Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][OH:11])([CH3:4])([CH3:3])[CH3:2].[C:13]([O:28][C@H:29]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:30][C:31](O)=[O:32])(=[O:27])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C(Cl)CCl>[C:1]([O:5][C:6](=[O:12])[CH2:7][N:8]([CH2:9][CH2:10][OH:11])[C:31](=[O:32])[CH2:30][C@H:29]([O:28][C:13](=[O:27])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CNCCO
Reactant: CCCCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)O
Solvent: ClCCCl
Product: CCCCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)N(CCO)CC(=O)OC(C)(C)C
Yield: 52.6 %

Procedure:
In the same manner as described in Example 2-(5), N-(2-hydroxyethyl)glycine t-butyl ester (0.25 g, 1.43 mmol) was acylated with (R)-3-tetradecanoyloxytetradecanoic acid (0.714 g, 1.57 mmol) in the presence of EDC-Mel (0.466 g, 1.57 mmol) to give 0.46 g (51%) of N-(2-hydroxyethyl)-N-[(R)-3-tetradecanoyloxytetradecanoyl]glycine t-butyl ester as an amorphous solid: 1H NMR (CDCl3) δ 0.88 (t, 6 H, J=˜6.5 Hz), 1.15–1.7 (m, 51 H), 2.26 (t, 2 H, J=7.5 Hz), 2.60 (dd, 1 H, J=6.5, 15 Hz), 2.86 (dd, 1 H, J=6.7, 15 Hz), 3.40–4.15 (m, 7 H), 5.25 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[CH:4][CH:3]=1.[CH3:27][O:28][C:29](=[O:34])[CH2:30][CH2:31]CBr.C(=O)([O-])[O-].[K+].[K+]>>[CH3:27][O:28][C:29](=[O:34])[CH2:30][CH2:31][CH2:18][N:16]1[CH:17]=[C:12]([C:10](=[O:11])[CH2:9][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH:13]=[CH:14][C:15]1=[O:19]
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1
Reactant: COC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)CCCn1cc(C(=O)CC(c2ccc(Br)cc2)c2ccccc2C)ccc1=O

Procedure:
In analogy to example 161, step 1, 5-[3-(4-bromo-phenyl)-3-o-tolyl-propionyl]-1-methyl-1H-pyridin-2-one (example 162, step 3) was reacted with methyl-4-bromobutyrate in the presence of potassium carbonate to give the title compound as a colorless foam, MS (ESI+): m/z=496.2 [M+H]+.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[Cl:6][C@H:7]([CH3:11])[C:8](Cl)=[O:9]>C(Cl)(Cl)Cl>[CH2:1]([N:3]([CH2:4][CH3:5])[C:8](=[O:9])[C@H:7]([Cl:6])[CH3:11])[CH3:2]
Reactant: CCNCC
Reactant: C[C@@H](Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Product: CCN(CC)C(=O)[C@@H](C)Cl
Yield: 38 %

Procedure:
Diethylamine (153 g) is added to a solution, maintained at 20° C., of (R)-2-chloropropionyl chloride (87.7 g) in chloroform (600 cc), in the course of 1 hour. The reaction mixture is washed with distilled water (500 cc), with an aqueous 1N hydrochloric acid solution (3×500 cc) and then with distilled water (500 cc). The organic phase is dried over sodium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the vicinity of 30° C. The residue obtained is distilled under reduced pressure (17 Pa). (R)-N,N-Diethyl-2-chloropropionamide (43 g) in the form of a colourless oil [b.p.17Pa =75°-80° C.; [α]D20 =-43.3° (c=10; CHCl3)] is thereby obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[CH3:37][O:38][C:39](=[O:51])[C:40]1[CH:45]=[CH:44][C:43]([C:46]#[C:47]/[CH:48]=[CH:49]/Cl)=[CH:42][CH:41]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C.C(O)C.C1(C)C=CC=CC=1>[CH3:37][O:38][C:39](=[O:51])[C:40]1[CH:45]=[CH:44][C:43]([C:46]#[C:47]/[CH:48]=[CH:49]/[C:6]2[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=2)=[CH:42][CH:41]=1
Reactant: COC(=O)c1ccc(C#C/C=C/Cl)cc1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C#C/C=C/c2ccc(C=O)cc2)cc1
Temperature: 25 °C
Yield: 64.1 %

Procedure:
4-Formylphenylboronic acid (0.49 g), PdCl2(PPh3)2 (0.11 g), triphenylphosphine (78 mg) and potassium carbonate (0.82 g) were added to a toluene (3.5 mL)-ethanol (1.8 mL) solution of 4-((E)-4-chlorobut-3-en-1-yn-1-yl)benzoic acid methyl ester (0.70 g) as obtained by the method described in the patent (WO2008/154642), and the mixture was heated and refluxed for 3 hours in a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, ethyl acetate was added, the insolubles were filtered out, and the filtrate was concentrated under reduced pressure. IPE and IPA were added to the resulting residue, and the solids were filtered out, whereafter chloroform and OH type silica gel (10 g) were added. The insolubles were filtered out, and the filtrate was concentrated under reduced pressure to obtain 4-[(E)-4-(4-formylphenyl)but-3-en-1-yn-1-yl)benzoic acid methyl ester (orange solid) (0.59 g, 69%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([NH:13][CH3:14])=[N:11][N:12]=2)=[CH:4][CH:3]=1.[CH:15]1([NH:18][C:19](=[O:36])[C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[C:22](B3OC(C)(C)C(C)(C)O3)[CH:21]=2)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH:15]1([NH:18][C:19]([C:20]2[CH:25]=[C:24]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:9][C:10]([NH:13][CH3:14])=[N:11][N:12]=4)=[CH:4][CH:3]=3)[C:23]([CH3:26])=[CH:22][CH:21]=2)=[O:36])[CH2:16][CH2:17]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CNc1nnc(-c2ccc(I)cc2)o1
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
Product: CNc1nnc(-c2ccc(-c3cc(C(=O)NC4CC4)ccc3C)cc2)o1
Temperature: 80 °C

Procedure:
2-(4-Iodophenyl)-5-(methylamino)-1,3,4-oxadiazole (Intermediate 36) (30 mg), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (33 mg), tetrakis(triphenylphosphine)palladium (13 mg) and aqueous sodium carbonate (1M, 0.11 ml) in DME (3 ml) were mixed and heated at 80° C. for 18 hours. The reaction was purified by HPLC to give N-cyclopropyl-6-methyl-4′-[5-(methylamino)-1,3,4-oxadiazol-2-yl]-1,1′-biphenyl-3-carboxamide.
Reaction SMILES: [N+:1]([C:4]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][N:5]=1)([O-])=O.Cl[CH2:13][P:14](=[O:21])([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17].C(O[Na])(C)(C)C.Cl>CS(C)=O>[NH2:1][C:4]1[N:5]=[CH:6][C:7]([CH2:13][P:14](=[O:21])([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17])=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1cccnc1[N+](=O)[O-]
Reactant: CCOP(=O)(CCl)OCC
Agent: CC(C)(C)O[Na]
Agent: Cl
Solvent: CS(C)=O
Product: CCOP(=O)(Cc1cnc(N)c(OC)c1)OCC
Reaction time: 0.5 h
Yield: 19.2 %

Procedure:
A solution of 2-nitro-3-methoxypyridine (300 mg, 1.95 mmol) and diethyl chloromethylphosphonate (363 mg, 1.95 mmol) in DMSO (4 mL) was added dropwise to vigorously stirred solution of t-BuONa (0.561 g, 5.84 mmol) in DMSO (4 mL) at room temperature. The reaction mixture turned to deep orange immediately. Stirring was continued for 30 min, then the mixture was poured into 1 M HCl (aq) (10 mL). The product was extracted into ether (3×30 mL), dried over MgSO4, concentrated, and purified by silica gel chromatography (3% MeOH in DCM) to afford 102.6 mg of diethyl [(6-amino-5-methoxypyridin-3-yl)methyl]phosphonate (yield: 17%). 1H NMR (CD3OD, 400 MHz): δ=1.30 (t, J=6.8 Hz, 6 H), 3.45 (d, J=22.4 Hz, 2 H), 4.00 (s, 3 H), 4.09-4.17 (m, 4 H), 7.79 (t, J=2.4 Hz, 1 H), 7.97 (t, J=2.4 Hz, 1 H). MS (ES+): m/z 305.07 [MH+]. HPLC: tR=1.17 min (UPLC TOF, polar—3 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1.[F:48][C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([OH:55])[C:50]=1[CH2:56][CH2:57][NH:58][C:59](=[O:61])[CH3:60]>>[C:59]([NH:58][CH2:57][CH2:56][C:50]1[C:49]([F:48])=[CH:54][CH:53]=[CH:52][C:51]=1[O:55][CH2:32][CH2:31][O:30][CH:18]1[CH:17]([C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:4]3[CH:44]=[CH:45][CH:46]=[CH:47][C:3]=3[O:2][CH3:1])=[CH:16][CH:15]=2)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:19]1)(=[O:61])[CH3:60]
Reactant: CC(=O)NCCc1c(O)cccc1F
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2cccc(F)c2CCNC(C)=O)cc1

Procedure:
Analogously to Method G, 0.45 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-[2-(toluene-4-sulphonyloxy)ethoxy]piperidine-1-carboxylate (Example 14b) and 0.27 g of N-[2-(2-fluoro-6-hydroxyphenyl)ethyl]acetamide are reacted. The title compound is obtained as a yellow oil. Rf=0.58 (EtOAc); Rt=5.57.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([CH3:35])=[C:7]([NH:9][C:10](=[O:34])[C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[N:27]=[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:13][CH:12]=2)[CH:8]=1)=O.[CH:36]1([NH2:39])[CH2:38][CH2:37]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(O)(=O)C.ClCCl>[CH:36]1([NH:39][CH2:1][C:3]2[CH:4]=[CH:5][C:6]([CH3:35])=[C:7]([NH:9][C:10](=[O:34])[C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]4[N:27]=[C:26]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:12]=3)[CH:8]=2)[CH2:38][CH2:37]1
Reactant: Cc1ccc(C=O)cc1NC(=O)c1ccc(Nc2nc(-c3ccccc3)c3ccccc3n2)cc1
Reactant: NC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccc(CNC2CC2)cc1NC(=O)c1ccc(Nc2nc(-c3ccccc3)c3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.4 %

Procedure:
A mixture of N-(5-formyl-2-methylphenyl)-4-(4-phenylquinazolin-2-ylamino)benzamide (250 mg, 0.546 mmol), cyclopropylamine (238 μL, 3.44 mmol), dichloromethane (10 m:), tetrahydrofuran (2 drops) and acetic acid (2 drops) was stirred at rt for 1 h. Sodium triacetoxyborohydride (275 mg, 1.30 mmol) was added and the mixture was stirred overnight. The crude reaction was diluted with dichloromethane, washed with saturated sodium bicarbonate and saturated sodium chloride and dried over sodium sulfate. The solution was concentrated on a rotary evaporator and purified by HPLC to give a yellow solid (143 mg, 52%). 1H NMR (400 MHz, DMSO-d6): δ10.32 (s, 1H), 9.69 (s, 1H), 8.17-8.16 (d, 2H), 8.00-7.98 (s, 2H), 7.90-7.86 (m, 3H), 7.85-7.79 (m, 2H), 7.65-7.64 (m, 3H), 7.44-7.40 (t, 1H), 7.31 (s, 1H), 7.20-7.18 (d, 1H), 7.12-7.10 (d, 1H), 3.70 (s, 2H), 2.22 (s, 3H), 2.05 (m, 1H), 0.35-0.32 (m, 2H), 0.27-0.25 (m, 2H). MS (EI) for C32H29N5O: 500.2 (MH+).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[C:7]([O:11][C:12](=[O:38])[NH:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([CH:20]([OH:37])[CH:21]([OH:36])[CH2:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[CH:31]=3)[N:26]=[CH:25][C:24]=2Cl)[CH2:16][CH2:15]1)([CH3:10])([CH3:9])[CH3:8].C(P(C(C)(C)C)C1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1)(C)(C)C>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:7]([O:11][C:12](=[O:38])[NH:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([CH:20]([OH:37])[CH:21]2[O:36][C:24]3[CH:25]=[N:26][C:27]4[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][C:32]=4[C:23]=3[CH2:22]2)[CH2:16][CH2:15]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: COc1ccc2ncc(Cl)c(CC(O)C(O)[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccc2ccccc2c1-c1cccc2ccccc12)C(C)(C)C
Solvent: C1COCCO1
Product: COc1ccc2ncc3c(c2c1)CC(C(O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1)O3
Temperature: 100 °C
Reaction time: 3 h

Procedure:
Cesium carbonate (3.1 g, 9.46 mmol, 2.0 eq) is added at room temperature to a stirred solution of {trans-4-[3-(3-chloro-6-methoxy-quinolin-4-yl)-1,2-dihydroxy-propyl]-cyclohexyl}-carbamic acid tert-butyl ester (2.2 g, 4.73 mmol, 1.0 eq) in dioxane (70 mL), followed by palladium(II) acetate (159 mg, 0.71 mmol, 0.15 eq) and racemic-2-di-tert-butylphosphino-1,1′-binaphthyl (283 mg, 0.71 mmol, 0.15 eq). After 3 hours stirring at 100° C., solvent is removed and the residue is extracted with dichloromethane (3×100 mL) and water (100 mL). The combined organic layers are washed with brine, dried over sodium sulfate, filtered and concentrated to afford {trans-4-[hydroxy-(8-methoxy-1,2-dihydro-furo[2,3-c]quinolin-2-yl)-methyl]-cyclohexyl}-carbamic acid tert-butyl ester as a light grey solid (1.35 g, 67% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]([CH3:10])[C:8](=[O:11])[N:7]([CH3:12])[C:6](=[O:13])[C:5]=1[CH:14]=O)[CH3:2].Cl.[CH3:17][O:18][NH2:19]>>[CH3:17][O:18][N:19]=[CH:14][C:5]1[C:6](=[O:13])[N:7]([CH3:12])[C:8](=[O:11])[N:9]([CH3:10])[C:4]=1[O:3][CH2:1][CH3:2]
Reactant: CON
Reactant: CCOc1c(C=O)c(=O)n(C)c(=O)n1C
Agent: Cl
Product: CCOc1c(C=NOC)c(=O)n(C)c(=O)n1C

Procedure:
The process described in Method A was followed. 6-Ethoxy-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde (Example 16, Step 1) (0.168 g, 0.79 mmol) and methoxyamine hydrochloride (0.087 g, 1.04 mmol) were used to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[OH-].[Na+].C(O)=O>O1CCCC1.CCOCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([OH:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccc(F)cc2)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(O)CCC(O)c1ccc(-c2ccc(F)cc2)cc1
Temperature: -20 °C

Procedure:
To a solution of 2.75 gm (0.01 mol) of 4-(4'-fluoro-4-biphenylyl)-4-oxo-butyric acid in 50 ml of absolute tetrahydrofuran 0.20 gm (0.005 mol) of lithiumaluminumhydride in 50 ml of absolute tetrahydrofuran was added dropwide, while stirring and cooling at -20° C. After stirring for 4 hours at -20° C., the reaction mixture was poured into ice water and acidified with aqueous 50% sulfuric acid. Subsequently, the mixture was made alkaline by adding aqueous 20% sodium hydroxide, and was again acidified with formic acid. The precipitated semi-solid product was dissolved in ether, and after evaporating the ether, the crystalline residue was dissolved in acetone. From this solution the cyclohexylamine salt of 4-(4'-fluoro-4-biphenylyl)-4-hydroxy-butyric acid was precipitated by addition of cyclohexylamine, and the salt was recrystallized from ethyl acetate/absolute ethanol. Melting point 176°-178° C. (decomp.); yield: 2.2 gm.
Reaction SMILES: C(Cl)Cl.Cl[C:5]1[C:10]([C:11]#[N:12])=[CH:9][C:8]([C:13]2[CH:14]=[CH:15][C:16]3[N:17]([CH:19]=[CH:20][N:21]=3)[CH:18]=2)=[C:7]([CH3:22])[N:6]=1.[CH3:23][OH:24]>>[N:21]1[CH:20]=[CH:19][N:17]2[CH:18]=[C:13]([C:8]3[CH:9]=[C:10]([C:11]#[N:12])[C:5]([O:24][CH3:23])=[N:6][C:7]=3[CH3:22])[CH:14]=[CH:15][C:16]=12
Reactant: CO
Reactant: Cc1nc(Cl)c(C#N)cc1-c1ccc2nccn2c1
Solvent: ClCCl
Product: COc1nc(C)c(-c2ccc3nccn3c2)cc1C#N

Procedure:
In a solvent mixture of 30 ml of methylene chloride and 30 ml of methanol, 0.59 g of 2-chloro-5-(imidazo[1,2-a]pyridin-6-yl)-6-methyl-3-pyridinecarbonitrile described above was stirred under reflux for 3 hours. After cooling, the solvent was removed by distillation and chloroform-water was added to the residue. The chloroform was taken by fractionation. After washing with water and drying over magnesium sulfate, chloroform was removed by distillation under reduced pressure. The residue was recrystallized from benzene-n-hexane to obtain 0.75 g of 5-(imidazo[1,2-a]pyridin-6-yl)-2-methoxy-6-methyl-3-pyridinecarbonitrile.
Reaction SMILES: [CH2:1]1[S:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[Li]CCCC.CCCCCC.[Cl:18][C:19]1[N:24]=[CH:23][C:22]([CH2:25]Cl)=[CH:21][CH:20]=1.FC(F)(F)C(O)=O>C1COCC1.O>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][CH:1]2[CH2:2][CH2:3][CH2:4][S:5]2=[O:6])=[CH:23][N:24]=1
Reactant: O=S1CCCC1
Reactant: ClCc1ccc(Cl)nc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: O=S1CCCC1Cc1ccc(Cl)nc1
Temperature: -70 °C
Yield: 35 %

Procedure:
Tetramethylene sulfoxide (6.5 g, 62 mmol) was dissolved in 30 mL anhydrous THF, stirred and cooled to −70° C. and then treated with 2.5 M n-BuLi in hexane (24 mL, 61 mmol) over a period of 10 min. The temperature was raised to −20 to −30° C. (Liquid N2/o-xylene bath) and the mixture was stirred for a further 30 min The mixture was cooled to −70° C. and treated dropwise with a solution of 6-chloro-3-chloromethylpyridine in 15 mL THF. The reaction was stirred for 2 h at −70° C. and then treated dropwise with trifluoroacetic acid (8.0 g, 70 mmol). The mixture was warmed to room temperature, poured into 75 mL water and extracted with dichloromethane (2×50 mL). The combined organic extracts were washed with dilute sodium bicarbonate and saturated NaCl, dried over Na2SO4 and concentrated. The residue was chromatographed on silica gel with 5% methanol in dichloromethane to give 2.5 g of the desired sulfoxide as a brown oil in 35% yield.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[C:16]([N:19]([CH2:21][C:22](O)=[O:23])[CH3:20])(=[O:18])[CH3:17].[CH2:25]([O:27][C:28](=[O:38])[CH2:29][NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:26]>CN(C)C=O.C(Cl)(Cl)Cl>[CH2:25]([O:27][C:28](=[O:38])[CH2:29][N:30]([C:22](=[O:23])[CH2:21][N:19]([C:16](=[O:18])[CH3:17])[CH3:20])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:26]
Reactant: CCOC(=O)CNCc1ccccc1
Reactant: CC(=O)N(C)CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1ccccc1)C(=O)CN(C)C(C)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A cold solution of 1.65 g DCC in 3 ml dimethylformamide is added to a stirred ice-cooled solution of 1.0 g N-acetylsarcosine and 1.4 g N-benzylglycine ethylester in 9 ml dry dimethylformamide, and the resulting solution is stirred at 0° C. for 1 hour and then at room temperature for 2 hours. It is then filtered and the precipitate is washed with dimethylformamide. The filtrate and washings are combined and the solvent is evaporated to dryness in vacuo to yield a residue which is then dissolved in 30 ml chloroform, washed with 5% aq. NaHCO3 and water, and dried over anhydrous MgSO4. Evaporation of solvent produces the desired ester which is either isolated (m.p. 98°-101° C.) or hydrolyzed directly to form the corresponding acid, N-(N'-acetylsarcosyl)-N-benzylglycine.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:33]=[CH:32][C:9]2[CH2:10][C@@H:11]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[C:12](=[O:26])[N:13]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:14][C:8]=2[CH:7]=1.Br[C:35]1[N:40]=[CH:39][CH:38]=[CH:37][N:36]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[O:26]=[C:12]1[C@H:11]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:10][C:9]2[CH:32]=[CH:33][C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:1][C:35]3[N:40]=[CH:39][CH:38]=[CH:37][N:36]=3)=[CH:7][C:8]=2[CH2:14][N:13]1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1
Reactant: Brc1ncccn1
Reactant: COC(=O)C[C@@H]1Cc2ccc(OCCCN)cc2CN(Cc2ccc(C(F)(F)F)cc2)C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C[C@@H]1Cc2ccc(OCCCNc3ncccn3)cc2CN(Cc2ccc(C(F)(F)F)cc2)C1=O
Temperature: 25 °C
Yield: 40.7 %

Procedure:
A solution of methyl (S)-8-(3-amino-1-propyloxy)-3-oxo-2-[4-(trifluoromethyl)benzyl]-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate (0.09 g, 0.19 mmol), 2-bromopyrimidine (0.09 g, 0.57 mmol) and diisopropylethylamine (0.17 mL, 0.98 mmol) in DMF (2 mL) was heated at 80° C. for 18 h. The reaction was allowed to cool to RT and was concentrated to give a yellow residue. Flash chromatography on silica gel (2% MeOH/EtOAc) gave the title compound (42 mg) as a clear oil. MS (ES) m/e 543.1 (M+H)+.
Reaction SMILES: CN(C)C=O.Br[C:7]1[CH:8]=[N:9][C:10]([CH3:13])=[N:11][CH:12]=1.C([Sn](CCCC)(CCCC)[C:19]([O:21][CH2:22][CH3:23])=[CH2:20])CCC.[F-].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)C>[CH2:22]([O:21][C:19]([C:7]1[CH:8]=[N:9][C:10]([CH3:13])=[N:11][CH:12]=1)=[CH2:20])[CH3:23]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1ncc(Br)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=C(OCC)c1cnc(C)nc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 101.1 %

Procedure:
To a N,N-dimethylformamide (10 mL) solution of 5-bromo-2-methylpyrimidine (0.50 g), tributyl(1-ethoxyethenyl)stannane (1.5 g) and bis(triphenylphosphine)palladium(II) dichloride (0.14 g) were added, and the resultant was stirred at 100° C. for 1 hour. After standing to cool to room temperature, an aqueous potassium fluoride solution (20 mL) and diethyl ether (20 mL) were added to the reaction solution, and the resultant was stirred. Insoluble material was filtered off through Celite, and the filtrate was subjected to extraction with diethyl ether. The organic layer was dried over magnesium sulfate, and the desiccant was filtered off. Then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (OH-type silica gel; hexane/ethyl acetate-gradient elution=90/10→75/25) to obtain the title compound (0.48 g) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]3[C:7](=[CH:18][NH:19][CH:20]=3)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1.CC(C)([O-])C.[K+].Br[CH2:30][C:31]([O:33][CH3:34])=[O:32]>CN(C)C=O.O>[CH3:34][O:33][C:31](=[O:32])[CH2:30][N:19]1[CH:20]=[C:6]2[C:7]([CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]3[CH:3]=[C:2]([Cl:1])[CH:22]=[CH:21][C:5]=32)=[CH:18]1
Reactant: COC(=O)CBr
Reactant: Fc1ccccc1C1=NCc2c[nH]cc2-c2ccc(Cl)cc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cn1cc2c(c1)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Reaction time: 0.25 h

Procedure:
In one portion 2.0 g (6.4 mmol) of 8-chloro-6-(2-fluorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine was added to a solution of 0.9 g (8 mmol) of potassium t-butoxide in 30 ml of dimethylformamide which was cooled to 0°. After stirring for 15 min, 0.7 ml (7.5 mmol) of methyl bromoacetate was added. The mixture was stirred for 5 min, diluted with water and extracted with ether. The ether solution was washed with water, dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. Purification of the residue by column chromatography gave a pale yellow oil.