Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[CH:6]([CH2:9][C:10]([OH:12])=[O:11])[CH2:7][O:8][C:4]=2[CH:3]=1.[NH2:15][C@@H:16]([CH3:31])[C:17]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[OH:18]>CO.C(O)(C)C>[NH2:15][C@@H:16]([CH3:31])[C:17]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[OH:18].[OH:1][C:2]1[CH:14]=[CH:13][C:5]2[C@H:6]([CH2:9][C:10]([OH:12])=[O:11])[CH2:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C(O)CC1COc2cc(O)ccc21
Agent: C[C@H](N)C(O)(c1ccccc1)c1ccccc1
Solvent: CC(C)O
Solvent: CO
Product: O=C(O)C[C@@H]1COc2cc(O)ccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A racemate (0.05 g) of (6-hydroxy-2,3-dihydro-1-benzofuran-3-yl)acetic acid was charged, a mixed solvent of methanol/isopropyl alcohol (1/4) was added, and the racemate was dissolved. (S)-2-Amino-1,1-diphenylpropan-1-ol (0.059 g, 1 eq) was added thereto, and the mixture was stirred at room temperature for 12 hr. The precipitated crystals were collected by filtration to give the title compound (0.037 g). 87.8% de
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:20][CH2:19][C:18]3[C@:13]([CH2:31][N:32]4[CH2:36][CH2:35][C@H:34]([OH:37])[CH2:33]4)([CH2:14][C:15]4[CH:23]=[N:22][N:21]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[C:16]=4[CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:38][C@@H:39]1[CH2:43][CH2:42][NH:41][CH2:40]1>>[F:30][C:27]1[CH:28]=[CH:29][C:24]([N:21]2[C:16]3[CH:17]=[C:18]4[C@:13]([CH2:31][N:32]5[CH2:36][CH2:35][C@H:34]([OH:37])[CH2:33]5)([CH2:14][C:15]=3[CH:23]=[N:22]2)[CH2:12][N:11]([S:8]([C:5]2[CH:6]=[N:7][C:2]([N:41]3[CH2:42][CH2:43][C@@H:39]([F:38])[CH2:40]3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:20][CH2:19]4)=[CH:25][CH:26]=1
Reactant: O=S(=O)(c1ccc(Cl)nc1)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(CN2CC[C@H](O)C2)C1
Reactant: F[C@@H]1CCNC1
Product: O=S(=O)(c1ccc(N2CC[C@@H](F)C2)nc1)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(CN2CC[C@H](O)C2)C1

Procedure:
The title compound was prepared by the method of Example 20 using (S)-1-[(S)-6-(6-chloropyridine-3-sulfonyl)-1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene-4a-ylmethyl]-pyrrolidin-3-ol and (R)-3-fluoropyrrolidine. LCMS (Method G): 597 (M+H)+, Retention time 3.30 minutes.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1B(O)O>>[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: COc1cccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc12
Product: COc1cccc2c(-c3ccc(F)cc3F)nc(Nc3cc(C)[nH]n3)cc12

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-5-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 2,4-difluoro-phenylboronic acid to give [1-(2,4-difluoro-phenyl)-5-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 367(MH+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:10]=[C:9]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[C-:31]#[N:32].[Na+].O>CS(C)=O>[C:31]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:10]=[C:9]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)#[N:32]
Reactant: BrCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.3 %

Procedure:
1-(6-Bromohexyl)-2,4,5-triphenylimidazole (27.6 g) in dry dimethylsulphoxide (70 ml) was added over 10 minutes to a mixture of sodium cyanide (3.68 g) in dimethyl-sulphoxide (50 ml) and the reaction was stirred at room temperature for 20 h. The reaction mixture was poured into water (300 ml) and extracted with dichloromethane (3×150 ml). The extracts were combined, washed with water, dried over anhydrous magnesium sulphate and evaporated to dryness in vacuo. Recrystallisation from diethyl ether and hexane gave 1-(6-cyanohexyl)-2,4,5-triphenylimidazole (24.19 g, 99%) as a white solid, m.p. 104°-6°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH2:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([S:25](Cl)(=[O:27])=[O:26])[CH:20]=1.CCN(CC)CC>C(Cl)Cl>[C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][S:25]([C:21]2[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=2)(=[O:27])=[O:26])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CC(C)(C)OC(=O)COc1cccc(CN)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)COc1cccc(CNS(=O)(=O)c2cccnc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.1 %

Procedure:
To a solution of (3-aminomethyl-phenoxy)-acetic acid tert-butyl ester (296 mg, 1.25 mmol) in CH2Cl2 at 0° C. was added pyridine-3-sulfonyl chloride hydrochloride (279 mg, 1.31 mmol) followed by Et3N (0.36 mL, 2.6 mmol). The reaction was stirred at room temperature for 24 h and was quenched with a 1:1 solution of water and saturated aqueous NaHCO3. The aqueous solution was washed with CH2Cl2 (3×). The combined organic solutions were dried (MgSO4), filtered, and concentrated. Medium pressure chromatography (1:1 hexanes:EtOAc) provided the title compound as a white solid (369.5 mg). 1H NMR (400 MHz, CDCl3) δ 9.04 (s, 1H), 8.75 (m, 1H), 8.09 (d, 1H), 7.44 (m, 1H), 7.15 (m, 1H), 6.76 (m, 3H), 5.23 (bs, 1H), 4.44 (s, 2H), 4.16 (d, 2H), 1.47 (s, 9H); MS 379 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].[NH2:16][C:17]1[CH:25]=[CH:24][C:20]2[NH:21][N:22]=[N:23][C:19]=2[CH:18]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[N:21]1[C:20]2[CH:24]=[CH:25][C:17]([NH:16][C:2]3[C:11]4[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=4)[N:5]=[CH:4][C:3]=3[C:14]#[N:15])=[CH:18][C:19]=2[NH:23][N:22]=1
Reactant: COc1cccc2c(Cl)c(C#N)cnc12
Reactant: Nc1ccc2[nH]nnc2c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cccc2c(Nc3ccc4nn[nH]c4c3)c(C#N)cnc12
Temperature: 100 °C

Procedure:
Using an analogous procedure to that described in Example 141, 218.6 mg (1 mmol) of 4-chloro-8-methoxy-3-quinolinecarbonitrile, 161.0 mg (1.2 mmol) of 5-aminobenzotriazole and 115.6 mg (1 mmol) of pyridine hydrochloride in 10 mL of 2-ethoxyethanol was heated at 100° C. for 1 hr. The work up gave 213.5 mg (67.6%) of the product as a yellow solid, m.p.>250 C., mass (electrospray, m/e): M+H 316.9. HRCIMS: calcd 316.107 for C17H12N6O (M+), obsd 316.1079.
Reaction SMILES: [C:1]1([C:7]2[N:16]3[C:10]([CH2:11][C:12](=[O:21])[NH:13][C:14]4[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=43)=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:25][C:26]([N:28]([CH:35]([CH3:37])[CH3:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27]>CN(C=O)C.[Cl-].[Na+].O>[CH:35]([N:28]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:26](=[O:27])[CH2:25][N:13]1[C:12](=[O:21])[CH2:11][C:10]2[N:16]([C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8][N:9]=2)[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]1=2)([CH3:37])[CH3:36]
Reactant: CC(C)N(C(=O)CBr)c1ccccc1
Reactant: O=C1Cc2nnc(-c3ccccc3)n2-c2ccccc2N1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)N(C(=O)CN1C(=O)Cc2nnc(-c3ccccc3)n2-c2ccccc21)c1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 72.4 %

Procedure:
To a solution of 1-phenyl-4H,6H-2,3,6,10b-tetraaza-benzo[e]azulen-5-one (Preparation 4(A)) (2.5 g, 9.05 mmol) in DMF (40 mL) at 0° C. was added sodium hydride (60% in oil, 0.36 g, 9.0 mmol). The reaction was warmed to room temperature and was stirred for 40 minutes. The reaction was cooled to −6° C. and a solution of 2-bromo-N-isopropyl-N-phenyl-acetamide (Preparation 1(A)) (2.55 g, 9.95 mmol) in DMF (20 mL) was added to the reaction mixture dropwise over 0.5 hour, maintaining the internal reaction temperature below −3° C. The reaction mixture was stirred for 105 minutes below −3° C. and brine (200 mL) was added. The aqueous solution was washed with ethyl acetate (200 mL). The organic layer was washed with brine, dried over sodium sulfate, and concentrated to ⅓ volume. Hexanes were slowly added until a solid crashed out. The white solid was collected by filtration and was rinsed with ether and hexanes to give 2.96 g of N-isopropyl-2-(5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-N-phenyl-acetamide. MS 452 (M+1). This intermediate was carried forward according to Example 3(B), Steps A and B above to afford 2-[4-(1H-indazol-3-ylmethyl)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-N-phenyl-acetamide as a racemic mixture.
Reaction SMILES: [NH2:1][CH:2]1[CH2:5][CH:4]([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:13]=[C:14]([C@@H:17]4[CH2:21][CH2:20][CH2:19][N:18]4[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[NH:15][CH:16]=3)=[CH:8][CH:7]=2)[CH2:3]1.[N:29]1([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:36][CH2:35][CH2:34][C@H:30]1[C:31](O)=[O:32].CC(C)N=C=NC(C)C>ClCCl>[C:25]([O:24][C:22]([N:18]1[CH2:19][CH2:20][CH2:21][C@H:17]1[C:14]1[NH:15][CH:16]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([CH:4]3[CH2:3][CH:2]([NH:1][C:31]([C@@H:30]4[CH2:34][CH2:35][CH2:36][N:29]4[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:32])[CH2:5]3)=[CH:7][CH:8]=2)[N:13]=1)=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2ccc(C3CC(N)C3)cc2)c[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NC1CC(c2ccc(-c3c[nH]c([C@@H]4CCCN4C(=O)OC(C)(C)C)n3)cc2)C1
Reaction time: 8 h
Yield: 59 %

Procedure:
To a solution of (S)-tert-butyl 2-(4-(4-(3-aminocyclobutyl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (A9) (330 mg, 0.86 mmol) in dichloromethane (60 mL), N-Boc-L-Pro-OH (204 mg, 0.95 mmol), and DIC (0.2 mL) were added at rt. After stirring overnight, the reaction mixture was diluted with methylene chloride (50 mL), and washed with saturated aqueous NaHCO3, dried with Na2SO4. After removal of the solvent, the crude product was purified by silica gel column chromatography (n-hexane/ethyl acetate=2:1) to afford the product (S)-tert-butyl 2-(3-(4-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-4-yl)phenyl)cyclobutylcarbamoyl)pyrrolidine-1-carboxylate (A10) (294 mg, 59% yield).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:25]1[CH:30]=[CH:29][CH2:28][CH2:27][CH2:26]1>C(Cl)Cl.CCOCC>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH:26]1[CH2:27][CH2:28][CH2:29][CH2:30][O:25]1
Reactant: OCCCCCBr
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: BrCCCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a solution of 5-bromopentanol (10 g) in DCM (150 mL) was added pyridinium p-toluenesulfonate (1.5 g) followed by 3,4-dihydro-2H-pyran (8.1 mL) and the reaction mixture was stirred at room temperature under nitrogen for 21 hours. The solution was diluted with ether then washed with diluted brine (1:1 brine:water, 140 mL) before the organics were dried over sodium sulfate, filtered and evaporated. Purification was by silica gel chromatography eluting with 0 to 50% ethyl acetate in cyclohexane to afford the subtitled compound as a colourless liquid. Yield 14.14 g.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:5]=1)([O-])=O.[H][H]>CCOC(C)=O.[Pd]>[NH2:1][C:4]1[O:8][C:7]([C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])o1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(N)o1
Reaction time: 2 h

Procedure:
A solution of 100 mg of methyl 5-nitro-2-furoate (Lancaster Synthesis, Windham, N.H., USA) in 20 ml of EtOAc was stirred with 20 mg of Pd/C (10%) under one atmospheric pressure of hydrogen gas. After at RT for 2 hours, the mixture was filtered through a celite pad and concentrated. Pure methyl 5-amino-2-furoate was obtained by purification on a fresh silica gel column eluted with 30% EtOAc in hexane.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:9]=[C:5]([C:6](O)=[O:7])[C:4]=1[C:16](O)=[O:17].B#B>O1CCCC1>[F:1][C:2]([F:19])([F:20])[C:3]1[C:11]([C:12]([F:14])([F:15])[F:13])=[CH:10][CH:9]=[C:5]([CH2:6][OH:7])[C:4]=1[CH2:16][OH:17]
Reactant: O=C(O)c1ccc(C(F)(F)F)c(C(F)(F)F)c1C(=O)O
Agent: B#B
Solvent: C1CCOC1
Product: OCc1ccc(C(F)(F)F)c(C(F)(F)F)c1CO

Procedure:
3,4-Bis(trifluoromethyl)phtalic acid (33 g., 0.11 mol.) in 70 ml. of tetrahydrofuran is refluxed with 450 ml. of 1.0 M diborane in tetrahydrofuran for four hours. Excess diborane is destroyed with water to yield 3,4-bis(trifluoro- methyl)-1,2-benzenedimethanol.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N:25]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[N:26]2)[CH:20]=1.CCN(C(C)C)C(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:30]([C:27]3[CH:28]=[CH:29][N:25]([C:21]4[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=4)[N:26]=3)=[O:31])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: O=C(O)c1ccn(-c2cccnc2)n1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1ccn(-c2cccnc2)n1
Yield: 90.5 %

Procedure:
The title compound was prepared from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.058 g, 0.307 mmol), 1-(pyridin-3-yl)-1H-pyrazole-3-carboxylic acid (0.080 g, 0.307 mmol), DIPEA (0.160 ml, 0.921 mmol), HOBt hydrate (0.071 g, 0.460 mmol) and EDCI (0.088 g, 0.460 mmol) using the method of Example 274 affording 0.120 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.18 (d, 3H), 4.38 (m, 2H), 4.50 (m, 1H), 6.89 (d, 1H), 6.95 (d, 1H), 7.59 (m, 1H), 7.90 (m, 3H), 8.04 (d, 1H), 8.30 (m, 1H), 8.38 (d, 1H), 8.60 (d, 1H), 8.65 (d, 1H), 9.19 (d, 1H).
Reaction SMILES: O[C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1ccc(C(=O)O)c(O)n1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1ccc(C(=O)O)c(Cl)n1
Yield: 72 %

Procedure:
2-Hydroxy-6-methyl-nicotinic acid (3.6 g, 0.02 m) was heated at 125° for 2 hours with phosphorus oxychloride (10 ml). The reaction mixture was poured onto ice, the solid was collected and crystallised from aqueous ethanol to give colourless fine needles of 2-chloro-6-methylnicotinic acid (72%).
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:13](=[O:20])[CH2:14][CH:15]([OH:19])[C:16]=1OC)([O:3][CH2:4][CH3:5])=[O:2].C([Al](CC)CC)C.[CH:28]#[N:29].C1C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:13](=[O:20])[CH2:14][CH:15]([OH:19])[C:16]=1[C:28]#[N:29])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: C#N
Reactant: CCOC(=O)CCCCCCC1=C(OC)C(O)CC1=O
Agent: CC[Al](CC)CC
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: CCOC(=O)CCCCCCC1=C(C#N)C(O)CC1=O
Yield: 44.4 %

Procedure:
The procedure similar to that of Step 3 (a) of Example 1 was repeated using 9.4 g of 2-(6'-carbethoxyhexyl)-3-methoxy-4-hydroxy- 2-cyclopenten-1-one, 8.2 g of triethyl aluminum, 2.0 g of hydrocyanic acid, and a mixed solvent of benzene and toluene to provide 4.1 g of oily 2-(6'-carbethoxyhexyl)-3-cyano-4-hydroxy-2-cyclopenten-1-one.
Reaction SMILES: C([O:8][N:9]1[CH:12]([CH2:13][O:14]CC2C=CC=CC=2)[CH:11]([N:22]2[CH:37]=[CH:36][C:26]([NH:27][C:28](=[O:35])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:25][C:23]2=[O:24])[C:10]1=[O:38])C1C=CC=CC=1.[H][H]>CO.[Ni]>[OH:8][N:9]1[CH:12]([CH2:13][OH:14])[CH:11]([N:22]2[CH:37]=[CH:36][C:26]([NH:27][C:28](=[O:35])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:25][C:23]2=[O:24])[C:10]1=[O:38]
Reactant: O=C(Nc1ccn(C2C(=O)N(OCc3ccccc3)C2COCc2ccccc2)c(=O)n1)c1ccccc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: O=C(Nc1ccn(C2C(=O)N(O)C2CO)c(=O)n1)c1ccccc1

Procedure:
1-N-Benzyloxy-3-(N-benzoylcytosin-1-yl)-4-benzyloxymethyl-2-azetidinone (10mmole) is taken up in methanol (50 ml) and hydrogenated using Raney nickel (5 g) and hydrogen at a pressure of 40 psi for 6 hours. The reaction mixture is filtered, the catalyst washed with methanol (20 ml) and the combined fractions are concentrated to afford the product as a solid.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([OH:3])=[O:2].[N:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1>C(OC(=O)C)(=O)C>[N:12]1[CH:17]=[CH:16][C:15](/[CH:18]=[CH:8]/[C:7]2[CH:10]=[CH:11][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=2)=[CH:14][CH:13]=1
Reactant: Cc1ccncc1
Reactant: O=Cc1ccc(C(=O)O)cc1
Solvent: CC(=O)OC(C)=O
Product: O=C(O)c1ccc(/C=C/c2ccncc2)cc1

Procedure:
4-Carboxybenzaldehyde (2.03 g, 13.3 mmol, Aldrich) and 4-picoline (1.24 g, 13.3 mmol, Aldrich) were placed in a round-bottomed flask, to which a 20 mL of acetic anhydride was added. The reaction mixture was heated to reflux for 24 h. The solid was filtered and the solid was washed with acetic acid then with water before being dried in vacuo, at 50° C. overnight to give the title compound as an off white solid (426 mg, 14%).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH3:17])[C:9]([N:11]1[CH2:14][CH:13]([C:15]#[N:16])[CH2:12]1)=[O:10])(C)(C)C.[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22]>C(Cl)Cl>[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22].[NH2:7][C@H:8]([CH3:17])[C:9]([N:11]1[CH2:12][CH:13]([C:15]#[N:16])[CH2:14]1)=[O:10]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CC(C#N)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](N)C(=O)N1CC(C#N)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [(R)-2-(3-cyanoazetidin-1-yl)-1-methyl-2-oxo-ethyl]-carbamic acid tert-butyl ester (860 mg, 3.4 mmol) in CH2Cl2 (20 mL) was added trifluoroacetic acid (4.0 mL). The reaction mixture was stirred at room temperature for 2 h then concentrated to afford 1-((R)-2-amino-propionyl)-azetidine-3-carbonitrile trifluoroacetate as a pale yellow oil which was used without further purification.
Reaction SMILES: S(=O)(O)[O-].[O:5]([C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C-:20]#[N:21].[Na+].C(OC(C)C)(C)C>C(O)(=O)C.O.CN(C)C=O>[C:20]([CH:15]([OH:16])[C:14]1[CH:17]=[CH:18][CH:19]=[C:12]([O:5][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:13]=1)#[N:21]
Reactant: [C-]#N
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: N#CC(O)c1cccc(Oc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
20 g of anhydrous combination bisulfite of m-phenoxy-benzaldehyde were added under an inert atmosphere to 80 ml of anhydrous dimethylformamide and then 3.3 g of anhydrous sodium cyanide were added thereto at 0° C. under an inert atmosphere. The mixture was stirred at 0° C. for 45 minutes after which a sample of the reaction mixture was taken to verify by chromatography analysis that the conversion was complete. The reaction mixture was poured into a mixture of ice, water, acetic acid and isopropyl ether and the mixture was stirred and decanted. The aqueous phase was extracted with isopropyl ether and the combined organic phases were washed with water, dried and evaporated to dryness to obtain 13.8 g of α-cyano-3-phenoxy-benzyl alcohol.
Reaction SMILES: O.[OH-].[Li+].O.C([O:7][C:8]([C:10]1[CH:11]=[N:12][N:13]([C:15]2[NH:24][C:23](=[O:25])[C:22]3[C:17](=[CH:18][C:19]4[CH2:29][CH2:28][CH2:27][CH2:26][C:20]=4[CH:21]=3)[N:16]=2)[CH:14]=1)=[O:9])C>C1COCC1>[O:25]=[C:23]1[C:22]2[C:17](=[CH:18][C:19]3[CH2:29][CH2:28][CH2:27][CH2:26][C:20]=3[CH:21]=2)[N:16]=[C:15]([N:13]2[CH:14]=[C:10]([C:8]([OH:9])=[O:7])[CH:11]=[N:12]2)[NH:24]1
Reactant: CCOC(=O)c1cnn(-c2nc3cc4c(cc3c(=O)[nH]2)CCCC4)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnn(-c2nc3cc4c(cc3c(=O)[nH]2)CCCC4)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.3 %

Procedure:
Lithium hydroxide monohydrate (25.5 mg, 0.608 mmol) and water (0.45 mL) were added to 1-(4-oxo-3,4,6,7,8,9-hexahydro-benzo[g]quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (87.5 mg, 0.259 mmol) in THF (0.55 mL). The reaction mixture was stirred at room temperature for 18 h and was then concentrated. The residue was redissolved in water (5 mL) and this solution was brought to pH 1 with 1M aqueous HCl. The resulting precipitate was collected and dried to yield the titled compound (76.6 mg, 95% yield). MS (ESI/Cl): mass calcd. for C16H14N4O3, 310.1; m/z found, 311.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 13.00 (s, 1H), 12.61 (s, 1H), 8.91 (s, 1H), 8.24 (s, 1H), 7.83 (s, 1H), 7.40 (s, 1H), 2.89 (br d, J=4.7 Hz, 4H), 1.84-1.72 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([OH:19])=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:23])[C:6]=2[CH:24]=1.[CH2:25](O)[CH2:26][CH2:27][CH2:28][CH3:29]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([O:19][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:23])[C:6]=2[CH:24]=1
Reactant: Cc1c(S(=O)(=O)Nc2cccc(C(=O)O)c2)sc2ccc(Cl)cc12
Reactant: CCCCCO
Product: CCCCCOC(=O)c1cccc(NS(=O)(=O)c2sc3ccc(Cl)cc3c2C)c1
Yield: 76 %

Procedure:
The product was prepared from 3-{[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]amino}benzoic acid (21 mg, 0.055 mmol) (Intermediate 19) and 1-pentanol (8.8 mg, 0.100 mmol) according to the General Procedure 7, described in Example 107. The title compound was obtained in 76% yield (18.8 mg). 1H NMR (500 MHz, CDCl3) δ ppm 0.89-0.95 (m, 3 H) 1.32-1.42 (m, 4 H) 1.67-1.75 (m, 2 H) 2.45 (s, 3 H) 4.26 (t, J=6.77 Hz, 2 H) 6.87 (s, 1 H) 7.36 (dd, J=8.10, 7.63 Hz, 1 H) 7.42 (ddd, J=8.10, 2.36, 1.25 Hz, 1 H) 7.44 (dd, J=8.70, 1.95 Hz, 1 H) 7.69-7.73 (m, 3 H) 7.84 (ddd, J=7.63, 1.50, 1.25 Hz, 1 H). MS (ESI+) m/z 452 [M+H]+.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Li]CCCC.[CH2:34]([C:36]1[CH:41]=[CH:40][C:39]([CH2:42][C:43]([CH3:47])([CH3:46])[CH:44]=O)=[CH:38][CH:37]=1)[CH3:35]>>[CH3:44][C:43]([CH3:46])([CH:47]=[CH:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:42][C:39]1[CH:38]=[CH:37][C:36]([CH2:34][CH3:35])=[CH:41][CH:40]=1
Reactant: c1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCc1ccc(CC(C)(C)C=O)cc1
Agent: [Br-]
Agent: [Li]CCCC
Product: CCc1ccc(CC(C)(C)C=CCc2ccccc2)cc1
Yield: 51.2 %

Procedure:
Starting from phenethyltriphenylphosphonium bromide (2.23 g, 4.98 mmol, 1.0 equiv.), n-BuLi (1.6 M in hexanes, 3.1 mL, 4.98 mmol, 1.0 equiv.) and 3-(4-ethylphenyl)-2,2-dimethylpropanal (1.42 g, 7.48 mmol, 1.5 equiv.), 0.71 g (51%) of the title compound as a colorless oil was obtained after purification by flash chromatography on SiO2 (cyclohexane/EtOAc 997:3).