436, found: 436. Anal. calc'd for C22H29NO4S2 : C, 60.66; H, 6.71; N, 3.22; Found: C, 60.57; H, 6.47; N, 3.14.
Reaction SMILES: Br[C:2]1[C:3]([CH3:10])=[N:4][C:5]([CH3:9])=[CH:6][C:7]=1[CH3:8].C([Li])CCC.[B:16](OC)([O:19]C)[O:17]C.[Cl-].[NH4+]>C1COCC1>[CH3:10][C:3]1[C:2]([B:16]([OH:19])[OH:17])=[C:7]([CH3:8])[CH:6]=[C:5]([CH3:9])[N:4]=1
Reactant: Cc1cc(C)c(Br)c(C)n1
Reactant: COB(OC)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(C)c(B(O)O)c(C)n1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
3-bromo-2,4,6-trimethylpyridine (CAS No. 23079-73-4; Prasenjit Mal etc., Journal of Organic Chemistry, 68(9), pp. 3446-3453) (1 g) was added to THF (20 mL). The solution was cooled to −78° C., and n-butyllithium (1.63 M solution in n-hexane, 3.37 mL) was added, followed by stirring at the same temperature for 30 minutes. Trimethyl borate (0.78 mL) was added to the reaction mixture, and the mixture was stirred at −78° C. for 10 minutes and at room temperature for 50 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the reaction mixture was concentrated under reduced pressure. The resulting residue was partitioned between oil and water by adding water and DCM. The aqueous layer was concentrated under reduced pressure. DCM and ethanol were added to the resulting residue. The insoluble matter was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (242 mg). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 2.50 (s, 3H), 2.63 (s, 3H), 2.67 (s, 3H), 7.52 (s, 1H).
Reaction SMILES: [NH2:1][C:2]([CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH3:20])=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)=O.[Cl-].[Na+].P(Cl)(Cl)(Cl)=O.O>ClCCCl>[C:2]([CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][CH3:20])=[CH:15][CH:16]=2)[CH2:6][CH2:5]1)#[N:1]
Reactant: CCCOc1ccc(CN2CCC(C(N)=O)CC2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: ClCCCl
Product: CCCOc1ccc(CN2CCC(C#N)CC2)cc1
Temperature: 25 °C
Yield: 56.1 %

Procedure:
A mixture of 27.0 grams (0.10 mole) of 4-aminocarbonyl-N-(4-propoxyphenylmethyl)piperidine in 200 mL of 1,2-dichloroethane was stirred at ambient temperature, and 8.0 grams (0.14 mole) of sodium chloride, followed by 9.2 grams (0.06 mole) of phosphorous oxychloride were added. The reaction mixture was then warmed to reflux, where it stirred for about 1.75 hours. The reaction mixture was cooled to ambient temperature and about 350 mL of water was added. The aqueous layer was separated, washed with two portions of diethyl ether, and then made basic with aqueous 5% sodium hydroxide. The mixture was extracted with two portions of diethyl ether. The combined extracts were washed with an aqueous solution saturated with sodium chloride. The organic layer was dried with sodium sulfate and poured through a pad of silica gel. The silica gel pad was washed with 1000 mL of diethyl ether. The combined eluants were concentrated under reduced pressure, yielding 14.5 grams of 4-cyano-N-(4-propoxyphenylmethyl)piperidine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:17])[N:4]([C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[CH:10]=2)[N:5]=[CH:6][C:7]=1Br.[OH-:18].[K+]>C(O)C.O>[Br:1][C:2]1[C:3](=[O:17])[N:4]([C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[CH:10]=2)[N:5]=[CH:6][C:7]=1[OH:18]
Reactant: O=c1c(Br)c(Br)cnn1-c1cc(F)cc(F)c1
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=c1c(Br)c(O)cnn1-c1cc(F)cc(F)c1

Procedure:
4,5-Dibromo-2-(3,5-difluorophenyl)pyridazin-3-one (1.5 g, 0.0041 moles) was suspended in ethanol (50 ml) and potassium hydroxide (0.8 g, 0.0123 moles) was added in water (8 ml). Refluxed for 4 hours with stirring. Evaporated to a low bulk and diluted with water. Acidified to pH2 with conc. hydrochloric acid and extracted with ethyl acetate. Washed with water and dried with anhydrous magnesium sulphate. Filtered and evaporated the filtrate to give an orange solid. Triturated with diethyl ether and dried in a desiccator to give the product as a cream solid. (0.7 g, 56%)