Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[CH:5]=[CH:4]1.[C:12]1(=O)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>CO>[C:12]1([C:5]2[C:6]3[C:11](=[N:10][CH:9]=[CH:8][CH:7]=3)[NH:3][CH:4]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=1
Reactant: O=C1CCCCC1
Reactant: c1cnc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: C1=C(c2c[nH]c3ncccc23)CCCC1
Temperature: 0 °C
Yield: 76.2 %

Procedure:
Methanol (150 mL) was added dropwise to a chilled (0° C.) 1 L flask containing sodium hydride (60% dispersion in mineral oil, 19.3 g, 480 mmol). To the stirred suspension was added 7-azaindole (10.2 g, 86 mmol) in MeOH (100 mL) and cyclohexanone (35 mL, 340 mmol) in MeOH (65 mL). The cloudy solution was refluxed for 24 h, then the solvent was removed under reduced pressure. The oily residue was cooled in an ice bath and 3 N HCl was added with vigorous stirring until the pH=8 (pH paper). The resulting yellow ppt. was collected by filtration, washed with H2O, triturated with tBME/C6H14 (1:1, 50 mL), and dried by toluene azeotrope to give the title compound as a white solid (13.0 g, 76% yield). 1H NMR (400 MHz, CDCl3) δ ppm 1.66-1.78 (m, 2H) 1.78-1.91 (m, 2H) 2.20-2.35 (m, 2H) 2.47 (d, J=1.76 Hz, 2H) 6.28 (d, J=3.78 Hz, 1H) 7.10 (dd, J=8.06, 4.78 Hz, 1H) 7.34 (s, 1H) 8.25 (dd, J=8.06, 1.26 Hz, 1H) 8.33 (dd, J=4.66, 1.39 Hz, 1H) 11.8 (br s, 1H); 13C NMR (100 MHz, CDCl3) δ ppm 22.43, 22.98, 25.65, 27.88, 115.52, 117.31, 118.32, 121.57, 122.16, 129.39, 131.07, 141.99, 149.53.
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[CH:9][N:8]2[CH:11]=[N:12][CH:13]=[C:7]2[C:6]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[F:22])=[O:4].[OH-].[Na+].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[NH2:47][O:48][CH2:49][C@@H:50]([OH:52])[CH3:51]>O.C(#N)C.C(O)=O>[OH:52][C@@H:50]([CH3:51])[CH2:49][O:48][NH:47][C:3]([C:5]1[CH:10]=[CH:9][N:8]2[CH:11]=[N:12][CH:13]=[C:7]2[C:6]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[F:22])=[O:4]
Reactant: C[C@H](O)CON
Reactant: COC(=O)c1ccn2cncc2c1Nc1ccc(Br)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O=CO
Solvent: O
Product: C[C@H](O)CONC(=O)c1ccn2cncc2c1Nc1ccc(Br)cc1F
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 26.4 %

Procedure:
To a solution of 8-(4-bromo-2-fluoro-phenylamino)-imidazo[1,5-a]pyridine-7-carboxylic acid methyl ester (587 mg, 1.61 mmol) in IMS (20 mL) was added a 1.0 M aqueous solution of sodium hydroxide (1.7 mL, 1.7 mmol). The reaction mixture was heated at 65° C. for 2 hours and then cooled to room temperature and concentrated in vacuo. The resulting residue was azeotroped with toluene, and then suspended in dioxane (15 mL). EDCI (614 mg, 3.2 mmol) and HOBt (432 mg, 3.2 mmol) were then added before the reaction mixture was stirred for 30 min at room temperature. (S)-1-Aminooxy-propan-2-ol hydrochloride (408 mg, 3.20 mmol) and N-N-diisopropylethylamine (1.1 mL, 6.44 mmol) were then added sequentially before the reaction mixture was stirred for 18 hours at room temperature. The reaction mixture was then concentrated under reduced pressure. The resultant residue was taken up in ethyl acetate, then washed with water followed by a saturated aqueous solution of sodium bicarbonate and brine, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0% to 10%, methanol in dichloromethane). The appropriate fractions were combined and concentrated to give a residue that was subjected to HPLC (Gemini 5 micron C18 250×21.20 mm column, 0.1% formic acid, acetonitrile in water, gradient 5% to 85%, ramp time 20 minutes) to afford the title compound as a pale yellow solid (180 mg, 26%). LCMS (method A): RT=6.55 min, [M+H]+=423/425. 1H NMR (CDCl3): 10.46 (1H, s), 8.75 (1H, s), 7.99 (1H, s), 7.39 (1H, d, J=7.36 Hz), 7.32 (1H, dd, J=9.31, 2.15 Hz), 7.28 (1H, d, J=8.83 Hz), 7.12 (1H, t, J=8.38 Hz), 6.63 (1H, s), 6.46 (1H, d, J=7.33 Hz), 4.10-4.01 (1H, m), 3.93 (1H, dd, J=11.43, 2.28 Hz), 3.70 (1H, t, J=10.42 Hz), 1.14 (3H, d, J=6.47 Hz).
Reaction SMILES: O1CCCC1.CS(O)(=O)=O.[Cl:11][C:12]1[N:21]=[C:20]2[C:15]([C:16](=[O:35])[C:17]([C:30]([O:32]CC)=[O:31])=[CH:18][N:19]2[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[F:29])=[CH:14][C:13]=1[F:36]>O>[Cl:11][C:12]1[N:21]=[C:20]2[C:15]([C:16](=[O:35])[C:17]([C:30]([OH:32])=[O:31])=[CH:18][N:19]2[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[F:29])=[CH:14][C:13]=1[F:36]
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(Cl)c(F)cc2c1=O
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2nc(Cl)c(F)cc2c1=O
Temperature: 25 °C
Yield: 89 %

Procedure:
A mixture of tetrahydrofuran (450 cm3), water (50 cm3), methanesulfonic acid (127 cm3) and ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (United Kingdom Patent Publication No. GB 2,191,776) was heated at reflux for 1 hour, and then cooled to 25° C. The resulting crystals were isolated, washed with tetrahydrofuran, and dried under vacuum to afford 41.3 g (89%) of the above-titled compound: m.p.=250° C.; (Found: C, 50.4; H, 1.7; Cl, 9.9; F, 16.0; N, 8.0. C15H6ClF3N2O3 requires C, 50.8; H, 1.7; Cl, 10.0; F, 16.1; N, 7.9%); 1H NMR (300 MHz, d6 -DMSO) δ 13.9 (s, 1H), 9.09 (s, 1H), 8.77 (d, J=7.5 Hz, 1H), 7.86 (td, J=5.9 and 8.8 Hz, 1H), 7.66 (ddd, J=2.7, 9.0 and 11.8 Hz, 1H), 7.39 (tm, J=8.6 Hz, 1H), 7.39 (tm, J=8.6 Hz, 1H); νmax (DRIFTS) cm-1 3130, 3060, 2947, 2885, 2821, 2723, 2637, 2594, 1734, 1641, 1623, 1579, 1544, 1516.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]([S:10]SCC)[CH3:9]>[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4].C1(C)C=CC=CC=1>[CH2:8]([S:10][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[OH:7])[CH3:9]
Reactant: Oc1ccccc1
Reactant: CCSSCC
Agent: [Zr+4]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CCSc1ccccc1O
Yield: 46.7 %

Procedure:
A similar run using phenol (142 g, 1.51 moles), toluene (150 ml), zirconium tetrachloride (6.0 g, 0.026 moles), and ethyl disulfide (62.0 g, 0.50 moles) gave ortho-(ethylthio)phenol (36.0 g, 46% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[C:6]([O:13][CH3:14])[CH:5]=1>[Pd].CO.ClCCl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([O:13][CH3:14])[CH:5]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(OC)c1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc(N)c(OC)c1
Reaction time: 8 h
Yield: 100.3 %

Procedure:
Palladium on carbon (10%, catalytic amount) was added to a solution of 3-methoxy-4-nitro-benzoic acid methyl ester (1.08 g, 5.11 mmol) in a mixture of methanol (40 mL) and dichloromethane (a few drops). The resulting mixture was stirred under nitrogen atmosphere (balloon pressure) overnight. The catalyst was filtered off on a CELITE™ pad and the solvent was evaporated to give 0.929 g of 4-amino-3-methoxy-benzoic acid methyl ester as a yellow solid.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[CH:16][C:15]([C:21](O)=[O:22])=[CH:14]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.CN(C)C(F)=[N+](C)C.[O:46]1[CH2:51][CH2:50][CH2:49][CH2:48][CH:47]1[O:52][NH2:53]>CN(C)C=O.O>[C:1]1([S:7]([NH:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[CH:16][C:15]([C:21]([NH:53][O:52][CH:47]2[CH2:48][CH2:49][CH2:50][CH2:51][O:46]2)=[O:22])=[CH:14]3)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NOC1CCCCO1
Reactant: O=C(O)c1cnc2ccc(NS(=O)(=O)c3ccccc3)cc2c1
Agent: CN(C)C(F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NOC1CCCCO1)c1cnc2ccc(NS(=O)(=O)c3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
6-[(Phenylsulfonyl)amino]quinoline-3-carboxylic acid (0.11 g, 0.335 mmol) was dissolved in N,N-dimethylformamide (2.5 mL) and triethylamine (0.14 mL, 1 mmol) was added. Tetramethylfluoroformamidinium hexafluorophosphate (0.106 g, 0.402 mmol) was added and the reaction mixture was allowed to stir at room temperature for 15 min. Then O-(tetrahydropyran-2-yl)hydroxylamine (0.0471 g, 0.402 mmol) was added and the reaction was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate three times. The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0-10% MeOH in methylene chloride gradient with 0.1% formic acid) to afford the product (Int-13, 0.027 g, 18%). LC-MS: (AA) ES+ 428.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:16])=[C:12]([CH3:15])[CH:13]=2)[NH:8][C:7]=1[Si](CC)(CC)CC)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CO.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>[Cl:16][C:11]1[CH:10]=[C:9]2[C:14]([C:6]([CH2:5][CH2:4][NH2:1])=[CH:7][NH:8]2)=[CH:13][C:12]=1[CH3:15]
Reactant: CC[Si](CC)(CC)c1[nH]c2cc(Cl)c(C)cc2c1CCN=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc2c(CCN)c[nH]c2cc1Cl

Procedure:
2-(6-chloro-5-methyl-1H-indol-3-yl)ethanamine was prepared according to method D Step V with 3-(2-azidoethyl)-6-chloro-5-methyl-2-(triethylsilyl)-1H-indole (0.654 g; 1.87 mmol) and triphenylphosphine (0.737 g; 2.81 mmol) in methanol (10 mL) and tetrabutylamonium fluoride (5.62 mL 1M) in THF (stirred for 36 hours).
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=O)=[CH:3][CH:2]=1.[CH2:17](OCC)C.CO.Cl>S(Cl)(Cl)=O.[Li].[Cu]>[C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:2]=[CH:3][C:4]([CH2:7][C:8](=[O:10])[CH3:17])=[CH:5][CH:6]=1
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Reactant: CCOCC
Agent: [Cu]
Agent: Cl
Agent: [Li]
Solvent: CO
Solvent: O=S(Cl)Cl
Product: CC(=O)Cc1ccc(-c2ccccc2)cc1
Temperature: 80 °C
Yield: 96 %

Procedure:
10.5 g of 4-biphenylylacetic acid was dissolved in 50 ml of thionyl chloride, and the solution was heated at 80° C. for 3 hours. Then, excess thionyl chloride was distilled off under reduced pressure. Benzene was added to the residue, and the solvent was again distilled off. This operation was repeated again. Then, the formed acid chloride was dissolved in 100 ml of ethyl ether. Separately, 23.7 g of cuprous iodide was suspended in 50 ml of ethyl ether, and 166 ml of a 1.5M methyllithium-ethyl ether solution was added thereto with stirring under cooling with ice to obtain a uniform solution. This solution was dropwise added to the ethyl ether solution of the acid chloride obtained by the above reaction under a nitrogen atmosphere while stirring and cooling to -70° C. After completion of the dropwise addition, the mixture was stirred at the same temperature for further one hour. Then, methanol was added thereto to decompose the excess copper lithium reagent. Ethyl ether and 2N hydrochloric acid were added to the reaction solution. After removing the formed insoluble matters by filtration, the filtrate was subjected to liquid separation. The organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent was separated by filtration, and then the solvent was distilled off under reduced pressure to obtain 9.93 g (yield: 96%) of the above-identified compound as colorless oily substance.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]#[C:11][C:12]1[N:17]=[C:16]([CH3:18])[C:15]([C:19]([O:21][CH3:22])=[O:20])=[C:14]([NH:23][C:24]2[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=2)[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.[Pd]>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]1[N:17]=[C:16]([CH3:18])[C:15]([C:19]([O:21][CH3:22])=[O:20])=[C:14]([NH:23][C:24]2[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=2)[N:13]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)c1c(C)nc(C#CCNC(=O)OC(C)(C)C)nc1Nc1cccc(C)c1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1c(C)nc(CCCNC(=O)OC(C)(C)C)nc1Nc1cccc(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 2-(3-(tert-butoxycarbonylamino)prop-1-ynyl)-4-methyl-6-(m-tolylamino)pyrimidine-5-carboxylate (0.190 g, 0.463 mmol) was dissolved in EtOH (4 mL). To this solution was added palladium on carbon (0.049 g, 0.046 mmol) and the resulting mixture was stirred overnight at RT under H2 atmosphere. The mixture was filtered through a pad of Celite, and the filtrate was evaporated to give the title compound as a brown oil, which was used in next step without further purification. [M+H] calc'd for C22H30N4O4, 415. found, 415.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([NH:31][CH2:32][CH2:33][NH2:34])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30].[OH-].[Na+].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][NH:34][CH2:33][CH2:32][NH:31][C:25]3[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:23]([O:22][CH3:21])[CH:24]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1ccc(NCCN)cc1OC
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(NCCNCCCN2CCc3cc(OC)c(OC)cc3CC2=O)cc1OC

Procedure:
Here, 3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-1-chloropropane (10 g, 0.0336 mol) is heated to 130° C. for 3 hours with 2-(3,4-dimethoxyphenylamino)-ethylamine (13 g, 0.066 mol). After cooling, the reaction mixture is distributed between sodium hydroxide solution and methylene chloride. The organic phase is separated, dried over sodium sulfate and concentrated. The residue is chromatographed on silica gel (eluant: methylene chloride/methanol/conc. ammonia: 90/10/0.25). The product thus obtained is converted into the dihydrochloride in the usual way.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[CH3:11].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.[CH:41]1([C@H:44]([NH:51][CH3:52])[CH2:45][N:46]2[CH2:49][CH:48]([OH:50])[CH2:47]2)[CH2:43][CH2:42]1>CN(C=O)C.C(Cl)Cl>[CH:41]1([C@H:44]([N:51]([CH3:52])[C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([F:1])=[C:3]([CH3:11])[CH:4]=2)[CH2:45][N:46]2[CH2:49][CH:48]([OH:50])[CH2:47]2)[CH2:43][CH2:42]1
Reactant: Cc1cc(C(=O)O)ccc1F
Reactant: CN[C@H](CN1CC(O)C1)C1CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N(C)[C@H](CN2CC(O)C2)C2CC2)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.9 %

Procedure:
4-Fluoro-3-methylbenzoic acid (0.095 g, 0.62 mmol), TBTU (0.226 g, 0.70 mmol) and 4-methylmorpholine (0.194 mL, 1.76 mmol) was mixed in DMF (2 mL). After 30 min at rt was (S)-1-(2-cyclopropyl-2-(methylamino)ethyl)azetidin-3-ol (Compound J3) (0.1 g, 0.59 mmol) added. The resultant mixture was stirred at rt overnight. Analysis by LCMS indicated formation of both mono and diacylated product. Additional TBTU (0.189 g, 0.59 mmol), 4-fluoro-3-methylbenzoic acid (0.091 g, 0.59 mmol) and NMM (0.129 mL, 1.17 mmol) were added to drive the reaction towards the diacylated product. The resultant mixture was stirred at rt overnight. The mixture was diluted with DCM (5 mL) and the organic phase was washed with NaHCO3 (saturated, 5 mL), filtered through a phase separator and concentrated under reduced pressure. The residue was dissolved in a mixture of MeOH (3 mL) and NaOH (aq. 3 mL, 1M) and the resultant mixture stirred at rt for 30 min. The solvents were evaporated and the crude mixture purified by preparative HPLC to give the title compound (54 mg, 30%). Mixture of rotamers: 1H NMR (400 MHz, CD3OD) δ −0.13-1.25, 2.01-2.48, 2.60-2.65, 2.73-3.22, 3.39-4.02, 4.21-4.45, 6.96-7.45. Total no of protons: 22. HRMS (M+H)+: calculated 307.1822. found 307.1827.
Reaction SMILES: O=[C:2]([CH3:15])[CH2:3][S:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1.Cl.[F:17][C:18]1[CH:19]=[C:20]([NH:24]N)[CH:21]=[CH:22][CH:23]=1>>[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:19]=1[C:3]([S:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1)=[C:2]([CH3:15])[NH:24]2
Reactant: CC(=O)CSc1cccc(CC(=O)O)c1
Reactant: NNc1cccc(F)c1
Agent: Cl
Product: Cc1[nH]c2cccc(F)c2c1Sc1cccc(CC(=O)O)c1

Procedure:
Prepared according to the procedure described in Example 2, Step 1, using the following starting materials: [3-(2-oxo-propylsulfanyl)-phenyl]-acetic acid and 3-fluorophenylhydrazine hydrochloride.
Reaction SMILES: C(O[NH:6][C@@H:7]([C:11]([OH:13])=O)[CH:8]=C=O)(C)(C)C.C(N(CC)CC)C.ClC(OCC)=O.[CH3:27][S:28][C:29]([CH3:36])([CH:31]([NH2:35])[CH:32]([CH3:34])[CH3:33])[CH3:30].Cl>C(OCC)(=O)C.C(O)CCC.O.C(O)(=O)C.CO.O1CCCC1>[CH3:27][S:28][C:29]([CH3:36])([CH:31]([NH:35][C:11](=[O:13])[C@@H:7]([CH3:8])[NH2:6])[CH:32]([CH3:34])[CH3:33])[CH3:30]
Reactant: CSC(C)(C)C(N)C(C)C
Reactant: CC(C)(C)ON[C@H](C=C=O)C(=O)O
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CSC(C)(C)C(NC(=O)[C@@H](C)N)C(C)C
Reaction time: 0.25 h

Procedure:
To a solution of 3.2 g. (0.017 mole) N-t-butoxy-carbonyl-D-alanine and 2.5 g. (0.017 mole) triethylamine in 100 ml. of tetrahydrofuran at -15° C. was added 1.63 ml. of ethyl chloroformate. After stirring for 15 minutes, 2.49 g. (0.017 mole) 2-methylthio-2,4-dimethyl3-aminopentane was added and the mixture stirred for one hour. The reaction mixture was diluted with ethyl acetate, washed with water, 5% aqueous citric acid (w/v), sodium bicarbonate solution and brine. The organic phase was evaporated to provide 6.0 g. of residue. This was taken up in 100 ml. methanol, 60 ml. of concentrated hydrochloric acid added and the mixture refluxed for one hour. After evaporation of methaol, the residue was taken up in water, washed with ether, the aqueous phase adjusted to pH 12 with sodium hydroxide and extracted with ethyl ether. Evaporation of the extracts gave 3.2 g. (87%) of product as a colorless oil Rf 0.56 (butanol/water/acetic acid-4:1:1 by volume).
Reaction SMILES: C([O:5][C:6](=[O:39])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:31][NH:32][C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34])(C)(C)C.N#N.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.[NH2:63][N:64]1[CH2:69][CH2:68][O:67][CH2:66][CH2:65]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:36]([O:35][C:33]([NH:32][CH2:31][C:10]1[CH:11]=[C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([NH:63][N:64]4[CH2:69][CH2:68][O:67][CH2:66][CH2:65]4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])[CH:13]=[CH:14][C:9]=1[CH2:8][CH2:7][C:6]([OH:5])=[O:39])=[O:34])([CH3:37])[CH3:38]
Reactant: NN1CCOCC1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CNC(=O)OC(C)C)c1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: Cc1oc(-c2ccc(NN3CCOCC3)cc2)nc1CCOc1ccc(CCC(=O)O)c(CNC(=O)OC(C)C)c1
Temperature: 100 °C

Procedure:
A solution of 3-[4-{2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-2-(isopropoxycarbonylamino-methyl)-phenyl]-propionic acid tert-butyl ester (120 mg, 0.200 mmol) in toluene (2.0 mL) in a sealed tube under a flow of N2 was treated Pd2(dba)3 (10 mg), 2-(di-t-butylphosphino)biphenyl (10 mg), N-aminomorpholine (29 mg, 0.28 mmol), and sodium t-butoxide (38 mg, 0.40 mmol). The tube was sealed and heated at 100° C. for 60 min. The mixture was cooled and purified using silica gel chromatography (5-10% MeOH/EtOAc) to yield the title compound directly (22 mg, 21%): MS (ESI) m/z 567.3 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[C:29]5[O:28][CH2:27][O:26][C:25]=5[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.C([O:39][C@@H:40]([CH3:44])[C:41](Cl)=[O:42])(=O)C>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]3[O:26][CH2:27][O:28][C:29]=3[C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:41](=[O:42])[C@@H:40]([OH:39])[CH3:44])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)N[C@H]1CC[C@H](NC(=O)[C@H](C)O)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f2) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [OH:1][CH:2](CO)[CH2:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8]>CO.O>[O:1]=[CH:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8]
Reactant: N#Cc1cccc(CC(O)CO)c1
Solvent: CO
Solvent: O
Product: N#Cc1cccc(CC=O)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of 3-(2,3-dihydroxypropyl)benzonitrile (2.7 g, 15.3 mmol) in MeOH/H2O (v/v=3:1, 40 mL) was added NaIO4 at 0° C. and then stirred at 0° C. for 1.5 h. The result mixture was filtered and the filtrate was concentrated to afford 3-(2-oxoethyl)benzonitrile, which was used next step without further purification.
Reaction SMILES: [C:1]1([C:7](=[CH:19][C:20]2[CH:25]=[N:24][CH:23]=[CH:22][N:21]=2)[C:8]([O:10][C@@H:11]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.[Pd]>[C:1]1([CH:7]([CH2:19][C:20]2[CH:25]=[N:24][CH:23]=[CH:22][N:21]=2)[C:8]([O:10][C@@H:11]2[CH:16]3[CH2:15][CH2:14][N:13]([CH2:18][CH2:17]3)[CH2:12]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(=Cc1cnccn1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C(O[C@H]1CN2CCC1CC2)C(Cc1cnccn1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.9 %

Procedure:
A solution of (R)-3-quinuclidinyl 2-phenyl-3-(pyrazin-2-yl)acrylate (see Preparation 4) (350 mg) in ethanol (20 ml) containing 10% palladium-on-carbon (30 mg) was stirred for 24 hours under an atmosphere of hydrogen [344.7 kPa (50 psi)] at room temperature. The mixture was filtered and evaporated to leave the title compound as an oil (320 mg, 91%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[NH:18][C:19]([C:32]3[CH:37]=[CH:36][N:35]=[C:34]([S:38][CH3:39])[N:33]=3)=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[N:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:40]OC(OC)N(C)C>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[N:18]([CH3:40])[C:19]([C:32]3[CH:37]=[CH:36][N:35]=[C:34]([S:38][CH3:39])[N:33]=3)=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=3)[N:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: CSc1nccc(-c2[nH]c(C3CCN(C(=O)OCc4ccccc4)CC3)nc2-c2cccc(C(F)(F)F)c2)n1
Solvent: Cc1ccccc1
Product: CSc1nccc(-c2c(-c3cccc(C(F)(F)F)c3)nc(C3CCN(C(=O)OCc4ccccc4)CC3)n2C)n1

Procedure:
To a stirring solution of 4-[5-(2-methylthiopyrimidin-4-yl)-4-(3-trifluoromethylphenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid benzyl ester (Example 1E) (4.0 g, 7.22 mmole) in toluene (80 mL) was added dimethylformamide dimethyl acetal (4.0 mL) and the mixture heated to reflux for 18 hours. The reaction was cooled, concentrated in vacuo to a foam and chromatographed on silica using 5% acetone/methylene chloride to give upon concentration of the product containing fractions the title compound 2.78 g.