Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Cl:12][CH2:13][CH2:14][C:15](Cl)=[O:16].C(N(CC)CC)C.[OH-].[Na+]>C(Cl)Cl>[Cl:12][CH2:13][CH2:14][C:15]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2)=[O:16]
Reactant: Nc1cccc2ncccc12
Reactant: O=C(Cl)CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCCl)Nc1cccc2ncccc12
Reaction time: 8 h
Yield: 30 %

Procedure:
In 60 ml of methylene chloride was dissolved 4.5 g of 5-aminoquinoline, and 10.5 g of 3-chloropropionyl chloride and 9 g of triethylamine were then added thereto. After the liquid was allowed to stand at room temperature overnight, a 1 N aqueous sodium hydroxide solution was added to the liquid, and the latter was then extracted with methylene chloride. The extract was washed twice with an aqueous sodium bicarbonate solution, was then dried, and was concentrated to obtain crystals. The latter were washed with methylene chloride, and filtered to obtain 2.2 g of 5-(3-chloropropionamido)quinoline in a crystalline state.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][NH2:9])[CH2:4][CH2:3]1.[CH2:10]([N:12]1[C:16]2=[N:17][C:18]3[C:23]([C:24](Cl)=[C:15]2[CH:14]=[N:13]1)=[CH:22][C:21]([O:26][CH3:27])=[CH:20][CH:19]=3)[CH3:11].CS(C)=O.CCOCC>CO>[CH2:10]([N:12]1[C:16]2=[N:17][C:18]3[C:23]([C:24]([NH:9][CH2:8][CH:5]4[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]4)=[C:15]2[CH:14]=[N:13]1)=[CH:22][C:21]([O:26][CH3:27])=[CH:20][CH:19]=3)[CH3:11]
Reactant: NCC1CCC(O)CC1
Reactant: CCn1ncc2c(Cl)c3cc(OC)ccc3nc21
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: CO
Product: CCn1ncc2c(NCC3CCC(O)CC3)c3cc(OC)ccc3nc21
Temperature: 25 °C
Yield: 31.3 %

Procedure:
A mixture of 4-hydroxycyclohexylmethylamine (2.2 g, 17.05 mmol), 1-ethyl-4-chloro-6-methoxy-1H-pyrazolo[3,4-b]quinoline (2.0 g, 7.66 mmol) and DMSO was heated at 110°-120° C. under a nitrogen atmosphere for 16 hours. The reaction mixture was poured into ice-water and the mixture was extracted with CH2Cl2 (4×50 ml). The organic layers were combined, dried over MgSO4 and evaporated to dryness. The residue was purified by column chromatography on silica gel eluting with CH2Cl2 /methanol (9/1), followed by a second silica gel column eluting with ethyl acetate to afford 1.3 g of crude product. The crude product was dissolved in warm methanol, cooled to room temperature and treated with an equivalent amount of methanesuflonic acid. Ether was added to the mixture and the solid which formed was collected by filtration, washed with ether and recrystallized from isopropanol to afford 0.85 g of 1-ethyl-6-methoxy-N-(4-hydroxycyclohexylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine.CH3SO3H, as yellow crystals, m.p. 256°-258° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[S:11](Cl)(=[O:13])=[O:12].[CH2:15]([NH2:18])[CH2:16][CH3:17].C(N(CC)C(C)C)(C)C.Cl.Cl.[CH3:30][C:31]1[N:35]([CH:36]2[CH2:42][C@H:41]3[N:43]([CH2:44][CH2:45][C:46]4([C:52]5[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=5)[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]4)[C@H:38]([CH2:39][CH2:40]3)[CH2:37]2)[C:34]2[CH:58]=[CH:59][CH:60]=[CH:61][C:33]=2[N:32]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:49]2[CH2:48][CH2:47][C:46]([CH2:45][CH2:44][N:43]3[C@H:41]4[CH2:40][CH2:39][C@@H:38]3[CH2:37][CH:36]([N:35]3[C:34]5[CH:58]=[CH:59][CH:60]=[CH:61][C:33]=5[N:32]=[C:31]3[CH3:30])[CH2:42]4)([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[CH2:51][CH2:50]2)=[O:8])=[CH:4][C:3]=1[S:11]([NH:18][CH2:15][CH2:16][CH3:17])(=[O:13])=[O:12]
Reactant: O=C(O)c1ccc(Cl)c(S(=O)(=O)Cl)c1
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2ccccc2)CCNCC1
Reactant: CCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCNS(=O)(=O)c1cc(C(=O)N2CCC(CCN3[C@@H]4CC[C@H]3CC(n3c(C)nc5ccccc53)C4)(c3ccccc3)CC2)ccc1Cl
Reaction time: 4 h
Yield: 43.6 %

Procedure:
To a stirred solution of 4-chloro-3-(chlorosulfonyl)benzoic acid (25.4 mg, 0.1 mmol) in dichloromethane (3 mL) was added propylamine (9 μL, 0.11 mmol), N,N-diisopropylethylamine (39 mg, 0.3 mmol) and 4-N,N-dimethylaminopyridine (2 mg, 0.016 mmol). After the resultant mixture was stirred overnight, a solution of 2-methyl-1-{(1R,5S)-8-[2-(4-phenyl piperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole dihydrochloride (50 mg, 0.1 mmol) in N,N-dimethylforamide (3 mL) was added and followed by addition of N,N-diisopropylethylamine (39 mg, 0.3 mmol) and HATU (38 mg. 0.1 mmol). The reaction mixture was stirred for further 4 hours before it was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The combined organic extracts were dried over anhydrous sodium sulfate. After evaporation of solvents, the residue was purified by flash chromatography, eluting with a gradient of 0-8% methanol in ethyl acetate to afford 2-chloro-5-[(4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]-N-propylbenzenesulfonamide as solid (30 mg, 43%). 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.65 (s, 2H), 7.38 (t, J=7.5 Hz, 2H), 7.30-7.23 (m, 4H), 7.19-7.12 (m, 2H), 5.10 (t, J=6.0 Hz, 1H), 4.64-4.59 (m, 1H), 4.19 (br, 1H), 3.48 (br, 1H), 3.34-3.35 (m, 4H), 2.90 (q, J=6.3 Hz, 2 H), 2.57 (s, 3H), 2.42-2.34 (m, 3H), 2.20 (br, 1H), 1.94-1.78 (m, 10H), 1.62 (d, J=6.4 Hz, 2H), 1.54-1.45 (m, 2H), 0.88 (t, J=7.5 Hz, 3H). HRMS m/z (M+H)+ calcd: 688.3088, obsd: 688.3063.
Reaction SMILES: [CH3:1][NH2:2].[O:3]=[C:4]1[NH:9][C:8]2[CH:10]=[C:11]([C:14]([N:16]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[O:19][CH2:18][CH:17]3[CH2:26][C:27](OCC)=[O:28])=[O:15])[CH:12]=[CH:13][C:7]=2[O:6][CH2:5]1>CO>[CH3:1][NH:2][C:27](=[O:28])[CH2:26][CH:17]1[N:16]([C:14]([C:11]2[CH:12]=[CH:13][C:7]3[O:6][CH2:5][C:4](=[O:3])[NH:9][C:8]=3[CH:10]=2)=[O:15])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[O:19][CH2:18]1
Reactant: CN
Reactant: CCOC(=O)CC1COc2ccccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Solvent: CO
Product: CNC(=O)CC1COc2ccccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
Methylamine (370 mL) was added slowly into a solution of ethyl {4-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]-3,4-dihydro-2H-1,4-benzoxazin-3-yl}acetate (Intermediate 4, 10.7 g, 26.9 mmol) in MeOH (640 mL) at rt. The resulting mixture was stirred at rt for 16 h. The organic solvent was removed by evaporation under reduced pressure. The crude product was purified by re-crystallization from MeOH to afford the title compound (10.3 g, 100%) as a white power.
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:22]#[C:23][C:24]3[CH:34]=[CH:33][C:27]([C:28]([O:30]CC)=[O:29])=[CH:26][CH:25]=3)[CH:5]=[CH:4][C:3]1=2.O[Li].O>C1COCC1.O>[CH3:1][C:2]1([CH3:35])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:22]#[C:23][C:24]3[CH:34]=[CH:33][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C(C)(C)C)cc2)=CCC3(C)C)cc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1ccc(C2=CCC(C)(C)c3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)cc1

Procedure:
A solution of 80.0 mg (0.173 mmol) of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(4-(1,1-dimethylethyl)phenyl)-2-naphthalenyl)ethynyl]benzoate (Compound 6) and 18.1 mg (0.432 mmol) of LiOH-H2O in 6 ml of THF/water (3:1, v/v), was stirred overnight at room temperature. The reaction mixture was extracted with hexanes, and the remaining aqueous layer acidified with 1 M HCl, and then extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give the title compound as a colorless solid. 1H NMR (d6-DMSO): δ 7.82 (2H, d, J=8.2 Hz), 7.44 (6H, m), 7.25 (2H, d, J=8.3 Hz), 7.02 (1H, s), 6.01 (1H, t, J=4.6 Hz), 2.32 (2H, d, J=4.7 Hz), 1.32 (9H, s), 1.29 (6H, s).
Reaction SMILES: [C:1]([CH2:6][N:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)([O:3][CH2:4][CH3:5])=[O:2].[Li]N(C(C)C)C(C)C.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([C:37]([CH:44]([CH3:46])[CH3:45])([CH2:40][CH2:41][CH2:42]I)[C:38]#[N:39])[CH:32]=[CH:33][C:34]=1[O:35][CH3:36]>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[C:1]([CH:6]([N:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[CH2:42][CH2:41][CH2:40][C:37]([C:31]1[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:29]([O:28][CH3:27])[CH:30]=1)([C:38]#[N:39])[CH:44]([CH3:46])[CH3:45])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: COc1ccc(C(C#N)(CCCI)C(C)C)cc1OC
Reactant: CCOC(=O)CN=Cc1ccc(OC)c(OC)c1
Agent: [Li]N(C(C)C)C(C)C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(CCCC(C#N)(c1ccc(OC)c(OC)c1)C(C)C)N=Cc1ccc(OC)c(OC)c1

Procedure:
The resulting imine of formula 24 is then deprotonated using a suitable strong base, and allowed to react with a compound of formula 22 to produce a compound of formula 25 (step 2). For example, 1-(carboethoxy)methyliminomethyl-3,4-dimethoxybenzene (24) is suspended in a solution of LiNiPr2 in THF/HMPA at -78° C., then reacted with 2-(3,4-dimethoxyphenyl)-2-isopropyl-2-(3-iodopropyl)acetonitrile (22) to produce N-[1-carboethoxy-5-(3,4-dimethoxyphenyl)-5-cyano-5-(isopropyl)pentyl]iminomethyl-3,4-dimethoxybenzene (25).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)=[O:17].F[C:26]1[C:31]([CH:32]2[CH2:36][CH2:35][C:34]([C:38]([F:41])([F:40])[F:39])([OH:37])[CH2:33]2)=[CH:30][CH:29]=[CH:28][N:27]=1.CN1C(=O)CCC1>C(OCC)(=O)C>[NH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][C:26]2[C:31]([C@H:32]3[CH2:36][CH2:35][C@@:34]([OH:37])([C:38]([F:40])([F:41])[F:39])[CH2:33]3)=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:20][CH:19]=1)=[O:17]
Reactant: OC1(C(F)(F)F)CCC(c2cccnc2F)C1
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: O=C(c1ccc(Oc2ncccc2[C@H]2CC[C@@](O)(C(F)(F)F)C2)cc1)c1nc2ccccc2[nH]1
Temperature: 200 °C

Procedure:
To a vial containing cesium carbonate (1634 mg, 5.02 mmol), (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (717 mg, 3.01 mmol), and 3-(2-fluoropyridin-3-yl)-1-(trifluoromethyl)cyclopentanol (500 mg, 2.006 mmol) was added NMP (13.400 ml). The mixture was heated at 200° C. for 5 h with microwave irradiation. The reaction mixture was diluted with ethyl acetate and washed with 5N NaOH before drying the organic layer over magnesium sulfate, filtering, and concentrating under reduced pressure. The resulting orange oil was purified by column chromatography (ethyl acetate/dichloromethane) to give a pale orange oil. The material was diluted with ethyl acetate and washed with water and 10 N NaOH before separating the mixture by SFC into its components, which consisted of two products identified as enantiomers by NMR. MS (ESI, pos. ion) m/z: 468.2 (M+1). IC50 (uM) +++++.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[NH:32][C:33](=[O:38])[C:34]([OH:37])([CH3:36])[CH3:35])[NH:28][C:27](=[O:39])[CH2:26]2>>[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[NH:32][C:33](=[O:38])[C:34]([OH:37])([CH3:36])[CH3:35])[NH:28][C:27](=[O:39])[C:26]2=[CH:20][C:3]1[NH:4][C:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Reactant: CC(C)(O)C(=O)Nc1cc2c(cc1F)CC(=O)N2
Product: Cc1c(C=C2C(=O)Nc3cc(NC(=O)C(C)(C)O)c(F)cc32)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Yield: 63.3 %

Procedure:
The title compound was prepared under the same conditions as described in Example 15 with 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-2-methyl-propionamide as starting materials to give N-{5-fluoro-3-[3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxy-2-methyl-propionamide (46 mg, 63.3%) as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.[CH3:16][C:17]1[CH:26]=[C:25]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH:28]2[CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.CN(C=O)C>[CH3:16][C:17]1[CH:26]=[C:25]([N:27]2[CH2:32][CH2:31][N:30]([C:5](=[O:6])/[CH:4]=[CH:3]/[C:2]([F:9])([F:8])[F:1])[CH2:29][CH:28]2[CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1
Reactant: COC(=O)CC1CNCCN1c1cc(C)nc2ccccc12
Reactant: O=C(O)/C=C/C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)CC1CN(C(=O)/C=C/C(F)(F)F)CCN1c1cc(C)nc2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(E)-4,4,4-Trifluorobut-2-enoic acid (15.4 mg, 0.08 mmol) was dissolved in DCM (1 ml), oxalyl chloride was added (9.4 μl, 0.11 mmol) followed by a drop of DMF. The mixture was stirred for 10 minutes at room temperature. Methyl 2-[1-(2-methyl-4-quinolyl)piperazin-2-yl]acetate (33.6 mg, 0.1 mmol) was dissolved in DMF (1 ml) together with diisopropylethylamine (44 μl, 0.25 mmol), the solutions were combined and the resulting mixture was stirred at room temperature overnight. The volatiles were removed under reduced pressure and the residue was purified by preparative HPLC (gradient of water containing 0.1% NH3 and acetonitrile) to yield 3.9 mg (0.0093 mmol, 9%).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[C:22](Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>>[CH3:13][N:10]1[CH2:9][CH2:8][C:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([O:6][C:5]2[CH:20]=[CH:21][C:2]([NH:1][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:3][CH:4]=2)[CH2:12][CH2:11]1
Reactant: CN1CCC(Oc2ccc(N)cc2)(c2ccccc2)CC1
Reactant: CC(C)(C)C(=O)Cl
Product: CN1CCC(Oc2ccc(NC(=O)C(C)(C)C)cc2)(c2ccccc2)CC1

Procedure:
from 4-(4-aminophenoxy)-1-methyl-4-phenylpiperidine and pivaloyl chloride.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[Mg]Br.[CH:10]12[CH2:16][CH:13]([CH:14]=[CH:15]1)[CH2:12][CH:11]2[CH:17]=[O:18]>>[CH:1]12[CH2:7][CH:4]([CH:3]=[CH:2]1)[CH2:5][CH2:6]2.[CH:10]12[CH2:16][CH:13]([CH2:14][CH2:15]1)[CH2:12][CH:11]2[CH2:17][OH:18]
Reactant: Br[Mg]C1CC2CCC1C2
Reactant: O=CC1CC2C=CC1C2
Product: C1=CC2CCC1C2
Product: OCC1CC2CCC1C2

Procedure:
2-norbornyl magnesiumbromide (200 ml; 0.1 mol in THF) solution was poured into a round-bottom flask and 14 g of 5-norbornene-2-carboxaldehyde (0.11 mol) was slowly dropped thereinto and the reactant was reacted at 45° C. for about 20 hours.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6](O)[CH:7]([CH3:10])[C:8]#[CH:9].C(=O)([O-])[OH:13].[Na+]>CC(C)=O.O>[OH:1][CH:5]1[CH:4]=[CH:3][C:2](=[O:13])[CH:6]1[CH:7]([CH3:10])[C:8]#[CH:9]
Reactant: O=C([O-])O
Reactant: C#CC(C)C(O)c1ccco1
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: C#CC(C)C1C(=O)C=CC1O
Reaction time: 48 h
Yield: 52 %

Procedure:
1-(2-Furyl)-2-methyl-3-butyn-1-ol (15 g, 0.1 mole) was dissolved in a 2:1 mixture (150 ml) of acetone and water in a reactor, and p-toluenesulfonic acid (3 g) was dried. Thereafter, reaction was carried out at 50° to 60° C. for about 48 hours with stirring. After completion of the reaction, the reaction solution was cooled and neutralized with addition of a saturated aqueous solution (30 ml) of sodium hydrogen carbonate, followed by extraction with a solvent. The extrect was washed with water, dried and concentrated. The residue obtained was distilled under reduced pressure to obtain 7.8 g (yield, 52%) of pure (±)-3-hydroxy-2-(1-methyl-2-propynyl)-4-cyclopenten-1-one having a boiling point of 110°-115° C./3 mmHg.
Reaction SMILES: C([O:8][C:9]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]2[C:10]=1[C:11]([CH3:21])=[C:12]([CH3:20])[NH:13]2)C1C=CC=CC=1.C(O)C>[Pd].C1CCCCC1>[CH3:20][C:12]1[NH:13][C:14]2[C:10]([C:11]=1[CH3:21])=[C:9]([OH:8])[CH:17]=[CH:16][C:15]=2[O:18][CH3:19]
Reactant: COc1ccc(OCc2ccccc2)c2c(C)c(C)[nH]c12
Agent: [Pd]
Solvent: C1CCCCC1
Solvent: CCO
Product: COc1ccc(O)c2c(C)c(C)[nH]c12

Procedure:
0.14 mole (39.5 g) of 4-benzyloxy-2,3-dimethyl-7-methoxyindole and 4 g of 10% palladium-on-charcoal in 120 ml of 96° ethanol to which have been added 80 ml of cyclohexane is heated under reflux. After 1 hour 30 minutes the catalyst is removed by hot filtration. The desired product is obtained by concentrating the filtrate to dryness. It is purified by dissolving it hot in isopropyl ether, filtering in the presence of charcoal and evaporating the filtrate to dryness. It melts at 164° C.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH2:7][CH:3]([C:4]([OH:6])=[O:5])[CH2:2]1.[OH-].[Na+].[CH2:12]([O:19][C:20](Cl)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>C(OCC)C>[CH2:12]([O:19][C:20]([N:1]1[CH2:9][CH2:8][CH2:7][CH:3]([C:4]([OH:6])=[O:5])[CH2:2]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)C1CCCNC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C(O)C1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 112.9 %

Procedure:
To a solution of nipecotic acid (10 g, 63.6 mmol) in 1 N NaOH (2.5 g in 64 mL water, 63.6 mmol) at 0° C. was alternately added benzyloxycarbonyl chloride (10.9 mL, 76.5 mmol) in diethyl ether (50 mL) and 1 N NaOH (5 g in 128 mL water, 127.2 mmol) in five portions. The reaction mixture was stirred at 0° C. for 2 h, and at ambient temperature for 24 h. Then this was made acidic with 10% HCl and the solid formed was filtered and dried (vacuum oven, 45° C.) to obtain the title compound (18.9 g, 113%). MS (ESI) m/e 264 (M+H)+.
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][C@H:11]2[N:21]3[C:22]4[N:13]([C:14](=[O:24])[CH:15]=[CH:16][C:17]=4[CH:18]=[CH:19][C:20]3=[O:23])[CH2:12]2)[CH2:6][CH2:5]1.C(N(CC)CC)C.[O:32]1[C:36]2[CH:37]=[C:38]([CH:41]=O)[CH:39]=[CH:40][C:35]=2[CH2:34][CH2:33]1>C(Cl)(Cl)Cl.CO>[ClH:1].[O:32]1[C:36]2[CH:37]=[C:38]([CH2:41][NH:3][CH:4]3[CH2:5][CH2:6][N:7]([CH2:10][C@H:11]4[N:21]5[C:22]6[N:13]([C:14](=[O:24])[CH:15]=[CH:16][C:17]=6[CH:18]=[CH:19][C:20]5=[O:23])[CH2:12]4)[CH2:8][CH2:9]3)[CH:39]=[CH:40][C:35]=2[CH2:34][CH2:33]1
Reactant: O=Cc1ccc2c(c1)OCC2
Reactant: NC1CCN(C[C@@H]2Cn3c(=O)ccc4ccc(=O)n2c43)CC1
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=c1ccc2ccc(=O)n3c2n1C[C@H]3CN1CCC(NCc2ccc3c(c2)OCC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 26 %

Procedure:
A solution of (1R)-1-[(4-amino-1-piperidinyl)methyl]-1,2-dihydro-4H,9H-imidazo[1,2,3-ij]-1,8-naphthyridine-4,9-dione dihydrochloride (for a preparation see Example 5A(j)) (133 mg, 0.356 mmol) and triethylamine (0.124 ml, 0.891 mmol) in chloroform (4.5 ml) and methanol (0.5 ml) at rt was stirred at rt for 15 min then 2,3-dihydro-1-benzofuran-6-carbaldehyde (44 mg, 0.297 mmol) in chloroform (2 ml) was added dropwise at rt. The reaction mixture was stirred at rt overnight. The reaction was quenched with NaHCO3 (aq) (20 ml), extracted with 20% MeOH/DCM (3×30 ml). The combined organic layers were dried over MgSO4, filtered, evaporated and chromatographed (0-50% MeOH/DCM). The relevant fractions were combined and evaporated to deliver the free base of the title compound as a pale yellow clear oil (18 mg, 0.04 mmol, 26%).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10](=[O:18])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[H][H]>[Pd].C(OCC)(=O)C>[CH3:1][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: C=C1CCCCCCCC(=O)CCCCCCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1CCCCCCCC(=O)CCCCCCC1
Yield: 94.1 %

Procedure:
500 mg (2 mmol) of 9-methylenecyclohexadecanone are introduced into 25 ml of ethyl acetate, and 25 mg of Pd/C are added thereto. Hydrogenation is then carried out at 40° C. and standard hydrogen pressure for 5 h. When the reaction is complete, the mixture is filtered over Celite, and the crude product is freed from solvent. Purification by flash chromatography (cyclohexane/EtOAc=25:1) gives 475 mg (94%) of a colorless oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[C:4]([CH2:10][CH3:11])[N:3]=1.[CH:12]1([CH2:17][NH:18][CH2:19][CH3:20])[CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH:12]1([CH2:17][N:18]([CH2:19][CH3:20])[C:2]2[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[C:4]([CH2:10][CH3:11])[N:3]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CCc1ccc(C#N)c(Cl)n1
Reactant: CCNCC1CCCC1
Product: CCc1ccc(C#N)c(N(CC)CC2CCCC2)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 62.7 %

Procedure:
2-Chloro-6-ethylpyridine-3-carbonitrile (500 mg, 3.00 mmol) synthesized by the method described in International Patent Publication WO1997/19078 and N-(cyclopentylmethyl)-N-ethylamine (1.50 g, 11.8 mmol) were mixed, and the mixture was stirred at 100° C. for 8 hours in an argon atmosphere. The mixture was further added with N-(cyclopentylmethyl)-N-ethylamine (0.19 g, 1.49 mmol), and stirred at 100° C. for 8 hours, and then the reaction mixture was azeotroped with toluene. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:1) to obtain 2-[(cyclopentylmethyl)(ethyl)amino]-6-ethylpyridine-3-carbonitrile (484 mg, 63%) as pale yellow oil.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH2:19][CH3:20])[C:8]([O:10]CCC)=[O:9])[CH2:2][CH3:3].[OH-].[K+].O>O1CCOCC1>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH2:19][CH3:20])[C:8]([OH:10])=[O:9])[CH2:2][CH3:3]
Reactant: CCCOC(=O)c1ccc(OCCC)c(OCCC)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCOc1ccc(C(=O)O)cc1OCCC
Yield: 94 %

Procedure:
A mixture of the product of Step A (0.94 g; 3.35 mmol), KOH (0.56 g; 10 mmol), H2O (2 ml) and dioxane was stirred at reflux overnight. After evaporation of solvents under reduced pressure, the residue was dissolved on H2O (5 ml) and insoluble material was removed by filtration. The filtrate was acidified to pH˜3 with diluted HCl and the product was taken up by extraction with CH2Cl2 (3×15 ml). The combined organic phase was dried over anhydrous MgSO4, filtered and filtrate evaporated to dryness to give the title compound (0.75 g; 94%) as creamy solid. 1H-NMR (CDCl3) 1.02-1.08 (m, 6H); 1.79-1.93 (m, 4H); 3.98-4.05 (m, 4H); 6.87 (d, 1H, J=8.5 Hz); 7.57 (d, 1H, J=2 Hz)); 7.7 (dd, 1H, J=2, 8.5 Hz).