Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]([CH3:40])[C@@H:12]1[CH2:19][N:18]2[C:20]3[CH:21]=[C:22]([C:33](O)=[O:34])[CH:23]=[CH:24][C:25]=3[C:26]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[C:17]2[C:16]2[CH:36]=[CH:37][CH:38]=[CH:39][C:15]=2[O:14][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.[CH3:45][O:46][CH:47]([O:55][CH3:56])[CH2:48][N:49]([CH3:54])[S:50]([NH2:53])(=[O:52])=[O:51].S(N)(N)(=O)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH:27]1([C:26]2[C:25]3[CH:24]=[CH:23][C:22]([C:33]([NH:53][S:50]([N:49]([CH2:48][CH:47]([O:46][CH3:45])[O:55][CH3:56])[CH3:54])(=[O:52])=[O:51])=[O:34])=[CH:21][C:20]=3[N:18]3[C:17]=2[C:16]2[CH:36]=[CH:37][CH:38]=[CH:39][C:15]=2[O:14][CH2:13][C@H:12]([N:11]([CH3:40])[CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:19]3)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: COC(CN(C)S(N)(=O)=O)OC
Reactant: CN(CCNC(=O)OC(C)(C)C)[C@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1
Agent: CN(C)c1ccncc1
Agent: NS(N)(=O)=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: COC(CN(C)S(=O)(=O)NC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N(C)CCNC(=O)OC(C)(C)C)COc1ccccc1-3)OC
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 44 %

Procedure:
To a solution of (7R)-7-[{2-[(tert-butoxycarbonyl)amino]ethyl}(methyl)amino]-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylic acid (0.15 M) in DCM were added sequentially EDC (1.8 eq), N-(2,2-dimethoxyethyl)-N-methylsulfamide (1.8 eq) (prepared as described in Step 1) and DMAP (1.2 eq). The mixture was stirred at 40° C. for 1.5 hours. Further EDC (0.48 eq) and sulfamide (0.5 eq) were introduced and heating continued for 1 h. The reaction was left to cool with stirring overnight. The reaction was diluted with EtOAc and washed with 1N HCl (aq). The aqueous was extracted with EtOAc and the organics combined, washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to leave a brown gum. The residue was purified by RP-HPLC (Waters Xterra column; MeCN/H2O/0.1% TFA gradient). Fractions containing the pure compound were combined and lyophilized to afford the product as a white powder (44%). MS (ES+) m/z 728 (M+H)+.
Reaction SMILES: CNC1C=CC(C(N[C@H](C(OCC)=O)CCC(OCC)=O)=O)=NC=1.[C:25]([O:29][C:30]([N:32]([C:34]1[CH:35]=[CH:36][C:37]([C:40]([O:42]C)=[O:41])=[N:38][CH:39]=1)[CH3:33])=[O:31])([CH3:28])([CH3:27])[CH3:26].CI.O>C(O)C>[C:25]([O:29][C:30]([N:32]([C:34]1[CH:35]=[CH:36][C:37]([C:40]([OH:42])=[O:41])=[N:38][CH:39]=1)[CH3:33])=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: COC(=O)c1ccc(N(C)C(=O)OC(C)(C)C)cn1
Agent: CCOC(=O)CC[C@H](NC(=O)c1ccc(NC)cn1)C(=O)OCC
Solvent: O
Solvent: CI
Solvent: CCO
Product: CN(C(=O)OC(C)(C)C)c1ccc(C(=O)O)nc1

Procedure:
Note (6): Diethyl N-[5-(methylamino)picolinoyl]-L-glutamate used as starting material was prepared as follows:-A mixture of methyl 5-(N-tert-butoxycarbonyl-N-methylamino)picolinate (prepared using the method described in the Journal of Medicinal Chemistry, 1980, 23, 1405 except that methyl iodide was used in place of 3-trifluoromethylbenzyl chloride; 1.13 g), aqueous N-sodium hydroxide solution (8.5 ml), water (21 ml) and ethanol (15 ml) was stirred at laboratory temperature for 16 hours. The mixture was concentrated to a volume of 5 ml, acidified to pH 4 with 2N-hydrochloric acid solution and extracted with ethyl acetate (2×40 ml). The combined extracts were dried over magnesium sulphate, filtered and evaporated to give 5-(N-tert-butoxycarbonyl-N-methylamino)picolinic acid (0.8 g).
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1)#[CH:2].CN1C(C)(C)CCCC1(C)C.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C)C1C=CN=CC=1.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.C(#N)C>[C:3]1([C:1]#[C:2][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: C#Cc1cccc2ccccc12
Reactant: CCOC(=O)Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN(C)c1ccncc1
Agent: CN1C(C)(C)CCCC1(C)C
Solvent: CC#N
Product: CCOC(=O)C#Cc1cccc2ccccc12
Yield: 35.3 %

Procedure:
First, ethyl 1-naphthylpropiolate was prepared. A mixture of 1-ethynylnaphthalene (7.7 g, 50.6 mmol), 4-(dimethylamino)pyridine (0.06 g, 0.5 mmol), 1,2,2,6,6-pentamethylpiperidine (8.8 g, 55.7 mmol), and acetonitrile (120 mL) was sparged with nitrogen for 10 min, and then tetrakis(triphenylphosphine)palladium(0) (1.3 g, 1.1 mmol) was added. The mixture was sparged with nitrogen for 10 min, heated to reflux, treated dropwise with ethyl chloroformate (12.1 g, 111.3 mmol), and held at reflux for 2 h. The reaction mixture was cooled to ambient and diluted with ligroin. The solution was washed three times with water and then with brine, dried (Na2SO4), and concentrated to deposit a brown oil. The crude product was purified by column chromatography to provide 4.0 g (36% of theory) of ethyl 1-naphthylpropiolate. 1H NMR (CDCl3): δ 1.40 (t, 3H), 4.33 (q, 2H), 7.50 (m, 3H), 7.90 (m, 3H), 8.30 (d, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[C:4]([CH3:18])[CH:3]=1.ClS([N:23]=[C:24]=[O:25])(=O)=O>ClCCl>[NH2:23][C:24]([O:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[C:4]([CH3:18])[CH:3]=1)=[O:25]
Reactant: Cc1cc(O)ccc1C(=O)OCc1ccccc1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: ClCCl
Product: Cc1cc(OC(N)=O)ccc1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 44.2 %

Procedure:
To a solution of phenylmethyl 4-hydroxy-2-methylbenzoate (687 mg, 2.82 mmol) in dichloromethane (8 ml) at 0° C., was added chlorosulfonyl isocyanate (1.20 g, 8.50 mmol). The reaction was allowed to warm to 25° C. and stirred for 20 h. The reaction mixture was concentrated then taken into ethyl acetate and washed with water. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, hexanes/ethyl acetate) to afford phenylmethyl 4-[(aminocarbonyl)oxy]-2-methylbenzoate (356 mg, 89%). 1H NMR (400 MHz, DMSO): 7.91-7.87 (d, 1H), 7.49-7.29 (m, 5H), 7.11-7.00 (m, 4H), 5.31 (s, 2H), 2.52 (s, 3H). MS (EI) for C16H15NO4: 286 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]([C:18]1[O:22][N:21]=[C:20]([CH3:23])[C:19]=1[CH3:24])[CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])(=[O:10])=[O:9].B([C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]([S:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)(=[O:39])=[O:38])[CH:29]=1)(O)O.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO>[CH3:23][C:20]1[C:19]([CH3:24])=[C:18]([N:11]([CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])[S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]([S:37]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)(=[O:39])=[O:38])[CH:29]=2)(=[O:10])=[O:9])[O:22][N:21]=1
Reactant: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccccc1Br
Reactant: O=S(=O)(c1ccccc1)n1cc(B(O)O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccccc1-c1cn(S(=O)(=O)c2ccccc2)c2ccccc12
Temperature: 77.5 °C
Yield: 44.8 %

Procedure:
After purging a solution of 2-bromo-N-(3,4-dimethyl-5-isoxazolyl)-N-[(2-methoxyethoxy)methyl]benzenesulfonamide (595 mg; 1.42 mmol) in 14 ml of toluene and 12 ml of EtOH with argon for 20 minutes, the title product of Step (C) (600 mg; 1.99 mmol) was added followed by 2M Na2CO3 (10 ml; previously purged with argon) and tetrakis(triphenylphosphine)palladium(0) (200 mg). The heterogeneous mixture was heated to 75-80° C. for 5 hrs. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (50 ml) and water (25 ml). The aqueous layer was extracted with an additional 25 ml of ethyl acetate and the combined organic layers were washed with water (25 ml) and brine (25 ml). After drying (MgSO4) and decolorizing (Darco), the green solution was concentrated to afford a dark green residue which was chromatographed on a 5×12 cm silica gel column, using 2 L EtOAc:hexanes, 1:3, 1 L EtOAc:hexanes, 3:7 and 1 L EtOAc:hexanes, 35:65 as the mobile phase. The pure fractions were concentrated to afford 379 mg (45%) of the title product of this step as a blue-green foam.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[I:19]C1C=C(C=CC=1)N.N1C=CC=CC=1C=O>>[I:19][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(I)c1
Reactant: Clc1cccc(-n2nnc(-c3ccccn3)n2)c1
Agent: O=Cc1ccccn1
Product: Ic1cccc(-n2nnc(-c3ccccn3)n2)c1

Procedure:
Following the procedure described in EXAMPLE 1 for the synthesis of 2-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]pyridine, 3-iodoaniline (263 mg, 1.2 mmol) and pyridine-2-carboxaldehyde (128 mg, 1.2 mmol) were employed to obtain 2-[2-(3-iodophenyl)-2H-tetrazol-5-yl]pyridine as an orange solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)[CH3:2].[CH2:18]([O:21][CH:22]1[CH2:27][CH2:26][CH:25]([CH:28]2[CH2:33][CH2:32][CH:31](OS(C)(=O)=O)[CH2:30][CH2:29]2)[CH2:24][CH2:23]1)[CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:12][CH2:13][N:14]([CH:31]3[CH2:30][CH2:29][CH:28]([CH:25]4[CH2:24][CH2:23][CH:22]([O:21][CH2:18][CH2:19][CH3:20])[CH2:27][CH2:26]4)[CH2:33][CH2:32]3)[CH2:15][CH2:16]2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Reactant: CCCOC1CCC(C2CCC(OS(C)(=O)=O)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOC1CCC(C2CCC(N3CCN(c4ccc(C(=O)OCC)cc4)CC3)CC2)CC1
Temperature: 130 °C
Reaction time: 8 h
Yield: 13 %

Procedure:
A mixture of 4-piperazinylbenzoic acid ethyl ester (1.03 g), 4′-propoxy-4-methylsulfonyloxy-1,1′-bicyclohexane (1.4 g), potassium carbonate (0.91 g) in N,N-dimethylformamide (10 ml) was stirred for 8 hours at 130° C. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed with brine and dried, and the solvent was evaporated under reduced pressure. The residue was chromatographed on a column of silica gel eluting with dichloromethane/methyl alcohol (200:1) to give 4-[4-(4′-propoxy-1,1′-bicyclohexan-4-yl)piperazin-1-yl]benzoic acid ethyl ester (0.26 g).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[C:23]([F:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH3:34][O:35][CH2:36][C:37]([N:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[C:23]([F:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1)=[O:38]
Reactant: COc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCCNC4)c[nH]c23)c(OCC2CC2)cc1F
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1CCC[C@@H](NC(=O)c2c[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)ncnc23)C1

Procedure:
Starting from 4-(2-Cyclopropylmethoxy-4-fluoro-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-piperidin-3-ylamide hydrochloride (example A164) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][C:13]([C:15](O)=[O:16])=[CH:12][CH2:11][C@@H:10]1[C:18]1[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=1[F:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.Cl.[F:58][C:59]([F:70])([F:69])[C:60]1[N:61]=[C:62]2[CH2:67][NH:66][CH2:65][CH2:64][N:63]2[CH:68]=1>C1COCC1.CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]1[C@@H:10]([C:18]2[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=2[F:26])[CH2:11][CH:12]=[C:13]([C:15]([N:66]2[CH2:65][CH2:64][N:63]3[CH:68]=[C:60]([C:59]([F:70])([F:58])[F:69])[N:61]=[C:62]3[CH2:67]2)=[O:16])[CH2:14]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC(C(=O)O)=CC[C@@H]1c1cc(F)c(F)cc1F
Reactant: FC(F)(F)c1cn2c(n1)CNCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CC(C(=O)N2CCn3cc(C(F)(F)F)nc3C2)=CC[C@@H]1c1cc(F)c(F)cc1F
Temperature: 0 °C
Yield: 106.5 %

Procedure:
(4R,5S)-5-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-cyclohex-1-enecarboxylic acid (98.4 g) and EDCI (60.8 g 0.32 mol), HOBT (43 g, 0.32 mol) were mixed in THF/DMF (120 mL/120 mL). The mixture was cooled to 0° C. and diisopropylethyl amine (151.5 mL, 0.86 mol) was added slowly. The mixture was stirred for approximate twenty minutes, and then 2-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyrazine HCl salt (83.9 g, 0.32 mol) was added. The mixture was stirred overnight, and concentrated in vacuo. Ethyl acetate (1000 mL) was added followed by 1N HCl (750 mL). The mixture was extracted with ethyl acetate, and the combined organic extract was washed with saturated NaHCO3 (750 mL), water, and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give an oil (153.6 g). The crude amide (228 g) was dissolved in 470 mL of EtOH, and 1350 mL of hexanes was added with stirring. After stirring overnight, the solid was collected by filtration, washed with 450 mL of 50% Et2O/hexanes and then dried in vacuum at 45° C. to give 165.8 g (73%) of product as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][O:18][C:19]([CH3:24])([CH3:23])[C:20]([OH:22])=[O:21])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O.[CH3:27]O>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][O:18][C:19]([CH3:24])([CH3:23])[C:20]([O:22][CH3:27])=[O:21])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(OCc1nn(Cc2ccccc2)c2ccccc12)C(=O)O
Reactant: CO
Agent: Cl
Solvent: O
Product: COC(=O)C(C)(C)OCc1nn(Cc2ccccc2)c2ccccc12

Procedure:
A suspension of 2-[(1-benzyl-1H-indazol-3-yl)methoxy]-2-methylpropanoic acid (20 g; 0.062 mol) in methanol (300 ml) was treated at 0° C. with gaseous HCl for 4 hours. The mixture was then poured into water (500 ml) and the product was extracted with diethyl ether (3×250 ml). The combined organic phases were washed with 5% sodium bicarbonate solution (2×100 ml) and then with water (50 ml). The solvent was evaporated off under reduced pressure and the crude residue was purified by crystallization from hexane.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[C:17]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([S:24][CH3:25])[N:19]=3)=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH:6]=[CH:5][N:4]=1.C([N-]C(C)C)(C)C.[Li+].CCCCCCC.O1CCCC1.C(C1C=CC=CC=1)C.C(Cl)(Cl)(Cl)[Cl:55]>O1CCCC1>[Cl:55][C:16]1[N:11]2[N:10]=[C:9]([C:7]3[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=3)[C:17]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([S:24][CH3:25])[N:19]=3)=[C:12]2[CH:13]=[CH:14][CH:15]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: CSc1nccc(-c2nn3ccccc3c2-c2ccnc(SC)n2)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCc1ccccc1
Solvent: CCCCCCC
Product: CSc1nccc(-c2nn3c(Cl)cccc3c2-c2ccnc(SC)n2)n1
Reaction time: 0.25 h
Yield: 32 %

Procedure:
To a −78° C. solution of 2,3-bis[2-(methylsulfanyl)pyrimidin-4-yl]pyrazolo[1,5-a]pyridine (0.72 g, 2.0 mmol) in tetrahydrofuran (50 mL) was added a 2 M solution of lithium diisopropylamide in heptane/tetrahydrofuran/ethylbenzene (2.9 mL, 5.9 mmol) dropwise. The reaction mixture was stirred for 15 minutes, then carbon tetrachloride (5 mL) was added. The reaction mixture was stirred for 1 hour and quenched with brine and extracted with ethyl acetate (3×25 mL). The organic phase was washed with brine (3×25 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (1:9 acetone:dichloromethane) to give 260 mg (32%) of 7-chloro-2,3-bis[2-(methylsulfanyl)pyrimidin-4-yl]pyrazolo[1,5-a]pyridine. 7-Chloro-2,3-bis[2-(methylsulfanyl)pyrimidin-4-yl]pyrazolo[1,5-a]pyridine (0.098 g, 0.24 mmol) was dissolved in dichlormethane (3 mL) and cooled to 0° C. To the solution was added 3-chloroperoxybenzoic acid (0.13 g, 0.73 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight The mixture was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate, and concentrated under reduced pressure. To 7-chloro-2,3-bis[2-(methylsulfinyl)pyrimidin-4-yl]pyrazolo[1,5-a]pyridine (0.027 g, 0.062 mmol) was added 2-methoxyethylamine (2 mL) and the reaction was heated to 100° C. in a sealed tube overnight. The reaction mixture was cooled to room temperature and concentrated by evaporation under reduced pressure. The residue was purified by silica gel chromatography eluting with 1:1 acetone:dichloromethane to give 15 mg (49%) of N-(2-methoxyethyl)-2,3-bis{2-[(2-methoxyethyl)amino]pyrimidin-4-yl}pyrazolo[1,5-a]pyridin-7-amine. 1H NMR (CDCl3): δ 8.41 (d, 1H), 8.16 (d, 1H), 7.69 (d, 1H), 7.36 (d, 1H), 7.05 (m, 1H), 6.65 (d, 1H), 6.33 (t, 1H), 6.09 (d, 1H), 5.57 (m, 1H), 5.42 (t, 1H), 3.37–3.80 (m, 21H); MS m/z 494 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:16])=[O:5])[CH3:2].[CH3:17][C:18]1([CH3:29])[O:23][C:22](=[O:24])[C:21](=COC)[C:20](=[O:28])[O:19]1>C(O)C>[CH3:17][C:18]1([CH3:29])[O:23][C:22](=[O:24])[C:21](=[N:16][C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:9]=2[N:8]=[CH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:15]3)[C:20](=[O:28])[O:19]1
Reactant: COC=C1C(=O)OC(C)(C)OC1=O
Reactant: CCOC(=O)c1cnc2c(N)cccc2c1
Solvent: CCO
Product: CCOC(=O)c1cnc2c(N=C3C(=O)OC(C)(C)OC3=O)cccc2c1
Yield: 80 %

Procedure:
A mixture of 3-ethoxycarbonyl-8-amino-quinoline (9.9 g), 2,2-dimethyl-5-methoxymethylene-1,3-dioxan-4,6-dione (Monatsh. Chem., 98:564-78 (1967))(10.3 g) and ethanol (80 ml) was stirred at reflux for 2 hours. The mixture was cooled and filtered. The solid so obtained was washed with ethanol to give 8-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylideneamino)-3-ethoxycarbonylquinoline in 80% yield, mp 228-231° C.
Reaction SMILES: [OH2:1].I(O)(=O)(=O)=O.[CH:7](=[O:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>C(O)(C)(C)C>[O:13]=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]([OH:13])=[O:1]
Reactant: CCCCCC=O
Reactant: O
Agent: [O-][I+3]([O-])([O-])O
Solvent: CC(C)(C)O
Product: O=CCCCCCCCCCCC(=O)O
Temperature: 0 °C
Yield: 73 %

Procedure:
A 2.40 g (0.008 mol) sample of the acid was placed in a 250 mL Erlenmeyer flask and dissolved with 18 mL water and 9 mL tertiary butyl alcohol. The mixture was stirred continuously for homogeneity, followed by addition of 1.95 g (0.0086 mol) periodic acid in one portion. The reaction mixture was then stirred for 5 hours, after which 150 mL ice-cold water was added. The mixture was stirred for another 30 minutes and the resulting solid was vacuum-filtered to give crude 12-oxododecanoic acid. The acid was washed, then recrystallized with light petroleum (bp 35°-60° C.) to give 1.22 g 12-oxododecanoic acid (73% yield, m.p. 53°-54° C.) and hexanal. There was no attempt to isolate the hexanal.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[C:29](Cl)(Cl)=[O:30].C(N(CC)CC)C.[CH3:40][O:41][C:42](=[O:50])[C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([NH2:49])[CH:44]=1>C(Cl)Cl>[CH3:40][O:41][C:42](=[O:50])[C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([NH:49][C:29]([N:9]2[CH2:10][C@@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C@@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:28])=[O:30])[CH:44]=1
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: COC(=O)c1cccc(N)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cccc(NC(=O)N2C[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)c1
Yield: 63.4 %

Procedure:
In a manner similar to the method described in Example 4, rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (42.3 mg, 0.10 mmol) was reacted with phosgene solution (Aldrich, 20% in toluene, 0.12 mL, 0.12 mmol), in the presence of triethylamine (TEA, 30.0 mg, 0.30 mmol) in CH2Cl2 (2 mL) followed by reacting with 3-amino-benzoic acid methyl ester (Aldrich, 45.0 mg, 0.30 mmol) at rt for 30 min to give rac-3-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]amino}-benzoic acid methyl ester (38.1 mg, 62.9%) as a white amorphous which was used in the next step without further purification.
Reaction SMILES: O.[F:2][C:3]([F:20])([F:19])[C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[CH2:7][N:8]1[N:15]=[CH:14][C:12](=[O:13])[NH:11][C:9]1=[O:10]>[Zn].C(O)(=O)C>[F:19][C:3]([F:2])([F:20])[C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[CH2:7][N:8]1[C:9](=[O:10])[NH:11][C:12](=[O:13])[CH2:14][NH:15]1
Reactant: O=c1cnn(Cc2cccc(C(F)(F)F)c2)c(=O)[nH]1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: O=C1CNN(Cc2cccc(C(F)(F)F)c2)C(=O)N1
Yield: 49.6 %

Procedure:
A 1 liter three-necked flask equipped with a mechanical stirrer was charged with 300 ml of water and 60 ml of glacial acetic acid. 3 g of 1-(3'-trifluoromethylbenzyl)-6-aza uracil was added in one portion followed by the addition of 3.3 g of zinc powder in small portions. After the addition was terminated the mixture was stirred vigorously and refluxed for 36 hours after which the mixture was cooled in ice and filtered. The crystals obtained were recrystallized from iso-propanol to give 1.5 g (50%) of 2-(3'-trifluoromethylbenzyl)-hexahydro-1,2,4-triazine-3,5-dione; m.p. 152°.
Reaction SMILES: [CH:1]([Si:3]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:2].[C:22]1([PH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1CCCCC1>[C:10]1([Si:3]([CH2:1][CH2:2][P:28]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: c1ccc(Pc2ccccc2)cc1
Reactant: C=C[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCCCC1
Product: c1ccc(P(CC[Si](c2ccccc2)(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
The vinyl triphenyl silane was reacted with 10% excess of diphenyl phosphine. To maintain a homogeneous reaction mixture, a temperature of 80° and cyclohexane solvent were employed. After the usual u.v. initiated addition, the reaction mixture was allowed to cool to room temperature. This resulted in the crystallization of the triphenylsilylethyl diphenyl phosphine adduct. To obtain it in a pure form, the adduct was filtered and recrystallized from a four to one mixture of cyclohexane and toluene. A white crystalline product having a melting point of 128°-131° was obtained.