Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[O:6]=[C:7]1[CH2:16][CH2:15][CH2:14][C:13]2[C:12]([C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:10]=[CH:9][C:8]1=2.CO>C1COCC1>[OH:6][C:7]1([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)[CH2:16][CH2:15][CH2:14][C:13]2[C:12]([C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:10]=[CH:9][C:8]1=2
Reactant: COC(=O)c1cccc2c1CCCC2=O
Reactant: c1cscn1
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cccc2c1CCCC2(O)c1nccs1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To an oven-dried, N2-purged flask was added isopropyl magnesium chloride lithium chloride complex (7.91 mL, 10.3 mmol) and THF (18.4 mL) and the solution was cooled to 0° C. A solution of thiazole (0.813 g, 9.55 mmol) in THF (9.18 mL) was then added, and the reaction was stirred for 45 min at 0° C., and then cooled to −10° C. A solution of methyl 5-oxo-5,6,7,8-tetrahydronaphthalene-1-carboxylate (1.5 g, 7.34 mmol) in THF (9.18 mL) was then added, after which the reaction was allowed to warm to rt over a period of 4 h. MeOH (5 mL) was then added and the reaction was partitioned between water (50 mL) and EtOAc (50 mL). The aqueous phase was extracted with EtOAc (2×50 mL), then the combined organic phases were dried (MgSO4), filtered and concentrated. The product was purified by silica gel chromatography using a gradient solvent system of 0-70% EtOAc/DCM. The product-containing fractions were collected and concentrated to give racemic methyl 5-hydroxy-5-(thiazol-2-yl)-5,6,7,8-tetrahydronaphthalene-1-carboxylate as a yellow oil. The enantiomers were resolved by chiral SFC using a Chiral Technology AY-H 2.1×25 cm, 5 uM column, eluting with 20%-50% MeOH+0.25% dimethyl ethylamine/CO2. At a flow rate of 70 mL/min, the two enantiomers eluted at 2.38 min and 2.79 min.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.CN(C=O)C.F[C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([S:25][C:26]2[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=2)[CH:24]=1)[C:20]#[N:21]>CCOCC.[OH-].[Na+]>[I:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:17]2[CH:18]=[C:19]([CH:22]=[C:23]([S:25][C:26]3[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=3)[CH:24]=2)[C:20]#[N:21])=[CH:6][CH:5]=1
Reactant: Oc1ccc(I)cc1
Reactant: Cn1ccnc1Sc1cc(F)cc(C#N)c1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cn1ccnc1Sc1cc(C#N)cc(Oc2ccc(I)cc2)c1
Temperature: 160 °C
Reaction time: 0.25 h
Yield: 94.7 %

Procedure:
A mixture of NaH (60%, 312 mg, 7.8 mmol) in oil was rinsed with dry pentane by syringe (3×3 mL) and excess solvent removed under a steam of N2. Solid 4-iodophenol (1.72 g, 7.8 mmol) was added followed by 16 mL of DMF under ice-bath cooling which resulted in a vigorous evolution of gas. After 15 min, solid 3-fluoro-5-(1-methyl-1H-imidazol-2-ylsulfanyl)-benzonitrile (910 mg, 3.9 mmol) was added and the resulting mixture microwave heated at 160° C. for 10 min. After cooling to rt, the mixture was diluted with ether and 3 M aqueous NaOH and shaken. The organic layer was washed with water, brine, dried (MgSO4) and evaporated. The resulting 1.8 g of residue was adsorbed to 4.5 g SiO2 from CH2Cl2 and subjected to MPLC on a 40 g column of SiO2 eluting with % EtOAc in hexanes (time): 33% (10 min), 35-50% (20 min ramp) which provided 1.60 g (95%) of the title compound: 1H NMR (500 MHz, DMSO-d6): δ 3.63 (s, 3H), 6.82 (dd, 1H, J=2, 1 Hz), 6.90 (d, 2H, J=8 Hz), 7.13 (d, 1H, J=1 Hz), 7.26 (t, 1H, J=2 Hz), 7.37 (dd, 114, J=2, 1 Hz), 7.50 (d, 1H, J=1 Hz), 7.75 (d, 2H, J=8 Hz); LCMS (m/z): 434.3 [C17H12IN3OS+H]+.
Reaction SMILES: ClC(OCC(C)C)=O.CN1CCOCC1.[C:16]([OH:21])(=O)[C:17]#[C:18][CH3:19].[NH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[CH:28][C:27]([C:33]#[N:34])=[C:26]2[NH:35][C:36]1[CH:41]=[CH:40][C:39]([Br:42])=[C:38]([Br:43])[CH:37]=1>O1CCCC1>[Br:43][C:38]1[CH:37]=[C:36]([NH:35][C:26]2[C:25]3[C:30](=[CH:31][CH:32]=[C:23]([NH:22][C:16](=[O:21])[C:17]#[C:18][CH3:19])[CH:24]=3)[N:29]=[CH:28][C:27]=2[C:33]#[N:34])[CH:41]=[CH:40][C:39]=1[Br:42]
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1ccc(Br)c(Br)c1
Reactant: CC#CC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3ccc(Br)c(Br)c3)c2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.9 %

Procedure:
Isobutyl chloroformate (0.984 g, 7.18 mmol) and N-methylmorpholine (0.725 g, 7.18 mmol) were added to an ice cold solution of 0.604 g (7.18 mmol) of 2-butynoic acid in 25 mL of tetrahydrofuran. After 10 min, a solution of 1.20 g (2.87 mmol) of 6-amino-4-[(3,4-dibromophenyl)amino]-3-quinolinecarbonitrile in 12 mL of tetrahydrofuran was added dropwise. After stirring overnight at 25° C., volatile material was removed and the residue was slurried in water and filtered. The crude product was washed with boiling EtOAC and ethanol and dried in vacuo(50° C.) to give 0.651 g of brown solid: mass spectrum (electrospray, m/e): M+H 485.
Reaction SMILES: [F:1][C:2]([F:14])([C:7]1[N:11]=[CH:10][N:9]([CH2:12]O)[N:8]=1)[C:3]([F:6])([F:5])[F:4].S(Cl)([Cl:17])=O>ClCCl>[Cl:17][CH2:12][N:9]1[CH:10]=[N:11][C:7]([C:2]([F:14])([F:1])[C:3]([F:6])([F:5])[F:4])=[N:8]1
Reactant: OCn1cnc(C(F)(F)C(F)(F)F)n1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: FC(F)(F)C(F)(F)c1ncn(CCl)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.52 g of 3-(pentafluoroethyl)-1H-1,2,4-triazole 1-ylmethanol was dissolved to 50 ml of dichloromethane, and 2.7 ml of thionyl chloride was added to the solution, followed by stirring at room temperature for overnight. The reaction mixture was concentrated under reduced pressure to obtain 1.36 g of 1-(chloromethyl)-3-(pentafluoroethyl)-1H-1,2,4-triazole.
Reaction SMILES: Br[C:2]1[S:6][C:5]2[CH:7]=[C:8]([Br:10])[S:9][C:4]=2[CH:3]=1.[CH3:11][O:12][C:13](=[O:46])[NH:14][C@H:15]([C:19]([N:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[C:26]1[NH:27][C:28]([C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:32]=2)=[CH:29][N:30]=1)=[O:20])[CH:16]([CH3:18])[CH3:17]>>[CH3:11][O:12][C:13](=[O:46])[NH:14][C@H:15]([C:19]([N:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[C:26]1[NH:27][C:28]([C:31]2[CH:32]=[CH:33][C:34]([C:2]3[S:6][C:5]4[CH:7]=[C:8]([Br:10])[S:9][C:4]=4[CH:3]=3)=[CH:35][CH:36]=2)=[CH:29][N:30]=1)=[O:20])[CH:16]([CH3:18])[CH3:17]
Reactant: Brc1cc2sc(Br)cc2s1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3cc4sc(Br)cc4s3)cc2)[nH]1)C(C)C

Procedure:
Compound 62 was prepared from 2,5-dibromothieno[3,2-b]thiophene (1.678 mmol) and compound 8 (0.383 mmol), following the procedure as described for compound A1, to give compound 62 as a yellow solid in 15% yield. MS (ESI, EI+) m/z=587-589 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)=[CH:16][CH:15]=2)[CH2:9]1)=O)(C)(C)C.Cl.[OH-].[Na+]>C1COCC1.O1CCOCC1>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][NH:20][C:17]2[CH:16]=[CH:15][C:14]([CH:10]3[O:11][CH2:12][CH2:13][NH:8][CH2:9]3)=[CH:19][CH:18]=2)=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(NCc3ccc(Cl)cc3)cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: Clc1ccc(CNc2ccc(C3CNCCO3)cc2)cc1
Temperature: 60 °C
Yield: 70.4 %

Procedure:
To a stirred solution of (RS)-2-[4-(4-chloro-benzylamino)-phenyl]-morpholine-4-carboxylic acid tert-butyl ester (68 mg) in THF (2 ml) was added dropwise a solution of hydrogen chloride in dioxane (0.34 ml, 4 M solution) and the mixture was heated at 60° C. overnight. The mixture was then cooled to room temperature and poured into 1 M aq. sodium hydroxide solution. The mixture was extracted twice with ethyl acetate and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (Isolute® Flash-NH2 from Separtis; gradient: heptane/ethyl acetate/methanol) to afford (RS)-(4-chloro-benzyl)-(4-morpholin-2-yl-phenyl)-amine (36 mg, 70%) as a white solid. MS (ISP): 305.1 ([{37Cl}M+H]+), 303.2 ([{35Cl}M+H]+).
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:13]=3)[CH2:8][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Li:26])CCC>CCOCC>[C:1]([C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:13]=3)[CH2:8][C:7]=2[C:6]=1[Li:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: [Li]CCCC
Reactant: CC(C)(C)c1ccc2c(c1)Cc1cc(C(C)(C)C)ccc1-2
Solvent: CCOCC
Product: [Li]c1c(C(C)(C)C)ccc2c1Cc1cc(C(C)(C)C)ccc1-2
Temperature: -78 °C
Reaction time: 12 h

Procedure:
Preparation 1. A one-liter flask was charged with 2,7-di-tert-butylfluorene (50 g, 179.6 mmol) and a stir bar, capped with a rubber septum, and placed under a nitrogen atmosphere. Diethyl ether (about 300 mL) was added via a cannula, and the resulting mixture was cooled to −78° C. in a dry-ice bath. This mixture was stirred at this temperature as n-butyllithium (21.5 mL of 10 M in hexanes, 215 mmol) was added slowly via syringe. After the addition of n-butyllithium was complete, the reddish solution was slowly warmed to room temperature and stirred overnight (at least about 12 hours), to provide an ether solution of 2,7-di-tert-butylfluorenyl lithium.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11](C2C(=O)N(CC(C)C)N=C(C3C=CC(C)=C(F)C=3)C=2C)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:34][C:35]1[CH:63]=[CH:62][C:38]([CH2:39][N:40]2[C:45](=[O:46])[C:44]([CH2:47]OS(C)(=O)=O)=[CH:43][C:42]([C:53]3[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[C:55]([F:61])[CH:54]=3)=[N:41]2)=[CH:37][CH:36]=1.CN1CCNCC1>>[Cl:34][C:35]1[CH:36]=[CH:37][C:38]([CH2:39][N:40]2[C:45](=[O:46])[C:44]([CH2:47][N:11]3[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]3)=[CH:43][C:42]([C:53]3[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[C:55]([F:61])[CH:54]=3)=[N:41]2)=[CH:62][CH:63]=1
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(Cc3ccc(Cl)cc3)n2)cc1F
Agent: CN1CCNCC1
Product: COc1ccc(-c2cc(CN3CCN(C)CC3)c(=O)n(Cc3ccc(Cl)cc3)n2)cc1F
Yield: 39.5 %

Procedure:
Following the procedure of Example 1 (10), 2-(4-chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as pale brown prisms (yield: 39.5%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C(C(C(C(O)=O)O)O)(O)=O.[CH3:17][C@@H:18]1[CH2:22][CH2:21][CH2:20][NH:19]1.CC1C=CC(S(O[CH2:34][CH2:35][C:36]2[O:37][C:38]3[CH:44]=[CH:43][C:42]([C:45]4[CH:50]=[CH:49][C:48]([C:51]#[N:52])=[CH:47][CH:46]=4)=[CH:41][C:39]=3[CH:40]=2)(=O)=O)=CC=1>C(#N)C>[CH3:17][C@@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH2:34][CH2:35][C:36]1[O:37][C:38]2[CH:44]=[CH:43][C:42]([C:45]3[CH:50]=[CH:49][C:48]([C:51]#[N:52])=[CH:47][CH:46]=3)=[CH:41][C:39]=2[CH:40]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2cc3cc(-c4ccc(C#N)cc4)ccc3o2)cc1
Reactant: C[C@@H]1CCCN1
Agent: O=C(O)C(O)C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H]1CCCN1CCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Temperature: 55 °C

Procedure:
Potassium carbonate powder (2.28 kg, 16.5 mol, 325 mesh) and milled (2R)-2-methylpyrrolidine tartrate (1.78 kg, 7.48 mol) were combined in acetonitrile (37.4 kg) and heated at 55° C. with agitation for 36 hours. The mixture was chilled to about 25° C., and the product from Example 1C (2.07 kg, 4.98 mol) was added to the mixture in portions. The reaction mixture was heated at 65° C. with -agitation for about 48 hours. The mixture was cooled to about 25° C., filtered, and the filtrate was concentrated to a volume of about 10 L. The mixture was partitioned between toluene (32.3 kg) and 5% NaHCO3 solution (23.7 kg). The organic phase was separated and washed with 5% NaHCO3 solution (23.7 kg). The organic phase was then extracted with a mixture of CH3SO3H:N-methylpyrrolidinone:H2O (10:20:70 v/v/v) (32 kg, 8.0 kg respectively). The extract was treated with isopropyl acetate (32.5 kg) and the pH adjusted to about 12 with 50% NaOH solution (about. 4.9 kg) at about 30° C. After stirring, the organic phase was separated and the aqueous phase was extracted with isopropyl acetate (IPAC) (6.0 kg). The organic phases were combined, washed with 5% NaHCO3 (33 kg×3), distilled water (33 kg×2), distilled to a volume of about 10 L, and chased with IPAC (15.6 kg) to about 10 L. The mixture was diluted with isopropyl alcohol (14.5 kg) and concentrated to 10 L. Additional 14.5 kg of isopropyl alcohol was added and the solution concentrated to a volume of 10 L. The solution was treated with active carbon (Darco KB-B, 0.125 kg) and heated at 30° C. with stirring for 1 hour. The mixture was filtered through a pad of Celite® and the Celite® washed with isopropyl alcohol (6.3 kg). The filtrate (about 13 kg) was used directly in the next step (1.17 kg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:24](=O)[C:23](=[C:35](SC)[S:36][CH3:37])[CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].O.[NH2:42][NH2:43]>C(O)C>[C:1]([O:5][C:6](=[O:40])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:27]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:26][C:25]4[C:24]5=[N:42][NH:43][C:35]([S:36][CH3:37])=[C:23]5[CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CSC(SC)=C1CCc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2C1=O
Reactant: NN
Solvent: CCO
Solvent: O
Product: CSc1[nH]nc2c1CCc1nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc1-2
Temperature: 80 °C
Yield: 28.1 %

Procedure:
To a solution of tert-butyl(1-(4-(6-(bis(methylthio)methylene)-5-oxo-3-phenyl-5,6,7,8-tetrahydroquinolin-2-yl)phenyl)cyclobutyl)carbamate (200 mg, 0.35 mmol) in anhydrous ethanol (1.7 mL) was added hydrazine monohydrate (25 μL, 0.52 mmol). The reaction mixture was heated to 80° C. under a nitrogen atmosphere for 2 hours. After cooling to room temperature the reaction mixture was concentrated to dryness under reduced pressure, purified by Biotage chromatography (silica, hexane:ethyl acetate, gradient elution from 90:10 to 80:20) to give the desired product as a yellow solid (53 mg, 28% yield). 1H-NMR (500 MHz, CDCl3) δ 7.94 (1H, s), 7.16-7.24 (4H, m), 7.11-7.16 (3H, m), 7.06-7.10 (2H, m), 3.16 (2H, t), 2.83 (2H, t), 2.35 (3H, s), 2.15-2.45 (4H, br m), 1.88-2.01 (1H, m), 1.64-1.77 (1H, m), 1.00-1.35 (9H, br m). LCMS (Method A) RT=6.94 min, M+H+=539.15.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH:13]1[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].C(N(CC)CC)C.[C:38]([O:42][C:43]([NH:45][C@H:46]([C:48](O)=[O:49])[CH3:47])=[O:44])([CH3:41])([CH3:40])[CH3:39]>C(OCC)(=O)C>[C:38]([O:42][C:43]([NH:45][C@@H:46]([CH3:47])[C:48]([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][C@H:13]1[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])=[O:49])=[O:44])([CH3:41])([CH3:40])[CH3:39]
Reactant: O=C(OCc1ccccc1)C1Cc2ccccc2N1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccccc2C[C@H]1C(=O)OCc1ccccc1
Temperature: 30 °C

Procedure:
200 g of benzyl 2,3-dihydro-1H-indole-2-carboxylate para-toluenesulphonate, 66 ml of triethylamine and 1 litre of ethyl acetate are introduced into a stirred reactor, followed, after stirring for 10 minutes at ambient temperature, by 89 g of N-[tert-butyloxycarbonyl]-(S)-alanine and 151 g of O-(benzotriazol-1-yl)-1,1,3,3-bis(tetramethylene)uronium tetrafluoroborate. The heterogeneous mixture is then heated at 30° C. for 3 hours whilst stirring well and is then cooled to 0° C. and filtered.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:13])[NH:4]1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH3:21][S:22]([O:1][CH2:2][CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:13])[NH:4]1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1NC(CO)Cc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1Cc2ccccc2C(=O)N1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
Dissolve 3-(hydroxymethyl)-3,4-dihydro-2H-isoquinolin-1-one (6.0 g, 33.86 mmol) in DCM (60 mL) and add triethylamine (7.25 g, 67.72 mmol). Cool to 0° C. and add methanesulfonyl chloride (4.65 g, 40.63 mmol) drop-wise. Stir for one hour; dilute with DCM; and wash with water and then brine. Remove the solvents under reduced pressure to give the title compound (8.0 g, 92%). MS (m/z): 256 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:27])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].[CH3:28][C:29]1([CH3:45])[O:34][CH:33]([C:35]([NH:37][CH2:38][CH2:39][C:40](O)=[O:41])=[O:36])[C:32]([CH3:44])([CH3:43])[CH2:31][O:30]1>>[C:9]([NH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:40](=[O:41])[CH2:39][CH2:38][NH:37][C:35]([CH:33]1[C:32]([CH3:43])([CH3:44])[CH2:31][O:30][C:29]([CH3:45])([CH3:28])[O:34]1)=[O:36])(=[O:27])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CC1(C)OCC(C)(C)C(C(=O)NCCC(=O)O)O1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)NCCCCCCN
Product: CCCCCCCC/C=C\CCCCCCCC(=O)NCCCCCCNC(=O)CCNC(=O)C1OC(C)(C)OCC1(C)C
Yield: 47 %

Procedure:
N-(6-Aminohexyl)oleamide (3.81 g) and 2.59 g of 3-[N-(2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl)amino]propionic acid were reacted in the same manner as in Example 1 to obtain 2.92 g of the title compound (yield: 47%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C@@H:18]([CH3:22])[CH2:19][O:20][CH3:21])[CH:16]=1)[C:5]([NH:7][C:8]1[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=1)=[O:6].C[Si](C)(C)[N-][Si](C)(C)C.[Na+].C1COCC1.F[C:39]1[CH:46]=[CH:45][C:42]([C:43]#[N:44])=[CH:41][CH:40]=1>CN(C=O)C>[C:43]([C:42]1[CH:45]=[CH:46][C:39]([O:1][C:2]2[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C@@H:18]([CH3:22])[CH2:19][O:20][CH3:21])[CH:16]=2)[C:5]([NH:7][C:8]2[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=2)=[O:6])=[CH:40][CH:41]=1)#[N:44]
Reactant: N#Cc1ccc(F)cc1
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC[C@H](C)Oc1cc(Oc2ccc(C#N)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60 %

Procedure:
To a stirred solution of 3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide (0.164 mmol) in DMF (1 mL) was added a 1M solution of sodium hexamethyldisilazide in THF (0.164 mmol). The reaction was stirred at RT for 10 minutes before adding 4-fluorobenzonitrile (0.164 mmol) The reaction was stirred overnight at RT, then heated to 60° C. and stirred for a further 4 hours. The reaction was allowed to cool to RT, and treated with a further 0.2 equivalents of 4-fluorobenzonitrile and sodium hexamethyldisilazide, heated to 70° C. and stirred at this temperature for 3 hours. The reaction was cooled to RT, and treated with a further 0.2 equivalents of sodium hexamethyldisilazide, warmed to 70° C., and stirred at this temperature overnight. The solvent was removed in vacuo and the residual oil partitioned between ethyl acetate and water. The water layer was separated and re-extracted with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated to a residue which was chromatographed on silica, using 0-1% methanol in DCM as the eluent, to give the desired product (60% yield).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[NH:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[O:26]1[CH:28]([C:29]2[N:34]=[C:33]([CH3:35])[CH:32]=[CH:31][CH:30]=2)[CH2:27]1>CN(C)C=O>[OH:26][CH:28]([C:29]1[CH:30]=[CH:31][CH:32]=[C:33]([CH3:35])[N:34]=1)[CH2:27][N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[NH:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc3ccccc3[nH]2)CC1
Reactant: Cc1cccc(C2CO2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(C(O)Cn2c(NC3CCN(C(=O)OC(C)(C)C)CC3)nc3ccccc32)n1
Temperature: 40 °C
Reaction time: 1 h
Yield: 38.8 %

Procedure:
Reaction under N2 flow. NaH 60% (0.02 mol) was added to a mixture of 1,1-dimethyl-ethyl 4-(1H-benzimidazol-2-ylamino)-1-piperidinecarboxylate (0.02 mol) in N,N-di-methylformamide (100 ml). The mixture was stirred at 40° C. for 1 hour. 6-(Epoxyethyl)-2-picoline (0.02 mol) in a small amount of N,N-dimethylformamide was added. The mixture was stirred at 100° C. overnight. The solvent was evaporated. The residue was taken up in H2O and CH2Cl2. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 95/5 and 90/10). The pure fractions were collected and the solvent was evaporated, yielding 3.5 g of (±)-1,1-dimethylethyl 4-[[1-[2-hydroxy-2-(6-methyl-2-pyridinyl)ethyl]-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate (interm. 16).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([CH2:23][C:24]#[C:25][CH3:26])[C:21]3[C:20](=[O:27])[N:19]([CH2:28][O:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[C:18](=[O:36])[NH:17][C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:44][CH2:45][O:46][CH2:47][CH3:48]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([CH2:23][C:24]#[C:25][CH3:26])[C:21]3[C:20](=[O:27])[N:19]([CH2:28][O:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[C:18](=[O:36])[N:17]([CH2:44][CH2:45][O:46][CH2:47][CH3:48])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOCCBr
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2[nH]c(=O)n(COC(=O)C(C)(C)C)c(=O)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)n(COC(=O)C(C)(C)C)c(=O)n2CCOCC
Temperature: 60 °C
Reaction time: 2 h

Procedure:
4-[7-(2-Butynyl)-1-(2,2-dimethylpropionyloxymethyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (50 mg) and potassium carbonate (15 mg) were dissolved in N,N-dimethylformamide (1.2 ml), and 2-bromoethylethyl ether (12 μl) was added to the solution. The mixture was stirred at 60° C. for 2 hours, diluted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. After the organic layer was concentrated by distillation, the residue was purified by silica gel column chromatography to give 4-[7-(2-butynyl)-1-(2,2-dimethylpropionyloxymethyl)-3-(2-ethoxyethyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester from the elution fraction of hexane-ethyl acetate (2:1). The obtained 4-[7-(2-butynyl)-1-(2,2-dimethylpropionyloxymethyl)-3-(2-ethoxyethyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester was dissolved in a solvent mixture of tetrahydrofuran (1.0 ml) and methanol (0.5 ml), sodium hydride (5 mg) was added to the solution, and the mixture was stirred at room temperature for 1 hour. After the reaction mixture was neutralized with 2N hydrochloric acid and extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation to give 4-[7-(2-butynyl)-3-(2-ethoxyethyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester. A quarter of the obtained 4-[7-(2-butynyl)-3-(2-ethoxyethyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester was dissolved in trifluoroacetic acid (0.5 ml), and the solution was stirred at room temperature for 30 minutes. After the solvent was removed by distillation, a half of the residue was purified by HPLC with a reversed phase column using water-acetonitrile-trifluoroacetic acid system as elution solvent to give 3.2 mg of the title compound.