Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[N+:12]([O-:14])=[O:13].[NH2:15][C:16]1[S:17][C:18]([CH3:23])=[CH:19][C:20]=1[C:21]#[N:22].Cl>C1COCC1>[C:8]([C:7]1[CH:10]=[CH:11][C:4]([NH:15][C:16]2[S:17][C:18]([CH3:23])=[CH:19][C:20]=2[C:21]#[N:22])=[C:5]([N+:12]([O-:14])=[O:13])[CH:6]=1)#[N:9]
Reactant: Cc1cc(C#N)c(N)s1
Reactant: N#Cc1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C#N)c(Nc2ccc(C#N)cc2[N+](=O)[O-])s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of sodium hydride (60%, 0.58 g) in THF (2 mL), was added 4-fluoro-3-nitro-benzonitrile (1.33 g, 8.0 mmol) and 2-amino-5-methyl-thiophene-3-carbonitrile (1.10 g, 8.0 mmol) in THF (10 mL), dropwise. The mixture was stirred at room temperature overnight. Two more batches of sodium hydride (60%, 0.50 g and 0.4 g) were added over the next 6 hours. After stirring for 3 days, the mixture was poured into ice-water (20 mL) and acidified to pH 3 with 6N hydrochloric acid (7 mL). The precipitate was filtered and washed with water. The solid was extracted with dichloromethane (35 mL). The solution was concentrated to a solid, and used in the next step without additional purification. LC-MS: m/z 285 (M+1), 307 (M+23). 1H NMR (CDCl3, 400 MHz): δ (ppm) 9.76 (s, 1H), 8.59 (s, 1H), 7.70 (d, 1H), 7.14 (d, 1H), 6.87 (s, 1H), 2.52 (s, 1H).
Reaction SMILES: O=C1CCCN1C1C=C(C=C(N2CCCC2=O)C=1)C(O)=O.[CH:22]1([CH2:25][O:26][C:27]2[CH:28]=[C:29]([CH:34]=[C:35]([N:37]3[CH2:41][CH2:40][CH2:39][C:38]3=[O:42])[CH:36]=2)[C:30]([O:32]C)=[O:31])[CH2:24][CH2:23]1>>[CH:22]1([CH2:25][O:26][C:27]2[CH:28]=[C:29]([CH:34]=[C:35]([N:37]3[CH2:41][CH2:40][CH2:39][C:38]3=[O:42])[CH:36]=2)[C:30]([OH:32])=[O:31])[CH2:23][CH2:24]1
Reactant: COC(=O)c1cc(OCC2CC2)cc(N2CCCC2=O)c1
Agent: O=C(O)c1cc(N2CCCC2=O)cc(N2CCCC2=O)c1
Product: O=C(O)c1cc(OCC2CC2)cc(N2CCCC2=O)c1

Procedure:
Prepared in an analogous manner to D8 from methyl 3-cyclopropylmethoxy-5-(2-oxopyrrolidin-1-yl)benzoate (D42).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.Cl>O1CCOCC1.O>[OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([S:23]([C:20]2[CH:19]=[CH:18][C:17]([O:16][CH3:15])=[CH:22][CH:21]=2)(=[O:25])=[O:24])[CH2:4]1
Reactant: OC[C@H]1CCNC1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1ccc(S(=O)(=O)N2CC[C@H](CO)C2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The 3(S)-hydroxymethylpyrrolidine (0.9 g, 8.90 mmol), triethylamine (1.80 g, 17.8 mmol, 2.0 equiv) in 1,4-dioxane (30 mL) and water (10 mL) is stirred at room temperature and then 4-methoxyphenylsulfonyl chloride (2.02 g, 9.80 mmol, 1.10 equiv) is added. The resulting solution is stirred at room temperature for 3 h. and then the solution is acidified to pH~1 with 1 N HCl. The solution is poured into water and then extracted with CH2Cl2. The organic extracts are dried (Na2SO4) and concentrated to an oil. The oil is purified by chromatography using 1/1 hexane/EtOAc as the eluent to afford the desired product as a colorless oil.
Reaction SMILES: [CH2:1]([C@H:5]1[C@H:9]([CH2:10][CH2:11][S:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:8]C(=O)[NH:6]1)[CH:2]([CH3:4])[CH3:3].O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>O1CCOCC1.O>[NH2:6][C@@H:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C@@H:9]([OH:8])[CH2:10][CH2:11][S:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)C[C@@H]1NC(=O)O[C@H]1CCSCCc1ccccc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)C[C@H](N)[C@@H](O)CCSCCc1ccccc1
Yield: 76.7 %

Procedure:
A solution of 4(S)-isobutyl-5(S)-[2-(phenethylmercapto)ethyl]-2-oxazolidinone (0.52 g, 1.69 mmol) and barium hydroxide octahydrate (1.06 g, 3.38 mmol) in dioxane (60 mL) and water (40 mL) was heated at reflux under N2 for 21 hours. The solid barium carbonate was filtered and the filtrate was partially evaporated. The residue was diluted with water and the resulting solution was extracted with ether. The organic extract was washed with brine solution, dried over MgSO4 and evaporated to a residue. Trituration with cold hexane gave 365 mg (77%) of product, m.p. 95°-96° C.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([NH:20]C(=O)OC(C)(C)C)[CH2:8][N:9]([CH3:19])[C:10]([O:12][CH2:13][CH2:14][Si](C)(C)C)=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:20][C@@H:7]([CH2:6][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)[CH2:8][N:9]([CH3:19])[C:10](=[O:11])[O:12][CH2:13][C:14]1[CH:4]=[CH:5][CH:1]=[CH:2][CH:3]=1
Reactant: CN(C[C@H](CC1CCCC1)NC(=O)OC(C)(C)C)C(=O)OCC[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C[C@@H](N)CC1CCCC1)C(=O)OCc1ccccc1
Yield: 210.7 %

Procedure:
A solution of (S)-tert-butyl 1-cyclopentyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-ylcarbamate (550 mg) in TFA/CH2Cl2 (10 mL, 20% v/v) was stirred for 2 hrs at 5° C. The reaction was neutralized with saturated aqueous NaHCO3 and extracted with CH2Cl2 (3×30 mL). The combined extracts were washed with saturated brine (30 mL), dried over Na2SO4, and evaporated to give (S)-benzyl 2-amino-3-cyclopentylpropyl(methyl)carbamate (420 mg) that was used without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C[Al](C)C.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([C:25]2([CH3:31])[CH2:29][CH2:28][O:27][C:26]2=[O:30])(=[O:24])=[O:23])=[CH:18][CH:17]=1>C(Cl)Cl.C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:26](=[O:30])[C:25]([S:22]([C:19]2[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][CH:20]=2)(=[O:24])=[O:23])([CH3:31])[CH2:29][CH2:28][OH:27])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(N)on1
Reactant: CC1(S(=O)(=O)c2ccc(Cl)cc2)CCOC1=O
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(NC(=O)C(C)(CCO)S(=O)(=O)c2ccc(Cl)cc2)on1
Temperature: 45 °C
Reaction time: 0.25 h
Yield: 61.9 %

Procedure:
To a solution of 3-tert-butyl-isoxazol-5-ylamine (0.421 g; 3.00 mmol) in methylene chloride (5 mL) was added dropwise trimethylaluminum (1.5 mL of a 2.0 M solution in toluene; 3.00 mmol). The mixture was stirred 15 minutes and 3-(4-chloro-benzenesulfonyl)-3-methyl-dihydro-furan-2-one (0.659 g; 2.40 mmol) added. The mixture was stirred 3 hours, heated to 45° C. for approximately 40 hours, cooled to room temperature and carefully quenched with 10% aqueous citric acid, aqueous sodium tartrate and chloroform. The organic layer was dried (MgSO4). Removal of the volatiles in vacuo provided a residue which was purified by silica gel chromatography using ethyl acetate and hexanes as the eluent. Removal of the volatiles from the product-rich fractions provided 0.616 g of the desired product. 1H NMR (CDCl3) δ 9.85 (bs, 1H), 7.75 (d, 2H), 7.55 (d, 2H), 6.24 (s, 1H), 3.97 (m, 1H), 3.85 (m, 1H), 2.62 (m, 1H), 2.32 (m, 1H), 1.65 (s, 3H), 1.32 (s, 9H). MS (ESI): m/e 415, 417 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[F:20][C:21]([F:31])([F:30])[C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1>CN(C=O)C.C(OCC)(=O)C>[F:20][C:21]([F:30])([F:31])[C:22]1[CH:29]=[CH:28][C:25]([CH2:26][O:1][C:2]2[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=2)=[CH:24][CH:23]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CCOC(=O)Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1cccc(OCc2ccc(C(F)(F)F)cc2)c1
Reaction time: 12 h

Procedure:
To a stirred solution of Ethyl 2-(3-hydroxyphenyl)acetate (7.3 g, 30.5 mmol) in DMF (20 ml) was added potassium carbonate (5.47 g, 39.6 mmol) at room temperature followed by drop wise addition of 4-Trifluoromethylbenzyl bromide (6.04 g, 33.6 mmol). The reaction mixture was stirred for 12 hours and taken in ethyl acetate, washed with water (2×), brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (hex:ether 5:1) to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][CH2:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([N:25]([CH3:27])[CH3:26])[CH2:21][CH2:20]1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([Cl:44])[C:30]=1[OH:45]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][CH2:18][C@H:19]2[CH2:20][CH2:21][C@H:22]([N:25]([CH3:27])[CH3:26])[CH2:23][CH2:24]2)=[CH:3][C:2]([C:33]2[CH:34]=[C:29]([Cl:28])[C:30]([OH:45])=[C:31]([Cl:44])[CH:32]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:15][CH2:16]1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CN(C)[C@H]1CC[C@H](CNc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Product: CN(C)[C@H]1CC[C@H](CNc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)cc23)CC1

Procedure:
Following general procedure F, (6-bromo-4-{[trans-4-(dimethylamino)cyclohexyl]methylamino}quinolin-3-yl)(cyclopropyl)methanone (66 mg, 0.153 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (65 mg, 0.230 mmol) to afford the desired product (38 mg, 50%) as a yellow solid: 1H NMR (300 MHz, CD3OD+Acetic Acid-d4) δ 9.24 (s, 1H), 8.49 (d, J=1.7 Hz, 1H), 8.10 (dd, J=8.8, 1.8 Hz, 1H), 7.95 (d, J=8.8 Hz, 1H), 7.68 (s, 2H), 3.90 (d, J=6.5 Hz, 2H), 2.85 (d, J=11.2 Hz, 6H), 2.15 (t, J=11.3 Hz, 4H), 2.01-1.74 (m, 2H), 1.61 (dd, J=21.6, 12.1 Hz, 2H), 1.46-1.07 (m, 7H); ESI MS m/z 512 [C28H31Cl2N3O2+H]+; HPLC 99.0% (AUC), tR=10.65 min.
Reaction SMILES: N1C=CN=C1.C(N(CC)CC)C.[CH:13]([OH:15])=O.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:34]=[C:33]([NH:35][C:36]3[CH:41]=[C:40]([O:42][CH3:43])[C:39]([O:44][CH3:45])=[C:38]([O:46][CH3:47])[CH:37]=3)[C:32]3=[C:48]([CH3:52])[N:49]=[C:50]([CH3:51])[N:31]3[N:30]=2)=[CH:25][CH:24]=1>ClCCl>[CH3:52][C:48]1[N:49]=[C:50]([CH3:51])[N:31]2[C:32]=1[C:33]([NH:35][C:36]1[CH:37]=[C:38]([O:46][CH3:47])[C:39]([O:44][CH3:45])=[C:40]([O:42][CH3:43])[CH:41]=1)=[N:34][C:29]([C:26]1[CH:25]=[CH:24][C:23]([NH:22][CH:13]=[O:15])=[CH:28][CH:27]=1)=[N:30]2
Reactant: O=CO
Reactant: COc1cc(Nc2nc(-c3ccc(N)cc3)nn3c(C)nc(C)c23)cc(OC)c1OC
Agent: O=C(Cl)C(=O)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(Nc2nc(-c3ccc(NC=O)cc3)nn3c(C)nc(C)c23)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
16 mg (0.24 mmol) of imidazole, 48 mg (0.48 mmol) of triethylamine and 11 mg (0.24 mmol) of formic acid are introduced into 4 ml dichloromethane under argon, cooled to 0° C. and treated dropwise with a solution of 30 mg (0.24 mmol) of oxalyl dichloride in dichloromethane. The mixture is allowed to warm to 20° C. and subsequently 100 mg (0.24 mmol) of N-[2-(4-aminophenyl)-5,7-dimethyl-imidazo[5,1-f][1,2,4]triazin-4-yl]-N-(3,4,5-trimethoxyphenyl)amine from example 3 are added thereto. It is stirred overnight and then washed with aqueous sodium hydrogencarbonate solution. The organic phase is dried and purified by flash chromatography (dichloromethane/methanol 100:1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]2)#[N:2].Cl.[NH2:20][OH:21].CCN(C(C)C)C(C)C>CCO>[OH:21][NH:20][C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]2)=[NH:2]
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(C#N)cc2C1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1Cc2ccc(C(=N)NO)cc2C1
Yield: 99.7 %

Procedure:
A product of Step C (0.22 g; 0.904 mmol), HCl×NH2OH (0.16 g; 2.3 mmol) and DIPEA (0.48 ml; 5 mmol) in anhydrous EtOH (3.5 ml) was refluxed for 2 h under N2. The solvents were removed under reduced pressure and the residue was diluted to 30 ml with EtOAc, washed with H2O (2×5 ml), brine, dried over anhydrous MgSO4, filtered and the filtrate evaporated to dryness to give the title compound (0.25 g; 100%) as colourless foam, which was used in next step without further purification.
Reaction SMILES: [C:1]1([C@@H:7]([NH:14][C:15]([C@H:17]2[N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19][S:18]2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:29].[OH-].[Na+]>C(Cl)Cl>[ClH:29].[C:1]1([C@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[NH:14][C:15]([C@H:17]2[NH:21][CH2:20][CH2:19][S:18]2)=[O:16])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCS[C@H]1C(=O)N[C@H](c1ccccc1)c1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(N[C@H](c1ccccc1)c1ccccn1)[C@H]1NCCS1
Temperature: -30 °C
Reaction time: 3 h

Procedure:
In a 6 L 4-neck flask, was added a solution containing a compound of general structure (V) (Intermediate 6, 60 g g, 150.18 mmol), e.g., tert-butyl (2S)-2-({[(R)-phenyl(pyridin-2-yl)methyl]amino}carbonyl)-1,3-thiazolidine-3-carboxylate, in DCM under argon atmosphere (1250 ml). At −30° C., a solution of HCl conc. (627 mL, 7509 mmol) was added slowly during a period of 40 minutes. The reaction mixture was stirred at −30° C. for 3 h 30. The reaction was kept at −30° C. and a solution of 1 L of NAOH 1M was added followed by 1250 mL of NaOH 5M so that to obtain pH=5. The last 50 mL of 5M NaOH solution were added at −10° C. due to formation if ice in the flask. The slurry was extracted with DCM (5×500 mL) and dried over MgSO4 and evaporated to almost dryness. The desired product, e.g., (2S)—N—[(R)-phenyl(pyridin-2-yl)methyl]-1,3-thiazolidine-2-carboxamide hydrochloride, was isolated and used for the next step without further purification and shows no trace of racemisation.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].C(O)C.[CH:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>Cl.O>[C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[C:3]=1[C:14]1[C:13]([CH:12]=[O:19])=[CH:18][CH:17]=[CH:16][CH:15]=1)[OH:2]
Reactant: Oc1cccc(O)c1
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=Cc1ccccc1-c1c(O)cccc1O

Procedure:
To a solution of 550 g. of resorcinol in 1 l. of ethanol were added 530 g. of benzaldehyde and 0.5 ml. of 35% conc. hydrochloric acid as a catalyst. The resulting mixture was heated under reflux for 90 minutes with stirring and, after completion of the reaction, the reaction mixture was poured into 5 l. of a cold water to give a pale brown powdery resin.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:8]([OH:9])=[CH:7][C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[S-:17][C:18]#N.[NH4+]>CO>[CH3:13][C:12]([C:10]1[CH:11]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([OH:16])=[C:7]([S:17][CH3:18])[C:8]=1[OH:9])([CH3:15])[CH3:14]
Reactant: N#C[S-]
Reactant: CC(C)(C)c1cc(C(C)(C)C)c(O)cc1O
Agent: [NH4+]
Solvent: CO
Product: CSc1c(O)c(C(C)(C)C)cc(C(C)(C)C)c1O
Reaction time: 24 h

Procedure:
A mixture of 4,6-di-t-butylresorcinol (25.0 g, 112 mmole) and ammonium thiocyanate (18.0 g, 235 mmole) in methanol (100 ml) was stirred for 24 hours. The mixture was cooled to 0° and chlorine gas was bubbled through the solution for one hour. After the mixture was stirred for an additional hour at 0°, ammonia gas was bubbled through for one hour. A solid was removed by filtration and the filrate was concentrated in vacuo. Chromatography on silica gel and recrystallization from hexane gave the title compound.
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:21])([F:20])[S:9]([O:12]S(C(F)(F)F)(=O)=O)(=[O:11])=[O:10].[C:22]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:27]=[CH:26][C:25]([CH2:28][N:29]2[C:38]3[C:33](=[C:34](O)[CH:35]=[CH:36][C:37]=3[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:32][CH2:31][C:30]2=[O:46])=[CH:24][CH:23]=1>ClCCl>[C:22]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:27]=[CH:26][C:25]([CH2:28][N:29]2[C:38]3[C:33](=[C:34]([O:12][S:9]([C:8]([F:21])([F:20])[F:7])(=[O:11])=[O:10])[CH:35]=[CH:36][C:37]=3[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:32][CH2:31][C:30]2=[O:46])=[CH:24][CH:23]=1
Reactant: O=C1CCc2c(O)ccc(-c3ccccc3)c2N1Cc1ccc(-c2ccccc2)cc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C1CCc2c(OS(=O)(=O)C(F)(F)F)ccc(-c3ccccc3)c2N1Cc1ccc(-c2ccccc2)cc1
Reaction time: 1 h

Procedure:
Pyridine (1.12 ml) and trifluoromethanesulfonic anhydride (1.99 ml) were added with stirring at 0° C. to an anhydrous dichloromethane solution (40 ml) of 1-(biphenyl-4-ylmethyl)-5-hydroxy-8-phenyl-3,4-dihydro-1H-quinolin-2-one (4.0 g), followed by stirring for 1 hour. The resulting mixture was concentrated under reduced pressure, water was added to the residue, and extraction with dichloromethane was performed. The extract was washed with water, an aqueous potassium hydrogensulfate solution and water in this order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to thereby obtain 5.45 g (yield: quantitative) of 1-(biphenyl-4-ylmethyl)-8-phenyl-5-trifluoromethanesulfonyloxy-3,4-dihydro-1H-quinolin-2-one as a white amorphous solid.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:8]=1[OH:14])([CH3:6])([CH3:5])[CH3:4].[CH2:15]([N:27]1[C:31](=[O:32])[CH:30]=[CH:29][C:28]1=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C(O)(C)(C)C>[C:3]([C:7]1[CH:12]=[C:11]([CH:30]2[CH2:29][C:28](=[O:33])[N:27]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:31]2=[O:32])[CH:10]=[C:9]([CH3:13])[C:8]=1[OH:14])([CH3:6])([CH3:5])[CH3:4]
Reactant: Cc1cccc(C(C)(C)C)c1O
Reactant: CCCCCCCCCCCCN1C(=O)C=CC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CCCCCCCCCCCCN1C(=O)CC(c2cc(C)c(O)c(C(C)(C)C)c2)C1=O

Procedure:
This compound is prepared by the procedure of Example 1 from 1.20 g (50 mmol) of sodium hydride, 8.21 g (50 mmol) of 2-tert-butyl-6-methylphenol, and 13.27 g (50 mmol) of N-n-dodecylmaleimide in tert-butyl alcohol. The residue is purified by preparative HPLC (8:2 heptane:ethyl acetate eluent) to give 4.70 g (22%) of a yellow wax.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[NH:10][N:9]=1)=[O:7])C>CO>[CH3:16][CH:15]([CH3:17])[CH2:14][CH2:13][C:11]1[NH:10][N:9]=[C:8]([C:6]([OH:7])=[O:5])[CH:12]=1
Reactant: CCOC(=O)c1cc(CCC(C)C)[nH]n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CCc1cc(C(=O)O)n[nH]1
Yield: 97.6 %

Procedure:
Freshly prepared aq. NaOH (10 M in H2O, 80.85 mmol) was added to a stirring, room temperature solution of 47 (3.40 g, 16.17 mmol) in MeOH (40.4 mL, 0.4 M) under N2. The reaction was then heated to reflux until the reaction was judged complete by HPLC (6 min): The reaction was concentrated and then dissolved in 14 mL H2O. 10% aq. HCl was added dropwise until the pH=2. The white solid that precipitated from the reaction was filtered off and washed with cold H2O. The solid was dried under vacuum overnight to obtain 2.8753 g (97.6%) of 48. (Note: An undesired impurity has a retention time of 9.522 min by HPLC.) 1H (CDCl3, 400 MHz): δ 6.61 (1H, s), 2.70 (2H, t, J=7.8 Hz), 1.63-1.51 (3H, m), 0.94 (6H, d, J=6.3 Hz) ppm. 13C (CDCl3, 100 MHz): δ 164.35, 149.48, 143.00, 107.34, 39.35, 28.71, 24.69, 22.65 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 22.65; CH2 carbons: 39.35, 24.69; CH carbons: 107.34, 28.71 ppm. HPLC: 9.522 min.
Reaction SMILES: CC(C)(OC([NH:7][C@H:8]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=1)[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[CH:18]=[CH:19][N:20]=[C:14]2[CH2:13]1)=[O:11])=O)C.[ClH:31]>CO>[ClH:31].[ClH:31].[NH2:7][C@H:8]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=1)[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[CH:18]=[CH:19][N:20]=[C:14]2[CH2:13]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2ccnc2C1)Cc1ccc(F)c(F)c1
Agent: Cl
Solvent: CO
Product: N[C@@H](CC(=O)N1CCn2ccnc2C1)Cc1ccc(F)c(F)c1

Procedure:
The title compound was prepared from 7-[(3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(3,4-difluorophenyl)butanoyl]-5,6,7,8-tetrahydroimidazo[1,2-α]pyrazine (72 mg, 0.171 mmol, from Step C), in 1.5 mL of methanol saturated with hydrogen chloride, using a procedure analogous to that described in Example 1, Step D. Concentration gave 66 mg of the title compound as a foamy solid. 1H NMR (500 MHz, CD3OD) δ 2.96-3.13 (m, 4H), 3.93 (m, 1H), 4.13 (m, 2H), 4.26-4.38 (m, 2H), 4.26-4.38 (m, 2H), 4.90-5.04 (m, 2H), 7.19-7.36 (m, 3H), 7.58 (m, 1H). ESI-MS 321 (M+1).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][S:10][C:11]2[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:19]([SH:21])#N.N>ClC1C=CC=CC=1Cl>[C:1]1([CH2:7][CH2:8][CH2:9][S:10][C:11]2[CH:12]=[CH:13][C:14]([N:15]=[C:19]=[S:21])=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccc(SCCCc2ccccc2)cc1
Reactant: N#CS
Agent: Cl
Agent: N
Solvent: Clc1ccccc1Cl
Product: S=C=Nc1ccc(SCCCc2ccccc2)cc1

Procedure:
6.4 g of the 4-(3'-phenyl-propylthio)-aniline obtained under (b) is dissolved in 50 ml of 1,2-dichlorobenzene, and the solution is saturated at room temperature, with stirring, with anhydrous hydrogen chloride. There is subsequently added 2.5 g of ammonium rhodanide, and the whole is heated, with the continuous introduction of hydrogen chloride, for 6 hours at 130° to 140°. The undissolved constituents are filtered off, and the filtrate is chromatographed through silica gel with 1,2-dichlorobenzene as the eluant. There is obtained pure 4-(3'-phenyl-propylthio)-phenyl-isothiocyanate having a refractive index of nD25 = 1.6672 (= Compound No. 1).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[NH2:24][CH:25]1[CH2:30][CH2:29][CH:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][NH:24][CH:25]2[CH2:30][CH2:29][CH:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:35])([CH3:37])[CH3:36])[CH2:27][CH2:26]2)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5]
Reactant: O=Cc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NC1CCC(NCc2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CC1
Yield: 50.1 %

Procedure:
Prepared according to the method described in Example 31b from 2-chloro-5-formyl-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.30 g, Example 31a), (4-aminocyclohexyl)-carbamic acid, 1,1-dimethylethyl ester (0.194 g, Journal of Organic Chemistry, 1996, 61(25), 8811-8818), sodium triacetoxyborohydride (0.135 g) and 1,2-dichloroethane (10 ml). The residue was purified by chromatography over silica gel eluting with ethyl acetate: iso-hexane (1:1) then ethyl acetate: ethanol (95:5) to give the subtitle compound as a colourless oil (0.24 g).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH:19]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH2:19][N:32]2[CH2:31][CH2:30][N:29]([CH:28]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[C:25]3[CH:24]=[CH:23][C:22]([F:21])=[CH:27][CH:26]=3)[CH2:34][CH2:33]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: Cc1ccc(-c2cc(CCC=O)nn2C(C)(C)C)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(CCCN3CCN(C(c4ccc(F)cc4)c4ccc(F)cc4)CC3)nn2C(C)(C)C)cc1

Procedure:
111 mg (86%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-p-tolyl-1H-pyrazol-3-yl)propanal (60 mg, 0.222 mmol), 1-(bis(4-fluorophenyl)methyl)piperazine (64 mg, 0.222 mmol), DIPEA (0.06 mL, 0.333 mmol) and NaBH(OAc)3 (141 mg, 0.666 mmol).