Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][NH:10][C:11]([C:13]1[N:14]=[CH:15][N:16]2[C:21](=[O:22])[N:20]([CH2:23][C:24]#[CH:25])[N:19]=[N:18][C:17]=12)=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[C:2]1([C:1]2[O:12][C:11]([C:13]3[N:14]=[CH:15][N:16]4[C:21](=[O:22])[N:20]([CH2:23][C:24]#[CH:25])[N:19]=[N:18][C:17]=34)=[N:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CCn1nnc2c(C(=O)NNC(=O)c3ccccc3)ncn2c1=O
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: C#CCn1nnc2c(-c3nnc(-c4ccccc4)o3)ncn2c1=O

Procedure:
N′-Benzoyl-4-oxo-3-(prop-2-ynyl)-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbohydrazide (0.15 mmol) and Burgess reagent (0.30 mmol) were heated under microwave irradiation in THF (1 mL) at 60° C. for 2 minutes (Max Power 100 W). The precipitate was filtered and washed with DCM to give the title compound. δH (DMSO-d6) 9.10 (1H, s), 8.13 (2H, m), 7.70 (3H, m), 5.20 (2H, d, J=2.8), 3.57 (1H, t, J=2.8).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.[Cl-].[Cl-].[Cl-].[Al+3].[Br:17]Br.CO>O>[Br:17][C:8]1[C:7]([Cl:12])=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2]([Cl:1])=[N:3]2
Reactant: BrBr
Reactant: Clc1ccc2nc(Cl)ccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: Clc1ccc2c(Br)c(Cl)ccc2n1
Temperature: 25 °C

Procedure:
2,6-Dichloroquinoline (30 g) and aluminium trichloride (60 g) were heated to 120° C. with stirring under a nitrogen atmosphere. Bromine (9.2 mL) was added dropwise over 1 hour and the mixture was then stirred at 120° C. for 1 hour before being cooled to room temperature. A methanol/deionised water mixture (150 mL, 1:1) was then slowly added and the mixture was concentrated in vacuo. Dichloromethane (500 mL) and deionised water (250 mL) were added, the layers were separated and the aqueous fraction was extracted with dichloromethane (2×250 mL). The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate (250 mL) before being dried, filtered and concentrated. Purification by chromatography (SiO2, isohexane:dichloromethane 7:3 as eluant) gave the title compound as a solid (27 g).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([NH2:13])=[NH:12])[CH:2]=1.[C:14]([CH2:19][C:20](OCC)=[O:21])(=O)[CH2:15][CH2:16][CH3:17].[O-]CC.[Na+]>C(O)C>[CH2:15]([C:14]1[N:13]=[C:11]([C:3]2[CH:2]=[N:1][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[NH:12][C:20](=[O:21])[CH:19]=1)[CH2:16][CH3:17]
Reactant: N=C(N)c1cnc2ccccc2c1
Reactant: CCCC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCc1cc(=O)[nH]c(-c2cnc3ccccc3c2)n1
Yield: 57.6 %

Procedure:
Quinoline-3-carboxamidine (314 mg), ethyl butyrylacetate (290 mg), and sodium ethoxide (21 wt % in ethanol, 1.1 mL) were refluxed for 48 h in 20 mL of ethanol. The solvent was evaporated and the residue was partitioned between ethyl acetate and brine. The ethyl acetate phase was dried with sodium sulfate and the solvent was evaporated. Silica gel chromatography (50:45:5 ethyl acetate/hexanes/methanol) provide 280 mg of 6-propyl-2-quinolin-3-yl-3H-pyrimidin-4-one.
Reaction SMILES: C(O)C.C(O[C:7]([CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[CH:17]=[CH:16]2)=[O:8])C.CC[O-].[Na+].[OH:28][CH2:29][CH2:30][NH:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>C(Cl)(Cl)Cl>[OH:28][CH2:29][CH2:30][N:31]([CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[C:7]([CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[CH:17]=[CH:16]2)=[O:8]
Reactant: CCOC(=O)CCCOc1ccc2[nH]c(=O)ccc2c1
Reactant: OCCNC1CCCCC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: O=C(CCCOc1ccc2[nH]c(=O)ccc2c1)N(CCO)C1CCCCC1

Procedure:
Into 100 ml of ethanol were added 2.7 g of 6-(3-ethoxycarbonylpropoxy)carbostyril, 0.5 g of sodium ethylate and 5 ml of N-(2-hydroxyethyl)cyclohexylamine and reacted in an autoclave under a pressure of 110 atomospher at 140°-150° C. for 6 hours. After the reaction was completed, the reaction mixture was cooled and was concentrated under a reduced pressure. The residue thus obtained was dissolved in 200 ml of chloroform and washed with 1% K2CO3 aqueous solution, a diluted hydrochloric acid and water in this order, then dried with anhydrous sodium sulfate. Then the solvent was removed by distillation and the residue thus obtained was purified by a silica-gel column chromatography [the silica-gel used as Wako C-200, and the solvent used was a mixture of chloroform:methanol=20:1 (V/V)]. The crude crystals thus obtained was recrystallized from chloroform-petroleum ether to obtain 0.9 g of 6-{3-[N-(2-hydroxyethyl)-N-cyclohexylaminocarbonyl]propoxy}carbostyril as in the form colorless needle-like crystals. Melting point: 165°-166° C.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13]([C:16]4[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=4)[CH:14]=3)[NH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1>CO.[Pd]>[CH:1]1([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13]([C:16]4[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=4)[CH:14]=3)[NH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Oc1cccc(-c2cnc3[nH]cc(C4=CCCCC4)c3c2)c1
Agent: [Pd]
Solvent: CO
Product: Oc1cccc(-c2cnc3[nH]cc(C4CCCCC4)c3c2)c1
Reaction time: 24 h
Yield: 37.2 %

Procedure:
A suspension of 3-(3-cyclohex-1-enyl-1H-pyrrolo[2,3-b]pyridine-5-yl)-phenol (6.7 mg, 0.023 mmol) and 10 wt % Pd/C (3 mg) in methanol (0.9 ml) was stirred for 24 h under H2 atmosphere. The reaction mixture was filtered through a silica plug, the solvent was evaporated to give 3-(3-cyclohexyl-1H-pyrrolo[2,3-b]pyridine-5-yl)-phenol as a white solid (2.5 mg, 37% yield). 1H NMR (500 MHz, MeOH-d4) δ 1.35 (m, 1H), 1.54 (m, 4H), 1.80 (m, 1H), 1.88 (m, 2H), 2.10 (m, 2H), 2.87 (m, 1H), 6.79 (dd, J=2.5, 8.0 Hz, 1H), 7.06 (t, J=2.0 Hz, 1H), 7.10 (d, J=7.5 Hz, 1H), 7.16 (s, 1H), 7.29 (t, J=8.0 Hz, 1H), 8.14 (d, J=2.0 Hz, 1H), 8.35 (d, J=2.0 Hz, 1H), 9.51 (broad s, 1H), 11.7 (s, 1H). MS: m/e 293 (M+H+).
Reaction SMILES: CC(CC(C)(C)C)C[C:4](O)=[O:5].[C:12]([OH:22])(=O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18](C)C>>[CH:13]1([CH2:12][OH:22])[CH2:14][CH2:15][CH:16]([CH2:4][OH:5])[CH2:17][CH2:18]1
Reactant: CC(C)CCCCCC(=O)O
Reactant: CC(CC(=O)O)CC(C)(C)C
Product: OCC1CCC(CO)CC1

Procedure:
3,5,5 trimethylhexanoic acid i.e. iso-nonanoic acid (5.87 moles).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([C:15]([F:18])([F:17])[F:16])[C:3]=1[C:4](Cl)=[O:5].[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([O:28][CH3:29])=[O:27])=[N:24][CH:25]=1.N1C=CC=CC=1.Cl>ClCCl>[F:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([C:15]([F:18])([F:17])[F:16])[C:3]=1[C:4]([NH:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([O:28][CH3:29])=[O:27])=[N:24][CH:25]=1)=[O:5]
Reactant: O=C(Cl)c1c(F)cc(C(F)(F)F)cc1C(F)(F)F
Reactant: COC(=O)c1ccc(N)cn1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NC(=O)c2c(F)cc(C(F)(F)F)cc2C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.1 %

Procedure:
A solution of 2-fluoro-4,6-bis(trifluoromethyl)benzoyl chloride (1.0 g, 3.39 mmol) and dichloromethane (5.0 mL) was added drop-wise to a mixture of methyl 5-aminopyridine-2-carboxylate (619.9 mg, 4.07 mmol), pyridine (824.1 μL, 10.18 mmol) in dichloromethane (20.00 mL) at 0° C. The mixture was allowed to warm to room temperature and was stirred at that temperature overnight. The mixture was poured into 1N HCl and dichloromethane. The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give a tan solid. The product was purified on column chromatography eluting with 10-100% ethyl acetate in hexanes to obtain methyl 5-[[2-fluoro-4,6-bis(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate (850 mg, 61%) as a white solid. ESI-MS m/z calc. 410.05. found 411.0 (M+1)+; Retention time: 0.62 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 11.59 (s, 1H), 8.86 (d, J=2.4 Hz, 1H), 8.48-8.41 (m, 1H), 8.34 (dd, J=8.6, 2.6 Hz, 1H), 8.20 (s, 1H), 8.15 (d, J=8.6 Hz, 1H), 3.89 (s, 3H) ppm.
Reaction SMILES: [CH3:1][C:2]1([C:5]([NH:7][NH2:8])=[O:6])[CH2:4][CH2:3]1.[C:9](Cl)(Cl)=[O:10]>C(Cl)Cl>[O:10]=[C:9]1[O:6][C:5]([C:2]2([CH3:1])[CH2:4][CH2:3]2)=[N:7][NH:8]1
Reactant: CC1(C(=O)NN)CC1
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Product: CC1(c2n[nH]c(=O)o2)CC1

Procedure:
85 gm of 1-methylcyclopropane carboxylic acid hydrazide was added to methylene chloride on a 3-neck 2-liter round bottom flask. The system was first cooled to 0°-5° C. and 590.5 gm of a 12.5% solution of phosgene added dropwise over a period of time. The system was then heated at reflux for 7 hours. The methylene chloride was removed by stripping. The product was washed with petroleum ether and filtered to give 66.6 gm of 5-oxo-2-(1'-methylcyclopropyl)-1,3,4-oxadiazoline as light brown crystals, melting point 68°-70° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH:7]([Se]C3C=CC=CC=3)[C:6]=2[N:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=O>ClCCl>[Cl:1][C:2]1[C:11]2[CH2:10][CH2:9][CH:8]=[CH:7][C:6]=2[N:5]=[CH:4][CH:3]=1
Reactant: Clc1ccnc2c1CCCC2[Se]c1ccccc1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Clc1ccnc2c1CCC=C2
Yield: 93.8 %

Procedure:
This compound was prepared from the product of Step 3 (9 g, 28 mmol), 86% 3-chloroperoxybenzoic acid (5.8 g, 29 mmol), and dichloromethane (150 ml) using the procedure outlined in Example 25, Step 2. Distillation gave the product (4.35 g) as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC)=O.CN1CCOCC1.Cl.[CH3:33][NH:34][O:35][CH3:36]>C(Cl)Cl.C1COCC1.C(Cl)Cl>[CH:14]1([CH2:13][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]([N:34]([O:35][CH3:36])[CH3:33])=[O:12])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCC1)C(=O)O
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)[C@H](CC1CCCC1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
To a flask charged with compound (S)-2-((tert-butoxycarbonyl)amino)-3-cyclopentylpropanoic acid (55.0 g, 214 mmol) was added THF/DCM (800 mL, 1:1). The solution was cooled to 0° C. and ethyl chloroformate (24.5 mL, 257 mmol) and NMM (28.4 mL, 257 mmol) was added dropwise sequentially. After addition, the mixture was stirred at 0° C. under nitrogen for 1 h. To the other flask charged with N,O-dimethylhydroxylamine HCl (25.0 g, 257 mmol) was added DCM (400 mL). The mixture was cooled to 0° C. and TEA (38.7 mL, 278 mmol) was added. The resulting mixture was transferred into the former reaction flask. The reaction mixture was allowed to warm to ambient temperature and stirred overnight. The reaction was then quenched with water (500 mL) and the two phases were separated. The organic phase was washed with water (500 mL), dried over anhydrous sodium sulfate, and concentrated to afford (S)-tert-butyl (3-cyclopentyl-1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate as colorless oil (60 g, 93% yield), which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:15][C:16]([CH:19]=[CH:20][CH2:21][CH2:22][CH3:23])=[CH:17][CH:18]=2)=[C:12]([CH3:24])[C:11]([C:25]2[N:26]([CH3:33])[C:27]([CH3:32])([CH3:31])[C:28](=[O:30])[N:29]=2)=[N:10]1>CO.[Pd]>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:15][C:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:17][CH:18]=2)=[C:12]([CH3:24])[C:11]([C:25]2[N:26]([CH3:33])[C:27]([CH3:32])([CH3:31])[C:28](=[O:30])[N:29]=2)=[N:10]1
Reactant: CCCC=Cc1ccc(-c2c(C)c(C3=NC(=O)C(C)(C)N3C)nn2-c2ccc(Cl)cc2Cl)s1
Agent: [Pd]
Solvent: CO
Product: CCCCCc1ccc(-c2c(C)c(C3=NC(=O)C(C)(C)N3C)nn2-c2ccc(Cl)cc2Cl)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.1 %

Procedure:
A mixture of 43 (118 mg, 0.24 mmol) and Pd—C (12 mg) in MeOH (8 mL) was stirred under 1 atm of H2 at room temperature for 2 h. The reaction mixture was filtered and the resulting filtrate was concentrated under reduced pressure to give the crude residue, which was subjected to purification by flash chromatography on silica gel with hexanes/ethyl acetate (1:1) to afford the product 44 (75 mg, 62%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.48 (d, 1H), 7.29 (m, 2H), 6.77 (d, 1H), 6.61 (d, 1H), 3.57 (s, 3H), 2.65 (m, 5H), 1.60 (m, 8H), 1.22 (m, 4H), 0.81 (t, 3H); ESMS m/z: 503.0 (M+1).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.Cl[CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:21]([CH3:23])=[C:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(C)[nH]c2c(-c3cc(CC)ccc3OCC3CC3)ncnc12
Reactant: C[Si](C)(C)CCOCCl
Product: CCOC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(-c3cc(CC)ccc3OCC3CC3)ncnc12

Procedure:
Starting from ethyl 4-[2-(cyclopropylmethoxy)-5-ethylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example D.a14) and commercially available (2-chloromethoxy-ethyl)-trimethyl-silane the title compound is obtained as yellow viscous oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:30])[C@@H:12]([OH:29])[CH2:13][O:14][C@H:15]([CH3:28])[CH2:16][O:17][Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])=[N:8][CH:9]=1.[Cl:31][C:32]1[C:33]([N:40]2[C:44]3=[N:45][CH:46]=[N:47][C:48](Cl)=[C:43]3[CH:42]=[N:41]2)=[C:34]([CH:37]=[CH:38][CH:39]=1)[C:35]#[N:36].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O.CCOC(C)=O>[Cl:31][C:32]1[CH:39]=[CH:38][CH:37]=[C:34]([C:35]#[N:36])[C:33]=1[N:40]1[C:44]2=[N:45][CH:46]=[N:47][C:48]([O:29][C@@H:12]([CH2:13][O:14][C@H:15]([CH3:28])[CH2:16][O:17][Si:18]([CH:25]([CH3:27])[CH3:26])([CH:19]([CH3:21])[CH3:20])[CH:22]([CH3:23])[CH3:24])[C:11]([NH:10][C:7]3[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][N:8]=3)=[O:30])=[C:43]2[CH:42]=[N:41]1
Reactant: CC(C)[Si](OC[C@@H](C)OC[C@H](O)C(=O)Nc1ccc(Cl)cn1)(C(C)C)C(C)C
Reactant: N#Cc1cccc(Cl)c1-n1ncc2c(Cl)ncnc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[Si](OC[C@@H](C)OC[C@H](Oc1ncnc2c1cnn2-c1c(Cl)cccc1C#N)C(=O)Nc1ccc(Cl)cn1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 78.8 %

Procedure:
Sodium hydride (60% dispersion in mineral oil) (93 mg, 2.32 mmol) was added to (S)—N-(5-chloropyridin-2-yl)-2-hydroxy-3-((R)-1-(triisopropylsilyloxy)propan-2-yloxy)propanamide (Intermediate AY2) (500 mg, 1.16 mmol) in anhydrous THF (25 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes and then 3-chloro-2-(4-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)benzonitrile (Intermediate AH6) (370 mg, 1.28 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was adjusted to pH 7 by addition of 1M citric acid and then diluted with water (20 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer re-extracted with EtOAc (2×50 mL). The combined organics were washed with saturated brine (75 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 50 to 100% EtOAc in isohexane to afford the product (626 mg, 79%). 1H NMR (400 MHz, CDCl3) δ 0.98-1.09 (21H, m), 1.13-1.17 (3H, m), 3.60-3.77 (3H, m), 4.20-4.33 (2H, m), 5.99-6.03 (1H, m), 7.60-7.70 (2H, m), 7.78-7.81 (1H, m), 7.85-5 7.87 (1H, m), 8.22-8.25 (2H, m), 8.50 (1H, d), 8.60 (1H, d), 8.82 (1H, s); m/z (ES−) (M−H)−=682; HPLC tR=4.04 min.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH2:12][C:11]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:15]([OH:17])=O)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-].Cl>C(Cl)Cl>[C:1]([N:9]1[CH2:14][CH2:13][CH2:12][C:11]2([CH2:18][C:19]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:15]2=[O:17])[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)N1CCCC(Cc2ccccc2)(C(=O)O)C1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C(c1ccccc1)N1CCCC2(Cc3ccccc3C2=O)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 51.3 %

Procedure:
A mixture of 1-benzoyl-3-benzyl-piperidine-3-carboxylic acid (6.71 g, 20.7 mmol) and thionyl chloride (2.70 g, 22.77 mmol) in dry CH2Cl2 (25 mL) was heated to reflux for 30 min. The resulting solution was concentrated in vacuum to give alight brown oil. A solution of this oil in dry CH2Cl2 (25 mL) was added dropwise to a mixture of AlCl3 (3.59 g, 26.91 mmol) in CH2Cl2 (10 mL) at 0° C. The mixture was stirred for 15 min at 0° C. and then heated to reflux for 45 min. The mixture was cooled and poured onto crushed ice and 12 N aq HCl. The organic layer was separated, washed with 3 N aq HCl, saturated Na2CO3, water and brine. Finally the organic layer was concentrated to give a residue, which was purified by silica gel column chromatography (petroleum/ethyl acetate 5:1 to 1:1) to afford 1′-benzoylspiro[indene-2,3′-piperidin]-1(3H)-one (3.24 g, 51%). 1H NMR (CD3OD, 400 MHz): δ=1.61 (m, 4H), 2.68 (m, 2H), 3.46 (m, 4H), 7.34 (m, 8H), 7.64 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]2[C:18](=[O:19])[CH:17]=[CH:16][C:15]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)=[N:14]2)[CH:7]=1)[CH3:2]>N.[Ni]>[CH2:1]([O:3][C:4](=[O:28])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]2[C:18](=[O:19])[CH:17]=[CH:16][C:15]([C:20]3[CH:21]=[CH:22][C:23]([CH2:26][NH2:27])=[CH:24][CH:25]=3)=[N:14]2)[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Nc1cccc(Cn2nc(-c3ccc(C#N)cc3)ccc2=O)c1
Agent: [Ni]
Agent: N
Product: CCOC(=O)Nc1cccc(Cn2nc(-c3ccc(CN)cc3)ccc2=O)c1
Reaction time: 16 h

Procedure:
26 mmol of ethyl{3-[6-oxo-3-(4-cyanophenyl)-6H-pyridazin-1-ylmethyl]-phenyl}carbamate are dissolved in 300 ml of methanolic ammonia solution (10%), 4 g of Raney Ni are added, and the mixture is hydrogenated at room temperature for 16 h under a hydrogen atmosphere (5 bar). The catalyst is separated off, rinsed with methanol, and the filtrate is evaporated.
Reaction SMILES: [NH:1]([C:32]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][C@H:10]([C:18]([NH:20][CH2:21][C:22]([O:24]CC1C=CC=CC=1)=[O:23])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])=[O:4].C1CC=CCC=1>CN(C=O)C.[C].[Pd]>[NH:1]([C:32]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][C@H:10]([C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:8])=[O:4]
Reactant: O=C(CNC(c1ccccc1)(c1ccccc1)c1ccccc1)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1=CCC=CC1
Solvent: CN(C)C=O
Product: O=C(O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)CNC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 88.9 %

Procedure:
1.3 g of Trt-Gly-Gly-Phe-Gly-OBn (193) obtained in item (3) above was dissolved in 20 ml of DMF to obtain a solution. To the obtained solution were added 0.5 g of a 10% palladium-carbon catalyst and 0.4 g of 1,4-cyclohexadiene, followed by a reaction at room temperature for 30 minutes, to thereby obtain a reaction mixture. The obtained reaction mixture was subjected to filtration to remove the catalyst, thereby obtaining a solution. The solvents were distilled off from the obtained solution under reduced pressure. The resultant residue was purified by silica gel column chromatography (silica gel: Art No. 9365, Silica gel 60, 200-400 mesh, manufactured and sold by Merck KGaA, Germany; eluent: chloroform/methanol ratio=7/1), thereby obtaining 1.0 g of Trt-Gly-Gly-Phe-Gly (190).
Reaction SMILES: C([C:9]1[C:10]([C:15]([OH:17])=[O:16])=[N:11][CH:12]=[CH:13][CH:14]=1)(=O)C1C=CC=CC=1.NC1C=CC=CC=1.[OH-].[Na+]>C1(C)C=CC=CC=1.C1C=CC=CC=1>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:9][C:10]=1[C:15]([OH:17])=[O:16]
Reactant: O=C(c1ccccc1)c1cccnc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: Nc1ccccc1
Solvent: c1ccccc1
Product: O=C(O)c1ccccn1
Temperature: 0 °C

Procedure:
1 mole of the benzoyl-pyridine-carboxylic acid (II) or the (heterocyclic-carbonyl)-pyridine-carboxylic acid (IV) and about 0.9 to 1.5 moles, preferably 1.0 to 1.2 moles of the heterocyclic compound (III) or the aniline compound (V) are added to about 3 to 30 moles of concentrated sulfuric acid, acetic anhydride or polyphosphoric acid, and the resulting mixture is allowed to react at a temperature of about 30° to 130° C for a period of from about 2 to 10 hours. The reaction product is then poured into 1 to 5 liters of ice-water to hydrolyze or dilute the condensing agent, and the resulting aqueous solution was made weakly acidic or neutral with dilute aqueous sodium hydroxide. Benzene or toluene is added thereto followed by stirring to transfer any unreacted heterocyclic compound or aniline compound to the benzene or toluene layer, which is then removed by separation. The residual aqueous layer is adjusted to a pH of about 11 to 12 with dilute aqueous sodium hydroxide and the precipitated solid is filtered, washed successively with water and a small amount of ethanol and dried to obtain in good yield a lactone color former of the pyridine-carboxylic acid represented by the formula (I) as substantially colorless of slightly colored crystals. Alternatively, the residual aqueous layer as obtained above, after removal of the benzene or toluene layer, is adjusted to a pH of 11 to 12 with dilute aqueous sodium hydroxide, and benzene or toluene is added to the resulting aqueous solution followed by stirring to transfer the lactone color former of pyridine-carboxylic acid to the benzene or toluene layer, which was then recovered by separation. Benzene or toluene was distilled off from the benzene or toluene layer. The residue was washed successively with water, a small amount of ethanol, benzene, lizroin or petroleum ether and dried. Further alternatively, the above reaction product is poured into 1 to 5 liters of ice-water to hydrohyze or dilute the condensing agent, and the resulting aqueous solution was adjusted to a pH of 11 to 12 with dilute aqueous sodium hydroxide. Benzene or toluene is added thereto followed by stirring to transfer the lactone color former of pyridine-carboxylic acid into the benzene or toluene layer which is then recovered by separation. The benzene or toluene layer is worked up in the same manner as described above. Thus, a substantially colorless or slightly colored lactone color former of pyridine-carboxylic acid represented by the formula [I] can be obtained in high yield. If necessary, the lactone color former of pyridine-carboxylic acid thus obtained can be recrystallized. The present invention, will now be illustrated by reference to the following Examples, but they are not to be construed as limiting the present invention.