Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[CH2:14][CH2:13][C:8]2([CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:7][CH2:6]1)[CH:2]([CH3:4])[CH3:3].[CH2:15]([O:17][CH:18]([O:27][CH2:28][CH3:29])[C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)[CH3:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(O)(=O)C.CN(C)C=O>[CH2:28]([O:27][CH:18]([O:17][CH2:15][CH3:16])[C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:11]2[CH2:10][CH2:9][C:8]3([CH2:7][CH2:6][N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:14][CH2:13]3)[CH2:12]2)=[CH:21][CH:20]=1)[CH3:29]
Reactant: CC(C)CN1CCC2(CCNC2)CC1
Reactant: CCOC(OCC)c1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOC(OCC)c1ccc(CN2CCC3(CCN(CC(C)C)CC3)C2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 61.5 %

Procedure:
To a 10% acetic acid-dimethylformamide (10 mL) solution of 8-isobutyl-2,8-diazaspiro[4.5]decane (600 mg) and 4-(diethoxymethyl)benzaldehyde (661 mg), sodium triacetoxyborohydride (1.30 g) was added. The reaction solution was stirred at room temperature for 14 hours. To the reaction solution, an aqueous 5N sodium hydroxide solution (10 mL) was added. The aqueous layer was extracted twice with dichloromethane (20 mL). The combined organic layer was washed with saturated sodium chloride solution (20 mL) and then dried over anhydrous magnesium sulfate. After removing the anhydrous magnesium sulfate by filtration, the filtrate was concentrated. The residue was purified by silica gel chromatography (ethyl acetate:methanol: 28% aqueous ammonia=1:0:0→100:5:1→100:10:2) to obtain the title compound (730 mg) having the following physical properties.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:3]=1[NH:4][CH:5]([CH3:7])[CH3:6].CCN(C(C)C)C(C)C.[CH:22]1([C:25](Cl)=[O:26])[CH2:24][CH2:23]1.O>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:3]=1[N:4]([CH:5]([CH3:7])[CH3:6])[C:25]([CH:22]1[CH2:24][CH2:23]1)=[O:26]
Reactant: CC(C)Nc1cc(F)ccc1Br
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)N(C(=O)C1CC1)c1cc(F)ccc1Br
Temperature: 20 °C
Reaction time: 24 h

Procedure:
2-Bromo-5-fluoro-N-(propan-2-yl)aniline E-1.7′″″ (2.20 g; 9.48 mmol) is suspended in 5 ml DCM and DIPEA (8.2 ml; 47.40 mmol) is added. Afterwards cyclopropanecarbonyl chloride (3.44 ml; 75.84 mmol) is added and the reaction mixture is stirred for 24 h at 20° C. The reaction mixture is poured into water and extracted with DCM. The combined organic layer is dried over MgSO4 and concentrated under reduced pressure. The crude product is purified using reversed phase chromatography (Method: prep. HPLC1).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:19]1)[CH:11]=[CH:10]2)(=O)=O.[C:31]([CH:35]1[CH2:40][CH2:39][C:38](=[CH2:41])[CH2:37][CH2:36]1)([CH3:34])([CH3:33])[CH3:32].C([O-])([O-])=O.[K+].[K+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>CC([O-])=O.CC([O-])=O.[Pd+2].CN1C(=O)CCC1>[C:31]([CH:35]1[CH2:36][CH2:37][C:38](=[CH:41][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[CH:13]=[C:12]([CH2:17][N:18]2[CH2:19][CH2:20][CH:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:22][CH2:23]2)[CH:11]=[CH:10]3)[CH2:39][CH2:40]1)([CH3:34])([CH3:33])[CH3:32]
Reactant: CCOC(=O)C1CCN(Cc2ccc3cc(OS(=O)(=O)C(F)(F)F)ccc3c2)CC1
Reactant: C=C1CCC(C(C)(C)C)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CN1CCCC1=O
Product: CCOC(=O)C1CCN(Cc2ccc3cc(C=C4CCC(C(C)(C)C)CC4)ccc3c2)CC1
Temperature: 120 °C
Reaction time: 12 h
Yield: 35.9 %

Procedure:
Into a sealed tube were added ethyl 1-((6-(trifluoromethylsulfonyloxy)naphthalen-2-yl)methyl)piperidine-4-carboxylate (500 mg, 1.12 mmol), 1-tert-butyl-4-methylenecyclohexane (340 mg, 2.24 mmol, 2 eq), K2CO3 (309 mg, 2.24 mmol, 2 eq), Xantphos (130 mg, 0.22 mmol, 0.2 eq), Pd(OAc)2 (25 mg, 0.11 mmol, 0.1 eq) and NMP (2 mL). The mixture was flushed with N2 for 5 min. Then the reaction was stirred at 120° C. for 12 h. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with water (5 mL*3). The organic solvent was removed in vacuum and the residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=2:1) to give ethyl 1-((6-((4-tert-butylcyclohexylidene)methyl)naphthalen-2-yl)methyl)piperidine-4-carboxylate (180 mg, yield: 35%) as a yellow solid. ESI-MS (M+1)+: 448.3. 1HNMR (400 MHz, CDCl3) δ: 7.76-7.73 (m, 2H), 7.68 (s, 1H), 7.61 (s, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.34 (d, J=8.8 Hz, 1H), 6.34 (s, 1H), 4.13 (q, J=8.8 Hz, 2H), 3.64 (s, 2H), 2.92-2.89 (m, 2H), 2.30-2.25 (m, 2H), 2.08-2.05 (m, 2H), 1.94-1.77 (m, 8H), 1.60 (br, 2H), 1.26-1.23 (m, 5H), 0.87 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:14])=[C:9]([C:11]([OH:13])=O)[N:10]=2)[N:7]=1.Cl.[CH2:16]([O:18][C:19](=[O:22])[CH2:20][NH2:21])[CH3:17].C(N(CC)CC)C>CN(C)C=O>[CH2:16]([O:18][C:19](=[O:22])[CH2:20][NH:21][C:11]([C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[N:7][N:6]2[C:8]=1[CH3:14])=[O:13])[CH3:17]
Reactant: Cc1c(C(=O)O)nc2ccc(Cl)nn12
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)c1nc2ccc(Cl)nn2c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
3.9 g of ethyl 6-chloro-3-methylimidazo[1,2-b]pyridazine-2-carboxylate was suspended in 40 ml of tetrahydrofuran; 30 ml of a 1 N aqueous solution of sodium hydroxide was added, followed by stirring at room temperature for 3 hours. The mixture was concentrated under reduced pressure. The residue was adjusted to pH 4 by the addition of 50 ml of water and 1 N hydrochloric acid; the crystal precipitated was collected by filtration and dried to yield 2.55 g of 6-chloro-3-methylimidazo[1,2-b]pyridazine-2-carboxylic acid. 1.27 g of this carboxylic acid was dissolved in 20 ml of N,N-dimethylformamide; 1.07 g of N,N′-carbonyldiimidazole was added, followed by stirring at room temperature for 30 minutes. To this mixture, 0.922 g of glycine ethyl ester hydrochloride and 0.915 ml of triethylamine were added, followed by further stirring for 3 hours. 60 ml of ice water was added to the reaction mixture; the crystal precipitated was collected by filtration, washed with water and dried to yield 1.18 g of the title compound.
Reaction SMILES: [C:1]([CH:5]1[C:10](=[O:11])[CH2:9][CH:8]([CH:12]2[CH2:17][CH2:16][CH2:15][S:14][CH2:13]2)[CH2:7][C:6]1=[O:18])(=O)[CH2:2][CH3:3].[Br:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH:27][CH2:28][O:29][NH2:30])=[CH:22][CH:21]=1>CO>[Br:19][C:20]1[CH:21]=[CH:22][C:23]([CH:26]=[CH:27][CH2:28][O:29][N:30]=[C:1]([C:5]2[C:10](=[O:11])[CH2:9][CH:8]([CH:12]3[CH2:17][CH2:16][CH2:15][S:14][CH2:13]3)[CH2:7][C:6]=2[OH:18])[CH2:2][CH3:3])=[CH:24][CH:25]=1
Reactant: CCC(=O)C1C(=O)CC(C2CCCSC2)CC1=O
Reactant: NOCC=Cc1ccc(Br)cc1
Solvent: CO
Product: CCC(=NOCC=Cc1ccc(Br)cc1)C1=C(O)CC(C2CCCSC2)CC1=O
Yield: 70.3 %

Procedure:
3.0 g (0.011 mol) of 2-propionyl-5-(3-tetrahydrothiopyranyl)-cyclohexane-1,3-dione and 3.0 g (0.013 mol) of 3-(4-bromophenyl)-prop-2-enyloxyamine in 100 ml of methanol were stirred for 16 hours at 20° C. The precipitated reaction product was filtered off under suction at 0° C. and washed with ice cold methanol and petroleum ether. Drying gave 3.7 g (68.4% of theory) of 2-[1-(3-(4-bromophenyl)-prop-2-enyloximino)-propyl]-3-hydroxy-5-(3-tetrahydrothiopyranyl)-cyclohex-2-en-1-one of melting point 97°-99° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[C:5]([N:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[NH2:8])=[O:6].[OH-].[Na+].[C-:18]1([C:23](Cl)=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19]1.[CH-:26]1[CH:30]=[CH:29][CH:28]=[CH:27]1.[Fe+2:31].O>C1(C)C=CC=CC=1>[C-:18]1([C:23]([NH:8][N:7]([C:5](=[O:6])[C:4]2[CH:13]=[CH:14][CH:15]=[C:2]([CH3:1])[CH:3]=2)[C:9]([CH3:12])([CH3:10])[CH3:11])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19]1.[CH-:26]1[CH:30]=[CH:29][CH:28]=[CH:27]1.[Fe+2:31]
Reactant: O=C(Cl)[c-]1cccc1
Reactant: Cc1cccc(C(=O)N(N)C(C)(C)C)c1
Agent: [Fe+2]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cccc(C(=O)N(NC(=O)[c-]2cccc2)C(C)(C)C)c1
Reaction time: 8 h

Procedure:
To a stirred mixture of N'-3-methylbenzoyl-N'-t-butylhydrazine (0.83 g, 4.0 mmol) and 50% aqueous sodium hydroxide (0.4 g, 5.0 mmol) in toluene (30 mL) was added 7 mL of a toluene solution of ferrocenoyl chloride (Example 2), at room temperature dropwise (addition time 2 hours). After the addition was completed water is added (5 mL) and the resulting mixture allowed to stand overnight, filtered and the filtrate washed with water and dried over MgSO4. Evaporation of the solvent yielded a brown oil which crystalized after rituration with hexane. N-ferrocenoyl-N'-3-methylbenzoyl-N'-t-butylhydrazine was obtained as a brown solid mp: 181°-184° C.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=1)=O.Cl.[CH3:24][C:25]1([CH3:30])[CH2:27][CH:26]1[CH2:28][NH2:29].C(N(C(C)C)CC)(C)C.[BH4-]>O.CO.C(Cl)Cl>[CH3:24][C:25]1([CH3:30])[CH2:27][CH:26]1[CH2:28][NH:29][CH2:1][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=1
Reactant: NC(=O)c1ccc(Oc2cccc3c(C=O)cccc23)nc1
Reactant: CC1(C)CC1CN
Agent: Cl
Agent: [BH4-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CO
Product: CC1(C)CC1CNCc1cccc2c(Oc3ccc(C(N)=O)cn3)cccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 6-(5-formylnaphthalen-1-yloxy)nicotinamide (Preparation 35) (200 mg, 0.68 mmol) and (2,2-dimethylcyclopropyl)methylamine hydrochloride (111 mg, 0.82 mmol) in a 1:1 mixture of MeOH/DCM (12 mL) was added PS-diisopropylethylamine (3.66 mmol/g, 374 mg, 1.37 mmol) and the reaction was stirred at rt for 16 h. PS-borohydride (2 mmol/g, 1.03 g, 2.05 mmol) was added and the reaction was stirred for 30 min Water (0.5 mL) was added and the mixture purified through an SCX column (10 g/70 mL) eluting with 1% NH4OH in MeOH. Solvent was removed in vacuo and the residue was triturated with EtOAc to give the title compound: RT=2.60 min; m/z (ES+)=376.2 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[N:9]([O-])=[O:10].[Na+].[OH-].[K+]>Cl.O>[CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([N:9]=[O:10])[CH2:4][CH2:3]1
Reactant: O=N[O-]
Reactant: CN1CCCNCC1
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: CN1CCCN(N=O)CC1
Temperature: 70 °C
Yield: 50 %

Procedure:
1-methylhomopiperazine (prepared as described by A. H. Sommers et al, in J. Amer. Chem. Soc. 76, 5805, 1954) (6.10 g, 0.0535 mole) was dissolved in concentrated hydrochloric acid (25 ml), cooled to 0°-5° C., stirred and treated dropwise with sodium nitrite (4.06 g) in water (10 ml). After addition the solution was allowed to come to room temperature, then heated for 1/2 hour at 70° C. The solution was cooled and basified with solid KOH and extracted with ether (3×100 ml). The dried (K2CO3) extracts yielded N-methyl-N'-nitrosohomopiperazine (3.80 g, 50%) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[NH:6][CH:5]=[C:4]([C:7]#[N:8])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+].[C:17]([O:21][C:22](=[O:27])[NH:23][CH2:24][CH2:25]Br)([CH3:20])([CH3:19])[CH3:18]>C(#N)C.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[C:17]([O:21][C:22](=[O:27])[NH:23][CH2:24][CH2:25][N:6]1[CH:5]=[C:4]([C:7]#[N:8])[C:3]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[C:2]1[F:1])([CH3:20])([CH3:19])[CH3:18]
Reactant: N#Cc1c[nH]c(F)c1-c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCn1cc(C#N)c(-c2ccccc2)c1F
Yield: 37.8 %

Procedure:
To a solution of 3.75 g (20.1 mmol) of 5-fluoro-4-phenyl-1H-pyrrole-3-carbonitrile in 101 ml of acetonitrile are added 1.6 g (40 mmol) of finely ground sodium hydroxide and 0.27 g (0.81 mmol) of tetrabutylammonium hydrogen sulfate, and the mixture is stirred vigorously for a few minutes, followed by adding 5.42 g (24.2 mmol) of tert-butyl(2-bromoethyl)carbamate (CAS 39684-80-5), and the mixture is then stirred for 18 hours at 90° C. After cooling, the solvent is evaporated off under reduced pressure and the residue is taken up in twice 125 ml of water. The product is extracted with ethyl acetate. The organic phase is then washed with saturated aqueous sodium chloride solution and dried over sodium sulfate, and the solvent is evaporated off under reduced pressure. The residue is purified by chromatography on a column of silica gel, eluting with a mixture of 15 to 50% ethyl acetate in cyclohexane, to give 2.5 g of tert-butyl{2-[4-cyano-2-fluoro-3-phenyl-1H-pyrrol-1-yl]ethyl}carbamate in the form of a brown oil.
Reaction SMILES: [CH:1]([NH2:3])=O.[NH2:4][C:5]1[S:6][C:7]2[CH2:22][C:17]3([O:21][CH2:20][CH2:19][O:18]3)[CH2:16][CH2:15][C:8]=2[C:9]=1[C:10](OCC)=[O:11].C([O-])=O.[NH4+]>>[O:18]1[CH2:19][CH2:20][O:21][C:17]21[CH2:16][CH2:15][C:8]1[C:9]3[C:10](=[O:11])[NH:3][CH:1]=[N:4][C:5]=3[S:6][C:7]=1[CH2:22]2
Reactant: CCOC(=O)c1c(N)sc2c1CCC1(C2)OCCO1
Reactant: NC=O
Agent: O=C[O-]
Agent: [NH4+]
Product: O=c1[nH]cnc2sc3c(c12)CCC1(C3)OCCO1
Temperature: 140 °C
Yield: 88 %

Procedure:
To a stirring 225 mL formamide solution of ethyl 2-amino-4,7-dihydro-5H-spiro[1-benzothiophene-6,2′-[1,3]dioxolane]-3-carboxylate (40.0 g, 0.142 mol) was added ammonium formate (17.8 g, 0.282 mol). The contents were stirred with heating at 140° C. for 16 h, after which time the heterogeneous contents were removed from heating, and allowed to cool to rt. The contents were filtered, the solid filter cake washed with water (2×60 mL), and suction dried overnight to afford the desired product as an off-white solid (33.0 g, 88%). 1H-NMR (DMSO-d6) δ 12.35 (broad s, 1H), 8.00 (s, 1H), 3.92 (s, 4H), 2.95 (t, 2H), 2.91 (s, 2H), 1.83 (t, 2H); LCMS RT=1.87 min; [M+H]+=265.2.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[C:10]=1[NH:16][CH2:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21].[C:23](Cl)(=O)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>ClCCl>[Cl:8][C:9]1[C:10]2[N:16]([CH2:17][CH2:18][CH2:19][N:20]([CH3:21])[CH3:22])[C:40]([CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH3:23])=[N:15][C:11]=2[CH:12]=[CH:13][CH:14]=1
Reactant: CN(C)CCCNc1c(N)cccc1Cl
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCc1nc2cccc(Cl)c2n1CCCN(C)C
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 55.3 %

Procedure:
Triethylamine (0.587 g) was added to a solution containing 3-chloro-N2-[3-(dimethylamino)propyl]-1,2-benzenediamine (1.100 g) in dichloromethane (22 ml), and then stearoyl chloride (1.610 g) was added thereto while being cooled with ice. After being stirred for 4.5 hours at room temperature, the reaction mixture was diluted with dichloromethane, washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. Concentrated hydrochloric acid (4.0 ml) was added to a solution containing the residue (3.451 g) in ethanol (24 ml). After being stirred for 4 hours at 90° C., the reaction mixture was concentrated. The residue, with ethyl acetate added thereto, was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue (2.95 g) was purified by silica gel column chromatography (silica gel 92 g, chloroform:methanol=1:0-100:1), thereby yielding the entitled compound (1.271 g) as pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([C@H:11]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)[CH2:12][CH2:13]O)[C:8](=[O:22])[C:7]2([CH3:24])[CH3:23].C1(C)C(S(Cl)(=O)=O)=CC=CC=1.[N:36]1C=CC=C[CH:37]=1>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([C@H:11]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)[CH2:12][CH2:13][NH:36][CH3:37])[C:8](=[O:22])[C:7]2([CH3:24])[CH3:23]
Reactant: c1ccncc1
Reactant: CC1(C)C(=O)N([C@@H](CCO)c2cccc(F)c2)c2c(F)cccc21
Agent: Cc1ccccc1S(=O)(=O)Cl
Solvent: CCOC(C)=O
Product: CNCC[C@@H](c1cccc(F)c1)N1C(=O)C(C)(C)c2cccc(F)c21
Reaction time: 6 h

Procedure:
7-fluoro-1-[(1S)-1-(3-fluorophenyl)-3-hydroxypropyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (0.25 g, 0.76 mmol) was dissolved in pyridine (5 mL) and toluenesufonyl chloride (0.19 g, 0.98 mmol) was added. Stirred for 6 hours then the reaction mixture was diluted with ethyl acetate and washed with water, 2N hydrochloric acid, saturated copper sulfate, 2N hydrochloric acid, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was immediately dissolved in methylamine (8M in ethanol, 25 mL) and stirred for 16 hours. The mixture was concentrated in vacuo and purified via chromatography (silica, 3% methanol saturated with ammonia in chloroform) to give 7-fluoro-1-[(1S)-1-(3-fluorophenyl)-3-(methylamino)propyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one as a colorless oil (0.16 g). The freebase was dissolved in ether (5 mL) and treated with 1N hydrochloric acid in ether (0.46 mL, 1.0 equivalent). The white precipitate was collected and dried under vacuum to give 123 mg (43% over three steps) 7-fluoro-1-[(1S)-1-(3-fluorophenyl)-3-(methylamino)propyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one hydrochloride.
Reaction SMILES: [C:1]1([C:7]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:12][C:11]3[C:13]4[C:18]([C:19](OC)=[C:20]([C:21]([O:23][CH3:24])=[O:22])[C:10]=3[CH:9]=[CH:8]2)=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CC[CH2:35][CH2:34]1.C([Mg]Br)=C.Cl>CCOCC>[C:1]1([C:7]2([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[O:12][C:11]3[C:13]4[C:18]([C:19]([CH:34]=[CH2:35])=[C:20]([C:21]([O:23][CH3:24])=[O:22])[C:10]=3[CH:9]=[CH:8]2)=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1c2c(c3ccccc3c1OC)OC(c1ccccc1)(c1ccccc1)C=C2
Reactant: C1CCOC1
Agent: C=C[Mg]Br
Agent: Cl
Solvent: CCOCC
Product: C=Cc1c(C(=O)OC)c2c(c3ccccc13)OC(c1ccccc1)(c1ccccc1)C=C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,2-diphenyl-5-methoxycarbonyl-6-methoxy-2H-naphtho[1,2-b]pyran (4.22 grams) was added to a reaction flask containing tetrahydrofuran (THF) (50 milliliters (mL)). Vinyl magnesium bromide solution (20 mL of 2.0 molar in tetrahydrofuran) was injected slowly into the solution. After stirring at room temperature for two hours, the reaction mixture was poured into a beaker containing a mixture of ice, hydrochloric acid and ether. The ether layer was separated, washed with water twice and dried over anhydrous sodium sulfate. The reaction product was induced to crystallize from an ether/hexane mixture yielding 2.95 grams of 2,2-diphenyl-5-methoxycarbonyl-6-vinyl-2H-naphtho[1,2-b]pyran which was used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:27]3[CH2:32][CH2:31][N:30]([C:33](=[O:35])C)[CH2:29][CH2:28]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[CH2:36]([N:38]=C=O)[CH3:37]>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:27]3[CH2:28][CH2:29][N:30]([C:33]([NH:38][CH2:36][CH3:37])=[O:35])[CH2:31][CH2:32]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CCN=C=O
Reactant: CC(=O)N1CCC(c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(N)nccn23)CC1
Product: CCNC(=O)N1CCC(c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(N)nccn23)CC1

Procedure:
4-(8-Amino-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl)-N-ethylpiperidine-1-carboxamide was synthesized using the same procedure as 1-{4-[8-amino-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl]piperidin-1-yl}ethanone except ethylisocyanate was used instead of acetic anhydride; yellow powder; MS (ES+): m/z 492.10 (70) [MH+], 493.11 (45) [MH+2], 211.41 (100) [MH-280]; HPLC: tR=2.08 min (polar-5 min/openlynx).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]3[C:14](=[O:15])[O:13][C:11](=[O:12])[C:9]=3[CH:10]=[C:5]2[CH:4]=[N:3]1.[Cl:16][C:17]1[C:18]([CH2:26][CH3:27])=[C:19]([C:21]([CH2:24][CH3:25])=[CH:22][CH:23]=1)[NH2:20]>O1CCCC1>[Cl:16][C:17]1[C:18]([CH2:26][CH3:27])=[C:19]([NH:20][C:14]([C:8]2[N:7]=[C:6]3[N:2]([CH3:1])[N:3]=[CH:4][C:5]3=[CH:10][C:9]=2[C:11]([OH:13])=[O:12])=[O:15])[C:21]([CH2:24][CH3:25])=[CH:22][CH:23]=1
Reactant: CCc1ccc(Cl)c(CC)c1N
Reactant: Cn1ncc2cc3c(nc21)C(=O)OC3=O
Solvent: C1CCOC1
Product: CCc1ccc(Cl)c(CC)c1NC(=O)c1nc2c(cnn2C)cc1C(=O)O
Reaction time: 12 h

Procedure:
In 100 ml of tetrahydrofuran was dissolved 8.0 g (39.4 mmol) of 1-methyl-pyrazolo[5,4-b]pyridine-5,6-dicarboxylic acid anhydride. After adding 7.23 g (39.4 mmol) of 3-chloro-2,6-diethylaniline to the solution obtained above, a reaction was carried out at ambient temperature for 12 hours.
Reaction SMILES: [CH2:1]1[O:3][CH:2]1[CH2:4][OH:5].[C:6]1([CH2:12][CH2:13][CH:14]([NH2:16])[CH3:15])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(O)(C)C>[C:6]1([CH2:12][CH2:13][CH:14]([NH:16][CH2:1][CH:2]([OH:3])[CH2:4][OH:5])[CH3:15])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(N)CCc1ccccc1
Reactant: OCC1CO1
Solvent: CC(C)O
Product: CC(CCc1ccccc1)NCC(O)CO
Temperature: 70 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A solution of glycidol (11.5 g, 0.155 mol) in isopropanol (25 ml) was added dropwise under N2 at 40° C. to a solution of 1-phenyl-3-butylamine in isopropanol (50 ml). After 1 hour, the solution was heated at 70° C. for 1.5 hours and then at room temperature overnight. The isopropanol was removed under reduced pressure and the residue distilled to yield 24 g (70%) of 94; b.p.0.2 140°-5° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]1[C:9](OC)([O:10]C)[CH2:8][CH2:7][N:6]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:5]1)[CH3:2].O.C(O)(C(F)(F)F)=O.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>>[CH2:1]([O:3][CH:4]1[C:9](=[O:10])[CH2:8][CH2:7][N:6]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:5]1)[CH3:2]
Reactant: CCOC1CN(C(=O)OC(C)(C)C)CCC1(OC)OC
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCOC1CN(C(=O)OC(C)(C)C)CCC1=O
Yield: 95.5 %

Procedure:
The same operation as in Example (90b) was performed using tert-butyl 3-ethoxy-4,4-dimethoxypiperidine-1-carboxylate obtained in Example (112a) (4.99 g, 14.2 mmol), a water/TFA mixed solution (1/1, 35 mL) and di-tert-butyl dicarbonate (4.37 g, 20 mol). The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=10/1, 5/1, 2/1, 1/1) to obtain 3.3 g of the title compound as a light brown oily substance (77%).