Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=C(F)C=C[C:3]=1[C:9]1[CH:10]=[C:11]([CH2:20]O)[C:12](=O)N(CC(C)C)N=1.[F:22][C:23]1[CH:24]=[C:25]([C:31]2[CH:32]=[C:33]([C:38]([O:40][CH3:41])=[O:39])[C:34](=[O:37])[NH:35][N:36]=2)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30].C1(CBr)CCCC1>>[CH:11]1([CH2:12][N:35]2[C:34](=[O:37])[C:33]([C:38]([O:40][CH3:41])=[O:39])=[CH:32][C:31]([C:25]3[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:23]([F:22])[CH:24]=3)=[N:36]2)[CH2:10][CH2:9][CH2:3][CH2:20]1
Reactant: COC(=O)c1cc(-c2ccc(OC)c(F)c2)n[nH]c1=O
Reactant: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(CO)c1=O
Agent: BrCC1CCCC1
Product: COC(=O)c1cc(-c2ccc(OC)c(F)c2)nn(CC2CCCC2)c1=O
Yield: 72 %

Procedure:
Following the procedure of Example 1 (6), 6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and cyclopentylmethyl bromide {J. Org. Chem., 36, 3103 (1971)} were reacted to yield the title compound as yellow needles (yield: 72.0%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10]OS(C)(=O)=O.[C-:16]#[N:17].[K+].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][C:16]#[N:17]
Reactant: CS(=O)(=O)OCCCc1ccccc1Br
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCCCc1ccccc1Br
Temperature: 60 °C
Reaction time: 16 h
Yield: 91.5 %

Procedure:
Methanesulfonyl chloride (7.7 mL, 97 mmol) in 100 mL dry THF is added to a solution of 3-(2-bromo-phenyl)-propan-1-ol (17.4 g, 80.9 mmol) and triethyl amine (14.7 g, 146 mmol) in 200 mL dry THF at 0° C. under an argon atmosphere. Water is added and the mixture is extracted with ethyl acetate. The organic phase is washed with brine, dried with MgSO4 and concentrated in vacuo to give 23 g (97%) methanesulfonic acid 3-(2-bromo-phenyl)-propyl ester as an oil. Methanesulfonic acid 3-(2-bromo-phenyl)-propyl ester (23g, 78 mmol) in 300 mL dry DMF is added to a suspension of potassium cyanide (15.3 g, 235 mmol) in dry DMF. The reaction mixture is stirred at 60° C. for 16 hours. Water is added and the mixture is extracted with ethyl acetate (3 times). The organic phase is washed with brine (twice), dried with MgSO4 and concentrated in vacuo. The residue is placed on a plug of silica gel and eluted with ethyl acetate/heptane (1:4) and concentrated in vacuo to give 16.0 g 4-(2-bromo-phenyl)-butyronitrile (91%) as an oil. 300 mL concentrated HCl is added to 4-(2-bromo-phenyl)-butyronitrile (16.0 g, 71 mmol) in 150 mL acetic acid. The reaction mixture is stirred at 60° C. for 16 hours. The reaction mixture concentrated in vacuo partly and is poured into water. The mixture is extracted with ethyl acetate (3 times). The organic phase is washed with brine (twice), dried with MgSO4 and concentrated in vacuo to give the title compound as a crystalline material.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[O:13][CH2:12][CH2:11][NH:10][CH2:9]1.C(N(CC)CC)C.Cl[C:22]1[N:27]=[C:26]([NH2:28])[C:25]([N+:29]([O-:31])=[O:30])=[CH:24][CH:23]=1.C(OCC)(=O)C>CS(C)=O>[N+:29]([C:25]1[C:26]([NH2:28])=[N:27][C:22]([N:10]2[CH2:11][CH2:12][O:13][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=3)[CH2:9]2)=[CH:23][CH:24]=1)([O-:31])=[O:30]
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: c1ccc(C2CNCCO2)nc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Nc1nc(N2CCOC(c3ccccn3)C2)ccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 18 h
Yield: 70.5 %

Procedure:
To a solution of 2-(pyridin-2-yl)morpholine hydrochloride (1000 mg, 4.22 mmol) and triethylamine (1.3 mL, 9.3 mmol) in dimethylsulfoxide (10 mL) was added 6-chloro-3-nitropyridin-2-amine (734 mg, 4.23 mmol). The reaction mixture was stirred at 100° C. for 18 h. The reaction mixture was cooled to room temperature. Ethyl acetate was added and the mixture was washed with water (20 mL). The aqueous layer was extracted with ethyl acetate (20 mL×2). The combined organics were washed with brine (20 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via flash chromatography (40-100% ethyl acetate in heptanes) to afford the title compound (0.897 g, 70%). 1H NMR (400 MHz, CDCl3) δ 3.08 (s, 1H), 3.18-3.29 (m, 1H), 3.83 (s, 1H), 4.20 (s, 1H), 4.41 (d, 1H), 4.63 (dd, 1H), 4.67-4.80 (m, 1H), 6.18 (s, 1H), 7.23-7.26 (m, 1H), 7.54 (s, 1H), 7.75 (s, 1H), 8.22 (s, 1H), 8.60 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=1[C:11]([O:13]CC)=[O:12].C(N(CC)CC)C.[CH2:27]([O:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1)/[CH:28]=[CH:29]/[CH2:30][CH2:31][CH2:32][CH3:33]>C(Cl)Cl>[CH2:27]([O:34][C:35]1[CH:36]=[CH:37][C:38]([C:39]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([OH:13])=[O:12])=[O:40])=[CH:42][CH:43]=1)/[CH:28]=[CH:29]/[CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCOC(=O)c1ccccc1Sc1ccccc1N
Reactant: CCCC/C=C/COc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC/C=C/COc1ccc(C(=O)Nc2ccccc2Sc2ccccc2C(=O)O)cc1
Yield: 79 %

Procedure:
In 30 ml of methylene chloride were dissolved 2.1 g of ethyl 2-(2-aminophenylthio)benzoate and 1.8 g of triethylamine, followed by dropwise addition of 2.2 g of (E)-4-(2-heptenyloxy)benzoyl chloride with ice-cooling and stirring. The mixture was stirred at room temperature for 10 hours, and then the methylene chloride was distilled off. The residue was diluted with water and extracted with ether. The ether layer was washed with diluted hydrochloric acid and saturated sodium hydrogen carbonate solution and dried and the ether was distilled off. The oily residue was dissolved in 50 ml of ethanol followed by addition of 7 ml of 10% aqueous sodium hydroxide solution, and the mixture was heated on a water bath for 40 minutes. After cooling, the reaction mixture was acidified with hydrochloric acid and diluted with water and the crystals separated out therefrom were collected by filtration and washed with water and aqueous ethanol in that order to give 2.8 g of the title compound as white crystals.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:18])[NH:7][C:8]1[C:9]([Cl:17])=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([OH:13])=O)[CH2:2][CH2:3][CH3:4].S(Cl)(Cl)=O.O1CCCC1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:35]=[C:36]3[CH:42]=[CH:41][NH:40][C:37]3=[N:38][CH:39]=2)[CH:29]=1.[Cl-].[Cl-].[Cl-].[Al+3]>CN(C)C=O.ClCCl>[CH2:1]([NH:5][C:6]([NH:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:10]([C:11]([C:42]2[C:36]3[C:37](=[N:38][CH:39]=[C:34]([C:30]4[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=4)[CH:35]=3)[NH:40][CH:41]=2)=[O:13])[C:9]=1[Cl:17])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: c1cncc(-c2cnc3[nH]ccc3c2)c1
Reactant: CCCCNC(=O)Nc1cccc(C(=O)O)c1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCNC(=O)Nc1cccc(C(=O)c2c[nH]c3ncc(-c4cccnc4)cc23)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.4 %

Procedure:
To 3-(3-Butyl-ureido)-2-chloro-benzoic acid (587, 103 mg, 0.000380 mol) was added dichloromethane (10 mL, 0.2 mol) followed by thionyl chloride (110 μL, 0.0015 mol) and 1 drop of dimethylformamide to give a suspension. The reaction was stirred at room temperature for 2 hours. Solid material was still present in the reaction mixture, so tetrahydrofuran (0.5 mL, 0.006 mol) was added and continued stirring at room temperature. The reaction became a clear solution after 2 hours, then stirred for another hour. All volatiles were removed under vacuum and the residue stripped from toluene, twice. The solid was then dried under high vacuum for 60 minutes and dissolved in dichloromethane (5 mL). This was added to 5-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine (89, 0.074 g 0.00038 mol, prepared as described in Example 17) which had been treated with aluminum trichloride (0.25 g, 0.0019 mol) in dichloromethane (10 mL) for 1 hour. The reaction was stirred at room temperature overnight, then quenched with methanol (5 mL). The resulting solution was extracted with ethyl acetate and water with added saturated sodium bicarbonate to adjust pH˜8. The organic layer was washed with sodium bicarbonate and brine and dried over magnesium sulfate and filtered. The organic layer was concentrated and purified by silica gel column chromatography eluting with 2% methanol in dichloromethane followed by 5% methanol in dichloromethane to give the compound as a white solid (P-1828, 45 mg, 26%).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.[N:15]12[CH2:22][CH2:21][CH:18]([CH2:19][CH2:20]1)[CH:17](O)[CH2:16]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.ClCCl>[N:15]12[CH2:22][CH2:21][CH:18]([CH2:19][CH2:20]1)[CH:17]([O:1][C:2]1[CH:14]=[CH:13][C:12]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[NH:5][C:4]=3[CH:3]=1)[CH2:16]2
Reactant: Oc1ccc2c(c1)[nH]c1ccccc12
Reactant: OC1CN2CCC1CC2
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: c1ccc2c(c1)[nH]c1cc(OC3CN4CCC3CC4)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.4 %

Procedure:
To a 0° C. mixture of 2-hydroxy-9H-carbazole (369 mg, 2.02 mmol; Aldrich), quinuclidin-3-ol (260 mg, 2.05 mmol; Aldrich), and triphenylphosphine (646 mg, 2.47 mmol; Aldrich) in THF (10 mL) was added diethylazodicarboxylate (320 μL, 2.03 mmol; Lancaster). After 1 h, the reaction mixture was allowed to warm to room temperature and was stirred for 3 d. The mixture was diluted with dichloromethane, washed with saturated aq. NaHCO3, dried over MgSO4, and purified by flash chromatography (80 g silica gel, eluting with 1-16% of 10% NH4OH/MeOH in CH2Cl2) to afford the title compound as an oil (350 mg, 1.20 mmol, 59% yield). Trituration of the oil with ethyl acetate produced a solid. 1H NMR (300 MHz, methanol-d4) δ 7.92 (1H, d, J=6 Hz), 7.90 (1H, d, J=8 Hz), 7.37 (1H, d, J=8 Hz), 7.26 (1H, ddd, J=7, 7, 1 Hz), 7.10 (1H, ddd, J=8, 8, 1 Hz), 6.92 (1H, d, J=2 Hz), 6.78 (1H, dd, J=8, 2 Hz), 4.59 (1H, m), 3.36 (1H, ddd, J=14, 8, 2 Hz), 3.04-2.75 (5H, m), 2.22 (1H, m), 2.11 (1H, m), 1.88-1.65 (2H, m), 1.51 (1H, m). MS (DCI/NH3): m/z 293 (M+1)+. Anal. Calcd. for C19H20N2O.0.1C4H8O2: C, 77.36; H, 6.96; N, 9.30. Found: C, 77.04; H, 7.23; N, 9.45.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:16])[CH2:4][O:5][C:6]1[C:14]2[NH:13][C:12](=[O:15])[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[CH2:17]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]2)=[CH:27][CH:26]=1)(=[O:24])=[O:23])[CH2:18][CH2:19][CH3:20]>>[CH2:17]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][CH:34]([NH:1][CH2:2][C@H:3]([OH:16])[CH2:4][O:5][C:6]3[C:14]4[NH:13][C:12](=[O:15])[NH:11][C:10]=4[CH:9]=[CH:8][CH:7]=3)[CH2:33][CH2:32]2)=[CH:27][CH:26]=1)(=[O:23])=[O:24])[CH2:18][CH2:19][CH3:20]
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Reactant: CCCCNS(=O)(=O)c1ccc(N2CCC(=O)CC2)cc1
Product: CCCCNS(=O)(=O)c1ccc(N2CCC(NC[C@H](O)COc3cccc4[nH]c(=O)[nH]c34)CC2)cc1

Procedure:
The title compound was prepared from 4-((2S)-3-amino-2-hydroxy-propoxy)-1,3-dihydro-benzoimidazol-2-one and Reference Example 11, N-butyl-4-(4-oxo-piperidin-1-yl)-benzenesulfonamide, according to the procedure of Example 1 as an off-white solid; mp 69-75° C.; 1H NMR (300 MHz, DMSO-d6) δ 0.79 (t, 3H), 1.10-1.40 (m, 6H), 1.75-1.90 (m, 2H), 2.67 (t, 2H), 2.10-3.00 (m, 5H), 3.70-4.10 (m, 5H), 6.55 (d, 3H), 6.62 (d, 1H), 6.83 (t, 1H), 7.00 (d, 2H), 7.52 (d, 2H), 10.45-10.80 (m, 2H); MS (ES) m/z: 518.1 (MH+); HRMS Calcd. for C25H36N5O5 S (MH+): 518.2437. Found: 518.2446.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2([NH:11][C:12]([C:14]3([NH:17][C:18]([C:20]4[N:24]5[C@@:25]([CH2:38][C:39]6[CH:44]=[CH:43][C:42]([C:45]#[N:46])=[CH:41][CH:40]=6)([CH3:37])[C:26](=[O:36])[N:27]([C:28]6[CH:33]=[C:32]([Cl:34])[CH:31]=[C:30]([Cl:35])[CH:29]=6)[C:23]5=[N:22][CH:21]=4)=[O:19])[CH2:16][CH2:15]3)=[O:13])[CH2:10][CH2:9]2)[CH:3]=1.[CH3:47][S:48]([NH2:51])(=[O:50])=[O:49].N(CC(O)=O)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu]I>[CH3:47][S:48]([NH:51][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2([NH:11][C:12]([C:14]3([NH:17][C:18]([C:20]4[N:24]5[C@@:25]([CH2:38][C:39]6[CH:44]=[CH:43][C:42]([C:45]#[N:46])=[CH:41][CH:40]=6)([CH3:37])[C:26](=[O:36])[N:27]([C:28]6[CH:33]=[C:32]([Cl:34])[CH:31]=[C:30]([Cl:35])[CH:29]=6)[C:23]5=[N:22][CH:21]=4)=[O:19])[CH2:16][CH2:15]3)=[O:13])[CH2:10][CH2:9]2)[CH:3]=1)(=[O:50])=[O:49]
Reactant: CS(N)(=O)=O
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)NC4(c5cc(I)ccn5)CC4)CC3)n21
Agent: [Cu]I
Agent: CNCC(=O)O
Agent: O=P([O-])([O-])[O-]
Product: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)NC4(c5cc(NS(C)(=O)=O)ccn5)CC4)CC3)n21

Procedure:
(R)-5-(4-Cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid {1-[1-(4-iodo-pyridin-2-yl)-cyclopropylcarbamoyl]-cyclopropyl}-amide (50 mg, 0.065 mmol), methanesulfonamide (7.4 mg, 0.078 mmol), sarcosine (1.2 mg, 0.13 mmol), copper (I) iodide 0.76 mg, 0.004 mmol) and potassium phosphate (33.9 mg, 0.126 mmol) were combined in a Biotage microwave tube and flushed with Ar. The reaction was diluted with DMF and sealed.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15]C)=[C:6]([C:8]2[C:13](N)=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1.C1COCC1.[H+].[B-](F)(F)(F)F.N([O-])=O.[Na+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:15][C:13]3[C:8](=[N:9][CH:10]=[CH:11][CH:12]=3)[C:6]=2[CH:7]=1
Reactant: COc1ccc(Cl)cc1-c1ncccc1N
Agent: F[B-](F)(F)F
Agent: O=N[O-]
Agent: [H+]
Solvent: O
Solvent: C1CCOC1
Product: Clc1ccc2oc3cccnc3c2c1
Temperature: -10 °C
Reaction time: 8 h
Yield: 75.6 %

Procedure:
The 500 mL round-bottom flask, equipped with magnetic stirrer and reflux condenser was charged with 2-(5-chloro-2-methoxyphenyl)pyridin-3-amine (9.00 g, 39 mmol), 70 mL THF, 70 mL HBF4 (50% in water) and 40 mL H2O. Reaction mixture was cooled to −10° C., and solution of sodium nitrite (5.6 g in 20 mL water) was added dropwise. Reaction mixture was warmed gradually to room temperature and stirred overnight. The reaction mixture was diluted with 500 mL of water and extracted with ethyl acetate (4×50 mL). Organic fractions were combined, dried over sodium sulfate and evaporated, the residue was subjected to column chromatography on silica gel with hexane/ethyl acetate 9/1 mixture, providing 8-chlorobenzofuro[3,2-b]pyridine (6.00 g, colorless needles from hexane/ethyl acetate).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]1([CH2:17][CH2:18][OH:19])([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12]1.C(N(CC)CC)C>ClCCl>[C:11]1([CH2:17][CH:18]=[O:19])([CH2:14][CH:15]=[O:16])[CH2:13][CH2:12]1
Reactant: OCCC1(CCO)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=CCC1(CC=O)CC1
Temperature: -50 °C
Reaction time: 0.17 h

Procedure:
7.0 ml (79.9 mmol) of oxalyl chloride were dissolved in 45 ml of abs. dichloromethane, the mixture was cooled to −50° C. and a solution of 10.9 ml (163.6 mmol) of DMSO in 45 ml of abs. dichloromethane was added dropwise. After the end of the addition, the mixture was stirred at −50° C. for another 10 min, and 4.0 g (30.7 mmol) of 2,2′-cyclopropane-1,1-diyldiethanol, dissolved in 45 ml of abs. dichloromethane, were then added slowly. The resulting suspension was stirred at −50° C. for 10 min and then cooled to −78° C., and a solution of 44.5 ml (320 mmol) of triethylamine in 75 ml of abs. dichloromethane was added dropwise. After the end of the addition, the reaction mixture was stirred at −78° C. for 30 min and then slowly warmed to RT and subsequently washed with saturated aqueous sodium bisulphate solution. The organic phase was dried over sodium sulphate and concentrated under reduced pressure. This gave 5.10 g of the target product as an orange oil (crude product of a purity of about 70%, about 92% of theory).
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]1[CH:16]([C:17]([OH:19])=O)[CH:15]2[O:20][CH:12]1[CH2:13][CH2:14]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:21]1([CH2:27][CH2:28][OH:29])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CO.C(Cl)Cl>[CH2:1]([O:8][C:9]([CH:11]1[CH:16]([C:17]([N:24]2[CH2:25][CH2:26][N:21]([CH2:27][CH2:28][OH:29])[CH2:22][CH2:23]2)=[O:19])[CH:15]2[O:20][CH:12]1[CH2:13][CH2:14]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1C2CCC(O2)C1C(=O)OCc1ccccc1
Reactant: OCCN1CCNCC1
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(OCc1ccccc1)C1C2CCC(O2)C1C(=O)N1CCN(CCO)CC1
Temperature: 25 °C

Procedure:
To a solution of compound 10 (3.00 g, 11.6 mmol) in CH2Cl2 at 0° C. (60 mL) was added piperazine-1-ethanol (11) (1.82 g, 14.0 mmol), EDC (3.12 g, 16.3 mmol), HOBt (0.20 g) and DIPEA (5.8 mL, 34.9 mmol). The mixture was allowed to warm to RT over 16 h. TLC (5% MeOH/CH2Cl2) showed no starting material. The reaction mixture was diluted with CH2Cl2 (50 mL), washed with water (2×40 mL) and dried. Evaporation of organic layer gave a residue. The residue was triturated with diisopropyl ether (20 mL) to get 3-[4-(2-hydroxy-ethyl)-piperazine-1-carbonyl]-7-oxa-bicyclo[2.2.1]heptane-2-carboxylic acid benzyl ester (12) as a white solid. Yield: 3.24 g (72%). Mp 72-75 C. 1H NMR (300 MHz, CDCl3) δ 1.42-1.56 (m, 2H); 1.76-1.82 (m, 2H); 2.02 (s, 2H); 2.29-2.51 (m, 4H); 2.90 (d, J=6.4 Hz, 1H); 3.08 (d, J=6.1 Hz, 1H); 3.18-3.24 (m, 2H); 3.41 (bs, 1H); 3.60 (t, J=2.3 Hz, 2H); 3.69 (bs, 1H); 4.90 (dd, J=6.8 Hz, 2.3 Hz, 2H); 5.08 (s, 2H); 7.28-7.40 (m, 5H).
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH:17]=[O:18])[CH:15]=3)[N:10]([C:19]([NH:21][C:22]3[S:23][C:24]([Cl:27])=[CH:25][N:26]=3)=[O:20])[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2].[CH3:28][Mg]Br>O1CCCC1.[Cl-].[NH4+]>[C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH:17]([OH:18])[CH3:28])[CH:15]=3)[N:10]([C:19]([NH:21][C:22]3[S:23][C:24]([Cl:27])=[CH:25][N:26]=3)=[O:20])[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(C=O)cc12
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(C(C)O)cc12
Reaction time: 1 h
Yield: 91 %

Procedure:
The 1′-acetyl-N-(5-chlorothiazol-2-yl)-5-formylspiro[indoline-3,3′-pyrrolidine]-1-carboxamide (30.0 mg, 0.074 mmol) obtained in Step 2 of Example 401 was dissolved in tetrahydrofuran (1.4 mL). Thereafter, methyl magnesium bromide (1 M tetrahydrofuran solution, 224 μL) was added to the above obtained solution under cooling on ice, and the thus obtained mixture was then stirred at the same temperature as above for 1 hour. Thereafter, the reaction solution was diluted with a saturated aqueous solution of ammonium chloride, and was then extracted with chloroform. The organic layer was washed with brine, and was then dried over anhydrous sodium sulfate, followed by concentration in vacuo. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=10:1) to obtain the captioned compound (28.1 mg, 91%) in the form of a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[CH2:18].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C([O-])(=O)C.[Na+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(Cl)Cl.CCCCC>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:2]([CH:18]=[CH:17][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:7]=1
Reactant: C=Cc1ccccn1
Reactant: Clc1ccc(OCc2ccccc2)c(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCCCC
Product: Clc1ccc(OCc2ccccc2)c(C=Cc2ccccn2)c1
Yield: 57.6 %

Procedure:
124.4 g (417.8 mmol) of 2-Bromo-4-chlorobenzyloxybenzene, 54.8 ml (501.4 mmol) of 2-vinylpyridine, 4.69 g (20.9 mmol) palladium acetate, 25.4 g (83.6 mmol) tritolylphosphine, and 48 g (584.9 mmol) sodium acetate are heated together in 200 ml DMF at 165° C. (oil bath temperature) under nitrogen for 8 hours. The cooled mixture is evaporated to dryness in vacuo. The residue is then diluted with Et2O:DCM (3:1, 1 L) and washed with sodium carbonate solution (1M, 3×1 L). The aqueous washings are extracted with Et2O:DCM (3:1, 1L) and the combined organic extract dried using MgSO4, filtered through celite, and evaporated to dryness to leave an orange solid. Flash chromatography (SiO2, DCM:pentane 3:1) gave a yellow solid which was triturated with pentane (600 ml) to give the title compound as a pale yellow solid (77.5 g, 58%), m.p. 105.2-105.8° C. 6H (250 MHz, CDCl3) 8.60 (d, J=4.5 Hz, 1H), 7.96 (d, J=16.3 Hz, 1H), 7.64-7.60 (m, 2H), 7.46-7.34 (m, 7H), 7.24 (d, J=16.6 Hz, 1H), 7.18-7.11 (m, 1H), 6.95 (d, J=8.9 Hz, 1H), 5.16 (s, 2H).
Reaction SMILES: Cl.[CH2:2]1[C:7]2([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][N:3]1[C:13]([C:15]1[CH:23]=[C:22]2[C:18]([CH2:19][CH2:20][C@H:21]2[NH:24][C:25](=[O:33])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])=[CH:17][CH:16]=1)=[O:14].C(N(CC)CC)C.Cl.Cl[C:43]1[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=1.C([O-])(O)=O.[Na+]>C(O)CCC.C(OCC)(=O)C>[Cl:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:25]([NH:24][C@H:21]1[C:22]2[C:18](=[CH:17][CH:16]=[C:15]([C:13]([N:3]3[CH2:4][CH2:5][CH2:6][C:7]4([CH2:8][CH2:9][N:10]([C:43]5[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=5)[CH2:11][CH2:12]4)[CH2:2]3)=[O:14])[CH:23]=2)[CH2:19][CH2:20]1)=[O:33]
Reactant: O=C(N[C@@H]1CCc2ccc(C(=O)N3CCCC4(CCNCC4)C3)cc21)c1ccccc1Cl
Reactant: Clc1ccncc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1CCc2ccc(C(=O)N3CCCC4(CCN(c5ccncc5)CC4)C3)cc21)c1ccccc1Cl
Temperature: 110 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
A mixture of (R)—N-(6-(2,9-diazaspiro[5.5]undecane-2-carbonyl)-2,3-dihydro-1H-inden-1-yl)-2-chlorobenzamide hydrochloride (0.491 mmol, 1.0 eq.), triethylamine (5.0 eq.) and 4-chloropyridine hydrochloride (3.0 eq.) in n-butanol (13 ml) was stirred at 110° C. overnight. Ethyl acetate and sat. NaHCO3 solution were added and the aqueous phase was extracted with ethyl acetate a further 4×. The combined organic phases were washed 1× with sat. NaCl solution, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (silica, ethyl acetate/ethanol/ammonia (25% aq) 100:10:1) to obtain the desired product (H-54). Yield: 73%
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[N:16]=[C:15](Cl)[C:14]([F:18])=[CH:13][C:10]=1[C:11]#[N:12].CS(C)=O.[C:23]([N:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH:28]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:27]1)(=[O:25])[CH3:24]>C(OCC)(=O)C>[C:23]([N:26]1[CH2:31][CH2:30][CH:29]([NH:32][C:15]2[C:14]([F:18])=[CH:13][C:10]([C:11]#[N:12])=[C:9]([Cl:8])[N:16]=2)[CH:28]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:27]1)(=[O:25])[CH3:24]
Reactant: CC(=O)N1CCC(N)C(NC(=O)OC(C)(C)C)C1
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)N1CCC(Nc2nc(Cl)c(C#N)cc2F)C(NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.7 %

Procedure:
Triethylamine (0.096 ml) and 2,6-dichloro-5-fluoronicotinonitrile (109 mg) were added to a DMSO (2 ml) solution containing tert-butyl (1-acetyl-4-aminopiperidin-3-yl)carbamate (147 mg) obtained in the 4th step, followed by stirring at room temperature for 1 hour. Ethyl acetate was added to the reaction solution. The reaction solution was washed with water and saturated saline and dried over anhydrous sodium sulfate. Next, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1 to 2:3). A light yellow solid of tert-butyl (1-acetyl-4-((6-chloro-5-cyano-3-fluoropyridin-2-yl)amino)piperidin-3-yl)carbamate (91 mg) was thus obtained.